Selegiline-induced postural hypotension in Parkinson's disease: a longitudinal study on the effects of drug withdrawal. OBJECTIVES: The United Kingdom Parkinson's Disease Research Group (UKPDRG) trial found an increased mortality in patients with Parkinson's disease (PD) randomized to receive 10 mg selegiline per day and L-dopa compared with those taking L-dopa alone. Recently, we found that therapy with selegiline and L-dopa was associated with selective systolic orthostatic hypotension which was abolished by withdrawal of selegiline. This unwanted effect on postural blood pressure was not the result of underlying autonomic failure. The aims of this study were to confirm our previous findings in a separate cohort of patients and to determine the time course of the cardiovascular consequences of stopping selegiline in the expectation that this might shed light on the mechanisms by which the drug causes orthostatic hypotension. METHODS: The cardiovascular responses to standing and head-up tilt were studied repeatedly in PD patients receiving selegiline and as the drug was withdrawn. RESULTS: Head-up tilt caused systolic orthostatic hypotension which was marked in six of 20 PD patients on selegiline, one of whom lost consciousness with unrecordable blood pressures. A lesser degree of orthostatic hypotension occurred with standing. Orthostatic hypotension was ameliorated 4 days after withdrawal of selegiline and totally abolished 7 days after discontinuation of the drug. Stopping selegiline also significantly reduced the supine systolic and diastolic blood pressures consistent with a previously undescribed supine pressor action. CONCLUSION: This study confirms our previous finding that selegiline in combination with L-dopa is associated with selective orthostatic hypotension. The possibilities that these cardiovascular findings might be the result of non-selective inhibition of monoamine oxidase or of amphetamine and metamphetamine are discussed.
Warfarin-induced artery calcification is accelerated by growth and vitamin D. The present studies demonstrate that growth and vitamin D treatment enhance the extent of artery calcification in rats given sufficient doses of Warfarin to inhibit gamma-carboxylation of matrix Gla protein, a calcification inhibitor known to be expressed by smooth muscle cells and macrophages in the artery wall. The first series of experiments examined the influence of age and growth status on artery calcification in Warfarin-treated rats. Treatment for 2 weeks with Warfarin caused massive focal calcification of the artery media in 20-day-old rats and less extensive focal calcification in 42-day-old rats. In contrast, no artery calcification could be detected in 10-month-old adult rats even after 4 weeks of Warfarin treatment. To directly examine the importance of growth to Warfarin-induced artery calcification in animals of the same age, 20-day-old rats were fed for 2 weeks either an ad libitum diet or a 6-g/d restricted diet that maintains weight but prevents growth. Concurrent treatment of both dietary groups with Warfarin produced massive focal calcification of the artery media in the ad libitum-fed rats but no detectable artery calcification in the restricted-diet, growth-inhibited group. Although the explanation for the association between artery calcification and growth status cannot be determined from the present study, there was a relationship between higher serum phosphate and susceptibility to artery calcification, with 30% higher levels of serum phosphate in young, ad libitum-fed rats compared with either of the groups that was resistant to Warfarin-induced artery calcification, ie, the 10-month-old rats and the restricted-diet, growth-inhibited young rats. This observation suggests that increased susceptibility to Warfarin-induced artery calcification could be related to higher serum phosphate levels. The second set of experiments examined the possible synergy between vitamin D and Warfarin in artery calcification. High doses of vitamin D are known to cause calcification of the artery media in as little as 3 to 4 days. High doses of the vitamin K antagonist Warfarin are also known to cause calcification of the artery media, but at treatment times of 2 weeks or longer yet not at 1 week. In the current study, we investigated the synergy between these 2 treatments and found that concurrent Warfarin administration dramatically increased the extent of calcification in the media of vitamin D-treated rats at 3 and 4 days. There was a close parallel between the effect of vitamin D dose on artery calcification and the effect of vitamin D dose on the elevation of serum calcium, which suggests that vitamin D may induce artery calcification through its effect on serum calcium. Because Warfarin treatment had no effect on the elevation in serum calcium produced by vitamin D, the synergy between Warfarin and vitamin D is probably best explained by the hypothesis that Warfarin inhibits the activity of matrix Gla protein as a calcification inhibitor. High levels of matrix Gla protein are found at sites of artery calcification in rats treated with vitamin D plus Warfarin, and chemical analysis showed that the protein that accumulated was indeed not gamma-carboxylated. These observations indicate that although the gamma-carboxyglutamate residues of matrix Gla protein are apparently required for its function as a calcification inhibitor, they are not required for its accumulation at calcification sites.
Hemolysis of human erythrocytes induced by tamoxifen is related to disruption of membrane structure. Tamoxifen (TAM), the antiestrogenic drug most widely prescribed in the chemotherapy of breast cancer, induces changes in normal discoid shape of erythrocytes and hemolytic anemia. This work evaluates the effects of TAM on isolated human erythrocytes, attempting to identify the underlying mechanisms on TAM-induced hemolytic anemia and the involvement of biomembranes in its cytostatic action mechanisms. TAM induces hemolysis of erythrocytes as a function of concentration. The extension of hemolysis is variable with erythrocyte samples, but 12.5 microM TAM induces total hemolysis of all tested suspensions. Despite inducing extensive erythrocyte lysis, TAM does not shift the osmotic fragility curves of erythrocytes. The hemolytic effect of TAM is prevented by low concentrations of alpha-tocopherol (alpha-T) and alpha-tocopherol acetate (alpha-TAc) (inactivated functional hydroxyl) indicating that TAM-induced hemolysis is not related to oxidative membrane damage. This was further evidenced by absence of oxygen consumption and hemoglobin oxidation both determined in parallel with TAM-induced hemolysis. Furthermore, it was observed that TAM inhibits the peroxidation of human erythrocytes induced by AAPH, thus ruling out TAM-induced cell oxidative stress. Hemolysis caused by TAM was not preceded by the leakage of K(+) from the cells, also excluding a colloid-osmotic type mechanism of hemolysis, according to the effects on osmotic fragility curves. However, TAM induces release of peripheral proteins of membrane-cytoskeleton and cytosol proteins essentially bound to band 3. Either alpha-T or alpha-TAc increases membrane packing and prevents TAM partition into model membranes. These effects suggest that the protection from hemolysis by tocopherols is related to a decreased TAM incorporation in condensed membranes and the structural damage of the erythrocyte membrane is consequently avoided. Therefore, TAM-induced hemolysis results from a structural perturbation of red cell membrane, leading to changes in the framework of the erythrocyte membrane and its cytoskeleton caused by its high partition in the membrane. These defects explain the abnormal erythrocyte shape and decreased mechanical stability promoted by TAM, resulting in hemolytic anemia. Additionally, since membrane leakage is a final stage of cytotoxicity, the disruption of the structural characteristics of biomembranes by TAM may contribute to the multiple mechanisms of its anticancer action.
Effects of long-term pretreatment with isoproterenol on bromocriptine-induced tachycardia in conscious rats. It has been shown that bromocriptine-induced tachycardia, which persisted after adrenalectomy, is (i) mediated by central dopamine D2 receptor activation and (ii) reduced by 5-day isoproterenol pretreatment, supporting therefore the hypothesis that this effect is dependent on sympathetic outflow to the heart. This study was conducted to examine whether prolonged pretreatment with isoproterenol could abolish bromocriptine-induced tachycardia in conscious rats. Isoproterenol pretreatment for 15 days caused cardiac hypertrophy without affecting baseline blood pressure and heart rate. In control rats, intravenous bromocriptine (150 microg/kg) induced significant hypotension and tachycardia. Bromocriptine-induced hypotension was unaffected by isoproterenol pretreatment, while tachycardia was reversed to significant bradycardia, an effect that was partly reduced by i.v. domperidone (0.5 mg/kg). Neither cardiac vagal nor sympathetic tone was altered by isoproterenol pretreatment. In isolated perfused heart preparations from isoproterenol-pretreated rats, the isoproterenol-induced maximal increase in left ventricular systolic pressure was significantly reduced, compared with saline-pretreated rats (the EC50 of the isoproterenol-induced increase in left ventricular systolic pressure was enhanced approximately 22-fold). These results show that 15-day isoproterenol pretreatment not only abolished but reversed bromocriptine-induced tachycardia to bradycardia, an effect that is mainly related to further cardiac beta-adrenoceptor desensitization rather than to impairment of autonomic regulation of the heart. They suggest that, in normal conscious rats, the central tachycardia of bromocriptine appears to predominate and to mask the bradycardia of this agonist at peripheral dopamine D2 receptors.
Recurrent use of newer oral contraceptives and the risk of venous thromboembolism. The epidemiological studies that assessed the risk of venous thromboembolism (VTE) associated with newer oral contraceptives (OC) did not distinguish between patterns of OC use, namely first-time users, repeaters and switchers. Data from a Transnational case-control study were used to assess the risk of VTE for the latter patterns of use, while accounting for duration of use. Over the period 1993-1996, 551 cases of VTE were identified in Germany and the UK along with 2066 controls. Totals of 128 cases and 650 controls were analysed for repeat use and 135 cases and 622 controls for switching patterns. The adjusted rate ratio of VTE for repeat users of third generation OC was 0.6 (95% CI:0.3-1.2) relative to repeat users of second generation pills, whereas it was 1.3 (95% CI:0.7-2.4) for switchers from second to third generation pills relative to switchers from third to second generation pills. We conclude that second and third generation agents are associated with equivalent risks of VTE when the same agent is used repeatedly after interruption periods or when users are switched between the two generations of pills. These analyses suggest that the higher risk observed for the newer OC in other studies may be the result of inadequate comparisons of pill users with different patterns of pill use.
Differential effects of systemically administered ketamine and lidocaine on dynamic and static hyperalgesia induced by intradermal capsaicin in humans. We have examined the effect of systemic administration of ketamine and lidocaine on brush-evoked (dynamic) pain and punctate-evoked (static) hyperalgesia induced by capsaicin. In a randomized, double-blind, placebo-controlled, crossover study, we studied 12 volunteers in three experiments. Capsaicin 100 micrograms was injected intradermally on the volar forearm followed by an i.v. infusion of ketamine (bolus 0.1 mg kg-1 over 10 min followed by infusion of 7 micrograms kg-1 min-1), lidocaine 5 mg kg-1 or saline for 50 min. Infusion started 15 min after injection of capsaicin. The following were measured: spontaneous pain, pain evoked by punctate and brush stimuli (VAS), and areas of brush-evoked and punctate-evoked hyperalgesia. Ketamine reduced both the area of brush-evoked and punctate-evoked hyperalgesia significantly and it tended to reduce brush-evoked pain. Lidocaine reduced the area of punctate-evoked hyperalgesia significantly. It tended to reduce VAS scores of spontaneous pain but had no effect on evoked pain. The differential effects of ketamine and lidocaine on static and dynamic hyperalgesia suggest that the two types of hyperalgesia are mediated by separate mechanisms and have a distinct pharmacology.
Ketamine sedation for the reduction of children's fractures in the emergency department. BACKGROUND: There recently has been a resurgence in the utilization of ketamine, a unique anesthetic, for emergency-department procedures requiring sedation. The purpose of the present study was to examine the safety and efficacy of ketamine for sedation in the treatment of children's fractures in the emergency department. METHODS: One hundred and fourteen children (average age, 5.3 years; range, twelve months to ten years and ten months) who underwent closed reduction of an isolated fracture or dislocation in the emergency department at a level-I trauma center were prospectively evaluated. Ketamine hydrochloride was administered intravenously (at a dose of two milligrams per kilogram of body weight) in ninety-nine of the patients and intramuscularly (at a dose of four milligrams per kilogram of body weight) in the other fifteen. A board-certified emergency physician skilled in airway management supervised administration of the anesthetic, and the patients were monitored by a registered nurse. Any pain during the reduction was rated by the orthopaedic surgeon treating the patient according to the Children's Hospital of Eastern Ontario Pain Scale (CHEOPS). RESULTS: The average time from intravenous administration of ketamine to manipulation of the fracture or dislocation was one minute and thirty-six seconds (range, twenty seconds to five minutes), and the average time from intramuscular administration to manipulation was four minutes and forty-two seconds (range, sixty seconds to fifteen minutes). The average score according to the Children's Hospital of Eastern Ontario Pain Scale was 6.4 points (range, 5 to 10 points), reflecting minimal or no pain during fracture reduction. Adequate fracture reduction was obtained in 111 of the children. Ninety-nine percent (sixty-eight) of the sixty-nine parents present during the reduction were pleased with the sedation and would allow it to be used again in a similar situation. Patency of the airway and independent respiration were maintained in all of the patients. Blood pressure and heart rate remained stable. Minor side effects included nausea (thirteen patients), emesis (eight of the thirteen patients with nausea), clumsiness (evident as ataxic movements in ten patients), and dysphoric reaction (one patient). No long-term sequelae were noted, and no patients had hallucinations or nightmares. CONCLUSIONS: Ketamine reliably, safely, and quickly provided adequate sedation to effectively facilitate the reduction of children's fractures in the emergency department at our institution. Ketamine should only be used in an environment such as the emergency department, where proper one-on-one monitoring is used and board-certified physicians skilled in airway management are directly involved in the care of the patient.
