Naloxone in the management of hepatic encephalopathy.

BACKGROUND/AIM: This study aimed to assess the effectiveness and safety of naloxone in the management of hepatic encephalopathy (HE). METHODS: Cochrane collaboration methodology was used in a meta-analysis of randomized controlled trials of naloxone therapy for HE. RESULTS: Seventeen randomized trials were identified with 15 studies involving 1054 patients meeting criteria for inclusion. Naloxone use was associated with a significant improvement in HE [relative risk (RR) 1.46; 95% confidence interval (CI) 1.27-1.67; P = 0.0005]. This comparison showed statistical heterogeneity (P < 0.10, and χ2 = 44.93). Subgroup analysis indicated naloxone administered parenterally by intermittent or continuous infusions to be effective (RR 1.34; 95% CI 1.17-1.53; P < 0.0001). A significant in trials by infusion route (RR 1.42; 95% CI 1.19-1.69; P < 0.0001) interaction was observed. CONCLUSIONS: Naloxone may improve HE. However, published data are limited.

Neurotoxicity following addition of intravenous valproate to lamotrigine therapy.

Reversible neurotoxic symptoms were observed in three adult patients with absence status epilepticus on lamotrigine (LTG) therapy after administration of an IV bolus followed by oral valproic acid (VPA). Neurotoxicity was likely related to elevated serum LTG levels, as improvement correlated with discontinuing or reducing LTG dosage.

Vagus nerve stimulation for partial seizures.

BACKGROUND: Vagus nerve stimulation (VNS) has recently been introduced as an adjunct for treating patients with seizures. The aim of this systematic review was to overview the current evidence for the effects of vagus nerve stimulation, when used as an adjunctive treatment for patients with drug-resistant partial epilepsy. OBJECTIVES: To determine the effects of VNS high-level stimulation compared to low-level (presumed subtherapeutic dose) stimulation. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group trials register, MEDLINE (January 1966 to October 2000) and The Cochrane Controlled Trials Register (Cochrane Library Issue 4, 2000). SELECTION CRITERIA: Randomized, double-blind controlled trials of VNS comparing high and low stimulation paradigms. Studies in adults or children with drug-resistant partial seizures. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion and extracted data. The following outcomes were assessed: (a) 50% or greater reduction in total seizure frequency; (b) treatment withdrawal (any reason); (c) side effects. Primary analyses were intention to treat. Sensitivity best and worst case analyses were also undertaken. Summary odds ratios (ORs) were estimated for each outcome. MAIN RESULTS: Results of the overall efficacy analysis show that VNS stimulation using the high stimulation paradigm was significantly better than low stimulation. The overall OR (95% Confidence Interval (CI)) for 50% responders across all studies is 1.93 (1.1,3.3). This effect did not vary substantially and remained statistically significant for both the best and worst case scenarios. Results for the outcome "withdrawal of allocated treatment" suggest that VNS is well tolerated as no significant difference was found between the high and low stimulation groups, and withdrawals were rare. Statistically significant adverse effects associated with implantation (low versus baseline) were hoarseness, cough, pain and paresthesia. Statistically significant adverse effects associated with stimulation (high versus low) were hoarseness and dyspnea, suggesting the implantation is associated with hoarseness, but the stimulation produces additional hoarseness. REVIEWER'S CONCLUSIONS: VNS for partial seizures appears to be an effective and well tolerated treatment. Adverse effects of hoarseness, cough, pain, paresthesias and dyspnea are associated with the treatment but appear to be reasonably well tolerated as dropouts were rare. Typical central nervous system adverse effects of antiepileptic drugs such as ataxia, dizziness, fatigue, nausea and somnolence were not statistically significantly associated with VNS treatment.

Benzodiazepines in the home treatment of acute seizures.

Prompt home treatment of dangerous seizures or upsetting relapses can prevent the effects of prolonged seizures and offer patients and their families an alternative to emergency medical treatment. The choice of benzodiazepine and route of administration should be based on patients' clinical presentation and acceptance. The challenge for the practitioner is to select the patients for whom home use of benzodiazepines will be appropriate, safe, and cost-effective.

Increased seizure frequency associated with felbamate withdrawal in adults.

