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Biomedical subjects

R E Ramsay

Publications and source records attributed to R E Ramsay.

At least 19 recordsLinked to original sources
PubMed2005

New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine.

OBJECTIVE: To determine the relative tolerability and efficacy of two newer antiepileptic drugs, lamotrigine (LTG) and gabapentin (GBP), as compared to carbamazepine (CBZ) in older patients with epilepsy. METHODS: This was an 18-center, randomized, double-blind, double dummy, parallel study of 593 elderly subjects with newly diagnosed seizures. Patients were randomly assigned to one of three treatment groups: GBP 1,500 mg/day, LTG 150 mg/day, CBZ 600 mg/day. The primary outcome measure was retention in trial for 12 months. RESULTS: Mean age was 72 years. The most common etiology was cerebral infarction. Patients had multiple medical conditions and took an average of seven comedications. Mean plasma levels at 6 weeks were as follows: GBP 8.67 +/- 4.83 microg/mL, LTG 2.87 +/- 1.60 microg/mL, CBZ 6.79 +/- 2.92 microg/mL. They remained stable throughout the trial. Early terminations: LTG 44.2%, GBP 51%, CBZ 64.5% (p = 0.0002). Significant paired comparisons: LTG vs CBZ: p < 0.0001; GBP vs CBZ: p = 0.008. Terminations for adverse events: LTG 12.1%, GBP 21.6%, CBZ 31% (p = 0.001). Significant paired comparisons: LTG vs CBZ: p < 0.0001; LTG vs GBP: p = 0.015. There were no significant differences in seizure free rate at 12 months. CONCLUSIONS: The main limiting factor in patient retention was adverse drug reactions. Patients taking lamotrigine (LTG) or gabapentin (GBP) did better than those taking carbamazepine. Seizure control was similar among groups. LTG and GBP should be considered as initial therapy for older patients with newly diagnosed seizures.

Aged↗
PubMed2004

Rapid infusion with valproate sodium is well tolerated in patients with epilepsy.

Many IV antiepileptic drugs administered in emergency situations to patients with prolonged seizures have serious adverse effects. For this reason, the authors conducted a multicenter, open-label, prospective, dose-escalation study of IV valproate sodium administered to patients with epilepsy at rates of infusion of up to 6 mg/kg/minute and doses of up to 30 mg/kg. Valproate sodium had no clinically significant negative effects on blood pressure and pulse rate and caused only mild-to-moderate, reversible adverse events.

Acute Disease↗
PubMed2003

Safety and tolerance of rapidly infused Depacon. A randomized trial in subjects with epilepsy.

BACKGROUND: Valproate sodium injection (Depacon(R)) is an intravenous form of valproate for use in absence and complex partial seizures when circumstances preclude oral administration. Certain situations may warrant larger and more rapid infusions than permitted by the original labeling. This study evaluated the safety of more rapid infusions. METHODS: Subjects with epilepsy were randomized in a 2:1 ratio to receive up to 15 mg/kg of valproate sodium infused at 3.0 or 1.5 mg/kg/min. Up to four infusions were allowed within 24 h to achieve target plasma valproate concentrations of 50-100 mcg/ml. Primary safety endpoints were the changes in the 5-min and minimum post-first infusion blood pressures (BPs). RESULTS: One hundred twelve subjects were treated, (3.0 mg/kg/min group: n=72, 1.5 mg/kg/min group: n=40). No significant treatment differences were detected for changes in the primary BP endpoints. Two subjects in the 3.0 mg/kg/min group had potentially clinically significant low systolic BP values during the study. Similar proportions of subjects in the two groups reported adverse events during or within 6 h following the first infusion. CONCLUSIONS: Valproate sodium injection dosages up to 15 mg/kg and rates of 1.5 and 3.0 mg/kg/min were well tolerated in this population.

Adolescent↗
PubMed2001

Fosphenytoin: pharmacokinetics and tolerance of intramuscular loading doses.

