Prostate resection, an operation in which part of the prostate is removed, has been the standard therapy for benign prostate hyperplasia for decades. In recent years, treatments based on removing prostate tissue using heat have been developed. These include microwave therapy, ultrasound, and needle ablation.

A recent study in the” Journal of Urology” compared the success of prostate resection and transurethral needle ablation in 121 men with benign prostate hyperplasia. The men were randomly assigned to receive one of the procedures, and their progress was followed for six months. In addition to several measures of symptoms, the researchers evaluated objective measures of free urinary flow and pressure flow. The study took place at seven centers around the United States.

Measured after treatment and again six months later, both procedures produced significant improvements in symptoms, quality-of-life, and free urine and pressure flow. Resection, however, produced significantly more improvement in urine flow than ablation. There were no other differences between the two groups at six months after treatment.

The researchers also wanted to know if objective measures of urinary flow can predict how well patients will respond to treatment. These measures, however, did not predict response either right after treatment or at the six-month follow-up. The researchers concluded that these tests do not help doctors decide which treatment is best for each individual patient.

Even though there was no difference in how much patient symptoms improved, resection did decrease urinary obstruction more than ablation. On the other hand, the degree of obstruction did not predict how well patients would respond to treatment. The researchers concluded that more research is needed in this area before conclusions about the “best” treatment can be made.

Answer. My experience with valproate [Depakote] has been in adults, in which population it is very well-tolerated and rarely the cause of any significant cognitive problems; it can sometimes cause drowsiness, but this is usually mild and dose-related. You may be interested in a Swiss study by Despland [ref: Schweiz Rundsch Med Prax Oct 1994] that reviewed the literature on valproate use in epilepsy from 1976 to 1994 (the drug has been used in Switzerland since 1967). This author found valproate “to be a remarkably safe and effective antiepileptic drug…in children and adults.”

It is associated with fewer neurologic side effects than other major antiepileptic drugs, and “…had minimal impact on cognitive function and was associated with fewer cognitive and behavioral problems than phenytoin [Dilantin] and phenobarbital.”

Side effects of valproate can include weight gain, mild GI effects, tremor, and hair loss, but these may respond to dosage adjustment or other measures. Keep in mind, also, that seizures themselves often leave childen feeling helpless, scared, and “different” from other kids, so that the valproate may, indeed, be an important ally in your daughter’s quality of life. I would suggest, in any case, that you discuss the question of long-term effects on learning and creativity with your daughter’s physician.

The compensatory respiratory response to hypoxemia involves an increase in minute ventilation, which may lead to respiratory alkalosis. The hypoxic condition can increase capillary permeability and leakage of fluid into the surrounding interstitium, leading to the more severe disorders of high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). These conditions are more serious, require emergency medical attention, and are beyond the scope of this review.

Pathophysiology

Acute mountain sickness is the most common of the high altitude pathologies. It manifests as influenza-like symptoms, including headache, malaise, and anorexia. It usually becomes clinically apparent 6 to 48 hours after rapid ascent to high altitudes (>8,000 feet). This syndrome occurs in about 25% of people at 8,000 feet but increases in incidence as the elevation increases. The most effective prevention is slow ascent or a 2- to 4-day acclimatization at intermediate altitudes (6,000 to 8,000 feet) followed by gradual ascent. Worsening of symptoms warrants descent to at least 1,650 feet lower than the altitude at which symptoms began. It should be noted that despite the importance of keeping physically fit, training (at lower levels) will not facilitate the adaptive process, nor will it minimize one’s chances of getting AMS.

Pharmacologic Approaches

It is important for pharmacists to be able to counsel and educate prospective recreationists regarding drugs that should be avoided or ones that may precipitate AMS. These include CNS depressants and drugs that may decrease ventilation and worsen hypoxia (e.g., ethanol, benzodiazepines).