OBJECTIVE: To characterize changes in seizure frequency following felbamate withdrawal. DESIGN: Nonrandomized, retrospective chart review of a case series. SETTING: Epilepsy program specializing in adults with uncontrolled epilepsy. PATIENT POPULATION: Forty-five ambulatory patients withdrawn from felbamate use. Patients were included if they had received felbamate for at least 1 month, were 18 years or older, had accurate seizure frequency documentation, had accurate documentation of all antiepileptic drugs, and received the same concomitant antiepileptic drugs before and after felbamate therapy, except for the possible addition of gabapentin. Patients were excluded if they had hematologic or hepatic toxic effects with felbamate, were unable to withdraw from felbamate treatment, had a progressive neurologic disorder, or participated in another drug trial. METHODS: When information became available on aplastic anemia and hepatotoxicity associated with felbamate, all patients were advised to taper their felbamate dosage over approximately 2 weeks. They received written instructions for tapering felbamate and adjusting concomitant antiepileptic drugs and kept calendars to note the number of seizures. The charts of all patients who received felbamate were evaluated for adherence to inclusion and exclusion criteria. Statistical analysis was performed using a log-linear model for count data. MAIN OUTCOME MEASURES: Seizure frequency during the 6 months before initiating felbamate therapy served as the baseline. Changes in seizure frequency were evaluated by comparing the number of seizures in the month felbamate was tapered and the 3 months after felbamate discontinuation with the baseline frequency. Comparisons were made between patients who started gabapentin therapy and those who did not and between felbamate responders and nonresponders. RESULTS: Felbamate withdrawal resulted in a significant (P=.02) increase in seizure frequency. Patients receiving gabapentin had a smaller increase in seizure frequency, but the difference was not statistically significant. There was no statistically significant difference in seizure frequency between felbamate responders and nonresponders. CONCLUSIONS: Felbamate withdrawal caused a significant increase in seizure frequency over the subsequent 3 months. These findings are important for clinical trial design and clinical practice.

Acute phenytoin toxicity followed by seizure breakthrough from a ticlopidine-phenytoin interaction.

OBJECTIVE: To review a case of a drug-drug interaction between phenytoin sodium and ticlopidine hydrochloride that resulted in acute phenytoin toxicity and permanent memory loss. CASE REPORT: A 63-year-old man who was maintained with a stable dose of phenytoin for treatment of seizures began treatment with ticlopidine following percutaneous transluminal angioplasty and stent placement. Within 3 weeks of beginning treatment with ticlopidine, he experienced acute clinical toxic effects of phenytoin with a maximum measured phenytoin concentration of 162.4 micromol/L. Phenytoin concentration decreased to 36 micromol/L after discontinuing treatment with ticlopidine and reducing the phenytoin dose. Subsequently, the patient developed probable complex partial status epilepticus. CONCLUSIONS: Ticlopidine is a metabolic inhibitor of several drugs. Because of the potential for acute and permanent adverse effects from a drug-drug interaction, phenytoin concentrations should be carefully monitored when beginning or ending ticlopidine therapy.

Impact of vancomycin therapeutic drug monitoring on patient care.

OBJECTIVE: To document differences in the outcome of vancomycin therapy in patients managed through a therapeutic drug monitoring (TDM) service and patients managed empirically, without the participation of a TDM service. DESIGN: Prospective, cohort study. SETTING: An 1100-bed, tertiary-care, teaching hospital. PATIENTS: Those who received vancomycin for more than four days, were at least 18 years old, had an estimated creatinine clearance of more than 0.33 mL/s (20 mL/min), were not neutropenic at the start of vancomycin therapy, and were not treated in a critical care unit were enrolled in the study. A total of 116 patients (61 TDM; 55 non-TDM) were monitored prospectively from June 1990 through March 1991. INTERVENTIONS: Patients in the TDM group had vancomycin drug therapy monitored daily by a pharmacist and vancomycin dosages adjusted following a pharmacokinetic analysis of vancomycin serum concentrations. For patients in the non-TDM group, the pharmacist only completed a data collection form. The patients and physicians were unaware of the monitoring. MAIN OUTCOME MEASURES: Duration of therapy, total vancomycin dosage, infection site, concomitant antibiotics, body temperature, and white blood cell counts were compared between the two groups. Length of stay data were also compared. Nephrotoxicity was evaluated by comparing serum creatinine concentration and estimated creatinine clearance. RESULTS: TDM of vancomycin appeared to reduce the incidence of vancomycin-related renal insufficiency (TDM 7 percent; non-TDM 24 percent). Patients managed through the TDM service received an average of 5 g less of vancomycin than did the patients in the non-TDM group. The duration of vancomycin therapy was an average of 2 days less for patients in the TDM group. Mean length of stay was 38.0 days for the TDM group and 44.5 days for the non-TDM group. Other measures of efficacy, infection site, and concomitant antibiotics were the same for both groups. CONCLUSIONS: TDM of vancomycin was associated with fewer cases of vancomycin-related renal insufficiency. Vancomycin efficacy was not compromised by TDM. Provision of TDM for vancomycin therapy aided in patient management.