Serotonergic antidepressants and urinary incontinence. Many new serotonergic antidepressants have been introduced over the past decade. Although urinary incontinence is listed as one side effect of these drugs in their package inserts there is only one report in the literature. This concerns 2 male patients who experienced incontinence while taking venlafaxine. In the present paper the authors describe 2 female patients who developed incontinence secondary to the selective serotonin reuptake inhibitors paroxetine and sertraline, as well as a third who developed this side effect on venlafaxine. In 2 of the 3 cases the patients were also taking lithium carbonate and beta-blockers, both of which could have contributed to the incontinence. Animal studies suggest that incontinence secondary to serotonergic antidepressants could be mediated by the 5HT4 receptors found on the bladder. Further research is needed to delineate the frequency of this troubling side effect and how best to treat it.
Repeated transient anuria following losartan administration in a patient with a solitary kidney. We report the case of a 70-year-old hypertensive man with a solitary kidney and chronic renal insufficiency who developed two episodes of transient anuria after losartan administration. He was hospitalized for a myocardial infarction with pulmonary edema, treated with high-dose diuretics. Due to severe systolic dysfunction losartan was prescribed. Surprisingly, the first dose of 50 mg of losartan resulted in a sudden anuria, which lasted eight hours despite high-dose furosemide and amine infusion. One week later, by mistake, losartan was prescribed again and after the second dose of 50 mg, the patient developed a second episode of transient anuria lasting 10 hours. During these two episodes, his blood pressure diminished but no severe hypotension was noted. Ultimately, an arteriography showed a 70-80% renal artery stenosis. In this patient, renal artery stenosis combined with heart failure and diuretic therapy certainly resulted in a strong activation of the renin-angiotensin system (RAS). Under such conditions, angiotensin II receptor blockade by losartan probably induced a critical fall in glomerular filtration pressure. This case report highlights the fact that the angiotensin II receptor antagonist losartan can cause serious unexpected complications in patients with renovascular disease and should be used with extreme caution in this setting.
Antidepressant-induced mania in bipolar patients: identification of risk factors. BACKGROUND: Concerns about possible risks of switching to mania associated with antidepressants continue to interfere with the establishment of an optimal treatment paradigm for bipolar depression. METHOD: The response of 44 patients meeting DSM-IV criteria for bipolar disorder to naturalistic treatment was assessed for at least 6 weeks using the Montgomery-Asberg Depression Rating Scale and the Bech-Rafaelson Mania Rating Scale. Patients who experienced a manic or hypomanic switch were compared with those who did not on several variables including age, sex, diagnosis (DSM-IV bipolar I vs. bipolar II), number of previous manic episodes, type of antidepressant therapy used (electroconvulsive therapy vs. antidepressant drugs and, more particularly, selective serotonin reuptake inhibitors [SSRIs]), use and type of mood stabilizers (lithium vs. anticonvulsants), and temperament of the patient, assessed during a normothymic period using the hyperthymia component of the Semi-structured Affective Temperament Interview. RESULTS: Switches to hypomania or mania occurred in 27% of all patients (N = 12) (and in 24% of the subgroup of patients treated with SSRIs [8/33]); 16% (N = 7) experienced manic episodes, and 11% (N = 5) experienced hypomanic episodes. Sex, age, diagnosis (bipolar I vs. bipolar II), and additional treatment did not affect the risk of switching. The incidence of mood switches seemed not to differ between patients receiving an anticonvulsant and those receiving no mood stabilizer. In contrast, mood switches were less frequent in patients receiving lithium (15%, 4/26) than in patients not treated with lithium (44%, 8/18; p = .04). The number of previous manic episodes did not affect the probability of switching, whereas a high score on the hyperthymia component of the Semistructured Affective Temperament Interview was associated with a greater risk of switching (p = .008). CONCLUSION: The frequency of mood switching associated with acute antidepressant therapy may be reduced by lithium treatment. Particular attention should be paid to patients with a hyperthymic temperament, who have a greater risk of mood switches.
Caffeine-induced cardiac arrhythmia: an unrecognised danger of healthfood products. We describe a 25-year-old woman with pre-existing mitral valve prolapse who developed intractable ventricular fibrillation after consuming a "natural energy" guarana health drink containing a high concentration of caffeine. This case highlights the need for adequate labelling and regulation of such products.
Bladder retention of urine as a result of continuous intravenous infusion of fentanyl: 2 case reports. Sedation has been commonly used in the neonate to decrease the stress and pain from the noxious stimuli and invasive procedures in the neonatal intensive care unit, as well as to facilitate synchrony between ventilator and spontaneous breaths. Fentanyl, an opioid analgesic, is frequently used in the neonatal intensive care unit setting for these very purposes. Various reported side effects of fentanyl administration include chest wall rigidity, hypotension, respiratory depression, and bradycardia. Here, 2 cases of urinary bladder retention leading to renal pelvocalyceal dilatation mimicking hydronephrosis as a result of continuous infusion of fentanyl are reported.
Palpebral twitching in a depressed adolescent on citalopram. Current estimates suggest that between 0.4% and 8.3% of children and adolescents are affected by major depression. We report a favorable response to treatment with citalopram by a 15-year-old boy with major depression who exhibited palpebral twitching during his first 2 weeks of treatment. This may have been a side effect of citalopram as it remitted with redistribution of doses.
Oral contraceptives and the risk of myocardial infarction. BACKGROUND: An association between the use of oral contraceptives and the risk of myocardial infarction has been found in some, but not all, studies. We investigated this association, according to the type of progestagen included in third-generation (i.e., desogestrel or gestodene) and second-generation (i.e., levonorgestrel) oral contraceptives, the dose of estrogen, and the presence or absence of prothrombotic mutations METHODS: In a nationwide, population-based, case-control study, we identified and enrolled 248 women 18 through 49 years of age who had had a first myocardial infarction between 1990 and 1995 and 925 control women who had not had a myocardial infarction and who were matched for age, calendar year of the index event, and area of residence. Subjects supplied information on oral-contraceptive use and major cardiovascular risk factors. An analysis for factor V Leiden and the G20210A mutation in the prothrombin gene was conducted in 217 patients and 763 controls RESULTS: The odds ratio for myocardial infarction among women who used any type of combined oral contraceptive, as compared with nonusers, was 2.0 (95 percent confidence interval, 1.5 to 2.8). The adjusted odds ratio was 2.5 (95 percent confidence interval, 1.5 to 4.1) among women who used second-generation oral contraceptives and 1.3 (95 percent confidence interval, 0.7 to 2.5) among those who used third-generation oral contraceptives. Among women who used oral contraceptives, the odds ratio was 2.1 (95 percent confidence interval, 1.5 to 3.0) for those without a prothrombotic mutation and 1.9 (95 percent confidence interval, 0.6 to 5.5) for those with a mutation CONCLUSIONS: The risk of myocardial infarction was increased among women who used second-generation oral contraceptives. The results with respect to the use of third-generation oral contraceptives were inconclusive but suggested that the risk was lower than the risk associated with second-generation oral contraceptives. The risk of myocardial infarction was similar among women who used oral contraceptives whether or not they had a prothrombotic mutation.
Antithymocyte globulin in the treatment of D-penicillamine-induced aplastic anemia. A patient who received antithymocyte globulin therapy for aplastic anemia due to D-penicillamine therapy is described. Bone marrow recovery and peripheral blood recovery were complete 1 month and 3 months, respectively, after treatment, and blood transfusion or other therapies were not necessary in a follow-up period of more than 2 years. Use of antithymocyte globulin may be the optimal treatment of D-penicillamine-induced aplastic anemia.
Topiramate-induced nephrolithiasis. Topiramate is a recently developed antiepileptic medication that is becoming more widely prescribed because of its efficacy in treating refractory seizures. Urologists should be aware that this medication can cause metabolic acidosis in patients secondary to inhibition of carbonic anhydrase. In addition, a distal tubular acidification defect may result, thus impairing the normal compensatory drop in urine pH. These factors can lead to the development of calcium phosphate nephrolithiasis. We report the first two cases of topiramate-induced nephrolithiasis in the urologic literature.
Ifosfamide encephalopathy presenting with asterixis. CNS toxic effects of the antineoplastic agent ifosfamide (IFX) are frequent and include a variety of neurological symptoms that can limit drug use. We report a case of a 51-year-old man who developed severe, disabling negative myoclonus of the upper and lower extremities after the infusion of ifosfamide for plasmacytoma. He was awake, revealed no changes of mental status and at rest there were no further motor symptoms. Cranial magnetic resonance imaging and extensive laboratory studies failed to reveal structural lesions of the brain and metabolic abnormalities. An electroencephalogram showed continuous, generalized irregular slowing with admixed periodic triphasic waves indicating symptomatic encephalopathy. The administration of ifosfamide was discontinued and within 12 h the asterixis resolved completely. In the patient described, the presence of asterixis during infusion of ifosfamide, normal laboratory findings and imaging studies and the resolution of symptoms following the discontinuation of the drug suggest that negative myoclonus is associated with the use of IFX.
Prenatal dexamethasone programs hypertension and renal injury in the rat. Dexamethasone is frequently administered to the developing fetus to accelerate pulmonary development. The purpose of the present study was to determine if prenatal dexamethasone programmed a progressive increase in blood pressure and renal injury in rats. Pregnant rats were given either vehicle or 2 daily intraperitoneal injections of dexamethasone (0.2 mg/kg body weight) on gestational days 11 and 12, 13 and 14, 15 and 16, 17 and 18, or 19 and 20. Offspring of rats administered dexamethasone on days 15 and 16 gestation had a 20% reduction in glomerular number compared with control at 6 to 9 months of age (22 527+/-509 versus 28 050+/-561, P<0.05), which was comparable to the percent reduction in glomeruli measured at 3 weeks of age. Six- to 9-month old rats receiving prenatal dexamethasone on days 17 and 18 of gestation had a 17% reduction in glomeruli (23 380+/-587) compared with control rats (P<0.05). Male rats that received prenatal dexamethasone on days 15 and 16, 17 and 18, and 13 and 14 of gestation had elevated blood pressures at 6 months of age; the latter group did not have a reduction in glomerular number. Adult rats given dexamethasone on days 15 and 16 of gestation had more glomeruli with glomerulosclerosis than control rats. This study shows that prenatal dexamethasone in rats results in a reduction in glomerular number, glomerulosclerosis, and hypertension when administered at specific points during gestation. Hypertension was observed in animals that had a reduction in glomeruli as well as in a group that did not have a reduction in glomerular number, suggesting that a reduction in glomerular number is not the sole cause for the development of hypertension.
The risk of venous thromboembolism in women prescribed cyproterone acetate in combination with ethinyl estradiol: a nested cohort analysis and case-control study. BACKGROUND: Cyproterone acetate combined with ethinyl estradiol (CPA/EE) is licensed in the UK for the treatment of women with acne and hirsutism and is also a treatment option for polycystic ovary syndrome (PCOS). Previous studies have demonstrated an increased risk of venous thromboembolism (VTE) associated with CPA/EE compared with conventional combined oral contraceptives (COCs). We believe the results of those studies may have been affected by residual confounding. METHODS: Using the General Practice Research Database we conducted a cohort analysis and case-control study nested within a population of women aged between 15 and 39 years with acne, hirsutism or PCOS to estimate the risk of VTE associated with CPA/EE. RESULTS: The age-adjusted incidence rate ratio for CPA/EE versus conventional COCs was 2.20 [95% confidence interval (CI) 1.35-3.58]. Using as the reference group women who were not using oral contraception, had no recent pregnancy or menopausal symptoms, the case-control analysis gave an adjusted odds ratio (OR(adj)) of 7.44 (95% CI 3.67-15.08) for CPA/EE use compared with an OR(adj) of 2.58 (95% CI 1.60-4.18) for use of conventional COCs. CONCLUSIONS: We have demonstrated an increased risk of VTE associated with the use of CPA/EE in women with acne, hirsutism or PCOS although residual confounding by indication cannot be excluded.
