Structural abnormalities in the brains of human subjects who use methamphetamine.

We visualize, for the first time, the profile of structural deficits in the human brain associated with chronic methamphetamine (MA) abuse. Studies of human subjects who have used MA chronically have revealed deficits in dopaminergic and serotonergic systems and cerebral metabolic abnormalities. Using magnetic resonance imaging (MRI) and new computational brain-mapping techniques, we determined the pattern of structural brain alterations associated with chronic MA abuse in human subjects and related these deficits to cognitive impairment. We used high-resolution MRI and surface-based computational image analyses to map regional abnormalities in the cortex, hippocampus, white matter, and ventricles in 22 human subjects who used MA and 21 age-matched, healthy controls. Cortical maps revealed severe gray-matter deficits in the cingulate, limbic, and paralimbic cortices of MA abusers (averaging 11.3% below control; p < 0.05). On average, MA abusers had 7.8% smaller hippocampal volumes than control subjects (p < 0.01; left, p = 0.01; right, p < 0.05) and significant white-matter hypertrophy (7.0%; p < 0.01). Hippocampal deficits were mapped and correlated with memory performance on a word-recall test (p < 0.05). MRI-based maps suggest that chronic methamphetamine abuse causes a selective pattern of cerebral deterioration that contributes to impaired memory performance. MA may selectively damage the medial temporal lobe and, consistent with metabolic studies, the cingulate-limbic cortex, inducing neuroadaptation, neuropil reduction, or cell death. Prominent white-matter hypertrophy may result from altered myelination and adaptive glial changes, including gliosis secondary to neuronal damage. These brain substrates may help account for the symptoms of MA abuse, providing therapeutic targets for drug-induced brain injury.

methamphetamine

structural deficits in the human brain

methamphetamine

MA

MA

metabolic abnormalities

MA

cognitive impairment

MA

MA

MA

hypertrophy

methamphetamine

impaired memory performance

MA

hypertrophy

gliosis

neuronal damage

MA

brain injury


Disruption of hepatic lipid homeostasis in mice after amiodarone treatment is associated with peroxisome proliferator-activated receptor-alpha target gene activation.

Amiodarone, an efficacious and widely used antiarrhythmic agent, has been reported to cause hepatotoxicity in some patients. To gain insight into the mechanism of this unwanted effect, mice were administered various doses of amiodarone and examined for changes in hepatic histology and gene regulation. Amiodarone induced hepatomegaly, hepatocyte microvesicular lipid accumulation, and a significant decrease in serum triglycerides and glucose. Northern blot analysis of hepatic RNA revealed a dose-dependent increase in the expression of a number of genes critical for fatty acid oxidation, lipoprotein assembly, and lipid transport. Many of these genes are regulated by the peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated nuclear hormone receptor transcription factor. The absence of induction of these genes as well as hepatomegaly in PPARalpha knockout [PPARalpha-/-] mice indicated that the effects of amiodarone were dependent upon the presence of a functional PPARalpha gene. Compared to wild-type mice, treatment of PPARalpha-/- mice with amiodarone resulted in an increased rate and extent of total body weight loss. The inability of amiodarone to directly activate either human or mouse PPARalpha transiently expressed in human HepG2 hepatoma cells indicates that the effects of amiodarone on the function of this receptor were indirect. Based upon these results, we conclude that amiodarone disrupts hepatic lipid homeostasis and that the increased expression of PPARalpha target genes is secondary to this toxic effect. These results provide important new mechanistic information regarding the hepatotoxic effects of amiodarone and indicate that PPARalpha protects against amiodarone-induced hepatotoxicity.

amiodarone

Amiodarone

hepatotoxicity

amiodarone

Amiodarone

hepatomegaly

triglycerides

glucose

fatty acid

hepatomegaly

amiodarone

amiodarone

weight loss

amiodarone

hepatoma

amiodarone

amiodarone

hepatotoxic

amiodarone

amiodarone

hepatotoxicity


Safety and compliance with once-daily niacin extended-release/lovastatin as initial therapy in the Impact of Medical Subspecialty on Patient Compliance to Treatment (IMPACT) study.

Niacin extended-release/lovastatin is a new combination product approved for treatment of primary hypercholesterolemia and mixed dyslipidemia. This open-labeled, multicenter study evaluated the safety of bedtime niacin extended-release/lovastatin when dosed as initial therapy and patient compliance to treatment in various clinical practice settings. A total of 4,499 patients with dyslipidemia requiring drug intervention was enrolled at 1,081 sites. Patients were treated with 1 tablet (500 mg of niacin extended-release/20 mg of lovastatin) once nightly for 4 weeks and then 2 tablets for 8 weeks. Patients also received dietary counseling, educational materials, and reminders to call a toll-free number that provided further education about dyslipidemia and niacin extended-release/lovastatin. Primary end points were study compliance, increases in liver transaminases to >3 times the upper limit of normal, and clinical myopathy. Final study status was available for 4,217 patients (94%). Compliance to niacin extended-release/lovastatin was 77%, with 3,245 patients completing the study. Patients in the southeast and those enrolled by endocrinologists had the lowest compliance and highest adverse event rates. Flushing was the most common adverse event, reported by 18% of patients and leading to discontinuation by 6%. Incidence of increased aspartate aminotransferase and/or alanine aminotransferase >3 times the upper limit of normal was <0.3%. An increase of creatine phosphokinase to >5 times the upper limit of normal occurred in 0.24% of patients, and no cases of drug-induced myopathy were observed. Niacin extended-release/lovastatin 1,000/40 mg, dosed as initial therapy, was associated with good compliance and safety and had very low incidences of increased liver and muscle enzymes.

niacin extended-release/lovastatin

Niacin extended-release/lovastatin

hypercholesterolemia

dyslipidemia

niacin extended-release/lovastatin

dyslipidemia

niacin

lovastatin

dyslipidemia

niacin extended-release/lovastatin

myopathy

niacin extended-release/lovastatin

Flushing

aspartate

alanine

creatine

myopathy

Niacin extended-release/lovastatin


Protective effect of Terminalia chebula against experimental myocardial injury induced by isoproterenol.

Cardioprotective effect of ethanolic extract of Terminalia chebula fruits (500 mg/kg body wt) was examined in isoproterenol (200 mg/kg body wt) induced myocardial damage in rats. In isoproterenol administered rats, the level of lipid peroxides increased significantly in the serum and heart. A significant decrease was observed in the activity of the myocardial marker enzymes with a concomitant increase in their activity in serum. Histopathological examination was carried out to confirm the myocardial necrosis. T. chebula extract pretreatment was found to ameliorate the effect of isoproterenol on lipid peroxide formation and retained the activities of the diagnostic marker enzymes.

Terminalia chebula

myocardial injury

isoproterenol

isoproterenol

myocardial damage

isoproterenol

peroxides

necrosis

T. chebula extract

isoproterenol

peroxide


A case of postoperative anxiety due to low dose droperidol used with patient-controlled analgesia.

A multiparous woman in good psychological health underwent urgent caesarean section in labour. Postoperatively, she was given a patient-controlled analgesia device delivering boluses of diamorphine 0.5 mg and droperidol 0.025 mg. Whilst using the device she gradually became anxious, the feeling worsening after each bolus. The diagnosis of droperidol-induced psychological disturbance was not made straight away although on subsequent close questioning the patient gave a very clear history. After she had received a total of only 0.9 mg droperidol, a syringe containing diamorphine only was substituted and her unease resolved completely. We feel that, although the dramatic extrapyramidal side effects of dopaminergic antiemetics are well known, more subtle manifestations may easily be overlooked.

anxiety

droperidol

diamorphine

droperidol

droperidol

psychological disturbance

droperidol

diamorphine


Accurate patient history contributes to differentiating diabetes insipidus: a case study.

This case study highlights the important contribution of nursing in obtaining an accurate health history. The case discussed herein initially appeared to be neurogenic diabetes insipidus (DI) secondary to a traumatic brain injury. The nursing staff, by reviewing the patient's health history with his family, discovered a history of polydipsia and long-standing lithium use. Lithium is implicated in drug-induced nephrogenic DI, and because the patient had not received lithium since being admitted to the hospital, his treatment changed to focus on nephrogenic DI. By combining information from the patient history, the physical examination, and radiologic and laboratory studies, the critical care team demonstrated that the patient had been self-treating his lithium-induced nephrogenic DI and developed neurogenic DI secondary to brain trauma. Thus successful treatment required that nephrogenic and neurogenic DI be treated concomitantly.

diabetes insipidus

neurogenic diabetes insipidus

DI

traumatic brain injury

polydipsia

lithium

Lithium

nephrogenic DI

lithium

nephrogenic DI

lithium

nephrogenic DI

neurogenic DI

brain trauma

neurogenic DI


Factors contributing to ribavirin-induced anemia.

BACKGROUND AND AIM: Interferon and ribavirin combination therapy for chronic hepatitis C produces hemolytic anemia. This study was conducted to identify the factors contributing to ribavirin-induced anemia. METHODS: Eighty-eight patients with chronic hepatitis C who received interferon-alpha-2b at a dose of 6 MU administered intramuscularly for 24 weeks in combination with ribavirin administered orally at a dose of 600 mg or 800 mg participated in the study. A hemoglobin concentration of <10 g/dL was defined as ribavirin-induced anemia. RESULTS: Ribavirin-induced anemia occurred in 18 (20.5%) patients during treatment. A 2 g/dL decrease in hemoglobin concentrations in patients with anemia was observed at week 2 after the start of treatment. The hemoglobin concentration in patients with > or =2 g/dL decrease at week 2 was observed to be significantly lower even after week 2 than in patients with <2 g/dL decrease (P < 0.01). A significant relationship was observed between the rate of reduction of hemoglobin concentrations at week 2 and the severity of anemia (P < 0.01). Such factors as sex (female), age (> or =60 years old), and the ribavirin dose by body weight (12 mg/kg or more) were significant by univariate analysis. CONCLUSIONS: Careful administration is necessary in patients > or =60 years old, in female patients, and in patients receiving a ribavirin dose of 12 mg/kg or more. Patients who experience a fall in hemoglobin concentrations of 2 g/dL or more at week 2 after the start of treatment should be monitored with particular care.

ribavirin

anemia

Interferon

ribavirin

chronic hepatitis C

hemolytic anemia

ribavirin

anemia

chronic hepatitis C

ribavirin

ribavirin

anemia

Ribavirin

anemia

anemia

anemia

ribavirin

ribavirin


Oxidative damage precedes nitrative damage in adriamycin-induced cardiac mitochondrial injury.

The purpose of the present study was to determine if elevated reactive oxygen (ROS)/nitrogen species (RNS) reported to be present in adriamycin (ADR)-induced cardiotoxicity actually resulted in cardiomyocyte oxidative/nitrative damage, and to quantitatively determine the time course and subcellular localization of these postulated damage products using an in vivo approach. B6C3 mice were treated with a single dose of 20 mg/kg ADR. Ultrastructural damage and levels of 4-hydroxy-2-nonenal (4HNE)-protein adducts and 3-nitrotyrosine (3NT) were analyzed. Quantitative ultrastructural damage using computerized image techniques showed cardiomyocyte injury as early as 3 hours, with mitochondria being the most extensively and progressively injured subcellular organelle. Analysis of 4HNE protein adducts by immunogold electron microscopy showed appearance of 4HNE protein adducts in mitochondria as early as 3 hours, with a peak at 6 hours and subsequent decline at 24 hours. 3NT levels were significantly increased in all subcellular compartments at 6 hours and subsequently declined at 24 hours. Our data showed ADR induced 4HNE-protein adducts in mitochondria at the same time point as when mitochondrial injury initially appeared. These results document for the first time in vivo that mitochondrial oxidative damage precedes nitrative damage. The progressive nature of mitochondrial injury suggests that mitochondria, not other subcellular organelles, are the major site of intracellular injury.

adriamycin

mitochondrial injury

oxygen

nitrogen

adriamycin

ADR

cardiotoxicity

ADR

ADR

mitochondrial injury

mitochondrial oxidative damage

mitochondrial injury


Sotalol-induced coronary spasm in a patient with dilated cardiomyopathy associated with sustained ventricular tachycardia.

