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J P Mumford

Publications and source records attributed to J P Mumford.

At least 19 recordsLinked to original sources
PubMed1999

Double-blind substitution of vigabatrin and valproate in carbamazepine-resistant partial epilepsy. 012 Study group.

Patients from 12 countries reporting two or more partial seizures per month despite treatment with optimal doses of CBZ were randomised to additional vigabatrin (VGB, 2-4 g daily) or sodium valproate (VPA, 1-2 g daily) using a double-blind, double-dummy design. The study included a 6 month retrospective baseline on unchanged CBZ dosage, a month's prospective baseline, a short titration phase, and an assessment period lasting 3 months on duotherapy. CBZ was withdrawn over a further 2 months in responders ( > or = 50% monthly seizure reduction compared with baseline), who continued on alternative monotherapy for 3 or more months. If seizure control deteriorated, CBZ was reinstated and these patients were also followed up for 3 months. A total of 215 patients (108 VGB, 107 VPA) reporting a mean of seven partial seizures per month fulfilled the criteria for the intention-to-treat analysis. 53 and 51% of patients in the VGB and VPA group respectively achieved a monthly reduction in seizure numbers > or = 50%, respectively. 27 and 31% maintained alternative monotherapy. Overall, 17% (7% monotherapy, 10% duotherapy) of the VGB treated patients and 19% (8% monotherapy, 11% duotherapy) of the VPA group remained seizure-free during the final 3 month treatment period. VGB and VPA, which increase neuronal inhibition mediated by gamma aminobutyric acid, can be added to or substituted for CBZ when this Na+ channel blocker fails to control partial seizures. This lends credence to the hypothesis in support of a mechanistic approach to the management of epilepsy.

Adolescent↗
PubMed1999

Long-term treatment with vigabatrin - 10 years of clinical experience.

This report describes the long-term follow-up of 56 patients with refractory partial epilepsy who, within 3 months of vigabatrin add-on therapy (3 g/day), showed a reduction in monthly seizure frequency of more than 50%. The short-term (6 months) and long-term (5 years) effects of vigabatrin on seizure frequency in this patient cohort have been published separately. The reduction in seizure frequency appeared to be long-lasting in the patients followed-up (n = 36) and, importantly, a significant number of the patients (n = 7) became seizure-free, especially during long-term treatment. Thus, the efficacy of vigabatrin appears to be progressive, at least in patients who show an early response to treatment. These results are consistent with experimental findings that suggest that vigabatrin may have anti-epileptogenic and neuroprotective effects.

Anticonvulsants↗
PubMed1999

Once-daily versus twice-daily vigabatrin: is there a difference? The results of a double-blind pilot study.

PURPOSE: Vigabatrin (VGB) has been approved in Europe and is prescribed for either once or twice-daily administration. This choice has been based on the pharmacodynamic activity of VGB. The purpose of this study was to compare the efficacy and tolerability of these two different medication regimens. METHODS: The study design was a double-blind randomized two-period cross-over study in adults who had responded to add-on VGB for previously uncontrolled seizures. Each study period consisted of three months. Patients were maintained on the same daily dose of VGB to which they had demonstrated a clinical response. In addition to the primary efficacy criteria of seizure frequency on the two treatment regimens, this study included blinded ratings of overall efficacy and "well being" by both physician and patient. The primary tolerability criterion was the reported incidence of adverse events by phase. RESULTS: Fifty patients were initially entered into the study, and 13 patients withdrew before completion, only one reported as due to an adverse event. There was no statistical difference in seizure frequency or the tolerability of the medication. Blinded physician and patient rating scales for seizure control, and patient well being showed a nonstatistical trend toward once-daily administration as compared with twice-daily administration. CONCLUSIONS: This clinical study provides support for the pharmacological evidence that this preparation may be administered on a once or twice daily basis, depending on the individual patient's preference, total dosage and co-medication.

Adult↗
PubMed1999

Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms.

PURPOSE: Vigabatrin (VGB) has been shown to be an effective drug in the treatment of infantile spasms (West syndrome) in predominantly retrospective and open but also in prospective studies. This prospective, randomised, and placebo-controlled trial of VGB in infantile spasms was considered to be justified and feasible to confirm or refute these previous findings. METHODS: Forty children with newly diagnosed infantile spasms received either VGB or placebo for 5 days in a double blind, placebo-controlled, parallel-group study, after which all the infants continuing in the study were treated openly with VGB for a minimum of 24 weeks. RESULTS: Compared with baseline, at the end of the double-blind phase, the patients treated with VGB had a 78% (95% confidence interval, 55-89%) reduction in spasms compared with 26% (-56-65%) in the group treated with placebo (p = 0.020). Seven VGB-treated patients and two placebo-treated patients were spasm free on the final day of the double-blind period (p = 0.063). At the end of the study, 15 children (38% of the original 40 patients or 42% of the 36 patients who entered the open phase) were spasm free with VGB monotherapy. No patient withdrew from the study because of an adverse event. CONCLUSIONS: This unique randomized, placebo-controlled study is the first to demonstrate the efficacy of a specific drug in the treatment of West syndrome and supports the results of previously published open and prospective trials. It further confirms that VGB could be considered as the drug of first choice in treating infantile spasms.