Acetazolamide (Diamox and others) can be used in the treatment or prevention of acute mountain sickness. A carbonic anhydrase inhibitor, acetazolamide decreases both the incidence and the severity of AMS by causing a sodium and bicarbonate diuresis, preventing fluid retention, decreasing alkalosis, and causing a metabolic acidosis. The acidosis stimulates ventilation, decreasing hypoxemia during sleep. The effective treatment dose is 125 to 250 mg every 12 hours beginning within 24 hours of symptom onset and continuing with descent. Total doses up to 1.5 grams have been used. The drug can cause transient myopia and tingling of the fingers, toes, and lips, but it is generally well tolerated. Because of the diuretic effect and the problem associated with dehydration mentioned above, it is imperative that an acute awareness of fluid intake and balance be maintained. Acetazolamide also belongs to the sulfonamide drug class; thus, skin eruptions and photosensitivity should be a component of the counseling. An allergy to sulfa precludes its use.

Some medical wilderness experts also advocate dexamethasone (4 to 8 mg loading dose, followed by 4 mg every six hours orally or intramuscularly) by itself or in addition to acetazolamide. Treatment trials with dexamethasone have demonstrated marked improvement within 12 hours. Descent is usually required if dexamethasone is used. Discontinuation of the drug without descent usually leads to recurrence of symptoms.

Furosemide has been shown to be useful in the treatment of HAPE, but extensive evaluations in treating acute mountain sickness are lacking. If peripheral edema is prominent, diuretics (e.g., furosemide, thiazides) can be successfully used, as well as nonpharmacological treatment (i.e., salt restriction). Spontaneous diuresis usually occurs after descent to lower altitudes. The use of diuretics warrants that attention be paid to hydration status.

Adjunctive agents include analgesics such as ibuprofen, which was shown to be superior to placebo in reducing high altitude headache severity and speed of relief in one randomized controlled crossover trial of military personnel. Researchers theorized that a prostaglandin-induced increase in cerebral microvascular permeability may be a component of the pathology of AMS; thus, prostaglandin inhibitors may be of benefit. Acetaminophen is also recommended by some experts for mild headaches; however, the 5HT1D agonist sumatriptan was shown to be inferior to ibuprofen in a controlled trial and is not recommended at this point. Phenothiazines such as prochlorperazine (5 to 10 mg IM or orally) or promethazine (50 mg orally or rectally) may be beneficial for nausea and vomiting.

The prevention of acute mountain sickness should include a graded ascent that pivots around avoiding rapid ascent to sleeping altitudes above 8,000 feet and spending 2 to 3 days at 8,000 to 9,000 feet before going higher. Several agents have been studied to prevent AMS. Acetazolamide, 125 mg to 250 mg orally twice daily, starting 24 hours prior to ascent, has been shown to be effective in preventing acute mountain sickness. One study demonstrated that 500 mg of acetazolamide in sustained-release formulation taken once daily was as effective as 250 mg of immediate-release acetazolamide taken twice daily, but had fewer side effects. It is recommended that acetazolamide be continued for 2 to 5 days at high altitude while one acclimates. Taken prophylactically, acetazolamide has been shown to decrease the frequency of AMS by about 30% to 50%.

Dexamethasone has been evaluated in varied randomized trials and has demonstrated similar efficacy to acetazolamide in reducing the incidence of acute mountain sickness. Zell, et al. studied the combination of dexamethasone acetate (4 mg orally four times daily) and acetazolamide (250 mg twice daily), finding the combination to be significantly superior to either agent alone. Rock, et al. found that dexamethasone in a dosage as low as 4 mg every 12 hours was effective in reducing AMS symptoms. Johnson and Rock also suggest a preventative dose of dexamethasone 2 to 4 mg orally every 6 hours starting the day of ascent and continuing for 3 days at the higher altitude, then tapering the regimen off over 5 days. Some experts recommend reserving dexamethasone only for treatment of acute mountain sickness or for prophylaxis in people who are intolerant or allergic to acetazolamide.