Pseudoacromegaly induced by the long-term use of minoxidil. Acromegaly is an endocrine disorder caused by chronic excessive growth hormone secretion from the anterior pituitary gland. Significant disfiguring changes occur as a result of bone, cartilage, and soft tissue hypertrophy, including the thickening of the skin, coarsening of facial features, and cutis verticis gyrata. Pseudoacromegaly, on the other hand, is the presence of similar acromegaloid features in the absence of elevated growth hormone or insulin-like growth factor levels. We present a patient with pseudoacromegaly that resulted from the long-term use of minoxidil at an unusually high dose. This is the first case report of pseudoacromegaly as a side effect of minoxidil use.
Delirium during clozapine treatment: incidence and associated risk factors. BACKGROUND: Incidence and risk factors for delirium during clozapine treatment require further clarification. METHODS: We used computerized pharmacy records to identify all adult psychiatric inpatients treated with clozapine (1995-96), reviewed their medical records to score incidence and severity of delirium, and tested associations with potential risk factors. RESULTS: Subjects (n = 139) were 72 women and 67 men, aged 40.8 +/- 12.1 years, hospitalized for 24.9 +/- 23.3 days, and given clozapine, gradually increased to an average daily dose of 282 +/- 203 mg (3.45 +/- 2.45 mg/kg) for 18.9 +/- 16.4 days. Delirium was diagnosed in 14 (10.1 % incidence, or 1.48 cases/person-years of exposure); 71.4 % of cases were moderate or severe. Associated factors were co-treatment with other centrally antimuscarinic agents, poor clinical outcome, older age, and longer hospitalization (by 17.5 days, increasing cost); sex, diagnosis or medical co-morbidity, and daily clozapine dose, which fell with age, were unrelated. CONCLUSIONS: Delirium was found in 10 % of clozapine-treated inpatients, particularly in older patients exposed to other central anticholinergics. Delirium was inconsistently recognized clinically in milder cases and was associated with increased length-of-stay and higher costs, and inferior clinical outcome.
Treatment of Crohn's disease with fusidic acid: an antibiotic with immunosuppressive properties similar to cyclosporin. Fusidic acid is an antibiotic with T-cell specific immunosuppressive effects similar to those of cyclosporin. Because of the need for the development of new treatments for Crohn's disease, a pilot study was undertaken to estimate the pharmacodynamics and tolerability of fusidic acid treatment in chronic active, therapy-resistant patients. Eight Crohn's disease patients were included. Fusidic acid was administered orally in a dose of 500 mg t.d.s. and the treatment was planned to last 8 weeks. The disease activity was primarily measured by a modified individual grading score. Five of 8 patients (63%) improved during fusidic acid treatment: 3 at two weeks and 2 after four weeks. There were no serious clinical side effects, but dose reduction was required in two patients because of nausea. Biochemically, an increase in alkaline phosphatases was noted in 5 of 8 cases (63%), and the greatest increases were seen in those who had elevated levels prior to treatment. All reversed to pre-treatment levels after cessation of treatment. The results of this pilot study suggest that fusidic acid may be of benefit in selected chronic active Crohn's disease patients in whom conventional treatment is ineffective. Because there seems to exist a scientific rationale for the use of fusidic acid at the cytokine level in inflammatory bowel disease, we suggest that the role of this treatment should be further investigated.
Ketoconazole-induced neurologic sequelae. A 77-y-old patient developed weakness of extremities, legs paralysis, dysarthria and tremor 1 h after ingestion of 200 mg ketoconazole for the first time in his life. All complaints faded away within 24 h. Few days later, the patient used another 200 mg ketoconazole tablet, and within an hour experienced a similar clinical picture, which resolved again spontaneously within hours. Laboratory evaluations, including head CT scan, were normal. This case illustrates the need for close vigilance in adverse drug reactions, particularly in the elderly.
Reversible dilated cardiomyopathy related to amphotericin B therapy. We describe a patient who developed dilated cardiomyopathy and clinical congestive heart failure after 2 months of therapy with amphotericin B (AmB) for disseminated coccidioidomycosis. His echocardiographic abnormalities and heart failure resolved after posaconazole was substituted for AmB. It is important to recognize the rare and potentially reversible toxicity of AmB.
Cardioprotective effect of tincture of Crataegus on isoproterenol-induced myocardial infarction in rats. Tincture of Crataegus (TCR), an alcoholic extract of the berries of hawthorn (Crataegus oxycantha), is used in herbal and homeopathic medicine. The present study was done to investigate the protective effect of TCR on experimentally induced myocardial infarction in rats. Pretreatment of TCR, at a dose of 0.5 mL/100 g bodyweight per day, orally for 30 days, prevented the increase in lipid peroxidation and activity of marker enzymes observed in isoproterenol-induced rats (85 mg kg(-1) s. c. for 2 days at an interval of 24 h). TCR prevented the isoproterenol-induced decrease in antioxidant enzymes in the heart and increased the rate of ADP-stimulated oxygen uptake and respiratory coupling ratio. TCR protected against pathological changes induced by isoproterenol in rat heart. The results show that pretreatment with TCR may be useful in preventing the damage induced by isoproterenol in rat heart.
Evaluation of the anticocaine monoclonal antibody GNC92H2 as an immunotherapy for cocaine overdose. The illicit use of cocaine continues in epidemic proportions and treatment for cocaine overdose remains elusive. Current protein-based technology offers a new therapeutic venue by which antibodies bind the drug in the blood stream, inactivating its toxic effects. The therapeutic potential of the anticocaine antibody GNC92H2 was examined using a model of cocaine overdose. Swiss albino mice prepared with intrajugular catheters were tested in photocell cages after administration of 93 mg/kg (LD50) of cocaine and GNC92H2 infusions ranging from 30 to 190 mg/kg. GNC92H2 was delivered 30 min before, concomitantly or 3 min after cocaine treatment. Significant blockade of cocaine toxicity was observed with the higher dose of GNC92H2 (190 mg/kg), where premorbid behaviors were reduced up to 40%, seizures up to 77% and death by 72%. Importantly, GNC92H2 prevented death even post-cocaine injection. The results support the important potential of GNC92H2 as a therapeutic tool against cocaine overdose.
Electrocardiographic evidence of myocardial injury in psychiatrically hospitalized cocaine abusers. The electrocardiograms (ECG) of 99 cocaine-abusing patients were compared with the ECGs of 50 schizophrenic controls. Eleven of the cocaine abusers and none of the controls had ECG evidence of significant myocardial injury defined as myocardial infarction, ischemia, and bundle branch block.
Valproate-induced encephalopathy. Valproate-induced encephalopathy is a rare syndrome that may manifest in otherwise normal epileptic individuals. It may even present in patients who have tolerated this medicine well in the past. It is usually but not necessarily associated with hyperammonemia. The EEG shows characteristic triphasic waves in most patients with this complication. A case of valproate-induced encephalopathy is presented. The problems in diagnosing this condition are subsequently discussed.
Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans. Abnormal processing of somatosensory inputs in the central nervous system (central sensitization) is the mechanism accounting for the enhanced pain sensitivity in the skin surrounding tissue injury (secondary hyperalgesia). Secondary hyperalgesia shares clinical characteristics with neurogenic hyperalgesia in patients with neuropathic pain. Abnormal brain responses to somatosensory stimuli have been found in patients with hyperalgesia as well as in normal subjects during experimental central sensitization. The aim of this study was to assess the effects of gabapentin, a drug effective in neuropathic pain patients, on brain processing of nociceptive information in normal and central sensitization states. Using functional magnetic resonance imaging (fMRI) in normal volunteers, we studied the gabapentin-induced modulation of brain activity in response to nociceptive mechanical stimulation of normal skin and capsaicin-induced secondary hyperalgesia. The dose of gabapentin was 1,800 mg per os, in a single administration. We found that (i) gabapentin reduced the activations in the bilateral operculoinsular cortex, independently of the presence of central sensitization; (ii) gabapentin reduced the activation in the brainstem, only during central sensitization; (iii) gabapentin suppressed stimulus-induced deactivations, only during central sensitization; this effect was more robust than the effect on brain activation. The observed drug-induced effects were not due to changes in the baseline fMRI signal. These findings indicate that gabapentin has a measurable antinociceptive effect and a stronger antihyperalgesic effect most evident in the brain areas undergoing deactivation, thus supporting the concept that gabapentin is more effective in modulating nociceptive transmission when central sensitization is present.
Ketoconazole induced torsades de pointes without concomitant use of QT interval-prolonging drug. Ketoconazole is not known to be proarrhythmic without concomitant use of QT interval-prolonging drugs. We report a woman with coronary artery disease who developed a markedly prolonged QT interval and torsades de pointes (TdP) after taking ketoconazole for treatment of fungal infection. Her QT interval returned to normal upon withdrawal of ketoconazole. Genetic study did not find any mutation in her genes that encode cardiac IKr channel proteins. We postulate that by virtue of its direct blocking action on IKr, ketoconazole alone may prolong QT interval and induce TdP. This calls for attention when ketoconazole is administered to patients with risk factors for acquired long QT syndrome.
Cerebral vasculitis following oral methylphenidate intake in an adult: a case report. Methylphenidate is structurally and functionally similar to amphetamine. Cerebral vasculitis associated with amphetamine abuse is well documented, and in rare cases ischaemic stroke has been reported after methylphenidate intake in children. We report the case of a 63-year-old female who was treated with methylphenidate due to hyperactivity and suffered from multiple ischaemic strokes. We consider drug-induced cerebral vasculitis as the most likely cause of recurrent ischaemic strokes in the absence of any pathological findings during the diagnostic work-up. We conclude that methylphenidate mediated vasculitis should be considered in patients with neurological symptoms and a history of methylphenidate therapy. This potential side-effect, though very rare, represents one more reason to be very restrictive in the use of methylphenidate.
Pilocarpine seizures cause age-dependent impairment in auditory location discrimination. Children who have status epilepticus have continuous or rapidly repeating seizures that may be life-threatening and may cause life-long changes in brain and behavior. The extent to which status epilepticus causes deficits in auditory discrimination is unknown. A naturalistic auditory location discrimination method was used to evaluate this question using an animal model of status epilepticus. Male Sprague-Dawley rats were injected with saline on postnatal day (P) 20, or a convulsant dose of pilocarpine on P20 or P45. Pilocarpine on either day induced status epilepticus; status epilepticus at P45 resulted in CA3 cell loss and spontaneous seizures, whereas P20 rats had no cell loss or spontaneous seizures. Mature rats were trained with sound-source location and sound-silence discriminations. Control (saline P20) rats acquired both discriminations immediately. In status epilepticus (P20) rats, acquisition of the sound-source location discrimination was moderately impaired. Status epilepticus (P45) rats failed to acquire either sound-source location or sound-silence discriminations. Status epilepticus in rat causes an age-dependent, long-term impairment in auditory discrimination. This impairment may explain one cause of impaired auditory location discrimination in humans.
Ethambutol-associated optic neuropathy. INTRODUCTION: Ethambutol is used in the treatment of tuberculosis, which is still prevalent in Southeast Asia, and can be associated with permanent visual loss. We report 3 cases which presented with bitemporal hemianopia. CLINICAL PICTURE: Three patients with ethambutol-associated toxic optic neuropathy are described. All 3 patients had loss of central visual acuity, colour vision (Ishihara) and visual field. The visual field loss had a bitemporal flavour, suggesting involvement of the optic chiasm. TREATMENT: Despite stopping ethambutol on diagnosis, visual function continued to deteriorate for a few months. Subsequent improvement was mild in 2 cases. In the third case, visual acuity and colour vision normalised but the optic discs were pale. OUTCOME: All 3 patients had some permanent loss of visual function. CONCLUSIONS: Ethambutol usage is associated with permanent visual loss and should be avoided if possible or used with caution and proper ophthalmological follow-up. The author postulates that in cases of ethambutol associated chiasmopathy, ethambutol may initially affect the optic nerves and subsequently progress to involve the optic chiasm.