A 54-year-old man with severe left ventricular dysfunction due to dilated cardiomyopathy was referred to our hospital for symptomatic incessant sustained ventricular tachycardia (VT). After the administration of nifekalant hydrochloride, sustained VT was terminated. An alternate class III agent, sotalol, was also effective for the prevention of VT. However, one month after switching over nifekalant to sotalol, a short duration of ST elevation was documented in ECG monitoring at almost the same time for three consecutive days. ST elevation with chest discomfort disappeared since he began taking long-acting diltiazem. Coronary vasospasm may be induced by the non-selective beta-blocking properties of sotalol.

Sotalol

coronary spasm

dilated cardiomyopathy

ventricular tachycardia

ventricular dysfunction

dilated cardiomyopathy

ventricular tachycardia

VT

nifekalant hydrochloride

VT

sotalol

VT

nifekalant

sotalol

diltiazem

Coronary vasospasm

sotalol


Effects of the antidepressant trazodone, a 5-HT 2A/2C receptor antagonist, on dopamine-dependent behaviors in rats.

RATIONALE: 5-Hydroxytryptamine, via stimulation of 5-HT 2C receptors, exerts a tonic inhibitory influence on dopaminergic neurotransmission, whereas activation of 5-HT 2A receptors enhances stimulated DAergic neurotransmission. The antidepressant trazodone is a 5-HT 2A/2C receptor antagonist. OBJECTIVES: To evaluate the effect of trazodone treatment on behaviors dependent on the functional status of the nigrostriatal DAergic system. METHODS: The effect of pretreatment with trazodone on dexamphetamine- and apomorphine-induced oral stereotypies, on catalepsy induced by haloperidol and apomorphine (0.05 mg/kg, i.p.), on ergometrine-induced wet dog shake (WDS) behavior and fluoxetine-induced penile erections was studied in rats. We also investigated whether trazodone induces catalepsy in rats. RESULTS: Trazodone at 2.5-20 mg/kg i.p. did not induce catalepsy, and did not antagonize apomorphine (1.5 and 3 mg/kg) stereotypy and apomorphine (0.05 mg/kg)-induced catalepsy. However, pretreatment with 5, 10 and 20 mg/kg i.p. trazodone enhanced dexamphetamine stereotypy, and antagonized haloperidol catalepsy, ergometrine-induced WDS behavior and fluoxetine-induced penile erections. Trazodone at 30, 40 and 50 mg/kg i.p. induced catalepsy and antagonized apomorphine and dexamphetamine stereotypies. CONCLUSIONS: Our results indicate that trazodone at 2.5-20 mg/kg does not block pre- and postsynaptic striatal D2 DA receptors, while at 30, 40 and 50 mg/kg it blocks postsynaptic striatal D2 DA receptors. Furthermore, at 5, 10 and 20 mg/kg, trazodone blocks 5-HT 2A and 5-HT 2C receptors. We suggest that trazodone (5, 10 and 20 mg/kg), by blocking the 5-HT 2C receptors, releases the nigrostriatal DAergic neurons from tonic inhibition caused by 5-HT, and thereby potentiates dexamphetamine stereotypy and antagonizes haloperidol catalepsy.

trazodone

dopamine

trazodone

trazodone

trazodone

dexamphetamine

apomorphine

oral stereotypies

catalepsy

haloperidol

apomorphine

ergometrine

fluoxetine

trazodone

catalepsy

Trazodone

catalepsy

apomorphine

apomorphine

catalepsy

trazodone

dexamphetamine

haloperidol

catalepsy

ergometrine

fluoxetine

Trazodone

catalepsy

apomorphine

dexamphetamine

trazodone

trazodone

trazodone

dexamphetamine

haloperidol

catalepsy


Swallowing abnormalities and dyskinesia in Parkinson's disease.

Gastrointestinal abnormalities in Parkinson's disease (PD) have been known for almost two centuries, but many aspects concerning their pathophysiology have not been completely clarified. The aim of this study was to characterize the oropharyngeal dynamics in PD patients with and without levodopa-induced dyskinesia. Fifteen dyskinetic, 12 nondyskinetic patients, and a control group were included. Patients were asked about dysphagia and evaluated with the Unified Parkinson's Disease Rating Scale Parts II and III and the Hoehn and Yahr scale. Deglutition was assessed using modified barium swallow with videofluoroscopy. Nondyskinetic patients, but not the dyskinetic ones, showed less oropharyngeal swallowing efficiency (OPSE) for liquid food than controls (Dunnett, P = 0.02). Dyskinetic patients tended to have a greater OPSE than nondyskinetic (Dunnett, P = 0.06). Patients who were using a higher dose of levodopa had a greater OPSE and a trend toward a smaller oral transit time (Pearson's correlation, P = 0.01 and 0.08, respectively). Neither the report of dysphagia nor any of the PD severity parameters correlated to the videofluoroscopic variables. In the current study, dyskinetic patients performed better in swallowing function, which could be explained on the basis of a greater levodopa dose. Our results suggest a role for levodopa in the oral phase of deglutition and confirm that dysphagia is not a good predictor of deglutition alterations in PD.

Swallowing abnormalities

dyskinesia

Parkinson's disease

Gastrointestinal abnormalities

Parkinson's disease

PD

PD

levodopa

dyskinesia

dyskinetic

dysphagia

Parkinson's Disease

barium

dyskinetic

Dyskinetic

levodopa

dysphagia

PD

dyskinetic

levodopa

levodopa

dysphagia

PD


Inhibition of nuclear factor-kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin.

BACKGROUND: Animals treated with gentamicin can show residual areas of interstitial fibrosis in the renal cortex. This study investigated the expression of nuclear factor-kappaB (NF-kappaB), mitogen-activated protein (MAP) kinases and macrophages in the renal cortex and structural and functional renal changes of rats treated with gentamicin or gentamicin + pyrrolidine dithiocarbamate (PDTC), an NF-kappaB inhibitor. METHODS: 38 female Wistar rats were injected with gentamicin, 40 mg/kg, twice a day for 9 days, 38 with gentamicin + PDTC, and 28 with 0.15 M NaCl solution. The animals were killed 5 and 30 days after these injections and the kidneys were removed for histological and immunohistochemical studies. The results of the immunohistochemical studies were scored according to the extent of staining. The fractional interstitial area was determined by morphometry. RESULTS: Gentamicin-treated rats presented a transitory increase in plasma creatinine levels. Increased ED-1, MAP kinases and NF-kappaB staining were also observed in the renal cortex from all gentamicin-treated rats compared to control (p < 0.05). The animals killed on day 30 also presented fibrosis in the renal cortex despite the recovery of renal function. Treatment with PDTC reduced the functional and structural changes induced by gentamicin. CONCLUSIONS: These data show that inhibition of NF-kappaB activation attenuates tubulointerstitial nephritis induced by gentamicin.

tubulointerstitial nephritis

gentamicin

gentamicin

fibrosis

gentamicin

gentamicin

pyrrolidine dithiocarbamate

PDTC

gentamicin

gentamicin

PDTC

NaCl

Gentamicin

creatinine

gentamicin

fibrosis

PDTC

gentamicin

tubulointerstitial nephritis

gentamicin


Glucose metabolism in patients with schizophrenia treated with atypical antipsychotic agents: a frequently sampled intravenous glucose tolerance test and minimal model analysis.

BACKGROUND: While the incidence of new-onset diabetes mellitus may be increasing in patients with schizophrenia treated with certain atypical antipsychotic agents, it remains unclear whether atypical agents are directly affecting glucose metabolism or simply increasing known risk factors for diabetes. OBJECTIVE: To study the 2 drugs most clearly implicated (clozapine and olanzapine) and risperidone using a frequently sampled intravenous glucose tolerance test. DESIGN: A cross-sectional design in stable, treated patients with schizophrenia evaluated using a frequently sampled intravenous glucose tolerance test and the Bergman minimal model analysis. SETTING: Subjects were recruited from an urban community mental health clinic and were studied at a general clinical research center. Patients Fifty subjects signed informed consent and 41 underwent the frequently sampled intravenous glucose tolerance test. Thirty-six nonobese subjects with schizophrenia or schizoaffective disorder, matched by body mass index and treated with either clozapine, olanzapine, or risperidone, were included in the analysis. MAIN OUTCOME MEASURES: Fasting plasma glucose and fasting serum insulin levels, insulin sensitivity index, homeostasis model assessment of insulin resistance, and glucose effectiveness. RESULTS: The mean +/- SD duration of treatment with the identified atypical antipsychotic agent was 68.3 +/- 28.9 months (clozapine), 29.5 +/- 17.5 months (olanzapine), and 40.9 +/- 33.7 (risperidone). Fasting serum insulin concentrations differed among groups (F(33) = 3.35; P = .047) (clozapine>olanzapine>risperidone) with significant differences between clozapine and risperidone (t(33) = 2.32; P = .03) and olanzapine and risperidone (t(33) = 2.15; P = .04). There was a significant difference in insulin sensitivity index among groups (F(33) = 10.66; P<.001) (clozapine<olanzapine<risperidone), with subjects who received clozapine and olanzapine exhibiting significant insulin resistance compared with subjects who were treated with risperidone (clozapine vs risperidone, t(33) = -4.29; P<.001; olanzapine vs risperidone, t(33) = -3.62; P = .001 [P<.001]). The homeostasis model assessment of insulin resistance also differed significantly among groups (F(33) = 4.92; P = .01) (clozapine>olanzapine>risperidone) (clozapine vs risperidone, t(33) = 2.94; P = .006; olanzapine vs risperidone, t(33) = 2.42; P = .02). There was a significant difference among groups in glucose effectiveness (F(30) = 4.18; P = .02) (clozapine<olanzapine<risperidone) with significant differences between clozapine and risperidone (t(30) = -2.59; P = .02) and olanzapine and risperidone (t(30) = -2.34, P = .03). CONCLUSIONS: Both nonobese clozapine- and olanzapine-treated groups displayed significant insulin resistance and impairment of glucose effectiveness compared with risperidone-treated subjects. Patients taking clozapine and olanzapine must be examined for insulin resistance and its consequences.

Glucose

schizophrenia

glucose

diabetes mellitus

schizophrenia

glucose

diabetes

clozapine

olanzapine

risperidone

glucose

schizophrenia

glucose

glucose

schizophrenia

schizoaffective disorder

clozapine

olanzapine

risperidone

glucose

insulin sensitivity

insulin resistance

glucose

clozapine

olanzapine

risperidone

clozapine

olanzapine

risperidone

clozapine

risperidone

olanzapine

risperidone

insulin sensitivity

clozapine

olanzapine

risperidone

clozapine

olanzapine

insulin resistance

risperidone

clozapine

risperidone

olanzapine

risperidone

insulin resistance

clozapine

olanzapine

risperidone

clozapine

risperidone

olanzapine

risperidone

glucose

clozapine

olanzapine

risperidone

clozapine

risperidone

olanzapine

risperidone

clozapine

olanzapine

insulin resistance

glucose

risperidone

clozapine

olanzapine

insulin resistance


Focal cerebral ischemia in rats: effect of phenylephrine-induced hypertension during reperfusion.