The literature reveals few data in regard to spironolactone (25 mg four times daily) use in AMS, suggesting it may have efficacy comparable to acetazolamide in preventing the symptoms of acute mountain sickness. This has not been confirmed with large randomized trials; thus, no recommendations can be forwarded.

Nifedipine, a calcium channel blocker, has also been studied, albeit less frequently. In the only randomized trial for prophylaxis of AMS, nifedipine was effective in reducing pulmonary arterial pressures, but not in oxygen exchange or the manifestations of acute mountain sickness. Most experts suggest it may be of use in HAPE (high altitude pulmonary edema), but do not recommend it for prevention of AMS.

The Johns Hopkins team sent questionnaires to 1,000 neurologists and 1,000 obstetricians; the response rate was 15.5%. Although 91% of the neurologists and 75% of the obstetricians reported that they treat epileptic women of childbearing age, only 4% of the neurologists and none of the obstetricians knew which of the six most commonly used antiepileptic drugs induce the more rapid metabolism of oral contraceptive, and which do not. Yet, 27% of the neurologists and 21% of the obstetricians reported that OC failures occurred in their patients during AED therapy. In addition, almost half of neurologists and one fourth of obstetricians underestimated the risks of birth defects for women taking antiepileptic drugs.

Certain AEDs-phenytoin, phenobarbital, carbamazepine, oxcarbazepine, primidone, and ethosuximide-induce the cytochrome P450 enzymes that metabolize synthetic estrogens (e.g., ethinyl estradiol and mestranol), causing a 40% reduction in serum levels. In addition, free progestin levels are decreased as a result of increased synthesis of hormone- binding globulins. The antiepileptic drugs valproic acid, gabapentin, vigabatrin, lamotrigine, topiramate, and tiagabine do not appear to induce hepatic P450 enzymes and are unlikely to interfere with oral contraceptives. The effect of felbamate on oral contraceptives is still under investigation.

The recommendation for women on antiepileptic drugs is to increase the oral contraceptive dose to 50 mcg estradiol, particularly if breakthrough bleeding occurs. However, according to Krauss et al, pregnancy may occur even at the highest dose level, sometimes with no warning of irregular bleeding. Because high doses increase the risk of thromboembolism (particularly in smokers and women over age 35), other forms of contraception should be considered as an alternative to oral contraceptives. An effective choice is the depot form of medroxyprogesterone (Depo-Provera), a potent contraceptive that has not been associated with failures due toantiepileptic drugs . By contrast, the levonorgestrol implant (Norplant) is not an effective alternative, according to Krauss et al. More than 30 unplanned pregnancies have occurred in women on AEDs who used Norplant.

“Our survey suggests that a large number of women in the United States with epilepsy are at risk for unplanned pregnancies while taking oral contraceptives,” said the Johns Hopkins investigators. Women with epilepsy should discuss reproductive issues with both a neurologist (who may be more familiar with the effects of antiepileptic drugs on oral contraceptives) and an obstetrician (who may be more familiar with the risks of birth defects).

In five placebo-controlled, double-blind clinical trials, topiramate significantly reduced the frequency of epileptic seizures, including refractory partial seizures. In dosage studies- topiramate given at 200, 400, 600, 800, and 1,000 mg per day-the 200-mg dose gave inconsistent results, and increasing the dose beyond 400 mg per day did not increase efficacy. One trial included 45 patients who received 400 mg/day; 44% responded with at least a 50% reduction in seizure frequency, compared with baseline. In a second trial, 35% of 23 patients who received the 400-mg/day dose showed a 50% reduction in seizure rate. By comparison, 24% of patients receiving the 200-mg/day dose showed a seizure reduction rate of about 27%, and approximately 36 to 46% of patients responded to 600, 800, and 1,000 mg/day with a 36 to 46% reduction in seizure rates (response generally decreased as the dosage was increased). Placebo patients showed little or no response, and often showed increases in seizure frequency. Based on overall clinical results, topiramate appears to be a more potent anticonvulsant than Warner Lambert’s gabapentin (with response rates of 22-26%) and GlaxoWellcome’s lamotrigine (seizure reduction, 25-36%).