Pharmacological evidence for the potential of Daucus carota in the management of cognitive dysfunctions. The present study was aimed at investigating the effects of Daucus carota seeds on cognitive functions, total serum cholesterol levels and brain cholinesterase activity in mice. The ethanolic extract of Daucus carota seeds (DCE) was administered orally in three doses (100, 200, 400 mg/kg) for seven successive days to different groups of young and aged mice. Elevated plus maze and passive avoidance apparatus served as the exteroceptive behavioral models for testing memory. Diazepam-, scopolamine- and ageing-induced amnesia served as the interoceptive behavioral models. DCE (200, 400 mg/kg, p.o.) showed significant improvement in memory scores of young and aged mice. The extent of memory improvement evoked by DCE was 23% at the dose of 200 mg/kg and 35% at the dose of 400 mg/kg in young mice using elevated plus maze. Similarly, significant improvements in memory scores were observed using passive avoidance apparatus and aged mice. Furthermore, DCE reversed the amnesia induced by scopolamine (0.4 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.). Daucus carota extract (200, 400 mg/kg, p.o.) reduced significantly the brain acetylcholinesterase activity and cholesterol levels in young and aged mice. The extent of inhibition of brain cholinesterase activity evoked by DCE at the dose of 400 mg/kg was 22% in young and 19% in aged mice. There was a remarkable reduction in total cholesterol level as well, to the extent of 23% in young and 21% in aged animals with this dose of DCE. Therefore, DCE may prove to be a useful remedy for the management of cognitive dysfunctions on account of its multifarious beneficial effects such as, memory improving property, cholesterol lowering property and anticholinesterase activity.
Cerebral haemorrhage induced by warfarin - the influence of drug-drug interactions. PURPOSE: To evaluate the frequency, severity and preventability of warfarin-induced cerebral haemorrhages due to warfarin and warfarin-drug interactions in patients living in the county of Osterg  tland, Sweden. METHODS: All patients with a diagnosed cerebral haemorrhage at three hospitals during the period 2000-2002 were identified. Medical records were studied retrospectively to evaluate whether warfarin and warfarin-drug interactions could have caused the cerebral haemorrhage. The proportion of possibly avoidable cases due to drug interactions was estimated. RESULTS: Among 593 patients with cerebral haemorrhage, 59 (10%) were assessed as related to warfarin treatment. This imply an incidence of 1.7/100,000 treatment years. Of the 59 cases, 26 (44%) had a fatal outcome, compared to 136 (25%) among the non-warfarin patients (p < 0.01). A warfarin-drug interaction could have contributed to the haemorrhage in 24 (41%) of the warfarin patients and in 7 of these (12%) the bleeding complication was considered being possible to avoid. CONCLUSIONS: Warfarin-induced cerebral haemorrhages are a major clinical problem with a high fatality rate. Almost half of the cases was related to a warfarin-drug interaction. A significant proportion of warfarin-related cerebral haemorrhages might have been prevented if greater caution had been taken when prescribing drugs known to interact with warfarin.
Carbamazepine-induced cardiac dysfunction. Characterization of two distinct clinical syndromes. A patient with sinus bradycardia and atrioventricular block, induced by carbamazepine, prompted an extensive literature review of all previously reported cases. From the analysis of these cases, two distinct forms of carbamazepine-associated cardiac dysfunction emerged. One patient group developed sinus tachycardias in the setting of a massive carbamazepine overdose. The second group consisted almost exclusively of elderly women who developed potentially life-threatening bradyarrhythmias or atrioventricular conduction delay, associated with either therapeutic or modestly elevated carbamazepine serum levels. Because carbamazepine is widely used in the treatment of many neurologic and psychiatric conditions, the recognition of the latter syndrome has important implications for the use of this drug in elderly patients.
Interaction between warfarin and levofloxacin: case series. Warfarin is the most widely used oral anticoagulant and is indicated for many clinical conditions. Levofloxacin, a fluoroquinolone, is one of the most commonly prescribed antibiotics in clinical practice and is effective against Gram-positive, Gram-negative, and atypical bacteria. While small prospective studies have not revealed any significant drug-drug interaction between warfarin and levofloxacin, several case reports have indicated that levofloxacin may significantly potentiate the anticoagulation effect of warfarin. We report 3 cases of serious bleeding complications that appear to be the result of the interaction between warfarin and levofloxacin. Physicians should be aware of this potential interaction and use caution when prescribing levofloxacin to patients taking warfarin.
Myocardial Fas ligand expression increases susceptibility to AZT-induced cardiomyopathy. BACKGROUND: Dilated cardiomyopathy (DCM) and myocarditis occur in many HIV-infected individuals, resulting in symptomatic heart failure in up to 5% of patients. Highly active antiretroviral therapy (HAART) has significantly reduced morbidity and mortality of acquired immunodeficiency syndrome (AIDS), but has resulted in an increase in cardiac and skeletal myopathies. METHODS AND RESULTS: In order to investigate whether the HAART component zidovudine (3'-azido-2',3'-deoxythymidine; AZT) triggers the Fas-dependent cell-death pathway and cause cytoskeletal disruption in a murine model of DCM, 8-week-old transgenic (expressing Fas ligand in the myocardium: FasL Tg) and non-transgenic (NTg) mice received water ad libitum containing different concentrations of AZT (0, 0.07, 0.2, and 0.7 mg/ml). After 6 weeks, cardiac function was assessed by echocardiography and morphology was assessed by histopathologic and immunohistochemical methods. NTg and untreated FasL Tg mice showed little or no change in cardiac structure or function. In contrast, AZT-treated FasL Tg mice developed cardiac dilation and depressed cardiac function in a dose-dependent manner, with concomitant inflammatory infiltration of both ventricles. These changes were associated with an increased sarcolemmal expression of Fas and FasL, as well as increased activation of caspase 3, translocation of calpain 1 to the sarcolemma and sarcomere, and increased numbers of cells undergoing apoptosis. These were associated with changes in dystrophin and cardiac troponin I localization, as well as loss of sarcolemmal integrity. CONCLUSIONS: The expression of Fas ligand in the myocardium, as identified in HIV-positive patients, might increase the susceptibility to HAART-induced cardiomyopathy due to activation of apoptotic pathways, resulting in cardiac dilation and dysfunction.
Acute vocal fold palsy after acute disulfiram intoxication. Acute peripheral neuropathy caused by a disulfiram overdose is very rare and there is no report of it leading to vocal fold palsy. A 49-year-old woman was transferred to our department because of quadriparesis, lancinating pain, sensory loss, and paresthesia of the distal limbs. One month previously, she had taken a single high dose of disulfiram (130 tablets of ALCOHOL STOP TAB, Shin-Poong Pharm. Co., Ansan, Korea) in a suicide attempt. She was not an alcoholic. For the first few days after ingestion, she was in a confused state and had mild to moderate ataxia and giddiness. She noticed hoarseness and distally accentuated motor and sensory dysfunction after she had recovered from this state. A nerve conduction study was consistent with severe sensorimotor axonal polyneuropathy. Laryngeal electromyography (thyroarytenoid muscle) showed ample denervation potentials. Laryngoscopy revealed asymmetric vocal fold movements during phonation. Her vocal change and weakness began to improve spontaneously about 3 weeks after transfer. This was a case of acute palsy of the recurrent laryngeal nerve and superimposed severe acute sensorimotor axonal polyneuropathy caused by high-dose disulfiram intoxication.
Norepinephrine signaling through beta-adrenergic receptors is critical for expression of cocaine-induced anxiety. BACKGROUND: Cocaine is a widely abused psychostimulant that has both rewarding and aversive properties. While the mechanisms underlying cocaine's rewarding effects have been studied extensively, less attention has been paid to the unpleasant behavioral states induced by cocaine, such as anxiety. METHODS: In this study, we evaluated the performance of dopamine beta-hydroxylase knockout (Dbh -/-) mice, which lack norepinephrine (NE), in the elevated plus maze (EPM) to examine the contribution of noradrenergic signaling to cocaine-induced anxiety. RESULTS: We found that cocaine dose-dependently increased anxiety-like behavior in control (Dbh +/-) mice, as measured by a decrease in open arm exploration. The Dbh -/- mice had normal baseline performance in the EPM but were completely resistant to the anxiogenic effects of cocaine. Cocaine-induced anxiety was also attenuated in Dbh +/- mice following administration of disulfiram, a dopamine beta-hydroxylase (DBH) inhibitor. In experiments using specific adrenergic antagonists, we found that pretreatment with the beta-adrenergic receptor antagonist propranolol blocked cocaine-induced anxiety-like behavior in Dbh +/- and wild-type C57BL6/J mice, while the alpha(1) antagonist prazosin and the alpha(2) antagonist yohimbine had no effect. CONCLUSIONS: These results indicate that noradrenergic signaling via beta-adrenergic receptors is required for cocaine-induced anxiety in mice.
Clonidine for attention-deficit/hyperactivity disorder: II. ECG changes and adverse events analysis. OBJECTIVE: To examine the safety and tolerability of clonidine used alone or with methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: In a 16-week multicenter, double-blind trial, 122 children with ADHD were randomly assigned to clonidine (n = 31), methylphenidate (n = 29), clonidine and methylphenidate (n = 32), or placebo (n = 30). Doses were flexibly titrated up to 0.6 mg/day for clonidine and 60 mg/day for methylphenidate (both with divided dosing). Groups were compared regarding adverse events and changes from baseline to week 16 in electrocardiograms and vital signs. RESULTS: There were more incidents of bradycardia in subjects treated with clonidine compared with those not treated with clonidine (17.5% versus 3.4%; p =.02), but no other significant group differences regarding electrocardiogram and other cardiovascular outcomes. There were no suggestions of interactions between clonidine and methylphenidate regarding cardiovascular outcomes. Moderate or severe adverse events were more common in subjects on clonidine (79.4% versus 49.2%; p =.0006) but not associated with higher rates of early study withdrawal. Drowsiness was common on clonidine, but generally resolved by 6 to 8 weeks. CONCLUSIONS: Clonidine, used alone or with methylphenidate, appears safe and well tolerated in childhood ADHD. Physicians prescribing clonidine should monitor for bradycardia and advise patients about the high likelihood of initial drowsiness.
Higher optical density of an antigen assay predicts thrombosis in patients with heparin-induced thrombocytopenia. OBJECTIVES: To correlate optical density and percent inhibition of a two-step heparin-induced thrombocytopenia (HIT) antigen assay with thrombosis; the assay utilizes reaction inhibition characteristics of a high heparin concentration. PATIENTS AND METHODS: Patients with more than 50% decrease in platelet count or thrombocytopenia (<150 x 10(9)/L) after exposure to heparin, who had a positive two-step antigen assay [optical density (OD) >0.4 and >50 inhibition with high concentration of heparin] were included in the study. RESULTS: Forty of 94 HIT patients had thrombosis at diagnosis; 54/94 had isolated-HIT without thrombosis. Eight of the isolated-HIT patients developed thrombosis within the next 30 d; thus, a total of 48 patients had thrombosis at day 30. At diagnosis there was no significant difference in OD between HIT patients with thrombosis and those with isolated-HIT. However, OD was significantly higher in all patients with thrombosis (n = 48, 1.34 +/- 0.89), including isolated-HIT patients who later developed thrombosis within 30 d (n = 8, 1.84 +/- 0.64) as compared to isolated-HIT patients who did not develop thrombosis (0.96 +/- 0.75; P = 0.011 and P = 0.008). The Receiver Operative Characteristic Curve showed that OD >1.27 in the isolated-HIT group had a significantly higher chance of developing thrombosis by day 30. None of these groups showed significant difference in percent inhibition. Multivariate analysis showed a 2.8-fold increased risk of thrombosis in females. Similarly, thrombotic risk increased with age and OD values. CONCLUSION: Higher OD is associated with significant risk of subsequent thrombosis in patients with isolated-HIT; percent inhibition, however, was not predictive.
Acute bronchodilating effects of ipratropium bromide and theophylline in chronic obstructive pulmonary disease. The bronchodilator effects of a single dose of ipratropium bromide aerosol (36 micrograms) and short-acting theophylline tablets (dose titrated to produce serum levels of 10-20 micrograms/mL) were compared in a double-blind, placebo-controlled crossover study in 21 patients with stable, chronic obstructive pulmonary disease. Mean peak forced expiratory volume in 1 second (FEV1) increases over baseline and the proportion of patients attaining at least a 15% increase in the FEV1 (responders) were 31% and 90%, respectively, for ipratropium and 17% and 50%, respectively, for theophylline. The average FEV1 increases during the 6-hour observation period were 18% for ipratropium and 8% for theophylline. The mean duration of action was 3.8 hours with ipratropium and 2.4 hours with theophylline. While side effects were rare, those experienced after theophylline use did involve the cardiovascular and gastrointestinal systems. These results show that ipratropium is a more potent bronchodilator than oral theophylline in patients with chronic airflow obstruction.
Complete atrioventricular block secondary to lithium therapy. Sinus node dysfunction has been reported most frequently among the adverse cardiovascular effects of lithium. In the present case, complete atrioventricular (AV) block with syncopal attacks developed secondary to lithium therapy, necessitating permanent pacemaker implantation. Serum lithium levels remained under or within the therapeutic range during the syncopal attacks. Lithium should be used with extreme caution, especially in patients with mild disturbance of AV conduction.