After 180 min of temporary middle cerebral artery occlusion in spontaneously hypertensive rats, the effect of phenylephrine-induced hypertension on ischemic brain injury and blood-brain barrier permeability was determined. Blood pressure was manipulated by one of the following schedules during 120 min of reperfusion: Control, normotensive reperfusion; 90/hypertension (90/HTN), blood pressure was increased by 35 mm Hg during the initial 90 min of reperfusion only; 15/hypertension (15/HTN), normotensive reperfusion for 30 min followed by 15 min of hypertension and 75 min of normotension. Part A, for eight rats in each group brain injury was evaluated by staining tissue using 2,3,5-triphenyltetrazolium chloride and edema was evaluated by microgravimetry. Part B, for eight different rats in each group blood-brain barrier permeability was evaluated by measuring the amount and extent of extravasation of Evans Blue dye. Brain injury (percentage of the ischemic hemisphere) was less in the 15/HTN group (16 +/- 6, mean +/- SD) versus the 90/HTN group (30 +/- 6), which was in turn less than the control group (42 +/- 5). Specific gravity was greater in the 15/HTN group (1.043 +/- 0.002) versus the 90/HTN (1.036 +/- 0.003) and control (1.037 +/- 0.003) groups. Evans Blue (mug g-1 of brain tissue) was greater in the 90/HTN group (24.4 +/- 6.0) versus the control group (12.3 +/- 4.1), which was in turn greater than the 15/HTN group (7.3 +/- 3.2). This study supports a hypothesis that during reperfusion, a short interval of hypertension decreases brain injury and edema; and that sustained hypertension increases the risk of vasogenic edema.

cerebral ischemia

phenylephrine

hypertension

middle cerebral artery occlusion

hypertensive

phenylephrine

hypertension

ischemic brain injury

hypertension

HTN

hypertension

HTN

hypertension

brain injury

2,3,5-triphenyltetrazolium chloride

edema

Brain injury

ischemic hemisphere

HTN

HTN

HTN

HTN

Evans Blue

HTN

HTN

hypertension

brain injury

edema

hypertension

vasogenic edema


People aged over 75 in atrial fibrillation on warfarin: the rate of major hemorrhage and stroke in more than 500 patient-years of follow-up.

OBJECTIVES: To determine the incidence of major hemorrhage and stroke in people aged 76 and older with atrial fibrillation on adjusted-dose warfarin who had been recently been admitted to hospital. DESIGN: A retrospective observational cohort study. SETTING: A major healthcare network involving four tertiary hospitals. PARTICIPANTS: Two hundred thirty-five patients aged 76 and older admitted to a major healthcare network between July 1, 2001, and June 30, 2002, with atrial fibrillation on warfarin were enrolled. MEASUREMENTS: Information regarding major bleeding episodes, strokes, and warfarin use was obtained from patients, relatives, primary physicians, and medical records. RESULTS: Two hundred twenty-eight patients (42% men) with a mean age of 81.1 (range 76-94) were included in the analysis. Total follow-up on warfarin was 530 years (mean 28 months). There were 53 major hemorrhages, for an annual rate of 10.0%, including 24 (45.3%) life-threatening and five (9.4%) fatal bleeds. The annual stroke rate after initiation of warfarin was 2.6%. CONCLUSION: The rate of major hemorrhage was high in this old, frail group, but excluding fatalities, resulted in no long-term sequelae, and the stroke rate on warfarin was low, demonstrating how effective warfarin treatment is.

atrial fibrillation

warfarin

hemorrhage

stroke

hemorrhage

stroke

atrial fibrillation

warfarin

atrial fibrillation

warfarin

bleeding

strokes

warfarin

warfarin

hemorrhages

stroke

warfarin

hemorrhage

stroke

warfarin

warfarin


Safety of celecoxib in patients with adverse skin reactions to acetaminophen (paracetamol) and nimesulide associated or not with common non-steroidal anti-inflammatory drugs.

BACKGROUND: Acetaminophen (paracetamol--P) and Nimesulide (N) are widely used analgesic-antipyretic/anti-inflammatory drugs. The rate of adverse hypersensitivity reactions to these agents is generally low. On the contrary non-steroidal anti-inflammatory drugs (NSAIDs) are commonly involved in such reactions. Celecoxib (CE) is a novel drug, with high selectivity and affinity for COX-2 enzyme. OBJECTIVE: We evaluated the tolerability of CE in a group of patients with documented history of adverse cutaneous reactions to P and N associated or not to classic NSAIDs. METHODS: We studied 9 patients with hypersensitivity to P and N with or without associated reactions to classic NSAIDs. The diagnosis of P and N-induced skin reactions was based in vivo challenge. The placebo was blindly administered at the beginning of each challenge. After three days, a cumulative dosage of 200 mg of CE in refracted doses were given. After 2-3 days, a single dose of 200 mg was administered. All patients were observed for 6 hours after each challenge, and controlled again after 24 hours to exclude delayed reactions. The challenge was considered positive if one or more of the following appeared: erythema, rush or urticaria-angioedema. RESULTS: No reaction was observed with placebo and eight patients (88.8%) tolerated CE. Only one patient developed a moderate angioedema of the lips. CONCLUSION: Only one hypersensitivity reaction to CE was documented among 9 P and N-highly NSAIDs intolerant patients. Thus, we conclude that CE is a reasonably safe alternative to be used in subjects who do not tolerate P and N.

celecoxib

skin reactions

acetaminophen

paracetamol

nimesulide

Acetaminophen

paracetamol

P

Nimesulide

N

hypersensitivity

Celecoxib

CE

CE

cutaneous reactions

P

N

hypersensitivity

P

N

P

N

skin reactions

CE

erythema

urticaria

angioedema

CE

angioedema

hypersensitivity

CE

P

N

CE

P

N


Case-control study of regular analgesic and nonsteroidal anti-inflammatory use and end-stage renal disease.

BACKGROUND: Studies on the association between the long-term use of aspirin and other analgesic and nonsteroidal anti-inflammatory drugs (NSAIDs) and end-stage renal disease (ESRD) have given conflicting results. In order to examine this association, a case-control study with incident cases of ESRD was carried out. METHODS: The cases were all patients entering the local dialysis program because of ESRD in the study area between June 1, 1995 and November 30, 1997. They were classified according to the underlying disease, which had presumably led them to ESRD. Controls were patients admitted to the same hospitals from where the cases arose, also matched by age and sex. Odds ratios were calculated using a conditional logistic model, including potential confounding factors, both for the whole study population and for the various underlying diseases. RESULTS: Five hundred and eighty-three cases and 1190 controls were included in the analysis. Long-term use of any analgesic was associated with an overall odds ratio of 1.22 (95% CI, 0.89-1.66). For specific groups of drugs, the risks were 1.56 (1.05-2.30) for aspirin, 1.03 (0.60-1.76) for pyrazolones, 0.80 (0.39-1.63) for paracetamol, and 0.94 (0.57-1.56) for nonaspirin NSAIDs. The risk of ESRD associated with aspirin was related to the cumulated dose and duration of use, and it was particularly high among the subset of patients with vascular nephropathy as underlying disease [2.35 (1.17-4.72)]. CONCLUSION: Our data indicate that long-term use of nonaspirin analgesic drugs and NSAIDs is not associated with an increased risk of ESRD. However, the chronic use of aspirin may increase the risk of ESRD.

end-stage renal disease

aspirin

end-stage renal disease

ESRD

ESRD

ESRD

ESRD

aspirin

pyrazolones

paracetamol

ESRD

aspirin

nephropathy

ESRD

aspirin

ESRD


Two cases of amisulpride overdose: a cause for prolonged QT syndrome.

Two cases of deliberate self-poisoning with 5 g and 3.6 g of amisulpride, respectively, are reported. In both cases, QT prolongation and hypocalcaemia were noted. The QT prolongation appeared to respond to administration of i.v. calcium gluconate.

amisulpride

overdose

prolonged QT syndrome

poisoning

amisulpride

QT prolongation

hypocalcaemia

QT prolongation

calcium gluconate


Growth-associated protein 43 expression in hippocampal molecular layer of chronic epileptic rats treated with cycloheximide.

PURPOSE: GAP43 has been thought to be linked with mossy fiber sprouting (MFS) in various experimental models of epilepsy. To investigate how GAP43 expression (GAP43-ir) correlates with MFS, we assessed the intensity (densitometry) and extension (width) of GAP43-ir in the inner molecular layer of the dentate gyrus (IML) of rats subject to status epilepticus induced by pilocarpine (Pilo), previously injected or not with cycloheximide (CHX), which has been shown to inhibit MFS. METHODS: CHX was injected before the Pilo injection in adult Wistar rats. The Pilo group was injected with the same drugs, except for CHX. Animals were killed between 30 and 60 days later, and brain sections were processed for GAP43 immunohistochemistry. RESULTS: Densitometry showed no significant difference regarding GAP43-ir in the IML between Pilo, CHX+Pilo, and control groups. However, the results of the width of the GAP43-ir band in the IML showed that CHX+Pilo and control animals had a significantly larger band (p = 0.03) as compared with that in the Pilo group. CONCLUSIONS: Our current finding that animals in the CHX+Pilo group have a GAP43-ir band in the IML, similar to that of controls, reinforces prior data on the blockade of MFS in these animals. The change in GAP43-ir present in Pilo-treated animals was a thinning of the band to a very narrow layer just above the granule cell layer that is likely to be associated with the loss of hilar cell projections that express GAP-43.

epileptic

cycloheximide

epilepsy

status epilepticus

pilocarpine

Pilo

cycloheximide

CHX

CHX

Pilo

Pilo

CHX

Pilo

CHX

Pilo

CHX

Pilo

Pilo

CHX

Pilo

Pilo


Nicotine antagonizes caffeine- but not pentylenetetrazole-induced anxiogenic effect in mice.

RATIONALE: Nicotine and caffeine are widely consumed licit psychoactive drugs worldwide. Epidemiological studies showed that they were generally used concurrently. Although some studies in experimental animals indicate clear pharmacological interactions between them, no studies have shown a specific interaction on anxiety responses. OBJECTIVES: The present study investigates the effects of nicotine on anxiety induced by caffeine and another anxiogenic drug, pentylenetetrazole, in mice. The elevated plus-maze (EPM) test was used to evaluate the effects of drugs on anxiety. METHODS: Adult male Swiss Webster mice (25-32 g) were given nicotine (0.05-0.25 mg/kg s.c.) or saline 10 min before caffeine (70 mg/kg i.p.) or pentylenetetrazole (15 and 30 mg/kg i.p.) injections. After 15 min, mice were evaluated for their open- and closed-arm time and entries on the EPM for a 10-min session. Locomotor activity was recorded for individual groups by using the same treatment protocol with the EPM test. RESULTS: Nicotine (0.05-0.25 mg/kg) itself did not produce any significant effect in the EPM test, whereas caffeine (70 mg/kg) and pentylenetetrazole (30 mg/kg) produced an anxiogenic effect, apparent with decreases in open-arm time and entry. Nicotine (0.25 mg/kg) pretreatment blocked the caffeine- but not pentylenetetrazole-induced anxiety. Administration of each drug and their combinations did not produce any effect on locomotor activity. CONCLUSIONS: Our results suggest that the antagonistic effect of nicotine on caffeine-induced anxiety is specific to caffeine, instead of a non-specific anxiolytic effect. Thus, it may extend the current findings on the interaction between nicotine and caffeine.

Nicotine

caffeine

pentylenetetrazole

Nicotine

caffeine

anxiety

nicotine

anxiety

caffeine

pentylenetetrazole

anxiety

nicotine

caffeine

pentylenetetrazole

Nicotine

caffeine

pentylenetetrazole

Nicotine

caffeine

pentylenetetrazole

anxiety

nicotine

caffeine

anxiety

caffeine

nicotine

caffeine


Long term hormone therapy for perimenopausal and postmenopausal women.