PURPOSE: Fosphenytoin (FPHT; Cerebyx) is well absorbed when given intramuscularly (IM). All prior pharmacokinetic studies had the first plasma sample obtained 30 min after IM administration. The objectives of this study were to determine the rate and extent of FPHT absorption and to evaluate the tolerability of IM FPHT compared with IM saline. METHODS: This was an open-label, double-blinded study in which patients received 10 mg/kg dose of IM FPHT in one gluteus and IM saline in the other gluteus. Half the patients received saline injection of equal volume to FPHT (up to 19.5 mL); the other half received 2 mL of saline. Neurologic examination, vital signs, PHT blood samples, injection site examination, and subjective pain scores at injection site were obtained before and at timed intervals for 6 h. RESULTS: Total PHT serum concentrations 10 microg/mL were obtained in 5 min in 14.3% of patients and in 26.3% after 10 min. More than half the patients had therapeutic serum concentrations at 30 min; 45.8% of patients reported no pain at either the FPHT or saline injection site. No significant difference in pain was noted between FPHT and saline injection sites at 60 min and thereafter. Early decrease in blood pressure occurred but was not clinically significant. Classic PHT-induced central nervous system (CNS) side effects were evident in one third of patients within 1 h after injection. CONCLUSIONS: (a) IM FPHT is rapidly absorbed (therapeutic levels achieved as early as 5-20 min). (b) IM FPHT is well tolerated by most patients irrespective of injection volume.

Adolescent↗
PubMed2000

Increased seizures after discontinuing carbamazepine: results from the gabapentin monotherapy trial.

Studies in patients with epilepsy undergoing telemetry evaluation for surgery have suggested that discontinuation of carbamazepine (CBZ) is associated with increased seizures. The period of observation in that setting, however, was limited to a few days. The authors reviewed the occurrence of seizures in patients with epilepsy who had all their antiepileptic medications discontinued during an 8-week period, converted to gabapentin monotherapy, and observed for 26 weeks as part of the gabapentin trial #945-082. Two hundred and seventy-five patients were enrolled. Kaplan-Meier estimates of time to exit for all patients showed that 18% of patients previously treated with CBZ completed the study as compared with 30% of the patients receiving other antiepileptic medications. Increase in the frequency of seizures was maximal in the 2 weeks following CBZ discontinuation. Seizures increased both in frequency and severity but no new seizure types were observed. The findings in this study show that removal of CBZ is associated with increased frequency of seizures in patients with a previous history of epilepsy with incompletely controlled seizures. The period of maximal increase was the first 2 weeks after CBZ discontinuation.

Acetates↗
PubMed2000

Fosphenytoin and phenytoin in patients with status epilepticus: improved tolerability versus increased costs.

Tonic-clonic status epilepticus (TCSE) is the most common neurological emergency and affects approximately 60000 patients each year in the US. The risk of complications increases substantially as TCSE lasts longer than 60 minutes. Ideally, drugs used to treat this condition should be well tolerated when administered as rapid intravenous infusions and should not interfere with patients' state of consciousness or cardiovascular and respiratory functions. Because of its efficacy, absence of sedation or respiratory suppression, intravenous phenytoin has largely replaced phenobarbital (phenobarbitone) as the second agent of choice (following the administration of a benzodiazepine) in the treatment of TCSE. While the efficacy of phenytoin in the treatment of acute seizures and TCSE is well established, the parenteral formulation of phenytoin has several inherent shortcomings which compromise its tolerability and limit the rate of administration. Intravenous phenytoin has been associated with fatal haemodynamic complications and serious reactions at the injection site including skin necrosis and amputation of extremities. Fosphenytoin, a phenytoin prodrug, has the same pharmacological properties as phenytoin but none of the injection site and cardiac rhythm complications of intravenous infusions of phenytoin. While fosphenytoin costs more than intravenous phenytoin, treating the acute and chronic complications of TCSE itself, and the complications of intravenous phenytoin can also be costly. All other factors being equal, there is no doubt that fosphenytoin is better tolerated and can be delivered faster than intravenous phenytoin; 2 measures that clearly improve outcome in patients with TCSE. The tolerability of intramuscular fosphenytoin also extends its use to clinical situations where prompt administration of a nondepressing anticonvulsant is indicated but secure intravenous access and cardiac monitoring are not available, such as treatment of seizures by rescue squads in the field and serial seizures in the institutionalised, elderly and other patients with intractable epilepsy.