Topiramate is given 50 mg/day initially, with a gradual increase during an 8-week titration period to a total of 400 mg/day in two divided doses. Oral bioavailability is about 80%, and food has no clinically significant effect on absorption. At dosages of 200 to 800 mg, serum concentrations are linearly dose related and there is not much intersubject variability. Plasma protein binding is less than 20%. Single-dose studies in healthy adults have revealed that the drug is about 20% metabolized, but with multiple dosing in patients taking other antiepileptic drugs, up to 50% of the dose is metabolized. Elimination is primarily renal, with 50 to 80% of the dose excreted as unchanged topiramate; elimination half-life is 20 to 30 hours. Age, gender, race, baseline seizure rate, and concomitant antiepileptic drugs do not appear to affect efficacy, although topiramate may interact with phenytoin (Dilantin/Warner Lambert) and carbamazepine (Tegretol/Novartis). Addition of topiramate to a regimen that includes phenytoin may require adjustment of the phenytoin dose; addition or withdrawal of phenytoin and/or carbamazepine to the topiramate regimen may require adjustment of the dose of topiramate.

At the 200- to 400-mg dose range, the most frequent adverse effects in clinical trials were psychomotor slowing (incidence about 17%), difficulty concentrating (8%), speech and language problems (about 6%), somnolence (30%), and fatigue (11-12%). These reactions were generally dose related. Similar side effects (although less frequent) were seen with lamotrigine and gabapentin. During clinical studies, 1.5% of topiramate-treated patients developed kidney stones, which represents a two- to fourfold increase over the normal rate of stone formation. This may be due to carbonic anhydrase inhibition, and is managed by increasing fluid intake. Another side effect thought to be related to carbonic anhydrase inhibition is paresthesia. Use of topiramate with other carbonic anhydrase inhibitors should be avoided. Approximately 11% of patients withdrew from clinical trials because of adverse events, primarily central nervous system (CNS) effects, paresthesias, and, at higher dosages, anorexia and weight loss.

Although topiramate has been approved only for adults, Johnson & Johnson is studying the drug in pediatric patients with epileptic disorders, including generalized seizures and Lennox-Gastaut syndrome.

In their review of the emergency treatment of status epilepticus, Runge and Allen divided the clinical presentation of status epilepticus into four groups: (1) prolonged seizures; (2) repeated generalized convulsive seizures with no interictal recovery; (3) nonconvulsive seizures that produce a continuous or fluctuating alteration in consciousness; and (4) repeated partial seizures manifested as focal motor convulsion or neurologic deficit without altered consciousness. Generalized tonic-clonic status epilepticus is the most dramatic and thus commands the most attention, according to Runge and Allen. However, all types of status epilepticus are neurologic emergencies that require immediate intervention to prevent brain damage. Whereas the level of mortality is usually determined by the underlying cause of the seizure, morbidity increases with the duration of the episode.

The mainstay of therapy for status epilepticus is the parenteral administration of an antiepileptic drug (AED), preferably by the intravenous (IV) route, although intramuscular (IM) injection may be necessary if prompt venous access is not available. The FDA has approved about two dozen antiepileptic drugs, but only four are commonly used parenterally: phenytoin, phenobarbital, diazepam, and lorazepam. Pentobarbital, thiopental, and midazolam are also used parenterally, although usually for refractory or end-stage status epilepticus. Lidocaine and propofol are also used, and valproic acid can be administered rectally or via nasogastric tube for absence seizures (a parenteral formulation is under investigation). None of these agents is without problems. For one thing, adverse CNS side effects are not uncommon. For another, these drugs require alkalinization and/or propylene glycol for solubilization; thus both IV and IM administration are highly irritating.