BACKGROUND: Hormone therapy (HT) is widely used for controlling menopausal symptoms. It has also been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women but the evidence supporting its use for these indications is largely observational. OBJECTIVES: To assess the effect of long-term HT on mortality, heart disease, venous thromboembolism, stroke, transient ischaemic attacks, breast cancer, colorectal cancer, ovarian cancer, endometrial cancer, gallbladder disease, cognitive function, dementia, fractures and quality of life. SEARCH STRATEGY: We searched the following databases up to November 2004: the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Biological Abstracts. Relevant non-indexed journals and conference abstracts were also searched. SELECTION CRITERIA: Randomised double-blind trials of HT (oestrogens with or without progestogens) versus placebo, taken for at least one year by perimenopausal or postmenopausal women. DATA COLLECTION AND ANALYSIS: Fifteen RCTs were included. Trials were assessed for quality and two review authors extracted data independently. They calculated risk ratios for dichotomous outcomes and weighted mean differences for continuous outcomes. Clinical heterogeneity precluded meta-analysis for most outcomes. MAIN RESULTS: All the statistically significant results were derived from the two biggest trials. In relatively healthy women, combined continuous HT significantly increased the risk of venous thromboembolism or coronary event (after one year's use), stroke (after 3 years), breast cancer (after 5 years) and gallbladder disease. Long-term oestrogen-only HT also significantly increased the risk of stroke and gallbladder disease. Overall, the only statistically significant benefits of HT were a decreased incidence of fractures and colon cancer with long-term use. Among relatively healthy women over 65 years taking continuous combined HT, there was a statistically significant increase in the incidence of dementia. Among women with cardiovascular disease, long-term use of combined continuous HT significantly increased the risk of venous thromboembolism. No trials focussed specifically on younger women. However, one trial analysed subgroups of 2839 relatively healthy 50 to 59 year-old women taking combined continuous HT and 1637 taking oestrogen-only HT, versus similar-sized placebo groups. The only significantly increased risk reported was for venous thromboembolism in women taking combined continuous HT; their absolute risk remained very low. AUTHORS' CONCLUSIONS: HT is not indicated for the routine management of chronic disease. We need more evidence on the safety of HT for menopausal symptom control, though short-term use appears to be relatively safe for healthy younger women.

menopausal symptoms

cardiovascular disease

osteoporosis

dementia

heart disease

venous thromboembolism

stroke

transient ischaemic attacks

breast cancer

colorectal cancer

ovarian cancer

endometrial cancer

gallbladder disease

dementia

fractures

oestrogens

progestogens

venous thromboembolism

stroke

breast cancer

gallbladder disease

oestrogen

stroke

gallbladder disease

fractures

colon cancer

dementia

cardiovascular disease

venous thromboembolism

oestrogen

venous thromboembolism

chronic disease


Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.

BACKGROUND & AIMS: Progress in the understanding of susceptibility factors to drug-induced liver injury (DILI) and outcome predictability are hampered by the lack of systematic programs to detect bona fide cases. METHODS: A cooperative network was created in 1994 in Spain to identify all suspicions of DILI following a prospective structured report form. The liver damage was characterized according to hepatocellular, cholestatic, and mixed laboratory criteria and to histologic criteria when available. Further evaluation of causality assessment was centrally performed. RESULTS: Since April 1994 to August 2004, 461 out of 570 submitted cases, involving 505 drugs, were deemed to be related to DILI. The antiinfective group of drugs was the more frequently incriminated, amoxicillin-clavulanate accounting for the 12.8% of the whole series. The hepatocellular pattern of damage was the most common (58%), was inversely correlated with age (P < .0001), and had the worst outcome (Cox regression, P < .034). Indeed, the incidence of liver transplantation and death in this group was 11.7% if patients had jaundice at presentation, whereas the corresponding figure was 3.8% in nonjaundiced patients (P < .04). Factors associated with the development of fulminant hepatic failure were female sex (OR = 25; 95% CI: 4.1-151; P < .0001), hepatocellular damage (OR = 7.9; 95% CI: 1.6-37; P < .009), and higher baseline plasma bilirubin value (OR = 1.15; 95% CI: 1.09-1.22; P < .0001). CONCLUSIONS: Patients with drug-induced hepatocellular jaundice have 11.7% chance of progressing to death or transplantation. Amoxicillin-clavulanate stands out as the most common drug related to DILI.

Drug-induced liver injury

drug-induced liver injury

DILI

DILI

liver damage

cholestatic

DILI

amoxicillin-clavulanate

jaundice

fulminant hepatic failure

bilirubin

jaundice

Amoxicillin-clavulanate

DILI


Morphological evaluation of the effect of d-ribose on adriamycin-evoked cardiotoxicity in rats.

The influence of d-ribose on adriamycin-induced myocardiopathy in rats was studied. Adriamycin in the cumulative dose of 25 mg/kg evoked fully developed cardiac toxicity. D-ribose in the multiple doses of 200 mg/kg did not influence ADR cardiotoxicity.

d-ribose

adriamycin

cardiotoxicity

d-ribose

adriamycin

myocardiopathy

Adriamycin

cardiac toxicity

D-ribose

ADR

cardiotoxicity


In vivo evidences suggesting the role of oxidative stress in pathogenesis of vancomycin-induced nephrotoxicity: protection by erdosteine.

The aims of this study were to examine vancomycin (VCM)-induced oxidative stress that promotes production of reactive oxygen species (ROS) and to investigate the role of erdosteine, an expectorant agent, which has also antioxidant properties, on kidney tissue against the possible VCM-induced renal impairment in rats. Rats were divided into three groups: sham, VCM and VCM plus erdosteine. VCM was administrated intraperitoneally (i.p.) with 200mgkg(-1) twice daily for 7 days. Erdosteine was administered orally. VCM administration to control rats significantly increased renal malondialdehyde (MDA) and urinary N-acetyl-beta-d-glucosaminidase (NAG, a marker of renal tubular injury) excretion but decreased superoxide dismutase (SOD) and catalase (CAT) activities. Erdosteine administration with VCM injections caused significantly decreased renal MDA and urinary NAG excretion, and increased SOD activity, but not CAT activity in renal tissue when compared with VCM alone. Erdosteine showed histopathological protection against VCM-induced nephrotoxicity. There were a significant dilatation of tubular lumens, extensive epithelial cell vacuolization, atrophy, desquamation, and necrosis in VCM-treated rats more than those of the control and the erdosteine groups. Erdosteine caused a marked reduction in the extent of tubular damage. It is concluded that oxidative tubular damage plays an important role in the VCM-induced nephrotoxicity and the modulation of oxidative stress with erdosteine reduces the VCM-induced kidney damage both at the biochemical and histological levels.

vancomycin

nephrotoxicity

erdosteine

vancomycin

VCM

oxygen

erdosteine

VCM

renal impairment

VCM

VCM

erdosteine

VCM

Erdosteine

VCM

malondialdehyde

MDA

renal tubular injury

superoxide

Erdosteine

VCM

MDA

VCM

Erdosteine

VCM

nephrotoxicity

atrophy

desquamation

necrosis

VCM

erdosteine

Erdosteine

VCM

nephrotoxicity

erdosteine

VCM

kidney damage


Does domperidone potentiate mirtazapine-associated restless legs syndrome?

There is now evidence to suggest a central role for the dopaminergic system in restless legs syndrome (RLS). For example, the symptoms of RLS can be dramatically improved by levodopa and dopamine agonists, whereas central dopamine D2 receptor antagonists can induce or aggravate RLS symptoms. To our knowledge, there is no previous report regarding whether domperidone, a peripheral dopamine D2 receptor antagonist, can also induce or aggravate symptoms of RLS. Mirtazapine, the first noradrenergic and specific serotonergic antidepressant (NaSSA), has been associated with RLS in several recent publications. The authors report here a depressed patient comorbid with postprandial dyspepsia who developed RLS after mirtazapine had been added to his domperidone therapy. Our patient started to have symptoms of RLS only after he had been treated with mirtazapine, and his RLS symptoms resolved completely upon discontinuation of his mirtazapine. Such a temporal relationship between the use of mirtazapine and the symptoms of RLS in our patient did not support a potentiating effect of domperione on mirtazapine-associated RLS. However, physicians should be aware of the possibility that mirtazapine can be associated with RLS in some individuals, especially those receiving concomitant dopamine D2 receptor antagonists.

domperidone

mirtazapine

restless legs syndrome

restless legs syndrome

RLS

RLS

levodopa

dopamine

dopamine

RLS

domperidone

dopamine

RLS

Mirtazapine

RLS

postprandial dyspepsia

RLS

mirtazapine

domperidone

RLS

mirtazapine

RLS

mirtazapine

mirtazapine

RLS

domperione

mirtazapine

RLS

mirtazapine

RLS

dopamine


Antiandrogenic therapy can cause coronary arterial disease.

AIM: To study the change of lipid metabolism by antiandrogen therapy in patients with prostate cancer. MATERIALS AND METHODS: We studied with a 2.5 years follow-up the changes in plasma cholesterols (C), triglycerides (TG), lipoproteins (LP), and apolipoproteins (Apo) B-100, A-I, and A-II pro fi les in 24 patients of mean age 60 years with low risk prostate cancer (stage: T1cN0M0, Gleason score: 2-5) during treatment with cyproterone acetate (CPA) without surgical management or radiation therapy. RESULTS: Significant decreases of HDL-C, Apo A-I and Apo A-II and an increase of triglyceride levels in VLDL were induced by CPA. After a period of 2.5 years on CPA treatment, four patients out of twenty-four were found to be affected by coronary heart disease. CONCLUSIONS: Ischaemic coronary arteriosclerosis with an incidence rate of 16.6% as caused by prolonged CPA therapy is mediated through changes in HDL cholesterol, Apo A-I and Apo A-II pro fi les, other than the well-known hyperglyceridemic effect caused by estrogen.

coronary arterial disease

prostate cancer

cholesterols

C

triglycerides

TG

prostate cancer

cyproterone acetate

CPA

triglyceride

CPA

CPA

coronary heart disease

coronary arteriosclerosis

CPA

cholesterol

hyperglyceridemic effect

estrogen


5-Fluorouracil cardiotoxicity induced by alpha-fluoro-beta-alanine.

Cardiotoxicity is a rare complication occurring during 5-fluorouracil (5-FU) treatment for malignancies. We herein report the case of a 70-year-old man with 5-FU-induced cardiotoxicity, in whom a high serum level of alpha-fluoro-beta-alanine (FBAL) was observed. The patient, who had unresectable colon cancer metastases to the liver and lung, was referred to us for chemotherapy from an affiliated hospital; he had no cardiac history. After admission, the patient received a continuous intravenous infusion of 5-FU (1000 mg/day), during which precordial pain with right bundle branch block occurred concomitantly with a high serum FBAL concentration of 1955 ng/ml. Both the precordial pain and the electrocardiographic changes disappeared spontaneously after the discontinuation of 5-FU. As the precordial pain in this patient was considered to have been due to 5-FU-induced cardiotoxicity, the administration of 5-FU was abandoned. Instead, oral administration of S-1 (a derivative of 5-FU), at 200 mg/day twice a week, was instituted, because S-1 has a strong inhibitory effect on dihydropyrimidine dehydrogenase, which catalyzes the degradative of 5-FU into FBAL. The serum FBAL concentration subsequently decreased to 352 ng/ml, the same as the value measured on the first day of S-1 administration. Thereafter, no cardiac symptoms were observed. The patient achieved a partial response 6 months after the initiation of the S-1 treatment. The experience of this case, together with a review of the literature, suggests that FBAL is related to 5-FU-induced cardiotoxicity. S-1 may be administered safely to patients with 5-FU-induced cardiotoxicity.

cardiotoxicity

alpha-fluoro-beta-alanine

Cardiotoxicity

malignancies

cardiotoxicity

alpha-fluoro-beta-alanine

FBAL

colon cancer

precordial pain

right bundle branch block

FBAL

precordial pain

precordial pain

cardiotoxicity

dihydropyrimidine

FBAL

FBAL

cardiac symptoms

FBAL

cardiotoxicity

cardiotoxicity


The influence of the time interval between monoHER and doxorubicin administration on the protection against doxorubicin-induced cardiotoxicity in mice.