Loss of seizure control associated with generic substitution of carbamazepine.

OBJECTIVE: We report two cases of lost seizure control associated with the generic substitution of carbamazepine, review pertinent literature, and discuss the impact of this substitution on patient care. DATA SOURCES: Case studies, abstracts, and research publications identified in MEDLINE and bibliographic review. DATA EXTRACTION: One author reviewed cases supplied by the other authors and abstracted information from published literature sources. DATA SYNTHESIS: The first case describes a 15-year-old boy who received valproic acid and carbamazepine for partial seizures. A change in government program policies caused him to receive generic carbamazepine. This resulted in loss of seizure control and a decrease in his serum carbamazepine concentration from 12.4 to 6.7 micrograms/mL. When his carbamazepine concentration returned to previous levels, seizure control was not reestablished. A second case involves a 21-year-old woman who substituted generic carbamazepine because of financial problems. After being seizure-free for at least five years on phenobarbital and carbamazepine, she experienced seizures related to the product change. Her carbamazepine concentration decreased from 11.8 to 8.5 micrograms/mL; she also became pregnant at that time. Seizure control was not reestablished. At least three other studies do not support these observations, but the tightly controlled conditions in these studies may not have simulated actual clinical practice. CONCLUSIONS: When generic substitution of carbamazepine is required, serum concentrations should be carefully monitored. The extra care required may negate the financial advantages of the substitution.

Pathophysiology and treatment of subarachnoid hemorrhage.

The pathophysiology and treatment of acute subarachnoid hemorrhage (SAH) are reviewed. SAH occurs when blood is released into the subarachnoid space, which surrounds the brain and spinal cord. Symptoms of SAH include severe headache, nausea, vomiting, neck pain, nuchal rigidity, and photophobia. The initial hemorrhage is fatal in 20-30% of patients. Complications of SAH include rebleeding, hydrocephalus, delayed cerebral ischemia associated with cerebral vasospasm, and seizures. The likelihood of rebleeding is increased by measures that rapidly lower intracranial pressure. The risk of developing hydrocephalus is associated with the volume of blood within the subarachnoid space and ventricular system. Cerebral vasospasm develops in 20-40% of patients, and up to 50% of affected patients die or suffer permanent neurological damage. Seizures occur in 5-15% of patients with SAH. Radiologic procedures form the foundation for the diagnosis of SAH. The most commonly used rating scale classifies the severity of SAH based on the clinical presentation of the patient. Surgery is the definitive treatment for the prevention of rebleeding. Hydrocephalus can only be treated surgically, most commonly by insertion of a drain. The only measures proved to be effective for treatment of delayed cerebral ischemia are volume expansion and the induction of hypertension. The calcium-channel blocker nimodipine was recently approved for treatment of arterial spasm in SAH. Intravenous nicardipine is also being studied for the same indication. These agents may improve clinical outcome substantially by limiting fixed neurological deficits. To prevent seizures, prophylactic antiepileptic therapy with phenytoin sodium is generally accepted. The SAH complications of rebleeding, hydrocephalus, delayed cerebral ischemia, and seizures are managed by surgical, drug, and fluid therapy.

Progabide-induced changes in carbamazepine metabolism.

Carbamazepine (CBZ) and carbamazepine 10,11 epoxide (CBZ-E) concentrations were measured during a safety and efficacy trial of progabide. The average CBZ and CBZ-E serum concentrations were calculated from serial measurements during placebo and active treatment periods. Significant decreases in CBZ and significant increases in CBZ-E were observed after the first dose of progabide, and these changes persisted during 3 months of active treatment. Ninety-five percent of the patients had increases in the epoxide/CBZ ratio at the end of 3 months of treatment. These changes are consistent with displacement of CBZ from protein binding sites and inhibition of CBZ-E metabolism induced by progabide and are analagous to the interaction between valproate and CBZ.