Protective effect of verapamil on gastric hemorrhagic ulcers in severe atherosclerotic rats. Studies concerning with pathogenesis of gastric hemorrhage and mucosal ulceration produced in atherosclerotic rats are lacking. The aim of this study is to examine the role of gastric acid back-diffusion, mast cell histamine release, lipid peroxide (LPO) generation and mucosal microvascular permeability in modulating gastric hemorrhage and ulcer in rats with atherosclerosis induced by coadministration of vitamin D2 and cholesterol. Additionally, the protective effect of verapamil on this ulcer model was evaluated. Male Wistar rats were challenged intragastrically once daily for 9 days with 1.0 ml/kg of corn oil containing vitamin D2 and cholesterol to induce atherosclerosis. Control rats received corn oil only. After gastric surgery, rat stomachs were irrigated for 3 h with either simulated gastric juice or normal saline. Gastric acid back-diffusion, mucosal LPO generation, histamine concentration, microvascular permeability, luminal hemoglobin content and ulcer areas were determined. Elevated atherosclerotic parameters, such as serum calcium, total cholesterol and low-density lipoprotein concentration were obtained in atherosclerotic rats. Severe gastric ulcers accompanied with increased ulcerogenic factors, including gastric acid back-diffusion, histamine release, LPO generation and luminal hemoglobin content were also observed in these rats. Moreover, a positive correlation of histamine to gastric hemorrhage and to ulcer was found in those atherosclerotic rats. This hemorrhagic ulcer and various ulcerogenic parameters were dose-dependently ameliorated by daily intragastric verapamil. Atherosclerosis could produce gastric hemorrhagic ulcer via aggravation of gastric acid back-diffusion, LPO generation, histamine release and microvascular permeability that could be ameliorated by verapamil in rats.
Recovery of tacrolimus-associated brachial neuritis after conversion to everolimus in a pediatric renal transplant recipient--case report and review of the literature. TAC has been shown to be a potent immunosuppressive agent for solid organ transplantation in pediatrics. Neurotoxicity is a potentially serious toxic effect. It is characterized by encephalopathy, headaches, seizures, or neurological deficits. Here, we describe an eight-and-a-half-yr-old male renal transplant recipient with right BN. MRI demonstrated hyperintense T2 signals in the cervical cord and right brachial plexus roots indicative of both myelitis and right brachial plexitis. Symptoms persisted for three months despite TAC dose reduction, administration of IVIG and four doses of methylprednisolone pulse therapy. Improvement and eventually full recovery only occurred after TAC was completely discontinued and successfully replaced by everolimus.
Valvular heart disease in patients with Parkinson's disease treated with pergolide. Course following treatment modifications. Valvular heart abnormalities have been reported in patients with Parkinson's disease (PD) treated with pergolide. However, the incidence and severity of these abnormalities vary from study to study and their course after drug withdrawal has not been systematically assessed. OBJECTIVES: To estimate the frequency and severity of valvular heart abnormality and its possible reversibility after drug withdrawal in a case-control study. METHODS: All PD patients in the Amiens area treated with pergolide were invited to attend a cardiologic assessment including transthoracic echocardiography. Thirty PD patients participated in the study. A second echocardiography was performed (median interval: 13 months) after pergolide withdrawal (n=10 patients). Controls were age- and sex-matched non-PD patients referred to the cardiology department. RESULTS: Compared to controls, aortic regurgitation (OR: 3.1; 95% IC: 1.1-8.8) and mitral regurgitation (OR: 10.7; 95% IC: 2.1-53) were more frequent in PD patients (tricuspid: NS). The number of affected valves (n=2.4+/-0.7) and the sum of regurgitation grades (n=2.8+/-1.09) were higher (p=0.008 and p=0.006, respectively) in the pergolide group. Severity of regurgitation was not correlated with pergolide cumulative dose. A restrictive pattern of valvular regurgitation, suggestive of the role of pergolide, was observed in 12/30 (40%) patients including two with heart failure. Pergolide was discontinued in 10 patients with valvular heart disease, resulting in a lower regurgitation grade (p=0.01) at the second transthoracic echocardiography and the two patients with heart failure returned to nearly normal clinical examination. This study supports the high frequency of restrictive valve regurgitation in PD patients treated with pergolide and reveals that a significant improvement is usual when the treatment is converted to non-ergot dopamine agonists.
Neuropsychiatric side effects after the use of mefloquine. This study describes neuropsychiatric side effects in patients after treatment with mefloquine. Reactions consisted mainly of seizures, acute psychoses, anxiety neurosis, and major disturbances of sleep-wake rhythm. Side effects occurred after both therapeutic and prophylactic intake and were graded from moderate to severe. In a risk analysis of neuropsychiatric side effects in Germany, it is estimated that one of 8,000 mefloquine users suffers from such reactions. The incidence calculation revealed that one of 215 therapeutic users had reactions, compared with one of 13,000 in the prophylaxis group, making the risk of neuropsychiatric reactions after mefloquine treatment 60 times higher than after prophylaxis. Therefore, certain limitations for malaria prophylaxis and treatment with mefloquine are recommended.
Massive proteinuria and acute renal failure after oral bisphosphonate (alendronate) administration in a patient with focal segmental glomerulosclerosis. A 61-year-old Japanese man with nephrotic syndrome due to focal segmental glomerulosclerosis was initially responding well to steroid therapy. The amount of daily urinary protein decreased from 15.6 to 2.8 g. Within 14 days of the oral bisphosphonate (alendronate sodium) administration, the amount of daily urinary protein increased rapidly up to 12.8 g with acute renal failure. After discontinuing the oral alendronate, the patient underwent six cycles of hemodialysis and four cycles of LDL apheresis. Urinary volume and serum creatinine levels recovered to the normal range, with urinary protein disappearing completely within 40 days. This report demonstrates that not only intravenous, but also oral bisphosphonates can aggravate proteinuria and acute renal failure.
Severe and long lasting cholestasis after high-dose co-trimoxazole treatment for Pneumocystis pneumonia in HIV-infected patients--a report of two cases. Pneumocystis pneumonia (PCP), a common opportunistic infection in HIV-infected individuals, is generally treated with high doses of co-trimoxazole. However, treatment is often limited by adverse effects. Here, we report two cases of severely immunocompromised HIV-infected patients who developed severe intrahepatic cholestasis, and in one patient lesions mimicking liver abscess formation on radiologic exams, during co-trimoxazole treatment for PCP. Whereas patient 1 showed lesions of up to 1 cm readily detectable on magnetic resonance imaging under prolonged co-trimoxazole treatment, therapy of patient 2 was switched early.
Confusion, a rather serious adverse drug reaction with valproic acid: a review of the French Pharmacovigilance database. INTRODUCTION: Confusion is an adverse drug reaction frequently observed with valproic acid. Some case reports are published in the literature but no systematic study from a sample of patients has been published. We performed this study in order to describe the main characteristics of this adverse drug reaction. METHODS: Using the French Pharmacovigilance database, we selected the cases of confusion reported since 1985 with valproic acid. RESULTS: 272 cases of confusion were reported with valproic acid: 153 women and 119 men. Confusion mostly occurred during the two first weeks following valproic acid exposure (39.7%). It was "serious" for almost 2/3 of the patients (62.5%) and its outcome favourable in most of the cases (82%). The occurrence of this ADR was more frequent in patients aged between 61 and 80 years. CONCLUSION: This work shows that confusion with valproic acid is a serious, rather frequent but reversible adverse drug reaction. It occurs especially in older patients and during the first two weeks of treatment.
Twin preterm neonates with cardiac toxicity related to lopinavir/ritonavir therapy. We report twin neonates who were born prematurely at 32 weeks of gestation to a mother with human immunodeficiency virus infection. One of the twins developed complete heart block and dilated cardiomyopathy related to lopinavir/ritonavir therapy, a boosted protease-inhibitor agent, while the other twin developed mild bradycardia. We recommend caution in the use of lopinavir/ritonavir in the immediate neonatal period.
Reversible myocardial hypertrophy induced by tacrolimus in a pediatric heart transplant recipient: case report. Tacrolimus is a potent immunosuppressant that is frequently used in organ transplantation. However, adverse effects include cardiac toxicity. Herein we describe transient myocardial hypertrophy induced by tacrolimus after heart transplantation. The hypertrophy caused no clinical symptoms but was noted because of elevation of plasma brain natriuretic peptide concentration and confirmed at echocardiography. Initially, allograft rejection was feared; however, myocardial biopsy samples revealed only interstitial edema and mild myocardial hypertrophy; neither cellular nor humoral rejection was detected. The blood tacrolimus concentration was higher than usual at that time; thus, tacrolimus dosage was reduced. Myocardial hypertrophy completely resolved upon reducing the target concentration of tacrolimus and did not recur, as confirmed at echocardiography and myocardial biopsy. Thus, we conclude that tacrolimus induces reversible myocardial hypertrophy. In patients receiving tacrolimus therapy, blood concentration should be carefully controlled and extreme attention paid to cardiac involvement.
Nimodipine prevents memory impairment caused by nitroglycerin-induced hypotension in adult mice. BACKGROUND: Hypotension and a resultant decrease in cerebral blood flow have been implicated in the development of cognitive dysfunction. We tested the hypothesis that nimodipine (NIMO) administered at the onset of nitroglycerin (NTG)-induced hypotension would preserve long-term associative memory. METHODS: The passive avoidance (PA) paradigm was used to assess memory retention. For PA training, latencies (seconds) were recorded for entry from a suspended platform into a Plexiglas tube where a shock was automatically delivered. Latencies were recorded 48 h later for a testing trial. Ninety-six Swiss-Webster mice (30-35 g, 6-8 wk), were randomized into 6 groups 1) saline (control), 2) NTG immediately after learning, 3) NTG 3 h after learning, 4) NTG and NIMO, 5) vehicle, and 6) NIMO alone. The extent of hypotension and changes in brain tissue oxygenation (PbtO(2)) and in cerebral blood flow were studied in a separate group of animals. RESULTS: All groups exhibited similar training latencies (17.0 +/- 4.6 s). Mice subjected to hypotensive episodes showed a significant decrease in latency time (178 +/- 156 s) compared with those injected with saline, NTG + NIMO, or delayed NTG (580 +/- 81 s, 557 +/- 67 s, and 493 +/- 146 s, respectively). A Kruskal-Wallis 1-way analysis of variance indicated a significant difference among the 4 treatment groups (H = 15.34; P < 0.001). In a separate group of mice not subjected to behavioral studies, the same dose of NTG (n = 3) and NTG + NIMO (n = 3) caused mean arterial blood pressure to decrease from 85.9 +/- 3.8 mm Hg sem to 31.6 +/- 0.8 mm Hg sem and from 86.2 +/- 3.7 mm Hg sem to 32.6 +/- 0.2 mm Hg sem, respectively. Mean arterial blood pressure in mice treated with NIMO alone decreased from 88.1 +/- 3.8 mm Hg to 80.0 +/- 2.9 mm Hg. The intergroup difference was statistically significant (P < 0.05). PbtO(2) decreased from 51.7 +/- 4.5 mm Hg sem to 33.8 +/- 5.2 mm Hg sem in the NTG group and from 38.6 +/- 6.1 mm Hg sem to 25.4 +/- 2.0 mm Hg sem in the NTG + NIMO groups, respectively. There were no significant differences among groups. CONCLUSION: In a PA retention paradigm, the injection of NTG immediately after learning produced a significant impairment of long-term associative memory in mice, whereas delayed induced hypotension had no effect. NIMO attenuated the disruption in consolidation of long-term memory caused by NTG but did not improve latency in the absence of hypotension. The observed effect of NIMO may have been attributable to the preservation of calcium homeostasis during hypotension, because there were no differences in the PbtO(2) indices among groups.
Phenylephrine but not ephedrine reduces frontal lobe oxygenation following anesthesia-induced hypotension. BACKGROUND: Vasopressor agents are used to correct anesthesia-induced hypotension. We describe the effect of phenylephrine and ephedrine on frontal lobe oxygenation (S(c)O(2)) following anesthesia-induced hypotension. METHODS: Following induction of anesthesia by fentanyl (0.15 mg kg(-1)) and propofol (2.0 mg kg(-1)), 13 patients received phenylephrine (0.1 mg iv) and 12 patients received ephedrine (10 mg iv) to restore mean arterial pressure (MAP). Heart rate (HR), MAP, stroke volume (SV), cardiac output (CO), and frontal lobe oxygenation (S(c)O(2)) were registered. RESULTS: Induction of anesthesia was followed by a decrease in MAP, HR, SV, and CO concomitant with an elevation in S(c)O(2). After administration of phenylephrine, MAP increased (51 +/- 12 to 81 +/- 13 mmHg; P < 0.001; mean +/- SD). However, a 14% (from 70 +/- 8% to 60 +/- 7%) reduction in S(c)O(2) (P < 0.05) followed with no change in CO (3.7 +/- 1.1 to 3.4 +/- 0.9 l min(-1)). The administration of ephedrine led to a similar increase in MAP (53 +/- 9 to 79 +/- 8 mmHg; P < 0.001), restored CO (3.2 +/- 1.2 to 5.0 +/- 1.3 l min(-1)), and preserved S(c)O(2). CONCLUSIONS: The utilization of phenylephrine to correct hypotension induced by anesthesia has a negative impact on S(c)O(2) while ephedrine maintains frontal lobe oxygenation potentially related to an increase in CO.