PURPOSE: Despite its well-known cardiotoxicity, the anthracyclin doxorubicin (DOX) continues to be an effective and widely used chemotherapeutic agent. DOX-induced cardiac damage presumably results from the formation of free radicals by DOX. Reactive oxygen species particularly affect the cardiac myocytes because these cells seem to have a relatively poor antioxidant defense system. The semisynthetic flavonoid monohydroxyethylrutoside (monoHER) showed cardioprotection against DOX-induced cardiotoxicity through its radical scavenging and iron chelating properties. Because of the relatively short final half-life of monoHER (about 30 min), it is expected that the time interval between monoHER and DOX might be of influence on the cardioprotective effect of monoHER. Therefore, the aim of the present study was to investigate this possible effect. METHODS: Six groups of 6 BALB/c mice were treated with saline, DOX alone or DOX (4 mg/kg i.v.) preceded by monoHER (500 mg/kg i.p.) with an interval of 10, 30, 60 or 120 min. After a 6-week treatment period and additional observation for 2 weeks, the mice were sacrificed. Their cardiac tissues were processed for light microscopy, after which cardiomyocyte damage was evaluated according to Billingham (in Cancer Treat Rep 62(6):865-872, 1978). Microscopic evaluation revealed that treatment with DOX alone induced significant cardiac damage in comparison to the saline control group (P<0.001). RESULTS: The number of damaged cardiomyocytes was 9.6-fold (95% CI 4.4-21.0) higher in mice treated with DOX alone than that in animals of the control group. The ratio of aberrant cardiomyocytes in mice treated with DOX preceded by monoHER and those in mice treated with saline ranged from 1.6 to 2.8 (mean 2.2, 95% CI 1.2-4.1, P=0.019). The mean protective effect by adding monoHER before DOX led to a significant 4.4-fold reduction (P<0.001, 95% CI 2.3-8.2) of abnormal cardiomyocytes. This protective effect did not depend on the time interval between monoHER and DOX administration (P=0.345). CONCLUSION: The results indicate that in an outpatient clinical setting monoHER may be administered shortly before DOX.

monoHER

doxorubicin

doxorubicin

cardiotoxicity

cardiotoxicity

doxorubicin

DOX

DOX

cardiac damage

DOX

oxygen

flavonoid

monohydroxyethylrutoside

monoHER

DOX

cardiotoxicity

iron

monoHER

monoHER

DOX

monoHER

DOX

DOX

monoHER

cardiomyocyte damage

Cancer

DOX

cardiac damage

DOX

DOX

monoHER

monoHER

DOX

monoHER

DOX

monoHER

DOX


Clinical evaluation of adverse effects during bepridil administration for atrial fibrillation and flutter.

BACKGROUND: Bepridil hydrochloride (Bpd) has attracted attention as an effective drug for atrial fibrillation (AF) and atrial flutter (AFL). However, serious adverse effects, including torsade de pointes (Tdp), have been reported. METHODS AND RESULTS: Adverse effects of Bpd requiring discontinuation of treatment were evaluated. Bpd was administered to 459 patients (361 males, 63+/-12 years old) comprising 378 AF and 81 AFL cases. Mean left ventricular ejection fraction and atrial dimension (LAD) were 66+/-11% and 40+/-6 mm, respectively. Adverse effects were observed in 19 patients (4%) during an average follow-up of 20 months. There was marked QT prolongation greater than 0.55 s in 13 patients, bradycardia less than 40 beats/min in 6 patients, dizziness and general fatigue in 1 patient each. In 4 of 13 patients with QT prolongation, Tdp occurred. The major triggering factors of Tdp were hypokalemia and sudden decrease in heart rate. There were no differences in the clinical backgrounds of the patients with and without Tdp other than LAD and age, which were larger and older in the patients with Tdp. CONCLUSION: Careful observation of serum potassium concentration and the ECG should always be done during Bpd administration, particularly in elderly patients.

bepridil

atrial fibrillation and flutter

atrial fibrillation

atrial flutter

Bepridil hydrochloride

Bpd

atrial fibrillation

AF

atrial flutter

AFL

torsade de pointes

Tdp

Bpd

Bpd

AF

AFL

QT prolongation

bradycardia

dizziness

fatigue

QT prolongation

Tdp

Tdp

hypokalemia

Tdp

Tdp

potassium

Bpd


Enhanced isoproterenol-induced cardiac hypertrophy in transgenic rats with low brain angiotensinogen.

We have previously shown that a permanent deficiency in the brain renin-angiotensin system (RAS) may increase the sensitivity of the baroreflex control of heart rate. In this study we aimed at studying the involvement of the brain RAS in the cardiac reactivity to the beta-adrenoceptor (beta-AR) agonist isoproterenol (Iso). Transgenic rats with low brain angiotensinogen (TGR) were used. In isolated hearts, Iso induced a significantly greater increase in left ventricular (LV) pressure and maximal contraction (+dP/dt(max)) in the TGR than in the Sprague-Dawley (SD) rats. LV hypertrophy induced by Iso treatment was significantly higher in TGR than in SD rats (in g LV wt/100 g body wt, 0.28 +/- 0.004 vs. 0.24 +/- 0.004, respectively). The greater LV hypertrophy in TGR rats was associated with more pronounced downregulation of beta-AR and upregulation of LV beta-AR kinase-1 mRNA levels compared with those in SD rats. The decrease in the heart rate (HR) induced by the beta-AR antagonist metoprolol in conscious rats was significantly attenuated in TGR compared with SD rats (-9.9 +/- 1.7% vs. -18.1 +/- 1.5%), whereas the effect of parasympathetic blockade by atropine on HR was similar in both strains. These results indicate that TGR are more sensitive to beta-AR agonist-induced cardiac inotropic response and hypertrophy, possibly due to chronically low sympathetic outflow directed to the heart.

isoproterenol

cardiac hypertrophy

angiotensin

isoproterenol

Iso

Iso

LV hypertrophy

Iso

LV hypertrophy

metoprolol

atropine

cardiac inotropic

hypertrophy


Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors.

BACKGROUND: Drug-induced long QT syndrome is a serious adverse drug reaction. Methadone prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of QT interval prolongation with methadone treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown. METHODS: We performed a systematic, retrospective study comparing active or former intravenous drug users receiving methadone and those not receiving methadone among all patients hospitalized over a 5-year period in a tertiary care hospital. A total of 167 patients receiving methadone fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving methadone. In addition to methadone dose, 15 demographic, biological, and pharmacological variables were considered as potential risk factors for QT prolongation. RESULTS: Among 167 methadone maintenance patients, the prevalence of QTc prolongation to 0.50 second((1/2)) or longer was 16.2% compared with 0% in 80 control subjects. Six patients (3.6%) in the methadone group presented torsades de pointes. QTc length was weakly but significantly associated with methadone daily dose (Spearman rank correlation coefficient, 0.20; P<.01). Multivariate regression analysis allowed attribution of 31.8% of QTc variability to methadone dose, cytochrome P-450 3A4 drug-drug interactions, hypokalemia, and altered liver function. CONCLUSIONS: QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding. Methadone dose, presence of cytochrome P-450 3A4 inhibitors, potassium level, and liver function contribute to QT prolongation. Long QT syndrome can occur with low doses of methadone.

long QT syndrome

methadone

long QT syndrome

Methadone

QT interval prolongation

methadone

methadone

methadone

methadone

methadone

methadone

QT prolongation

methadone

methadone

torsades de pointes

methadone

methadone

hypokalemia

QT interval prolongation

methadone

Methadone

potassium

QT prolongation

Long QT syndrome

methadone


Mechanisms of hypertension induced by nitric oxide (NO) deficiency: focus on venous function.

Loss of endothelial cell-derived nitric oxide (NO) in hypertension is a hallmark of arterial dysfunction. Experimental hypertension created by the removal of NO, however, involves mechanisms in addition to decreased arterial vasodilator activity. These include augmented endothelin-1 (ET-1) release, increased sympathetic nervous system activity, and elevated tissue oxidative stress. We hypothesized that increased venous smooth muscle (venomotor) tone plays a role in Nomega-nitro-L-arginine (LNNA) hypertension through these mechanisms. Rats were treated with the NO synthase inhibitor LNNA (0.5 g/L in drinking water) for 2 weeks. Mean arterial pressure of conscious rats was 119 +/- 2 mm Hg in control and 194 +/- 5 mm Hg in LNNA rats (P<0.05). Carotid arteries and vena cava were removed for measurement of isometric contraction. Maximal contraction to norepinephrine was modestly reduced in arteries from LNNA compared with control rats whereas the maximum contraction to ET-1 was significantly reduced (54% control). Maximum contraction of vena cava to norepinephrine (37% control) also was reduced but no change in response to ET-1 was observed. Mean circulatory filling pressure, an in vivo measure of venomotor tone, was not elevated in LNNA hypertension at 1 or 2 weeks after LNNA. The superoxide scavenger tempol (30, 100, and 300 micromol kg(-1), IV) did not change arterial pressure in control rats but caused a dose-dependent decrease in LNNA rats (-18 +/- 8, -26 +/- 15, and -54 +/- 11 mm Hg). Similarly, ganglionic blockade with hexamethonium caused a significantly greater fall in LNNA hypertensive rats (76 +/- 9 mm Hg) compared with control rats (35 +/- 10 mm Hg). Carotid arteries, vena cava, and sympathetic ganglia from LNNA rats had higher basal levels of superoxide compared with those from control rats. These data suggest that while NO deficiency increases oxidative stress and sympathetic activity in both arterial and venous vessels, the impact on veins does not make a major contribution to this form of hypertension.

hypertension

nitric oxide

NO

nitric oxide

NO

hypertension

arterial dysfunction

hypertension

NO

Nomega-nitro-L-arginine

LNNA

hypertension

NO

LNNA

LNNA

norepinephrine

LNNA

norepinephrine

LNNA

hypertension

LNNA

superoxide

tempol

LNNA

hexamethonium

LNNA

hypertensive

LNNA

superoxide

NO

hypertension


Association of DRD2 polymorphisms and chlorpromazine-induced extrapyramidal syndrome in Chinese schizophrenic patients.

AIM: Extrapyramidal syndrome (EPS) is most commonly affected by typical antipsychotic drugs that have a high affinity with the D2 receptor. Recently, many research groups have reported on the positive relationship between the genetic variations in the DRD2 gene and the therapeutic response in schizophrenia patients as a result of the role of variations in the receptor in modulating receptor expression. In this study, we evaluate the role DRD2 plays in chlorpromazine-induced EPS in schizophrenic patients. METHODS: We identified seven SNP(single nucleotide polymorphism) (-141Cins>del, TaqIB, TaqID, Ser311Cys, rs6275, rs6277 and TaqIA) in the DRD2 gene in 146 schizophrenic inpatients (59 with EPS and 87 without EPS according to the Simpson-Angus Scale) treated with chlorpromazine after 8 weeks. The alleles of all loci were determined by PCR (polymerase chain reaction). RESULTS: Polymorphisms TaqID, Ser311Cys and rs6277 were not polymorphic in the population recruited in the present study. No statistical significance was found in the allele distribution of -141Cins>del, TaqIB, rs6275 and TaqIA or in the estimated haplotypes (constituted by TaqIB, rs6275 and TaqIA) in linkage disequilibrium between the two groups. CONCLUSION: Our results did not lend strong support to the view that the genetic variation of the DRD2 gene plays a major role in the individually variable adverse effect induced by chlorpromazine, at least in Chinese patients with schizophrenia. Our results confirmed a previous study on the relationship between DRD2 and EPS in Caucasians.

chlorpromazine

extrapyramidal syndrome

schizophrenic

Extrapyramidal syndrome

EPS

schizophrenia

chlorpromazine

EPS

schizophrenic

schizophrenic

EPS

EPS

chlorpromazine

chlorpromazine

schizophrenia

EPS


Physical training decreases susceptibility to subsequent pilocarpine-induced seizures in the rat.