Adolescent↗
PubMed1998

Vigabatrin: placental transfer in vivo and excretion into breast milk of the enantiomers.

AIMS: Vigabatrin is a new antiepileptic medication consisting of a racemic mixture of 50% active S enantiomer and 50% inactive R enantiomer. Since patients suffering from epilepsy may become pregnant, it is important to understand the extent of placental transfer of such medication. METHODS: During steady-state, vigabatrin enantiomer concentrations were measured in maternal and umbilical blood and in breast milk of two patients. RESULTS: The concentration ratios from the umbilical vein to maternal plasma were R:0.068, S:0.16; 4h25 min after drug administration (case 1) and R: 1.39, S: 0.91; 9h after drug administration (case 2). The milk: plasma concentration ratio was lower than 1 at pre dose sampling in both cases, as well as 3 and 6 h post dose in one case. An estimate of the maximum amount of R and S enantiomers of vigabatrin that a suckling infant would ingest in a day is 3.6% and 1% of the weight-adjusted daily dose respectively. CONCLUSIONS: These results would suggest a slow placental transfer of the vigabatrin enantiomers and that the quantity ingested through milk is small.

Adult↗
PubMed1997

Double-blind study of lofexidine and clonidine in the detoxification of opiate addicts in hospital.

Twenty eight opiate addicted inpatients who had been stabilised on methadone took part in a double-blind randomised trial of clonidine and lofexidine (14 on each treatment) for opiate detoxification: clonidine or lofexidine dosage was titrated according to symptoms. The course of withdrawal symptoms was very similar with both treatments, representing an appreciable suppression of symptoms when compared with experiences of sudden methadone withdrawal, but lofexidine resulted in significantly less hypotension and adverse events. These results suggest that lofexidine is a valuable drug for opiate detoxification and may be more acceptable to patients wishing to withdraw from opiates.

Adrenergic alpha-Agonists↗
PubMed1997

Evidence for both in vivo and in vitro interaction between vigabatrin and alanine transaminase.

AIMS: Decreases in plasma alanine transaminase (ALA-T) activity of 20-100% have been reported following the use of vigabatrin (Sabril) in patients with uncontrolled epilepsy. This effect has a potential clinical significance as it may mask signs of early, underlying hepatic disease. It is particularly significant in a patient population known to have a higher than average risk of hepatotoxicity due to treatment with other anti-epilepsy drugs or to an independent, but concomitant, disease process. Vigabatrin is a highly specific enzyme antagonist. There is an almost 1000-fold difference between its activity against gamma-amino butyric acid aminotransaminase and ALA-T. However, some activity against other transaminases is not unexpected, and it, is important to determine the degree of vigabatrin's effect against ALA-T in man. METHODS: Two in vitro experiments, using serum samples spiked with vigabatrin, confirmed the presence of an interaction between vigabatrin and ALA-T, and formed the basis for the design of a study in five healthy male volunteers, in whom serum ALA-T activity was measured before and after a single dose of 1.5 g of vigabatrin. RESULTS: Serial sampling confirmed the presence of an in vivo interaction between vigabatrin and ALA-T, causing an inhibition of enzyme activity of 30-40%. A further 20% reduction was found in vitro in samples taken at the time of the peak plasma vigabatrin concentration after they had been stored for 6 h. CONCLUSIONS: The clinical significance of these findings is that the levels of ALA-T activity determined in patients receiving vigabatrin may be inaccurate. The "real' values must be assumed to be higher than those reported after routine testing. To obtain the most relistic measurement of ALA-T activity in patiets, samples should be taken at the times of trough plasma concentration and processed as soon as possible afterwards. Samples stored for any length of time at or above room temperature may also give even more false results.

Adult↗
PubMed1997

Optimizing the indication of vigabatrin in children with refractory epilepsy.