Delivery of paraldehyde in 5% dextrose and 0.9% sodium chloride injections through polyvinyl chloride i.v. sets and burettes.

The delivery of paraldehyde in 5% dextrose injection and 0.9% sodium chloride injection was studied, and the potential interaction between paraldehyde and plastic i.v. containers and sets was evaluated. Paraldehyde was mixed with either 5% dextrose injection or 0.9% sodium chloride injection in polyvinyl chloride (PVC) bags to form a 4% solution. The bags were fitted with standard i.v. administration sets or burettes with administration sets. The solutions were allowed to drip through the i.v. sets for six hours at room temperature. Samples were taken from the i.v. bag or burette and from the distal end of the i.v. sets at zero, two, four, and six hours. Paraldehyde concentrations were measured using a stability-indicating gas chromatographic method, and the presence of plasticizers was detected by a scanning ultraviolet spectrophotometer. The cumulative amount of paraldehyde delivered at the end of the administration set at six hours was 84% for 5% dextrose solutions in burettes, and 89% or 90% for all other solutions and i.v. sets. An ultraviolet-light-absorbing substance appeared in some of the samples, although a relationship between the presence of this substance and type of solution, time of sampling, or site of sample did not emerge. Particulate matter appeared after two hours in all burettes. Approximately 10%-16% of paraldehyde in 5% dextrose or 0.9% sodium chloride injection is lost when delivered from PVC i.v. bags through standard i.v. administration sets and burettes over a six-hour period.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of progabide on serum phenytoin and carbamazepine concentrations.

Progabide (PGB) is a gamma-aminobutyric acid (GABA)-agonist drug undergoing clinical evaluation for the treatment of spasticity, movement disorders, and epilepsy. Drug interactions were studied during a randomized, double-blind, crossover trial of the efficacy and toxicity of PGB in patients with partial seizures taking phenytoin (PHT) and carbamazepine (CBZ). In twenty-two of 32 patients (69%) receiving PGB, PHT dosage was reduced, while only four patients (12%) had their dosage reduced during placebo treatment (p less than 0.001). Carbamazepine dosage was decreased in five of 32 patients (16%) during the active treatment, while two patients (6%) had a dosage reduction when receiving placebo (p greater than 0.75). The mean PHT concentrations at the end of baseline, PGB, and placebo treatments were significantly different: 17.5, 20.4, and 16.8 mg/L, respectively (p less than 0.05). Nevertheless, careful adjustment of PHT dosage maintained serum concentration within +/- 25% of target values in both the PGB and placebo periods. Among patients who first received PGB and then placebo, PHT concentrations remained elevated relative to dose suggesting that PGB exerts a prolonged effect on PHT disposition. The addition of PGB to regimens including PHT results in a significant increase in serum PHT concentrations. This drug interaction most likely occurs as a result of PGB mediated inhibition of hepatic microsomal enzymes.

Use of nimodipine for prevention and treatment of cerebral arterial spasm in patients with subarachnoid hemorrhage.

The chemistry, pharmacology, pharmacokinetics, adverse effects, dosage, and availability of nimodipine are discussed, and the clinical use of nimodipine in preventing and treating cerebral arterial spasm in patients with subarachnoid hemorrhage is reviewed. Nimodipine is a highly lipid-soluble dihydropyridine derivative that readily crosses the blood-brain barrier. In animal studies, nimodipine has been shown to be effective in increasing cerebral blood flow; preventing vasoconstriction attributable to sympathetic stimulation, hypocapnia, and hypertension; and improving neurological outcome after cerebral ischemia. Nimodipine is reported to be 90% protein bound; its half-life is approximately 13 hours, with substantial interpatient variability. Nimodipine has been studied in the prevention and treatment of cerebral arterial spasm in patients with subarachnoid hemorrhage. In four open trials, in which nimodipine was administered orally, intravenously, topically during surgery, or by intracarotid injection, and in two double-blind, placebo-controlled trials, neurological outcomes were improved in patients receiving the drug. However, in both sets of trials nimodipine had limited effects on cerebral arterial spasm. Although nimodipine can cause hypotension, no serious adverse reactions to the drug were reported in clinical trials in patients with subarachnoid hemorrhage. Based on limited data currently available, nimodipine appears to improve neurological outcome in patients with subarachnoid hemorrhage. However, its efficacy in preventing or treating cerebral arterial spasm in these patients seems to be limited.