Anticonvulsants↗
PubMed2000

Epilepsy in the elderly.

The incidence of epilepsy is high in the elderly. Increasing awareness of this phenomenon has led to a better understanding of the predominant seizure types, their clinical manifestations, and the most appropriate treatment regimens. Carbamazepine, phenytoin, and valproic acid are considered to be first-line antiepileptic drugs (AEDs). However, the newer AEDs gabapentin, lamotrigine, and tiagabine also warrant consideration as first-line agents because of their efficacy and favorable side-effect profiles. This is particularly important because aging produces physical changes in the patient that can increase the likelihood of adverse effects. To select the appropriate drug and dosage for each individual, a variety of issues must be considered. These include age-related changes in body composition and physiology, as well as the pharmacokinetics, routes of administration, drug interactions, adverse-effect profiles, and cost of available agents.

Aged↗
PubMed1999

Skin eruption with gabapentin in a patient with repeated AED-induced Stevens-Johnson's syndrome.

Skin eruptions have been reported with the use of all antiepileptic drugs and there is a significant risk of cross-reactivity between these agents in causing serious eruptions such as Stevens-Johnson's syndrome. Gabepentin is usually considered a safe agent for patients with a previous history of drug allergies and there have been no cases of skin eruption reported to the gabapentin post marketing surveillance. We report a patient who had severe Stevens-Johnson's syndrome induced by phenytoin and later by carbamazepine. Subsequent use of gabapentin also resulted in a skin eruption which was limited to the lower extremities but without systemic or mucosal involvement. This case suggests that patients with a strong history of drug-induced idiosyncratic reactions may experience such reactions to gabapentin as well.

Acetates↗
PubMed1998

A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group.

BACKGROUND AND METHODS: Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. RESULTS: Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. CONCLUSIONS: As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.

Aged↗
PubMed1998

Surgical correction of scoliosis in patients with generalized seizures. Risk of vertebral body fracture.

STUDY DESIGN: A retrospective evaluation of the outcome of surgical management of progressive scoliosis in institutionalized patients with frequent, uncontrolled, generalized tonic clonic seizures. OBJECTIVES: To determine the safety and stability of internal fixation devices in patients with progressive scoliosis and intractable seizures. SUMMARY OF BACKGROUND DATA: Progressive scoliosis is a common problem in severely disabled patients. It has been the belief among some spine physicians that the coexistence of intractable seizures with progressive scoliosis is a contraindication for surgery, because most of the thoracic and lumbar spine is fixed and "unyielding" after internal fixations, increasing the risk of vertebral fractures. There have been reports of fracture of fixation devices, particularly Harrington rods, under conditions of massive trauma or mechanical stress, such as seizures. METHODS: The authors reviewed the outcome of six profoundly retarded institutionalized patients with a history of intractable seizures who underwent internal fixation of the spine between 1984 and 1987 because of progressive scoliosis. Seizure types and frequency of convulsion were obtained from the institutional charts. Follow-up radiographs of the spine obtained at 1, 3, and 6 months after the surgery and once a year thereafter were reviewed by the radiologist and orthopedic surgeon with special attention paid to fractures, stability of the fusion, and integrity of the instrumentation. RESULTS: Six patients underwent spinal fusion with internal spinal fixation, four patients with Harrington rods and two with Luque rods. All patients had refractory tonic clonic seizures ranging from 11 to 80 generalized tonic clonic convulsions per year for the 10-year follow-up period after surgery. There were no fractures, subluxation, or pseudoarthrosis of the fused vertebrae or the vertebral bodies adjacent to the fusion. There were no fractures of the instrumentation. CONCLUSIONS: The authors' findings suggest that when appropriate fusion is attained, the use of internal fixation devices is not contraindicated in the management of progressive scoliosis in patients with intractable seizures.

Adolescent↗
PubMed1998

Gabapentin bioavailability: effect of dose and frequency of administration in adult patients with epilepsy.