This review was conducted to evaluate the long-term prognosis of children responding to vigabatrin by examining the incidence of increased seizure frequency, loss of efficacy, and appearance of new seizures in a cohort of 196 children (mean age, 68.2 months; range, 2 months to 19 years) with drug-resistant epilepsy, who had received vigabatrin as add-on treatment in clinical trials. The results indicate that an increase in seizure frequency was uncommon, occurring in only 10% of children with highly drug-resistant epilepsy and that it usually appears shortly after the initiation of treatment. It was clearly not dose-dependent and most often occurred in patients with nonprogressive myoclonic epilepsy. No specific seizure type was specially involved and usually the problem reversed on discontinuing vigabatrin. Loss of efficacy was also uncommon (12% of patients), and again no specific seizure type was found to be associated. Epilepsy syndrome does seem to be a better predictor of loss of efficacy because it occurred most often in symptomatic generalized epilepsies and cryptogenic infantile spasms. A total of 21 patients (11%) developed genuinely new types of seizures. Fifteen of these patients developed new partial seizures that had little impact on the patients' overall clinical improvement. The new partial seizures were better tolerated than the initial seizure type which in most cases had disappeared. Approximately 3% of patients experienced new generalized seizures that aggravated their initial condition. These occurred most often in patients with nonprogressive myoclonic epilepsy; therefore vigabatrin should be used with particular caution in such patients.

Adolescent↗
PubMed1996

Vigabatrin as initial therapy for infantile spasms: a European retrospective survey. Sabril IS Investigator and Peer Review Groups.

PURPOSE: The efficacy and tolerability of vigabatrin (VGB) as an add-on therapy in the treatment of infantile spasm (IS) prompted physicians to explore its use as the first drug in this seizure type. METHODS: Our retrospective study included 250 infants diagnosed with IS; the data obtained were subjected to peer-group review. Of this infant population, 192 infants were considered to have classic IS and had received VGB as their first treatment for the spasms. There was a slight preponderance of boys (57%) in this population. Mean age of IS onset was 5.8 months; 60% had typical hypsarrhythmia. RESULTS: Initial suppression of spasms was obtained in 68% of infants with a median time to response of 4 days at an average VGB dose of 99 mg/kg/day. The best response was seen in those infants with tuberous sclerosis (96% response) and in those younger than 3 months at onset of spasms (90% response). Of these infants, 43 (22%) of 192 subsequently had other types of seizures, and a recurrence of infantile spasms occurred in 28 (21%) of 131 responders. At the end of this study, 96 of 192 infants who could be evaluated were seizure free with VGB monotherapy. Treatment appeared to be well tolerated, with only 33 (13%) infants with adverse events, of which the most common were somnolence (15 patients) and hyperkinesia (eight patients). In only two cases did adverse events require VGB withdrawal. CONCLUSION: This study supports the opinion that VGB may be considered an initial treatment for IS regardless of cause.

Age of Onset↗
PubMed1994

Vigabatrin.

The discovery of gamma-aminobutyric acid (GABA) as the first major inhibitory neurotransmitter and a program exploring the use of enzyme inhibition as a therapeutic tool provided the basis for the conception of vigabatrin (VGB, Sabril). This molecule, an analogue of GABA, has a highly specific activity as an enzyme-activated irreversible inhibitor of GABA-transaminase causing several-fold increases in the concentration of brain GABA. In animal models for epilepsy, it was found to have a rather different spectrum of activity than conventional antiepileptic drugs (AEDs). The clinical development of VGB was delayed by the finding of focal areas of reversible microvacuolation in the white matter of the brains of rodents and dogs. An extensive human safety program has confirmed that this finding is species specific and does not occur in humans. Clinically, VGB is well tolerated and has been shown to be specially effective in the management of partial seizures that have failed to respond to other AEDs. In most controlled studies, about 50% of patients with previously uncontrolled seizures have a 50% reduction in frequency and about 4-5% become seizure-free. In children, it also appears to be especially effective in the management of infantile spasms as well as in partial seizures. VGB offers a significant improvement in the management of epilepsy and is now under development as a first-line agent.

Animals↗
PubMed1992

Six-year follow-up study on the efficacy and safety of vigabatrin in patients with epilepsy.

Twenty-five patients with epilepsy (mostly with partial seizures) who had responded favourably to a short-term trial of add-on vigabatrin entered maintenance treatment. After 52 to 78 months, 15 patients continue to take the drug with good therapeutic response. Median monthly seizure frequency during the last 2 months on vigabatrin in all patients, including drop-outs, was 3.5 (range 0-74) as compared with 10 (range 3-98) during an initial placebo period (p < 0.01). Drop-outs were caused by adverse events in 2 cases (ataxia and psychotic symptoms respectively), seizure breakthrough in 4 cases and reasons unrelated to treatment in 4 patients. In most patients, side effects were absent or mild, the most frequent complaint being weight gain. It is concluded that the antiepileptic efficacy and good clinical tolerability of vigabatrin are generally maintained during long-term treatment for up to 6 years.

Adolescent↗
PubMed1991

Vigabatrin in drug-resistant partial epilepsy: a 5-year follow-up study.