Regular motor activity has many benefits for mental and physical condition but its implications for epilepsy are still controversial. In order to elucidate this problem, we have studied the effect of long-term physical activity on susceptibility to subsequent seizures. Male Wistar rats were subjected to repeated training sessions in a treadmill and swimming pool. Thereafter, seizures were induced by pilocarpine injections in trained and non-trained control groups. During the acute period of status epilepticus, we measured: (1) the latency of the first motor sign, (2) the intensity of seizures, (3) the time when it occurred within the 6-h observation period, and (4) the time when the acute period ended. All these behavioral parameters showed statistically significant changes suggesting that regular physical exercises decrease susceptibility to subsequently induced seizures and ameliorate the course of experimentally induced status epilepticus.

pilocarpine

seizures

epilepsy

seizures

seizures

pilocarpine

status epilepticus

seizures

seizures

status epilepticus


Tonic dopaminergic stimulation impairs associative learning in healthy subjects.

Endogenous dopamine plays a central role in salience coding during associative learning. Administration of the dopamine precursor levodopa enhances learning in healthy subjects and stroke patients. Because levodopa increases both phasic and tonic dopaminergic neurotransmission, the critical mechanism mediating the enhancement of learning is unresolved. We here probed how selective tonic dopaminergic stimulation affects associative learning. Forty healthy subjects were trained in a novel vocabulary of 45 concrete nouns over the course of 5 consecutive training days in a prospective, randomized, double-blind, placebo-controlled design. Subjects received the tonically stimulating dopamine-receptor agonist pergolide (0.1 mg) vs placebo 120 min before training on each training day. The dopamine agonist significantly impaired novel word learning compared to placebo. This learning decrement persisted up to the last follow-up 4 weeks post-training. Subjects treated with pergolide also showed restricted emotional responses compared to the PLACEBO group. The extent of 'flattened' affect with pergolide was related to the degree of learning inhibition. These findings suggest that tonic occupation of dopamine receptors impairs learning by competition with phasic dopamine signals. Thus, phasic signaling seems to be the critical mechanism by which dopamine enhances associative learning in healthy subjects and stroke patients.

impairs associative learning

dopamine

dopamine

levodopa

stroke

levodopa

dopamine

pergolide

dopamine

impaired novel word learning

pergolide

pergolide

dopamine

dopamine

dopamine

stroke


Minocycline-induced vasculitis fulfilling the criteria of polyarteritis nodosa.

A 47-year-old man who had been taking minocycline for palmoplantar pustulosis developed fever, myalgias, polyneuropathy, and testicular pain, with elevated C-reactive protein (CRP). Neither myeloperoxidase- nor proteinase-3-antineutrophil cytoplasmic antibody was positive. These manifestations met the American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Stopping minocycline led to amelioration of symptoms and normalization of CRP level. To our knowledge, this is the second case of minocycline-induced vasculitis satisfying the criteria. Differential diagnosis for drug-induced disease is invaluable even for patients with classical polyarteritis nodosa.

Minocycline

vasculitis

polyarteritis nodosa

minocycline

palmoplantar pustulosis

fever

myalgias

polyneuropathy

testicular pain

polyarteritis nodosa

minocycline

minocycline

vasculitis

polyarteritis nodosa


Intramuscular hepatitis B immune globulin combined with lamivudine in prevention of hepatitis B recurrence after liver transplantation.

BACKGROUND: Combined hepatitis B immune globulin (HBIg) and lamivudine in prophylaxis of the recurrence of hepatitis B after liver transplantation has significantly improved the survival of HBsAg positive patients. This study was undertaken to evaluate the outcomes of liver transplantation for patients with hepatitis B virus (HBV). METHODS: A retrospective chart analysis and a review of the organ transplant database identified 51 patients (43 men and 8 women) transplanted for benign HBV-related cirrhotic diseases between June 2002 and December 2004 who had survived more than 3 months. HBIg was administered intravenously during the first week and intramuscularly thereafter. RESULTS: At a median follow-up of 14.1 months, the overall recurrence rate in the 51 patients was 3.9% (2/51). The overall patient survival was 88.3%, and 82.4% after 1 and 2 years, respectively. A daily oral dose of 100 mg lamivudine for 2 weeks before transplantation for 10 patients enabled 57.1% (4/7) and 62.5% (5/8) of HBV-DNA and HBeAg positive patients respectively to convert to be negative. Intramuscular HBIg was well tolerated in all patients. CONCLUSION: Lamivudine combined with intramuscular HBIg can effectively prevent allograft from the recurrence of HBV after liver transplantation.

hepatitis B

lamivudine

hepatitis B

hepatitis B

lamivudine

hepatitis B

HBsAg

hepatitis B

cirrhotic diseases

lamivudine

HBeAg

Lamivudine


Anticonvulsant effect of eslicarbazepine acetate (BIA 2-093) on seizures induced by microperfusion of picrotoxin in the hippocampus of freely moving rats.

Eslicarbazepine acetate (BIA 2-093, S-(-)-10-acetoxy-10,11-dihydro-5H-dibenzo/b,f/azepine-5-carboxamide) is a novel antiepileptic drug, now in Phase III clinical trials, designed with the aim of improving efficacy and safety in comparison with the structurally related drugs carbamazepine (CBZ) and oxcarbazepine (OXC). We have studied the effects of oral treatment with eslicarbazepine acetate on a whole-animal model in which partial seizures can be elicited repeatedly on different days without changes in threshold or seizure patterns. In the animals treated with threshold doses of picrotoxin, the average number of seizures was 2.3+/-1.2, and average seizure duration was 39.5+/-8.4s. Pre-treatment with a dose of 30 mg/kg 2h before picrotoxin microperfusion prevented seizures in the 75% of the rats. Lower doses (3 and 10mg/kg) did not suppress seizures, however, after administration of 10mg/kg, significant reductions in seizures duration (24.3+/-6.8s) and seizure number (1.6+/-0.34) were found. No adverse effects of eslicarbazepine acetate were observed in the behavioral/EEG patterns studied, including sleep/wakefulness cycle, at the doses studied.

eslicarbazepine acetate

BIA 2-093

seizures

picrotoxin

Eslicarbazepine acetate

BIA 2-093

carbamazepine

CBZ

oxcarbazepine

OXC

eslicarbazepine acetate

seizures

seizure

picrotoxin

seizures

seizure

picrotoxin

seizures

seizures

seizures

seizure

eslicarbazepine acetate


Acute renal failure associated with prolonged intake of slimming pills containing anthraquinones.

Chinese herbal medicine preparations are widely available and often regarded by the public as natural and safe remedies for a variety of medical conditions. Nephropathy caused by Chinese herbs has previously been reported, usually involving the use of aristolochic acids. We report a 23-year-old woman who developed acute renal failure following prolonged use of a proprietary Chinese herbal slimming pill that contained anthraquinone derivatives, extracted from Rhizoma Rhei (rhubarb). The renal injury was probably aggravated by the concomitant intake of a non-steroidal anti-inflammatory drug, diclofenac. Renal pathology was that of hypocellular interstitial fibrosis. Spontaneous renal recovery occurred upon cessation of the slimming pills, but mild interstitial fibrosis and tubular atrophy was still evident histologically 4 months later. Although a causal relationship between the use of an anthraquinone-containing herbal agent and renal injury remains to be proven, phytotherapy-associated interstitial nephropathy should be considered in patients who present with unexplained renal failure.

Acute renal failure

anthraquinones

Chinese herbal

Nephropathy

Chinese herbs

aristolochic acids

acute renal failure

Chinese herbal

anthraquinone

renal injury

diclofenac

fibrosis

fibrosis

atrophy

anthraquinone

renal injury

nephropathy

renal failure


Chloroacetaldehyde as a sulfhydryl reagent: the role of critical thiol groups in ifosfamide nephropathy.

Chloroacetaldehyde (CAA) is a metabolite of the alkylating agent ifosfamide (IFO) and putatively responsible for renal damage following anti-tumor therapy with IFO. Depletion of sulfhydryl (SH) groups has been reported from cell culture, animal and clinical studies. In this work the effect of CAA on human proximal tubule cells in primary culture (hRPTEC) was investigated. Toxicity of CAA was determined by protein content, cell number, LDH release, trypan blue exclusion assay and caspase-3 activity. Free thiols were measured by the method of Ellman. CAA reduced hRPTEC cell number and protein, induced a loss in free intracellular thiols and an increase in necrosis markers. CAA but not acrolein inhibited the cysteine proteases caspase-3, caspase-8 and cathepsin B. Caspase activation by cisplatin was inhibited by CAA. In cells stained with fluorescent dyes targeting lysosomes, CAA induced an increase in lysosomal size and lysosomal leakage. The effects of CAA on cysteine protease activities and thiols could be reproduced in cell lysate. Acidification, which slowed the reaction of CAA with thiol donors, could also attenuate effects of CAA on necrosis markers, thiol depletion and cysteine protease inhibition in living cells. Thus, CAA directly reacts with cellular protein and non-protein thiols, mediating its toxicity on hRPTEC. This effect can be reduced by acidification. Therefore, urinary acidification could be an option to prevent IFO nephropathy in patients.

Chloroacetaldehyde

sulfhydryl

thiol

ifosfamide

nephropathy

Chloroacetaldehyde

CAA

ifosfamide

IFO

renal damage

tumor

IFO

sulfhydryl

SH

CAA

Toxicity

CAA

trypan blue

thiols

CAA

thiols

necrosis

CAA

acrolein

cysteine

cisplatin

CAA

CAA

CAA

cysteine

thiols

CAA

thiol

CAA

necrosis

thiol

cysteine

CAA

thiols

toxicity

IFO

nephropathy


Stereological methods reveal the robust size and stability of ectopic hilar granule cells after pilocarpine-induced status epilepticus in the adult rat.

Following status epilepticus in the rat, dentate granule cell neurogenesis increases greatly, and many of the new neurons appear to develop ectopically, in the hilar region of the hippocampal formation. It has been suggested that the ectopic hilar granule cells could contribute to the spontaneous seizures that ultimately develop after status epilepticus. However, the population has never been quantified, so it is unclear whether it is substantial enough to have a strong influence on epileptogenesis. To quantify this population, the total number of ectopic hilar granule cells was estimated using unbiased stereology at different times after pilocarpine-induced status epilepticus. The number of hilar neurons immunoreactive for Prox-1, a granule-cell-specific marker, was estimated using the optical fractionator method. The results indicate that the size of the hilar ectopic granule cell population after status epilepticus is substantial, and stable over time. Interestingly, the size of the population appears to be correlated with the frequency of behavioral seizures, because animals with more ectopic granule cells in the hilus have more frequent behavioral seizures. The hilar ectopic granule cell population does not appear to vary systematically across the septotemporal axis, although it is associated with an increase in volume of the hilus. The results provide new insight into the potential role of ectopic hilar granule cells in the pilocarpine model of temporal lobe epilepsy.

pilocarpine

status epilepticus

status epilepticus

seizures

status epilepticus

pilocarpine

status epilepticus

status epilepticus

seizures

seizures

pilocarpine

temporal lobe epilepsy


A prospective, open-label trial of galantamine in autistic disorder.