UNLABELLED: Gabapentin (GBP) is a non-metabolized antiepileptic drug that is eliminated by renal excretion and displays saturable, dose dependent absorption. The recommended dosing schedule for GBP is t.i.d. At large daily doses, oral bioavailability (F) may be improved by giving the daily dose more frequently. OBJECTIVE: To evaluate whether switching GBP dosage regimen from t.i.d. to q.i.d. results in increased oral bioavailability. METHODS: This study consisted of two parts; a computer simulated pharmacokinetic model and a clinical pharmacokinetic study in nine adult epileptic patients receiving 3600 mg/day and 11 receiving 4800 mg/day. All patients were evaluated during both t.i.d. and q.i.d. regimens. F were determined by calculation of percent of dose excreted unchanged using steady-state 24-h urine collections and were compared using a paired t-test. RESULTS: At 3600 mg/day, mean F following t.i.d. and q.i.d. dosing were 38.7+/-22.1% and 40.0+/-18.9%, respectively (P=0.738). At 4800 mg/day, mean F following t.i.d. and q.i.d. dosing were 29.2+/-16.2% and 35.6+/-17.6%, respectively (P=0.006). DISCUSSION: Good agreement was observed between values from this study and predicted values based on the pharmacokinetic model. Improved GBP F at doses of 3600 mg/day was not achieved with more frequent drug administration, and thus is not warranted. At 4800 mg/day, a 22% increase in F was observed with more frequent drug dosing. CONCLUSION: GBP F may be significantly increased by q.i.d. versus t.i.d. dosing, depending upon dose level. This increase in F however must be balanced against the inconvenience of more frequent dosing. Therapeutic drug level monitoring may aid in the evaluation of such pharmacokinetic maneuvers.

Acetates↗
PubMed1997

The mechanisms of the ocular autonomic dysfunction during the intracarotid amytal suppression test.

We report the eye findings during selective injections of amytal to the internal carotid artery and to trunk and branches of the middle cerebral artery in three patients. This report comes a propos of our previous observation that fairly dense visual obscuration (probably secondary retinal suppression by the amytal), pupillary dilatation (mydriasis) and impairment of visual accommodation (cycloplegia) are not uncommon during the intracarotid amytal suppression test (AST). Selective injections in these three cases offered additional-insight into the mechanisms of the autonomic dysfunction observed in the eye ipsilateral to injection of amytal (EII). Injection of amytal into the trunk and branches of the middle cerebral artery, above the origin of the ophthalmic artery, did not produce ocular autonomic changes in any of the three patients. Injection of amytal in the internal carotid, below the origin of the ophthalmic artery, resulted in pupillary dilatation in the EII in two of the three patients. Based on the anatomy of the vasculature and autonomic innervation of the eye, we postulate that the pupillary dilatation and deficit of visual accommodation observed after intracarotid amytal injection are secondary to parasympathetic suppression in the ciliary ganglion. Amytal reaches the ciliary ganglion via the posterior ciliary arteries, branches of the ophthalmic artery. In summary, injection of amytal in the internal carotid artery below the origin of the ophthalmic artery, but not above it, can impair visual acuity and in some cases, entirel suppress the vision in the EII secondary to retinal suppression. Dilatation of the pupil due to parasympathetic dysfunction is also common and is likely secondary to suppression of the ciliary ganglion in the orbit.

Amobarbital↗
PubMed1997

Pharmacokinetics and muscle histopathology of intramuscular valproate.

To determine the safety and pharmacokinetics of parenteral sodium valproate healthy mature greyhound dogs, were given intramuscular injections following intravenous injections. Dosings intravenously and intramuscularly were at 20, 40 and 60 mg/kg in the three groups. Intravenous infusion rates were constant. Sodium valproate solution concentrations of 300, 400 and 500 mg/ml were administered. Intramuscular valproate was quickly absorbed. Bio-availability approached 70%. Half life of 120 min was calculated. Toxic muscle necrosis was observed at all concentrations. Dosing valproate intramuscularly in humans is problematic in view of the muscle damage. Despite tissue damage sodium valproate was well absorbed intramuscularly. The intravenous injection of valproate at high concentrations, large doses and fast infusion rates produced no evidence of cardiotoxicity and levels of 180 micrograms/ml.

Animals↗
PubMed1997

Intramuscular fosphenytoin (Cerebyx) in patients requiring a loading dose of phenytoin.