Oral manifestations of "meth mouth": a case report. AIM: The aim of the documentation of this clinical case is to make clinicians aware of "meth mouth" and the medical risks associated with this serious condition. BACKGROUND: Methamphetamine is a very addictive, powerful stimulant that increases wakefulness and physical activity and can produce other effects such as cardiac dysrhythmias, hypertension, hallucinations, and violent behavior. Dental patients abusing methamphetamine can present with poor oral hygiene, xerostomia, rampant caries ("meth mouth"), and excessive tooth wear. Oral rehabilitation of patients using methamphetamine can be challenging. CASE DESCRIPTION: A 30-year-old Caucasian woman presented with dental pain, bad breath, and self-reported poor esthetics. A comprehensive examination including her medical history, panoramic radiograph, and intraoral examination revealed 19 carious lesions, which is not very common for a healthy adult. She reported her use of methamphetamine for five years and had not experienced any major carious episodes before she started using the drug. SUMMARY: The patient's medical and dental histories along with radiographic and clinical findings lead to a diagnosis of "meth mouth." Although three different dental treatment modalities (either conventional or implant-supported) have been offered to the patient since August 2007, the patient has yet to initiate any treatment. CLINICAL SIGNIFICANCE: This clinical case showing oral manifestations of meth mouth was presented to help dental practitioners recognize and manage patients who may be abusing methamphetamines. Dental practitioners also may be skeptical about the reliability of appointment keeping by these patients, as they frequently miss their appointments without reasonable justification.
Efficacy and safety of asenapine in a placebo- and haloperidol-controlled trial in patients with acute exacerbation of schizophrenia. Asenapine is approved by the Food and Drugs Administration in adults for acute treatment of schizophrenia or of manic or mixed episodes associated with bipolar I disorder with or without psychotic features. In a double-blind 6-week trial, 458 patients with acute schizophrenia were randomly assigned to fixed-dose treatment with asenapine at 5 mg twice daily (BID), asenapine at 10 mg BID, placebo, or haloperidol at 4 mg BID (to verify assay sensitivity). With last observations carried forward (LOCF), mean Positive and Negative Syndrome Scale total score reductions from baseline to endpoint were significantly greater with asenapine at 5 mg BID (-16.2) and haloperidol (-15.4) than placebo (-10.7; both P < 0.05); using mixed model for repeated measures (MMRM), changes at day 42 were significantly greater with asenapine at 5 and 10 mg BID (-21.3 and -19.4, respectively) and haloperidol (-20.0) than placebo (-14.6; all P < 0.05). On the Positive and Negative Syndrome Scale positive subscale, all treatments were superior to placebo with LOCF and MMRM; asenapine at 5 mg BID was superior to placebo on the negative subscale with MMRM and on the general psychopathology subscale with LOCF and MMRM. Treatment-related adverse events (AEs) occurred in 44% and 52%, 57%, and 41% of the asenapine at 5 and 10 mg BID, haloperidol, and placebo groups, respectively. Extrapyramidal symptoms reported as AEs occurred in 15% and 18%, 34%, and 10% of the asenapine at 5 and 10 mg BID, haloperidol, and placebo groups, respectively. Across all groups, no more than 5% of patients had clinically significant weight change. Post hoc analyses indicated that efficacy was similar with asenapine and haloperidol; greater contrasts were seen in AEs, especially extrapyramidal symptoms.
Suxamethonium induced prolonged apnea in a patient receiving electroconvulsive therapy. Suxamethonium causes prolonged apnea in patients in whom pseudocholinesterase enzyme gets deactivated by organophosphorus (OP) poisons. Here, we present a similar incident in a severely depressed patient who received electroconvulsive therapy (ECT). Prolonged apnea in our case ensued because the information about suicidal attempt by OP compound was concealed from the treating team.
Effects of pallidal neurotensin on haloperidol-induced parkinsonian catalepsy: behavioral and electrophysiological studies. OBJECTIVE: The globus pallidus plays a critical role in movement regulation. Previous studies have indicated that the globus pallidus receives neurotensinergic innervation from the striatum, and systemic administration of a neurotensin analog could produce antiparkinsonian effects. The present study aimed to investigate the effects of pallidal neurotensin on haloperidol-induced parkinsonian symptoms. METHODS: Behavioral experiments and electrophysiological recordings were performed in the present study. RESULTS: Bilateral infusions of neurotensin into the globus pallidus reversed haloperidol-induced parkinsonian catalepsy in rats. Electrophysiological recordings showed that microinjection of neurotensin induced excitation of pallidal neurons in the presence of systemic haloperidol administration. The neurotensin type-1 receptor antagonist SR48692 blocked both the behavioral and the electrophysiological effects induced by neurotensin. CONCLUSION: Activation of pallidal neurotensin receptors may be involved in neurotensin-induced antiparkinsonian effects.
Butyrylcholinesterase gene mutations in patients with prolonged apnea after succinylcholine for electroconvulsive therapy. BACKGROUND: patients undergoing electroconvulsive therapy (ECT) often receive succinylcholine as part of the anesthetic procedure. The duration of action may be prolonged in patients with genetic variants of the butyrylcholinesterase enzyme (BChE), the most common being the K- and the A-variants. The aim of the study was to assess the clinical significance of genetic variants in butyrylcholinesterase gene (BCHE) in patients with a suspected prolonged duration of action of succinylcholine after ECT. METHODS: a total of 13 patients were referred to the Danish Cholinesterase Research Unit after ECT during 38 months. We determined the BChE activity and the BCHE genotype using molecular genetic methods, the duration of apnea, time to sufficient spontaneous ventilation and whether neuromuscular monitoring was used. The duration of apnea was compared with published data on normal subjects. RESULTS: in 11 patients, mutations were found in the BCHE gene, the K-variant being the most frequent. The duration of apnea was 5-15 min compared with 3-5.3 min from the literature. Severe distress was noted in the recovery phase in two patients. Neuromuscular monitoring was used in two patients. CONCLUSION: eleven of 13 patients with a prolonged duration of action of succinylcholine had mutations in BCHE, indicating that this is the possible reason for a prolonged period of apnea. We recommend objective neuromuscular monitoring during the first ECT.
Ocular and auditory toxicity in hemodialyzed patients receiving desferrioxamine. During an 18-month period of study 41 hemodialyzed patients receiving desferrioxamine (10-40 mg/kg BW/3 times weekly) for the first time were monitored for detection of audiovisual toxicity. 6 patients presented clinical symptoms of visual or auditory toxicity. Moreover, detailed ophthalmologic and audiologic studies disclosed abnormalities in 7 more asymptomatic patients. Visual toxicity was of retinal origin and was characterized by a tritan-type dyschromatopsy, sometimes associated with a loss of visual acuity and pigmentary retinal deposits. Auditory toxicity was characterized by a mid- to high-frequency neurosensorial hearing loss and the lesion was of the cochlear type. Desferrioxamine withdrawal resulted in a complete recovery of visual function in 1 patient and partial recovery in 3, and a complete reversal of hearing loss in 3 patients and partial recovery in 3. This toxicity appeared in patients receiving the higher doses of desferrioxamine or coincided with the normalization of ferritin or aluminium serum levels. The data indicate that audiovisual toxicity is not an infrequent complication in hemodialyzed patients receiving desferrioxamine. Periodical audiovisual monitoring should be performed on hemodialyzed patients receiving the drug in order to detect adverse effects as early as possible.
Source of pain and primitive dysfunction in migraine: an identical site? Twenty common migraine patients received a one sided frontotemporal application of nitroglycerin (10 patients) or placebo ointment (10 patients) in a double blind study. Early onset migraine attacks were induced by nitroglycerin in seven out of 10 patients versus no patient in the placebo group. Subsequently 20 migraine patients, who developed an early onset attack with frontotemporal nitroglycerin, received the drug in a second induction test at other body areas. No early onset migraine was observed. Thus the migraine-inducing effect of nitroglycerin seems to depend on direct stimulation of the habitual site of pain, suggesting that the frontotemporal region is of crucial importance in the development of a migraine crisis. This is not consistent with a CNS origin of migraine attack.
Involvement of locus coeruleus and noradrenergic neurotransmission in fentanyl-induced muscular rigidity in the rat. Whereas muscular rigidity is a well-known side effect that is associated with high-dose fentanyl anesthesia, a paucity of information exists with regard to its underlying mechanism(s). We investigated in this study the possible engagement of locus coeruleus of the pons in this phenomenon, using male Sprague-Dawley rats anesthetized with ketamine. Under proper control of respiration, body temperature and end-tidal CO2, intravenous administration of fentanyl (50 or 100 micrograms/kg) consistently promoted an increase in electromyographic activity recorded from the gastrocnemius and abdominal rectus muscles. Such an induced muscular rigidity by the narcotic agent was significantly antagonized or even reduced by prior electrolytic lesions of the locus coeruleus or pretreatment with the alpha-adrenoceptor blocker, prazosin. Microinjection of fentanyl (2.5 micrograms/50 nl) directly into this pontine nucleus, on the other hand, elicited discernible electromyographic excitation. It is speculated that the induction of muscular rigidity by fentanyl may involve the coerulospinal noradrenergic fibers to the spinal motoneurons.
Chronic active hepatitis associated with diclofenac sodium therapy. Diclofenac sodium (Voltarol, Geigy Pharmaceuticals) is a non-steroidal anti-inflammatory derivative of phenylacetic acid. Although generally well-tolerated, asymptomatic abnormalities of liver function have been recorded and, less commonly, severe hepatitis induced by diclofenac. The patient described developed chronic active hepatitis after six months therapy with diclofenac sodium which progressed despite the withdrawal of the drug, a finding not previously reported.
Arterial hypertension as a complication of prolonged ketoconazole treatment. Two of 14 patients with Cushing's syndrome treated on a long-term basis with ketoconazole developed sustained hypertension. In both cases normal plasma and urinary free cortisol levels had been achieved following ketoconazole therapy, yet continuous blood pressure monitoring demonstrated hypertension 31 (patient 1) and 52 weeks (patient 2) after treatment. In patient 1, plasma levels of deoxycorticosterone and 11-deoxycortisol were elevated. In patient 2, in addition to an increase in both deoxycorticosterone and 11-deoxycortisol levels, plasma aldosterone values were raised, with a concomitant suppression of renin levels. Our findings show that long-term treatment with high doses of ketoconazole may induce enzyme blockade leading to mineralocorticoid-related hypertension.
Stroke associated with cocaine use. We describe eight patients in whom cocaine use was related to stroke and review 39 cases from the literature. Among these 47 patients the mean (+/- SD) age was 32.5 +/- 12.1 years; 76% (34/45) were men. Stroke followed cocaine use by inhalation, intranasal, intravenous, and intramuscular routes. Intracranial aneurysms or arteriovenous malformations were present in 17 of 32 patients studied angiographically or at autopsy; cerebral vasculitis was present in two patients. Cerebral infarction occurred in 10 patients (22%), intracerebral hemorrhage in 22 (49%), and subarachnoid hemorrhage in 13 (29%). These data indicate that (1) the apparent incidence of stroke related to cocaine use is increasing; (2) cocaine-associated stroke occurs primarily in young adults; (3) stroke may follow any route of cocaine administration; (4) stroke after cocaine use is frequently associated with intracranial aneurysms and arteriovenous malformations; and (5) in cocaine-associated stroke, the frequency of intracranial hemorrhage exceeds that of cerebral infarction.
Glycopyrronium requirements for antagonism of the muscarinic side effects of edrophonium. We have compared, in 60 adult patients, the cardiovascular effects of glycopyrronium 5 micrograms kg-1 and 10 micrograms kg-1 given either simultaneously or 1 min before edrophonium 1 mg kg-1. Significant differences between the four groups were detected (P less than 0.001). Both groups receiving 10 micrograms kg-1 showed increases in heart rate of up to 30 beat min-1 (95% confidence limits 28-32 beat min-1). Use of glycopyrronium 5 micrograms kg-1 provided greater cardiovascular stability and, given 1 min before the edrophonium, was sufficient to minimize early, edrophonium-induced bradycardias. This low dose of glycopyrronium provided good control of oropharyngeal secretions.