OBJECTIVE: Post-mortem studies have reported abnormalities of the cholinergic system in autism. The purpose of this study was to assess the use of galantamine, an acetylcholinesterase inhibitor and nicotinic receptor modulator, in the treatment of interfering behaviors in children with autism. METHODS: Thirteen medication-free children with autism (mean age, 8.8 +/- 3.5 years) participated in a 12-week, open-label trial of galantamine. Patients were rated monthly by parents on the Aberrant Behavior Checklist (ABC) and the Conners' Parent Rating Scale-Revised, and by a physician using the Children's Psychiatric Rating Scale and the Clinical Global Impressions scale. RESULTS: Patients showed a significant reduction in parent-rated irritability and social withdrawal on the ABC as well as significant improvements in emotional lability and inattention on the Conners' Parent Rating Scale--Revised. Similarly, clinician ratings showed reductions in the anger subscale of the Children's Psychiatric Rating Scale. Eight of 13 participants were rated as responders on the basis of their improvement scores on the Clinical Global Impressions scale. Overall, galantamine was well-tolerated, with no significant adverse effects apart from headaches in one patient. CONCLUSION: In this open trial, galantamine was well-tolerated and appeared to be beneficial for the treatment of interfering behaviors in children with autism, particularly aggression, behavioral dyscontrol, and inattention. Further controlled trials are warranted.

galantamine

autistic disorder

autism

galantamine

autism

autism

galantamine

irritability

galantamine

headaches

galantamine

autism

aggression

behavioral dyscontrol

inattention


Randomized comparison of olanzapine versus risperidone for the treatment of first-episode schizophrenia: 4-month outcomes.

OBJECTIVE: The authors compared 4-month treatment outcomes for olanzapine versus risperidone in patients with first-episode schizophrenia spectrum disorders. METHOD: One hundred twelve subjects (70% male; mean age=23.3 years [SD = 5.1]) with first-episode schizophrenia (75%), schizophreniform disorder (17%), or schizoaffective disorder (8%) were randomly assigned to treatment with olanzapine (2.5-20 mg/day) or risperidone (1-6 mg/day). RESULTS: Response rates did not significantly differ between olanzapine (43.7%, 95% CI=28.8%-58.6%) and risperidone (54.3%, 95% CI=39.9%-68.7%). Among those responding to treatment, more subjects in the olanzapine group (40.9%, 95% CI=16.8%-65.0%) than in the risperidone group (18.9%, 95% CI=0%-39.2%) had subsequent ratings not meeting response criteria. Negative symptom outcomes and measures of parkinsonism and akathisia did not differ between medications. Extrapyramidal symptom severity scores were 1.4 (95% CI=1.2-1.6) with risperidone and 1.2 (95% CI=1.0-1.4) with olanzapine. Significantly more weight gain occurred with olanzapine than with risperidone: the increase in weight at 4 months relative to baseline weight was 17.3% (95% CI=14.2%-20.5%) with olanzapine and 11.3% (95% CI=8.4%-14.3%) with risperidone. Body mass index at baseline and at 4 months was 24.3 (95% CI=22.8-25.7) versus 28.2 (95% CI=26.7-29.7) with olanzapine and 23.9 (95% CI=22.5-25.3) versus 26.7 (95% CI=25.2-28.2) with risperidone. CONCLUSIONS: Clinical outcomes with risperidone were equal to those with olanzapine, and response may be more stable. Olanzapine may have an advantage for motor side effects. Both medications caused substantial rapid weight gain, but weight gain was greater with olanzapine.

olanzapine

risperidone

schizophrenia

olanzapine

risperidone

schizophrenia

schizophrenia

schizophreniform disorder

schizoaffective disorder

olanzapine

risperidone

olanzapine

risperidone

olanzapine

risperidone

parkinsonism

akathisia

Extrapyramidal symptom

risperidone

olanzapine

weight gain

olanzapine

risperidone

olanzapine

risperidone

olanzapine

risperidone

risperidone

olanzapine

Olanzapine

weight gain

weight gain

olanzapine


Early paracentral visual field loss in patients taking hydroxychloroquine.

OBJECTIVE: To review the natural history and ocular and systemic adverse effects of patients taking hydroxychloroquine sulfate who attended an ophthalmic screening program. DESIGN: Retrospective study. RESULTS: Records of 262 patients who were taking hydroxychloroquine and screened in the Department of Ophthalmology were reviewed. Of the 262 patients, 14 (18%) of 76 who had stopped treatment at the time of the study experienced documented adverse effects. Systemic adverse effects occurred in 8 patients (10.5%) and ocular adverse effects, in 5 (6.5%). Thirty-five patients (13.4%) had visual field abnormalities, which were attributed to hydroxychloroquine treatment in 4 patients (1.5%). Three of the 4 patients were taking less than 6.5 mg/kg per day and all patients had normal renal and liver function test results. CONCLUSIONS: The current study used a protocol of visual acuity and color vision assessment, funduscopy, and Humphrey 10-2 visual field testing and shows that visual field defects appeared before any corresponding changes in any other tested clinical parameters; the defects were reproducible and the test parameters were reliable. Patients taking hydroxychloroquine can demonstrate a toxic reaction in the retina despite the absence of known risk factors. Screening, including Humphrey 10-2 visual field assessment, is recommended 2 years after the initial baseline and yearly thereafter.

visual field loss

hydroxychloroquine

hydroxychloroquine sulfate

hydroxychloroquine

visual field abnormalities

hydroxychloroquine

visual field defects

hydroxychloroquine


Peri-operative atrioventricular block as a result of chemotherapy with epirubicin and paclitaxel.

A 47-year-old woman presented for mastectomy and immediate latissimus dorsi flap reconstruction having been diagnosed with carcinoma of the breast 6 months previously. In the preceding months she had received neo-adjuvant chemotherapy with epirubicin, paclitaxel (Taxol) and cyclophosphamide. This had been apparently uncomplicated and she had maintained a remarkably high level of physical activity. She was found to be bradycardic at pre-operative assessment but had no cardiac symptoms. Second degree Mobitz type II atrioventricular block was diagnosed on electrocardiogram, and temporary transvenous ventricular pacing instituted in the peri-operative period. We discuss how evidence-based guidelines would not have been helpful in this case, and how chemotherapy can exhibit substantial cardiotoxicity that may develop over many years. We suggest that patients who have received chemotherapy at any time should have a pre-operative electrocardiogram even if they are asymptomatic.

atrioventricular block

epirubicin

paclitaxel

carcinoma of the breast

epirubicin

paclitaxel

Taxol

cyclophosphamide

bradycardic

atrioventricular block

cardiotoxicity


Risks and benefits of COX-2 inhibitors vs non-selective NSAIDs: does their cardiovascular risk exceed their gastrointestinal benefit? A retrospective cohort study.

OBJECTIVES: The risk of acute myocardial infarction (AMI) with COX-2 inhibitors may offset their gastrointestinal (GI) benefit compared with non-selective (NS) non-steroidal anti-inflammatory drugs (NSAIDs). We aimed to compare the risks of hospitalization for AMI and GI bleeding among elderly patients using COX-2 inhibitors, NS-NSAIDs and acetaminophen. METHODS: We conducted a retrospective cohort study using administrative data of patients > or =65 years of age who filled a prescription for NSAID or acetaminophen during 1999-2002. Outcomes were compared using Cox regression models with time-dependent exposures. RESULTS: Person-years of exposure among non-users of aspirin were: 75,761 to acetaminophen, 42,671 to rofecoxib 65,860 to celecoxib, and 37,495 to NS-NSAIDs. Among users of aspirin, they were: 14,671 to rofecoxib, 22,875 to celecoxib, 9,832 to NS-NSAIDs and 38,048 to acetaminophen. Among non-users of aspirin, the adjusted hazard ratios (95% confidence interval) of hospitalization for AMI/GI vs the acetaminophen (with no aspirin) group were: rofecoxib 1.27 (1.13, 1.42), celecoxib 0.93 (0.83, 1.03), naproxen 1.59 (1.31, 1.93), diclofenac 1.17 (0.99, 1.38) and ibuprofen 1.05 (0.74, 1.51). Among users of aspirin, they were: rofecoxib 1.73 (1.52, 1.98), celecoxib 1.34 (1.19, 1.52), ibuprofen 1.51 (0.95, 2.41), diclofenac 1.69 (1.35, 2.10), naproxen 1.35 (0.97, 1.88) and acetaminophen 1.29 (1.17, 1.42). CONCLUSION: Among non-users of aspirin, naproxen seemed to carry the highest risk for AMI/GI bleeding. The AMI/GI toxicity of celecoxib was similar to that of acetaminophen and seemed to be better than those of rofecoxib and NS-NSAIDs. Among users of aspirin, both celecoxib and naproxen seemed to be the least toxic.

COX-2 inhibitors

acute myocardial infarction

AMI

COX-2 inhibitors

non-steroidal anti-inflammatory drugs

AMI

GI bleeding

COX-2 inhibitors

acetaminophen

acetaminophen

aspirin

acetaminophen

rofecoxib

celecoxib

aspirin

rofecoxib

celecoxib

acetaminophen

aspirin

AMI

acetaminophen

aspirin

rofecoxib

celecoxib

naproxen

diclofenac

ibuprofen

aspirin

rofecoxib

celecoxib

ibuprofen

diclofenac

naproxen

acetaminophen

aspirin

naproxen

AMI

GI bleeding

AMI

toxicity

celecoxib

acetaminophen

rofecoxib

aspirin

celecoxib

naproxen


Quinine-induced arrhythmia in a patient with severe malaria.

It was reported that there was a case of severe malaria patient with jaundice who presented with arrhythmia (premature ventricular contraction) while getting quinine infusion was reported. A man, 25 years old, was admitted to hospital with high fever, chill, vomiting, jaundice. The patient was fully conscious, blood pressure 120/80 mmHg, pulse rate 100 x/minute, regular. On admission, laboratory examination showed Plasmodium falciparum (++++), total bilirubin 8.25 mg/dL, conjugated bilirubin 4.36 mg/dL, unconjugated bilirubin 3.89 mg/dL, potassium 3.52 meq/L Patient was diagnosed as severe malaria with jaundice and got quinine infusion in dextrose 5% 500 mg/8 hour. On the second day the patient had vomitus, diarrhea, tinnitus, loss of hearing. After 30 hours of quinine infusion the patient felt palpitation and electrocardiography (ECG) recording showed premature ventricular contraction (PVC) > 5 x/minute, trigemini, constant type--sinoatrial block, positive U wave. He was treated with lidocaine 50 mg intravenously followed by infusion 1500 mg in dextrose 5%/24 hour and potassium aspartate tablet. Quinine infusion was discontinued and changed with sulfate quinine tablets. Three hours later the patient felt better, the frequency of PVC reduced to 4 - 5 x/minute and on the third day ECG was normal, potassium level was 3.34 meq/L. He was discharged on 7th day in good condition. Quinine, like quinidine, is a chincona alkaloid that has anti-arrhythmic property, although it also pro-arrhythmic that can cause various arrhythmias, including severe arrhythmia such as multiple PVC. Administration of parenteral quinine must be done carefully and with good observation because of its pro-arrhythmic effect, especially in older patients who have heart diseases or patients with electrolyte disorder (hypokalemia) which frequently occurs due to vomiting and or diarrhea in malaria cases.