Fosphenytoin (Cerebyx), is a water soluble prodrug that is rapidly and completely converted to phenytoin. This study reports the injection-site tolerance and safety of intramuscular fosphenytoin (> 10 mg/kg doses) in 60 patients requiring a phenytoin loading dose. Patients received injections at single or multiple sites with volumes ranging from 4 to 30 ml per injection site. The majority of patients had no irritation (erythema, swelling, tenderness, bruising) or complaints of discomfort related to fosphenytoin injection either after injection (95%) or at follow-up (88%). Irritation, when reported, was mild in all cases. Forty of 60 patients (67%) reported transient side effects, primarily involving the central nervous system, such as nystagmus, dizziness or ataxia, which are commonly associated with phenytoin therapy. All patients received prescribed doses; no patient had an injection(s) stopped due to intolerance or side effects. No serious adverse events occurred with intramuscular fosphenytoin. In this study, intramuscular fosphenytoin was demonstrated to be a safe and well tolerated, and in many instances, a preferable alternative to other means of phenytoin loading.

Adolescent↗
PubMed1997

Status epilepticus associated with the combination of valproic acid and clomipramine.

An epileptic patient well controlled on valproic acid (VPA) developed a prolonged episode of status epilepticus 12 days after initiation of 75 mg of clomipramine (CMI) to treat depression. Serum level of VPA in the emergency room was unchanged from her previous levels; serum level of CMI was very elevated despite the relatively small dose of CMI. A pharmacokinetic interaction between VPA, an enzyme inhibitor, and CMI has not been described but seemed to have occurred in this patient. Decreased metabolism of CMI and its metabolites, increased free CMI fraction, and precipitation of a nonlinear saturation kinetic state has been described when CMI was used concomitantly with other highly protein-bound, enzyme-inhibiting compounds. This case provides reasonable evidence that the combination of VPA and CMI may result in elevation of levels of CMI and possibly of its metabolites and may precipitate seizures in patients with an underlying predisposition. The elevated serum level of CMI at the time of the seizures, despite the relatively small oral dose of the drug, suggests that VPA may have inhibited its metabolism and/or elimination.

Adult↗
PubMed1997

Changes in body weight with chronic, high-dose gabapentin therapy.

The authors reviewed changes in body weight in 44 patients treated with Gabapentin (GPN) for a period of 12 or more months. All patients had a seizure disorder and the dose of GPN was increased aiming at complete seizure control or until side effects limited further increase. Twenty-eight patients were receiving GPN dosages of > 3000 mg/day. Observed changes in body weight were as follows 10 patients gained more than 10% of their baseline weight, 15 patients gained 5% to 10% of baseline, 16 patients had no change, and 3 patients lost 5% to 10% of their initial weight. Weight increase started between the second and the third months of GPN treatment in most patients and tended to stabilize after 6 to 9 months of treatment, although the doses of GPN remained unchanged. Weight gain occurred in patients taking GPN in combination with each of the major antiepileptic drugs including Felbatol and also occurred with GPN monotherapy.

Acetates↗
PubMed1997

Gabapentin monotherapy: II. A 26-week, double-blind, dose-controlled, multicenter study of conversion from polytherapy in outpatients with refractory complex partial or secondarily generalized seizures. The US Gabapentin Study Group 82/83.

This study evaluated gabapentin monotherapy in 275 patients with medically refractory complex partial or secondarily generalized seizures who were taking one or two antiepileptic drugs (AEDs). Following an 8-week baseline, patients received randomized dosages of gabapentin (600, 1,200, or 2,400 mg/d) during a 26-week double-blind phase comprising 2 weeks gabapentin add-on therapy, an 8-week AED taper, and a 16-week gabapentin monotherapy period. Patients exited the study if they experienced a protocol-defined exit event. Results of outcome measures, including time to exit, completion rate, and mean time on monotherapy, showed no significant differences among dosage groups. Possible reasons for this lack of a dose-response relationship include withdrawal seizures and the limited range of gabapentin dosages studied. Overall, 20% of patients completed the study. Completion rates were higher among patients who had discontinued one AED (23%) than two AEDs (14%), and higher among patients who were not withdrawn from carbamazepine (27%) than among those who were (16%).

Acetates↗