Dipyridamole-induced myocardial ischemia. Angina and ischemic electrocardiographic changes occurred after administration of oral dipyridamole in four patients awaiting urgent myocardial revascularization procedures. To our knowledge, this has not previously been reported as a side effect of preoperative dipyridamole therapy, although dipyridamole-induced myocardial ischemia has been demonstrated to occur in animals and humans with coronary artery disease. Epicardial coronary collateral vessels were demonstrated in all four patients; a coronary "steal" phenomenon may be the mechanism of the dipyridamole-induced ischemia observed.
Reversibility of captopril-induced renal insufficiency after prolonged use in an unusual case of renovascular hypertension. We report a case of severe hypertension with an occluded renal artery to a solitary kidney, who developed sudden deterioration of renal function following treatment with captopril. His renal function remained impaired but stable during 2 years' treatment with captopril but returned to pre-treatment levels soon after cessation of the drug. This indicates reversibility in captopril-induced renal failure even after its prolonged use and suggests that no organic damage occurs to glomerular arterioles following chronic ACE inhibition.
Chorea associated with oral contraception. Three patients developed chorea while receiving oral contraceptives. Two were young patients whose chorea developed long after treatment had been started and disappeared soon after it had been discontinued. The third patient had acute amphetamine-induced chorea after prolonged oral contraception. Prolonged administration of female sex hormones is a possible cause of chorea in women who have not previously had chorea or rheumatic fever.
Intracranial pressure increases during alfentanil-induced rigidity. Intracranial pressure (ICP) was measured during alfentanil-induced rigidity in rats. Ten rats had arterial, central venous (CVP), and subdural cannulae inserted under halothane anesthesia. The animals were mechanically ventilated to achieve normocarbia (PCO2 = 42 +/- 1 mmHg, mean +/- SE). Following instrumentation, halothane was discontinued and alfentanil (125 mu/kg) administered iv during emergence from halothane anesthesia. In the five rats that developed somatic rigidity, ICP and CVP increased significantly above baseline (delta ICP 7.5 +/- 1.0 mmHg, delta CVP 5.9 +/- 1.3 mmHg). These variables returned to baseline when rigidity was abolished with metocurine. In five rats that did not become rigid, ICP and CVP did not change following alfentanil. These observations suggest that rigidity should be prevented when alfentanil, and, presumably, other opiates, are used in the anesthetic management of patients with ICP problems.
Verapamil-induced carbamazepine neurotoxicity. A report of two cases. Two patients with signs of carbamazepine neurotoxicity after combined treatment with verapamil showed complete recovery after discontinuation of the calcium entry blocker. Use of verapamil in combination with carbamazepine should either be avoided or prescribed only with appropriate adjustment of the carbamazepine dose (usually reduction of the carbamazepine dose by one half).
Serial studies of auditory neurotoxicity in patients receiving deferoxamine therapy. Visual and auditory neurotoxicity was previously documented in 42 of 89 patients with transfusion-dependent anemia who were receiving iron chelation therapy with daily subcutaneous deferoxamine. Twenty-two patients in the affected group had abnormal audiograms with deficits mostly in the high frequency range of 4,000 to 8,000 Hz and in the hearing threshold levels of 30 to 100 decibels. When deferoxamine therapy was discontinued and serial studies were performed, audiograms in seven cases reverted to normal or near normal within two to three weeks, and nine of 13 patients with symptoms became asymptomatic. Audiograms from 15 patients remained abnormal and four patients required hearing aids because of permanent disability. Since 18 of the 22 patients were initially receiving deferoxamine doses in excess of the commonly recommended 50 mg/kg per dose, therapy was restarted with lower doses, usually 50 mg/kg per dose or less depending on the degree of auditory abnormality, and with the exception of two cases no further toxicity was demonstrated. Auditory deterioration and improvement, demonstrated serially in individual patients receiving and not receiving deferoxamine, respectively, provided convincing evidence for a cause-and-effect relation between deferoxamine administration and ototoxicity. Based on these data, a plan of management was developed that allows effective yet safe administration of deferoxamine. A dose of 50 mg/kg is recommended in those without audiogram abnormalities. With mild toxicity, a reduction to 30 or 40 mg/kg per dose should result in a reversal of the abnormal results to normal within four weeks. Moderate abnormalities require a reduction of deferoxamine to 25 mg/kg per dose with careful monitoring. In those with symptoms of hearing loss, the drug should be stopped for four weeks, and when the audiogram is stable or improved, therapy should be restarted at 10 to 25 mg/kg per dose. Serial audiograms should be performed every six months in those without problems and more frequently in young patients with normal serum ferritin values and in those with auditory dysfunction.
Flurbiprofen in the treatment of juvenile rheumatoid arthritis. Thirty-four patients with juvenile rheumatoid arthritis, who were treated with flurbiprofen at a maximum dose of 4 mg/kg/day, had statistically significant decreases from baseline in 6 arthritis indices after 12 weeks of treatment. Improvements were seen in the number of tender joints, the severity of swelling and tenderness, the time of walk 50 feet, the duration of morning stiffness and the circumference of the left knee. The most frequently observed side effect was fecal occult blood (25% of patients); however, there was no other evidence of gastrointestinal (GI) bleeding in these patients. One patient was prematurely discontinued from the study for severe headache and abdominal pain. Most side effects were mild and related to the GI tract.
Triazolam-induced brief episodes of secondary mania in a depressed patient. Large doses of triazolam repeatedly induced brief episodes of mania in a depressed elderly woman. Features of organic mental disorder (delirium) were not present. Manic excitement was coincident with the duration of action of triazolam. The possible contribution of the triazolo group to changes in affective status is discussed.
Amiodarone-induced sinoatrial block. We observed sinoatrial block due to chronic amiodarone administration in a 5-year-old boy with primary cardiomyopathy, Wolff-Parkinson-White syndrome and supraventricular tachycardia. Reduction in the dosage of amiodarone resulted in the disappearance of the sinoatrial block and the persistence of asymptomatic sinus bradycardia.
Indomethacin-induced renal insufficiency: recurrence on rechallenge. We have reported a case of acute oliguric renal failure with hyperkalemia in a patient with cirrhosis, ascites, and cor pulmonale after indomethacin therapy. Prompt restoration of renal function followed drug withdrawal, while re-exposure to a single dose of indomethacin caused recurrence of acute reversible oliguria. Our case supports the hypothesis that endogenous renal prostaglandins play a role in the maintenance of renal blood flow when circulating plasma volume is diminished. Since nonsteroidal anti-inflammatory agents interfere with this compensatory mechanism and may cause acute renal failure, they should be used with caution in such patients.
Changes in heart size during long-term timolol treatment after myocardial infarction. The effect of long-term timolol treatment on heart size after myocardial infarction was evaluated by X-ray in a double-blind study including 241 patients (placebo 126, timolol 115). The follow-up period was 12 months. The timolol-treated patients showed a small but significant increase in heart size from baseline in contrast to a decrease in the placebo group. These differences may be caused by timolol-induced bradycardia and a compensatory increase in end-diastolic volume. The timolol-related increase in heart size was observed only in patients with normal and borderline heart size. In patients with cardiomegaly, the increase in heart size was similar in both groups. After re-infarction, heart size increased in the placebo group and remained unchanged in the timolol group.
Veno-occlusive liver disease after dacarbazine therapy (DTIC) for melanoma. A case of veno-occlusive disease of the liver with fatal outcome after dacarbazine (DTIC) therapy for melanoma is reported. There was a fulminant clinical course from start of symptoms until death. At autopsy the liver was enlarged and firm with signs of venous congestion. Small- and medium-sized hepatic veins were blocked by thrombosis. Eosinophilic infiltrations were found around the vessels. Published cases from the literature are reviewed and pertinent features discussed.
Effects of training on the extent of experimental myocardial infarction in aging rats. The effects of exercise on the severity of isoproterenol-induced myocardial infarction were studied in female albino rats of 20,40,60 and 80 weeks of age. The rats were trained to swim for a specific duration and for a particular period. The occurrence of infarcts were confirmed by histological methods. Elevations in the serum GOT and GPT were maximum in the sedentary-isoproterenols and minimum in the exercise-controls. These changes in the serum transaminases were associated with corresponding depletions in the cardiac GOT and GPT. However, age was seen to interfere with the responses exhibited by the young and old rats. Studies dealing with myocardial infarction are more informative when dealt with age.
A case of tardive dyskinesia caused by metoclopramide. Abnormal involuntary movements appeared in the mouth, tongue, neck and abdomen of a 64-year-old male patient after he took metoclopramide for gastrointestinal disorder in a regimen of 30 mg per day for a total of about 260 days. The symptoms exacerbated to a maximum in a month. When the metoclopramide administration was discontinued, the abnormal movements gradually improved to a considerable extent. Attention to the possible induction of specific tardive dyskinesia is called for in the use of this drug.
Blood pressure response to chronic low-dose intrarenal noradrenaline infusion in conscious rats. Sodium chloride solution (0.9%) or noradrenaline in doses of 4, 12 and 36 micrograms h-1 kg-1 was infused for five consecutive days, either intrarenally (by a new technique) or intravenously into rats with one kidney removed. Intrarenal infusion of noradrenaline caused hypertension at doses which did not do so when infused intravenously. Intrarenal compared with intravenous infusion of noradrenaline caused higher plasma noradrenaline concentrations and a shift of the plasma noradrenaline concentration-blood pressure effect curve towards lower plasma noradrenaline levels. These results suggest that hypertension after chronic intrarenal noradrenaline infusion is produced by relatively higher levels of circulating noradrenaline and by triggering of an additional intrarenal pressor mechanism.
Characterization of estrogen-induced adenohypophyseal tumors in the Fischer 344 rat. Pituitary tumors were induced in F344 female rats by chronic treatment with diethylstilbestrol (DES, 8-10 mg) implanted subcutaneously in silastic capsules. Over a range of 1-150 days of DES treatment, pairs of control and DES-treated rats were sacrificed, and their pituitaries dissociated enzymatically into single-cell preparations. The cell populations were examined regarding total cell recovery correlated with gland weight, intracellular prolactin (PRL) content and subsequent release in primary culture, immunocytochemical PRL staining, density and/or size alterations via separation on Ficoll-Hypaque and by unit gravity sedimentation, and cell cycle analysis, after acriflavine DNA staining, by laser flow cytometry. Total cell yields from DES-treated pituitaries increased from 1.3 times control yields at 8 days of treatment to 58.9 times control values by day 150. Intracellular PRL content ranged from 1.9 to 9.4 times control levels, and PRL release in vitro was significantly and consistently higher than controls, after at least 8 days of DES exposure. Beyond 8 days of DES exposure, the immunochemically PRL-positive proportion of cells increased to over 50% of the total population. Increased density and/or size and PRL content were indicated for the majority of the PRL cell population in both types of separation protocols. All these effects of DES were more pronounced among previously ovariectomized animals. The data extend the findings of other investigators, further establishing the DES-induced tumor as a model for study of PRL cellular control mechanisms.
Fatal aplastic anemia following topical administration of ophthalmic chloramphenicol. A 73-year-old woman died of aplastic anemia less than two months after undergoing cataract extraction and beginning topical therapy with chloramphenicol. The first signs of pancytopenia began within one month of the surgery. The pattern of the aplastic anemia was associated with an idiosyncratic response to chloramphenicol. This was the second report of fatal aplastic anemia after topical treatment with chloramphenicol for ocular conditions, although two cases of reversible bone marrow hypoplasia have also been reported. Any other suspected cases of ocular toxicity associated with topically applied chloramphenicol should be reported to the National Registry of Drug-Induced Ocular Side Effects, Oregon Health Sciences University, Portland, OR 97201.
Further observations on the electrophysiologic effects of oral amiodarone therapy. A case is presented of a reversible intra-Hisian block occurring under amiodarone treatment for atrial tachycardia in a patient without clear intraventricular conduction abnormalities. His bundle recordings showed an atrial tachycardia with intermittent exit block and greatly prolonged BH and HV intervals (40 and 100 msec, respectively). Thirty days after amiodarone discontinuation, His bundle electrograms showed atrial flutter without intra-Hisian or infra-Hisian delay. Amiodarone should be used with caution during long-term oral therapy in patients with or without clear intraventricular conduction defects.