Quinine

arrhythmia

severe malaria

severe malaria

jaundice

arrhythmia

premature ventricular contraction

quinine

fever

chill

vomiting

jaundice

bilirubin

bilirubin

bilirubin

potassium

severe malaria

jaundice

quinine

dextrose

vomitus

diarrhea

tinnitus

loss of hearing

quinine

palpitation

premature ventricular contraction

PVC

sinoatrial block

lidocaine

dextrose

potassium aspartate

Quinine

quinine

PVC

potassium

Quinine

quinidine

arrhythmic

arrhythmic

arrhythmias

arrhythmia

PVC

quinine

arrhythmic

heart diseases

electrolyte disorder

hypokalemia

vomiting

diarrhea

malaria


Penicillamine-related lichenoid dermatitis and utility of zinc acetate in a Wilson disease patient with hepatic presentation, anxiety and SPECT abnormalities.

Wilson's disease is an autosomal recessive disorder of hepatic copper metabolism with consequent copper accumulation and toxicity in many tissues and consequent hepatic, neurologic and psychiatric disorders. We report a case of Wilson's disease with chronic liver disease; moreover, in our patient, presenting also with high levels of state anxiety without depression, 99mTc-ECD-SPECT showed cortical hypoperfusion in frontal lobes, more marked on the left frontal lobe. During the follow-up of our patient, penicillamine was interrupted after the appearance of a lichenoid dermatitis, and zinc acetate permitted to continue the successful treatment of the patient without side-effects. In our case the therapy with zinc acetate represented an effective treatment for a Wilson's disease patient in which penicillamine-related side effects appeared. The safety of the zinc acetate allowed us to avoid other potentially toxic chelating drugs; this observation is in line with the growing evidence on the efficacy of the drug in the treatment of Wilson's disease. Since most of Wilson's disease penicillamine-treated patients do not seem to develop this skin lesion, it could be conceivable that a specific genetic factor is involved in drug response. Further studies are needed for a better clarification of Wilson's disease therapy, and in particular to differentiate specific therapies for different Wilson's disease phenotypes.

Penicillamine

lichenoid dermatitis

zinc acetate

Wilson disease

anxiety

Wilson's disease

copper

copper

toxicity

hepatic disorders

neurologic disorders

psychiatric disorders

Wilson's disease

chronic liver disease

anxiety

depression

penicillamine

lichenoid dermatitis

zinc acetate

zinc acetate

Wilson's disease

penicillamine

zinc acetate

Wilson's disease

Wilson's disease

penicillamine

skin lesion

Wilson's disease

Wilson's disease


A dramatic drop in blood pressure following prehospital GTN administration.

A male in his sixties with no history of cardiac chest pain awoke with chest pain following an afternoon sleep. The patient did not self medicate. The patient's observations were within normal limits, he was administered oxygen via a face mask and glyceryl trinitrate (GTN). Several minutes after the GTN the patient experienced a sudden drop in blood pressure and heart rate, this was rectified by atropine sulphate and a fluid challenge. There was no further deterioration in the patient's condition during transport to hospital. There are very few documented case like this in the prehospital scientific literature. The cause appears to be the Bezold-Jarish reflex, stimulation of the ventricular walls which in turn decreases sympathetic outflow from the vasomotor centre. Prehospital care providers who are managing any patient with a syncopal episode that fails to recover within a reasonable time frame should consider the Bezold-Jarisch reflex as the cause and manage the patient accordingly.

drop in blood pressure

GTN

chest pain

chest pain

oxygen

glyceryl trinitrate

GTN

GTN

drop in blood pressure

atropine sulphate

syncopal episode


Acute encephalopathy and cerebral vasospasm after multiagent chemotherapy including PEG-asparaginase and intrathecal cytarabine for the treatment of acute lymphoblastic leukemia.

A 7-year-old girl with an unusual reaction to induction chemotherapy for precursor B-cell acute lymphoblastic leukemia (ALL) is described. The patient developed acute encephalopathy evidenced by behavioral changes, aphasia, incontinence, visual hallucinations, and right-sided weakness with diffuse cerebral vasospasm on magnetic resonance angiography after the administration of intrathecal cytarabine. Vincristine, dexamethasone, and polyethylene glycol-asparaginase were also administered before the episode as part of induction therapy. Neurologic status returned to baseline within 10 days of the acute event, and magnetic resonance angiography findings returned to normal 4 months later.

Acute encephalopathy

cerebral vasospasm

PEG-asparaginase

cytarabine

acute lymphoblastic leukemia

acute lymphoblastic leukemia

ALL

acute encephalopathy

aphasia

incontinence

visual hallucinations

weakness

cerebral vasospasm

cytarabine

Vincristine

dexamethasone

polyethylene glycol-asparaginase


Comparison of valsartan/hydrochlorothiazide combination therapy at doses up to 320/25 mg versus monotherapy: a double-blind, placebo-controlled study followed by long-term combination therapy in hypertensive adults.

BACKGROUND: One third of patients treated for hypertension attain adequate blood pressure (BP) control, and multidrug regimens are often required. Given the lifelong nature of hypertension, there is a need to evaluate the long-term efficacy and tolerability of higher doses of combination anti-hypertensive therapies. OBJECTIVE: This study investigated the efficacy and tolerability of valsartan (VAL) or hydrochlorothiazide (HCTZ)-monotherapy and higher-dose combinations in patients with essential hypertension. METHODS: The first part of this study was an 8-week, multicenter, randomized, double-blind, placebo controlled, parallel-group trial. Patients with essential hypertension (mean sitting diastolic BP [MSDBP], > or =95 mm Hg and <110 mm Hg) were randomized to 1 of 8 treatment groups: VAL 160 or 320 mg; HCTZ 12.5 or 25 mg; VAL/HCTZ 160/12.5, 320/12.5, or 320/25 mg; or placebo. Mean changes in MSDBP and mean sitting systolic BP (MSSBP) were analyzed at the 8-week core study end point. VAL/HCTZ 320/12.5 and 320/25 mg were further investigated in a 54-week, open-label extension. Response was defined as MSDBP <90 mm Hg or a > or =10 mm Hg decrease compared to baseline. Control was defined as MSDBP <90 mm Hg compared with baseline. Tolerability was assessed by monitoring adverse events at randomization and all subsequent study visits and regular evaluation of hematology and blood chemistry. RESULTS: A total of 1346 patients were randomized into the 8-week core study (734 men, 612 women; 924 white, 291 black, 23 Asian, 108 other; mean age, 52.7 years; mean weight, 92.6 kg). All active treatments were associated with significantly reduced MSSBP and MSDBP during the core 8-week study, with each monotherapy significantly contributing to the overall effect of combination therapy (VAL and HCTZ, P < 0.001). Each combination was associated with significantly greater reductions in MSSBP and MSDBP compared with the monotherapies and placebo (all, P < 0.001). The mean reduction in MSSBP/MSDBP with VAL/HCTZ 320/25 mg was 24.7/16.6 mm Hg, compared with 5.9/7.0 mm Hg with placebo. The reduction in MSSBP was significantly greater with VAL/HCTZ 320/25 mg compared with VAL/HCTZ 160/12.5 mg (P < 0.002). Rates of response and BP control were significantly higher in the groups that received combination treatment compared with those that received monotherapy. The incidence of hypokalemia was lower with VAL/HCTZ combinations (1.8%-6.1%) than with HCTZ monotherapies (7.1%-13.3%). The majority of adverse events in the core study were of mild to moderate severity. The efficacy and tolerability of VAL/HCTZ combinations were maintained during the extension (797 patients). CONCLUSIONS: In this study population, combination therapies with VAL/HCTZ were associated with significantly greater BP reductions compared with either monotherapy, were well tolerated, and were associated with less hypokalemia than HCTZ alone.

valsartan

hydrochlorothiazide

hypertensive

hypertension

hypertension

hypertensive

valsartan

VAL

hydrochlorothiazide

HCTZ

essential hypertension

essential hypertension

VAL

HCTZ

VAL

HCTZ

VAL

HCTZ

VAL

HCTZ

VAL

HCTZ

VAL

HCTZ

VAL

HCTZ

hypokalemia

VAL

HCTZ

HCTZ

VAL

HCTZ

VAL

HCTZ

hypokalemia

HCTZ


Succimer chelation improves learning, attention, and arousal regulation in lead-exposed rats but produces lasting cognitive impairment in the absence of lead exposure.

BACKGROUND: There is growing pressure for clinicians to prescribe chelation therapy at only slightly elevated blood lead levels. However, very few studies have evaluated whether chelation improves cognitive outcomes in Pb-exposed children, or whether these agents have adverse effects that may affect brain development in the absence of Pb exposure. OBJECTIVES: The present study was designed to answer these questions, using a rodent model of early childhood Pb exposure and treatment with succimer, a widely used chelating agent for the treatment of Pb poisoning. RESULTS: Pb exposure produced lasting impairments in learning, attention, inhibitory control, and arousal regulation, paralleling the areas of dysfunction seen in Pb-exposed children. Succimer treatment of the Pb-exposed rats significantly improved learning, attention, and arousal regulation, although the efficacy of the treatment varied as a function of the Pb exposure level and the specific functional deficit. In contrast, succimer treatment of rats not previously exposed to Pb produced lasting and pervasive cognitive and affective dysfunction comparable in magnitude to that produced by the higher Pb exposure regimen. CONCLUSIONS: These are the first data, to our knowledge, to show that treatment with any chelating agent can alleviate cognitive deficits due to Pb exposure. These findings suggest that it may be possible to identify a succimer treatment protocol that improves cognitive outcomes in Pb-exposed children. However, they also suggest that succimer treatment should be strongly discouraged for children who do not have elevated tissue levels of Pb or other heavy metals.

Succimer

lead

cognitive impairment

lead

lead

Pb

Pb

Pb

succimer

Pb poisoning

Pb

impairments in learning

impairments in

Pb

Succimer

Pb

Pb

succimer

Pb

cognitive and affective dysfunction

cognitive dysfunction

affective dysfunction

Pb

cognitive deficits

Pb

succimer

Pb

succimer

Pb


Caffeine challenge test in panic disorder and depression with panic attacks.

Our aim was to observe if patients with panic disorder (PD) and patients with major depression with panic attacks (MDP) (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) respond in a similar way to the induction of panic attacks by an oral caffeine challenge test. We randomly selected 29 patients with PD, 27 with MDP, 25 with major depression without panic attacks (MD), and 28 healthy volunteers. The patients had no psychotropic drug for at least a 4-week period. In a randomized double-blind experiment performed in 2 occasions 7 days apart, 480 mg caffeine and a caffeine-free (placebo) solution were administered in a coffee form and anxiety scales were applied before and after each test. A total of 58.6% (n = 17) of patients with PD, 44.4% (n = 12) of patients with MDP, 12.0% (n = 3) of patients with MD, and 7.1% (n= 2) of control subjects had a panic attack after the 480-mg caffeine challenge test (chi(2)(3) = 16.22, P = .001). The patients with PD and MDP were more sensitive to caffeine than were patients with MD and healthy volunteers. No panic attack was observed after the caffeine-free solution intake. The patients with MD had a lower heart rate response to the test than all the other groups (2-way analysis of variance, group by time interaction with Greenhouse-Geisser correction: F(3,762) = 2.85, P = .026). Our data suggest that there is an association between panic attacks, no matter if associated with PD or MDP, and hyperreactivity to an oral caffeine challenge test.

Caffeine

panic disorder

depression

panic attacks

panic disorder

PD

major depression

panic attacks

MDP

Mental Disorders

panic attacks

caffeine

PD

MDP

major depression

panic attacks

MD

caffeine

caffeine

anxiety

PD

MDP

MD

panic attack

caffeine

PD

MDP

caffeine

MD

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caffeine

MD

panic attacks

PD

MDP

caffeine