First-line therapy for status epilepticus involves the intravenous administration of a benzodiazepine- diazepam or lorazepam-which controls seizures in 79% of patients. For patients who do not respond to the initial dose, a second dose is given, although repeated doses do cause respiratory and CNS depression. Phenytoin is considered a second-line drug; it has a prolonged infusion time and a slow onset of action, causes painful local reactions, and carries the risks of extravasation and tissue necrosis. Phenytoin is not water soluble, and so is formulated with 40% propylene glycol and 10% ethanol in water for injection, adjusted to pH 12. The alkaline pH is highly irritating and can seriously damage tissue, and the propylene glycol is associated with hypotension and probably with cardiac arrhythmias that may accompany the intravenous administration of phenytoin. Phenytoin cannot even be used intramuscular because of poor absorption, crystallization, and tissue destruction.

Recently, the FDA approved two new products for refractory seizures and/or status epilepticus: fosphenytoin (Cerebyx/Warner Lambert) and diazepam rectal gel (Diastat/Athena). Diazepam gel was approved for rectal administration in the management of selected, refractory, epileptic patients on stable antiepileptic drug regimens who require intermittent use of diazepam to control bouts of increased seizure activity. Parenteral fosphenytoin was approved for the control of generalized convulsive status epilepticus, for the prevention and treatment of seizures occurring during neurosurgery, and as short-term substitution for oral phenytoin.

Fosphenytoin is a phosphate ester of phenytoin that has been classified “1S” (new molecular entity) by the FDA. It is freely soluble in aqueous solutions, including standard intravenous solutions. After administration, fosphenytoin is rapidly converted (within 8-15 minutes) to phenytoin by phosphatases found in a number of tissues. Unlike phenytoin, fosphenytoin can be given rapidly IV and promptly achieves therapeutic levels. It is rapidly absorbed when given intramuscular, and is well tolerated. The drug is 100% bioavailable, and it is bioequivalent to phenytoin (10 mL fosphenytoin is equivalent to 5 mg intravenous phenytoin). Side effects are minor and transient. Unlike benzodiazepines and barbiturates, fosphenytoin does not cause respiratory or CNS depression; thus patients can breathe well enough to compensate for metabolic acidosis, and think well enough after recovery to cooperate with diagnostic evaluation.

In a study of 40 patients in status epilepticus who received fosphenytoin at a mean infusion rate of 92 mg/minute, seizures were terminated in 37 patients (85%) within 30 minutes of administration. Side effects included dizziness, nystagmus, and ataxia. In a comparative study of 90 patients given intravenous fosphenytoin and 22 given intravenous phenytoin, disruption of infusion occurred in 21% of IV fosphenytoin patients (primarily due to systemic burning, pruritus, and/or paresthesia) compared with 67% of IV phenytoin patients (primarily due to pain and burning at the infusion site). Paresthesia and pruritus were more common in fosphenytoin than phenytoin patients (paresthesias: 4.4% and 0%, respectively; pruritus: 49% and 4.5%, respectively). Pediatric studies have shown that fosphenytoin has the same efficacy, safety, tolerability, and pharmacokinetics in children aged 5 to 18 years as in adults (up to age 40).

Answer. There are now four main anticonvulsant (anti-epileptic) agents that are either established or being actively investigated as mood stabilizers: valproate (Depakote), carbamazepine (Tegretol), gabapentin (Neurontin) and lamotrigine (Lamictal). Another anticonvulsant, Topiramate (Topamax), is being investigated for this purpose.

Your question involves the conjunction of three factors: a double-blind condition, use of an anticonvulsant and rapid-cycling bipolar patients (i.e., those with four or more major mood swings per year). While I can’t give you a definitive answer as to the number of such studies, my review of the literature suggests that there are fewer than five that meet all three of your criteria. I refer you to papers by Denicoff et al (Journal of Clinical Psychiatry, 1997) and Bowden et al (Journal of the American Medical Association, March 23-30, 1994) for details.