We treated 75 patients with drug-resistant complex partial seizures and secondarily generalized seizures with vigabatrin as additional therapy for 6 months. Twenty-one patients either showed no benefit from vigabatrin treatment or had side effects. The remaining 54 patients entered into the long-term study. The median monthly seizure frequency decreased from 12.5 at baseline to 3.3 at the 3-month visit, and was 3.9 after 5 years of therapy in 28 patients who continued using the drug after the 5-year period. During 5 years of therapy with vigabatrin, 26 patients have withdrawn from the study because of various reasons: loss of efficacy (14), suspected side effects (5), noncompliance (3), administrative reasons (2), pregnancy (1), and epilepsy surgery (1). In all, 19 patients had a greater than 50% seizure frequency reduction at 5 years, representing 35% of the 54 patients who entered the long-term study, or 25% of the 75 patients who were initially recruited into the efficacy study.

Adolescent↗
PubMed1991

Vigabatrin.

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Aminocaproates↗
PubMed1991

Neuropathologic findings in patients receiving long-term vigabatrin therapy for chronic intractable epilepsy.

Vigabatrin is a new antiepileptic drug that acts by the irreversible inhibition of gamma-aminobutyric acid (GABA) aminotransferase. During animal safety testing, vigabatrin was found to cause reversible intramyelinic edema in the brains of rodents and dogs but not in primates. In humans, the drug is well tolerated, and extensive clinical, neurophysiologic, neurochemical, and psychometric testing has failed to demonstrate any evidence of neurotoxicity. Neuropathologic examination has now been carried out on 62 patients with refractory epilepsy, who were on vigabatrin therapy either prior to undergoing neurosurgery for their epilepsy or before death. A further ten similar cases have been included in the study from age-matched patients with refractory epilepsy who had not been treated with vigabatrin prior to surgery or death. None of the neuropathologic changes seen in the preclinical animals studies have been observed in the human cases. In no case was there considered to be any evidence of myelin microvacuolation or myelin sheath splitting that could be attributed to vigabatrin treatment. Demyelination has never been observed in either the animal or human material. These findings support the clinical tolerability seen in long-term treatment.

Adolescent↗
PubMed1989

The effect of different vigabatrin treatment regimens on CSF biochemistry and seizure control in epileptic patients.

1. Vigabatrin, 50 mg kg-1, was administered orally as add-on therapy to 11 patients with drug-resistant complex partial epilepsy as a single dose, then once every third day for 2 months, every other day for 2 months and daily for 1 month. 2. Lumbar punctures were carried out prior to treatment and at the end of each dosage regimen and cerebrospinal fluid (CSF) evaluated for concentrations of free and total GABA, homocarnosine (GABA-histidine dipeptide), homovanillic acid (HVA), 5-hydroxyindole acetic acid (5-HIAA) and vigabatrin. 3. Each regimen resulted in significant increases in CSF concentrations of free and total GABA and homocarnosine compared with the immediately preceding regimen. 4. CSF concentrations of HVA significantly increased after a single vigabatrin dose but returned to pre-treatment levels with subsequent dosing schedules. In contrast, 5-HIAA concentrations also increased with the single dose but were significantly decreased, compared with pre-treatment values, following alternate day and daily vigabatrin administration. 5. Seizure frequency progressively decreased with decreasing dosing interval. Daily vigabatrin administration was associated with greater than 50% decrease in seizures in 8 of the 10 patients treated.

Adult↗
PubMed1989

Meta-analysis of European placebo controlled studies of vigabatrin in drug resistant epilepsy.

1. A meta-analysis has been performed on nine placebo controlled trials of vigabatrin (GVG) administered as add-on therapy to patients suffering from drug resistant epilepsy. 2. There were two pilot placebo-controlled dose ranging studies, six double-blind crossover studies and a multicentre response controlled study. 3. There were a total of 398 patients entered and 390 have been evaluated for safety and 337 for efficacy. 4. In spite of the difficulties in the clinical evaluation of new antiepileptic drug, a reduction in seizure frequency was reported following the addition of vigabatrin to the concomitant medication in all studies. This was statistically significant in the larger of the two pilot studies, the multicentre study and three of the six double-blind studies. 5. There was a statistically significant reduction in seizures of in all six double-blind studies when the 98 patients suffering from complex partial seizures with or without generalisation were considered. Seventy two percent of these patients showed a greater than 25% reduction in seizure frequency. 6. Vigabatrin was well tolerated. The frequency of adverse events was similar to that reported elsewhere.

Aminocaproates↗
PubMed1989

Vigabatrin in the treatment of epilepsy: a long-term follow-up study.

Twenty-five adult epileptic patients who had shown a satisfactory clinical response to add-on vigabatrin under placebo-controlled conditions continued on long-term treatment for up to 47 months (median 22 months). The initially favourable therapeutic response was generally maintained throughout the observation period with an overall good clinical tolerance. No evidence of neurotoxicity was detected by multimodal evoked potentials monitoring.

Adult↗