Development of clear cell adenocarcinoma in DES-exposed offspring under observation. Two cases of clear cell adenocarcinoma of the vagina detected at follow-up in young women exposed in utero to diethylstilbestrol are reported. One patient, aged 23, had been followed for 2 years before carcinoma was diagnosed; the second patient, aged 22, had been seen on a regular basis for 5 years, 8 months. In both instances, suspicion of the presence of carcinoma was aroused by the palpation of a small nodule in the vaginal fornix. Hysterosalpingography was performed on both patients and, in 1 instance, an abnormal x-ray film was reflected by the gross appearance of the uterine cavity found in the surgical specimen.
Age-dependent sensitivity of the rat to neurotoxic effects of streptomycin. Streptomycin sulfate (300 mg/kg s.c.) was injected for various periods into preweanling rats and for 3 weeks into weanling rats. Beginning at 8 days of age, body movement and hearing were examined for 6 and up to 17 weeks, respectively. Abnormal movements and deafness occurred only in rats treated during the preweaning period; within this period the greatest sensitivities for these abnormalities occurred from 2 to 11-17 and 5 to 11 days of age, respectively, indicating that the cochlea is more sensitive to streptomycin than the site (vestibular or central) responsible for the dyskinesias.
Late, late doxorubicin cardiotoxicity. Cardiac toxicity is a major complication which limits the use of adriamycin as a chemotherapeutic agent. Cardiomyopathy is frequent when the total dose exceeds 600 mg/m2 and occurs within one to six months after cessation of therapy. A patient is reported who developed progressive cardiomyopathy two and one-half years after receiving 580 mg/m2 which apparently represents late, late cardiotoxicity.
Clomipramine-induced sleep disturbance does not impair its prolactin-releasing action. The present study was undertaken to examine the role of sleep disturbance, induced by clomipramine administration, on the secretory rate of prolactin (PRL) in addition to the direct drug effect. Two groups of supine subjects were studied under placebo-controlled conditions, one during the night, when sleeping (n = 7) and the other at daytime, when awake (n = 6). Each subject received a single 50 mg dose of clomipramine given orally 2 hours before blood collection. Plasma PRL concentrations were analysed at 10 min intervals and underlying secretory rates calculated by a deconvolution procedure. For both experiments the drug intake led to significant increases in PRL secretion, acting preferentially on tonic secretion as pulse amplitude and frequency did not differ significantly from corresponding control values. During the night clomipramine ingestion altered the complete sleep architecture in that it suppressed REM sleep and the sleep cycles and induced increased wakefulness. As the relative increase in PRL secretion expressed as a percentage of the mean did not significantly differ between the night and day time studies (46 +/- 19% vs 34 +/- 10%), it can be concluded that the observed sleep disturbance did not interfere with the drug action per se. The presence of REM sleep was shown not to be a determining factor either for secretory pulse amplitude and frequency, as, for both, mean nocturnal values were similar with and without prior clomipramine ingestion.
Acetazolamide-induced nephrolithiasis: implications for treatment of neuromuscular disorders. Carbonic anhydrase inhibitors can cause nephrolithiasis. We studied 20 patients receiving long-term carbonic anhydrase inhibitor treatment for periodic paralysis and myotonia. Three patients on acetazolamide (15%) developed renal calculi. Extracorporeal lithotripsy successfully removed a renal calculus in one patient and surgery removed a staghorn calculus in another, permitting continued treatment. Renal function remained normal in all patients. Nephrolithiasis is a complication of acetazolamide but does not preclude its use.
Sodium bicarbonate alleviates penile pain induced by intracavernous injections for erectile dysfunction. In an attempt to determine whether penile pain associated with intracorporeal injections could be due to the acidity of the medication, we performed a randomized study comparing the incidence of penile pain following intracorporeal injections with or without the addition of sodium bicarbonate to the intracorporeal medications. A total of 38 consecutive patients who presented to our clinic with impotence received 0.2 ml. of a combination of 3 drugs: 6 mg. papaverine, 100 micrograms. phentolamine and 10 micrograms. prostaglandin E1 with (pH 7.05) or without (pH 4.17) the addition of sodium bicarbonate (0.03 mEq.). Of the 19 patients without sodium bicarbonate added to the medication 11 (58%) complained of penile pain due to the medication, while only 1 of the 19 men (5%) who received sodium bicarbonate complained of penile pain. From these data we conclude that the penile pain following intracorporeal injections is most likely due to the acidity of the medication, which can be overcome by elevating the pH to a neutral level.
Persistent paralysis after prolonged use of atracurium in the absence of corticosteroids. Neuromuscular blocking agents (NMBAs) are often used for patients requiring prolonged mechanical ventilation. Reports of persistent paralysis after the discontinuance of these drugs have most often involved aminosteroid-based NMBAs such as vecuronium bromide, especially when used in conjunction with corticosteroids. Atracurium besylate, a short-acting benzylisoquinolinium NMBA that is eliminated independently of renal or hepatic function, has also been associated with persistent paralysis, but only when used with corticosteroids. We report a case of atracurium-related paralysis persisting for approximately 50 hours in a patient who was not treated with corticosteroids.
Improvement of levodopa-induced dyskinesia by propranolol in Parkinson's disease. Seven patients suffering from Parkinson's disease (PD) with severely disabling dyskinesia received low-dose propranolol as an adjunct to the currently used medical treatment. There was a significant 40% improvement in the dyskinesia score without increase of parkinsonian motor disability. Ballistic and choreic dyskinesia were markedly ameliorated, whereas dystonia was not. This study suggests that administration of low doses of beta-blockers may improve levodopa-induced ballistic and choreic dyskinesia in PD.
Iatrogenically induced intractable atrioventricular reentrant tachycardia after verapamil and catheter ablation in a patient with Wolff-Parkinson-White syndrome and idiopathic dilated cardiomyopathy. In a patient with WPW syndrome and idiopathic dilated cardiomyopathy, intractable atrioventricular reentrant tachycardia (AVRT) was iatrogenically induced. QRS without preexcitation, caused by junctional escape beats after verapamil or unidirectional antegrade block of accessory pathway after catheter ablation, established frequent AVRT attack.
A transient neurological deficit following intrathecal injection of 1% hyperbaric bupivacaine for unilateral spinal anaesthesia. We describe a case of transient neurological deficit that occurred after unilateral spinal anaesthesia with 8 mg of 1% hyperbaric bupivacaine slowly injected through a 25-gauge pencil-point spinal needle. The surgery and anaesthesia were uneventful, but 3 days after surgery, the patient reported an area of hypoaesthesia over L3-L4 dermatomes of the leg which had been operated on (loss of pinprick sensation) without reduction in muscular strength. Sensation in this area returned to normal over the following 2 weeks. Prospective multicentre studies with a large population and a long follow-up should be performed in order to evaluate the incidence of this unusual side effect. However, we suggest that a low solution concentration should be preferred for unilateral spinal anaesthesia with a hyperbaric anaesthetic solution (if pencil-point needle and slow injection rate are employed), in order to minimize the risk of a localized high peak anaesthetic concentration, which might lead to a transient neurological deficit.
Open-label assessment of levofloxacin for the treatment of acute bacterial sinusitis in adults. PURPOSE: To evaluate the efficacy and safety of levofloxacin (500 mg orally once daily for 10 to 14 days) in treating adult outpatients with acute bacterial sinusitis. PATIENTS AND METHODS: A total of 329 patients enrolled in the study at 24 centers. All patients had a pre-therapy Gram's stain and culture of sinus exudate obtained by antral puncture or nasal endoscopy. Clinical response was assessed on the basis of signs and symptoms and sinus radiograph or computed tomography results. Microbiologic cure rates were determined on the basis of presumed plus documented eradication of the pre-therapy pathogen(s). RESULTS: The most common pathogens were Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, and Moraxella catarrhalis. Of 300 clinically evaluable patients, 175 (58%) were cured and 90 (30%) were improved at the post-therapy evaluation, resulting in a clinical success rate of 88%. Thirty-five patients (12%) clinically failed treatment. The microbiologic eradication rate (presumed plus documented) among 138 microbiologically evaluable patients was 92%. Microbiologic eradication rates (presumed plus documented) of the most common pathogens ranged from 93% (M. catarrhalis) to 100% (S. pneumoniae) at the post-therapy visit. All but one of the 265 patients who were cured or improved at post-therapy returned for a long-term follow-up visit; 243 (92%) remained well 4 to 6 weeks after therapy; and 21 (8%) had a relapse of symptoms. Adverse events considered to be related to levofloxacin administration were reported by 29 patients (9%). The most common drug-related adverse events were diarrhea, flatulence, and nausea; most adverse events were mild to moderate in severity. CONCLUSION: The results of this study indicate that levofloxacin 500 mg once daily is an effective and safe treatment for acute bacterial sinusitis.
Suxamethonium-induced cardiac arrest and death following 5 days of immobilization. The present report describes a case of cardiac arrest and subsequent death as a result of hyperkalaemia following the use of suxamethonium in a 23-year-old Malawian woman. Five days after the onset of the symptoms of meningitis, the patient aspirated stomach contents and needed endotracheal intubation. Forty seconds after injection of suxamethonium, bradycardia and cardiac arrest occurred. Attempts to resuscitate the patient were not successful. The serum level of potassium was observed to be 8.4 mequiv L-1. Apart from the reduction in the patient's level of consciousness, there were no signs of motor neurone damage or of any of the other known predisposing conditions for hyperkalaemia following the administration of suxamethonium. It is postulated that her death was caused by hypersensitivity to suxamethonium, associated with her 5-day immobilization.
Pethidine-associated seizure in a healthy adolescent receiving pethidine for postoperative pain control. A healthy 17-year-old male received standard intermittent doses of pethidine via a patient-controlled analgesia (PCA) pump for management of postoperative pain control. Twenty-three h postoperatively he developed a brief self-limited seizure. Both plasma pethidine and norpethidine were elevated in the range associated with clinical manifestations of central nervous system excitation. No other risk factors for CNS toxicity were identified. This method allowed frequent self-dosing of pethidine at short time intervals and rapid accumulation of pethidine and norpethidine. The routine use of pethidine via PCA even for a brief postoperative analgesia should be reconsidered.
High incidence of primary pulmonary hypertension associated with appetite suppressants in Belgium. Primary pulmonary hypertension is a rare, progressive and incurable disease, which has been associated with the intake of appetite suppressant drugs. The importance of this association was evaluated in Belgium while this country still had no restriction on the prescription of appetite suppressants. Thirty-five patients with primary pulmonary hypertension and 85 matched controls were recruited over 32 months (1992-1994) in Belgium. Exposure to appetite-suppressants was assessed on the basis of hospital records and standardized interview. Twenty-three of the patients had previously taken appetite suppressants, mainly fenfluramines, as compared with only 5 of the controls (66 versus 6%, p<0.0001). Five patients died before the interview, all of them had taken appetite suppressants. In 8 patients the diagnosis of primary pulmonary hypertension was uncertain, 5 of them had taken appetite suppressants. The patients who had been exposed to appetite suppressants tended to be on average more severely ill, and to have a shorter median delay between onset of symptoms and diagnosis. A policy of unrestricted prescription of appetite suppressants may lead to a high incidence of associated primary pulmonary hypertension. Intake of appetite suppressants may accelerate the progression of the disease.
Memory facilitation and stimulation of endogenous nerve growth factor synthesis by the acetylcholine releaser PG-9. The effects of PG-9 (3alpha-tropyl 2-(p-bromophenyl)propionate), the acetylcholine releaser, on memory processes and nerve growth factor (NGF) synthesis were evaluated. In the mouse passive-avoidance test, PG-9 (10-30 mg/kg, i.p.), administered 20 min before the training session, prevented amnesia induced by both the non selective antimuscarinic drug scopolamine and the M1-selective antagonist S-(-)-ET-126. In the same experimental conditions, PG-9 (5-20 microg per mouse, i.c.v.) was also able to prevent antimuscarine-induced amnesia, demonstrating a central localization of the activity. At the highest effective doses, PG-9 did not produce any collateral symptoms as revealed by the Irwin test, and it did not modify spontaneous motility and inspection activity, as revealed by the hole-board test. PG-9 was also able to increase the amount of NGF secreted in vitro by astrocytes in a dose-dependent manner. The maximal NGF contents obtained by PG-9 were 17.6-fold of the control value. During culture, no morphological changes were found at effective concentrations of PG-9. The current work indicates the ability of PG-9 to induce beneficial effects on cognitive processes and stimulate activity of NGF synthesis in astroglial cells. Therefore, PG-9 could represent a potential useful drug able to improve the function of impaired cognitive processes.