In a recent review of lamotrigine and gabapentin, Dr. Nassir Ghaemi of Massachusetts General Hospital found only a small number of double-blind studies with these agents (International Drug Therapy Newsletter, April and May 1999). In many of the recent studies of lamotrigine and gabapentin, these agents have been used as adjuncts for most patients, rather than as the sole treatment, meaning that judgments about their efficacy must be put in this limited context.

For example, in three non-double blind studies, lamotrigine appeared useful in between 50-75% of rapidly cycling patients, but most of these patients were taking other mood stabilizers or medications. Regarding bipolar patients with concomitant “anxiety,” it is, of course, difficult to distinguish anxiety from agitation in manic patients. In either case, benzodiazepines such as lorazepam or clonazepam are frequently used.

Atypical antipsychotics like olanzapine are also finding a role as adjunctive agents in bipolar illness. Gabapentin appears to have anti-anxiety properties even in patients who are not bipolar, and thus would be a reasonable “add-on” for anxious bipolar patients.

The most frequently prescribed antiepileptic drugs are phenytoin, carbamazepine, and valproate, although in the past few years a number of new antiepileptic drugs have been approved. These new drugs were developed following major advances in the understanding of neurotransmitters and their receptors, and most enhance the activity of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain. Some also inhibit glutamate, the major excitatory neurotransmitter. Blocking glutamate has not been very successful, but augmenting GABA activity has been quite effective.

Gamma-aminobutyric acid is present in an estimated 60 to 70% of all synapses in the brain. It is formed from glutamate by the enzyme glutamic acid decarboxylase. After synaptic release, GABA is taken up into nerve cells or glial cells. In the neuron, gamma-aminobutyric acid either is re-released or is broken down by GABA transaminase into succinic semialdehyde; in the glial cell, it is metabolized, along with glutamate, by glutamine synthetase to form the amino acid glutamine, which is then transported back to the neuron and used to synthesize more glutamate and gamma-aminobutyric acid. When released into the synapse, GABA can bind to two different receptor complexes, designated A and B. GABA-A binds gamma-aminobutyric acid, benzodiazepines, barbiturates, and neurosteroids. When GABA-A is activated, it increases the inward flow of chloride through the nerve cell membrane, which hyperpolarizes the membrane and inhibits neuronal firing. Compounds that increase GABAergic activity via the GABA-A receptor are anticonvulsants, and those that antagonize GABA-A are convulsants.

Neuropharmacologists have discovered several ways to enhance GABA-A receptor activity: direct stimulation, inhibition of gamma-aminobutyric acid metabolism, and reduction of neuronal and/or glial GABA reuptake. Blocking gamma-aminobutyric acid reuptake is an especially fruitful area for drug discovery, because there are at least four different GABA transport mechanisms that mediate gamma-aminobutyric acid reuptake in neurons and glial cells. These transporters show different distributions within the central nervous system (CNS); for example, one is prominent in the substantia nigra, an area that plays a crucial role in the development of seizures.

Antiepileptic Drugs and Their Primary Mechanisms of Action

One of the most promising gamma-aminobutyric acid (GABA) reuptake inhibitors is tiagabine (Gabitril/Abbott), a novel antiepileptic drug that will probably receive final FDA approval during the first quarter of this year. Developed by researchers at the Danish pharmaceutical company NovoNordisk, tiagabine is a nipecotic acid derivative with an attached lipophilic group that enables the drug to cross the blood-brain barrier. This “rationally” designed drug is a potent, selective, and specific inhibitor of GABA reuptake into presynaptic neurons and glial cells, particularly those in the substantia nigra and associated areas. It binds one of the GABA reuptake transporters and shows no significant affinity for dopamine, norepinephrine, histamine, adenosine, serotonin, glutamate, or acetylcholine sites-either receptors or reuptake transporters.

Tiagabine has shown broad activity against a range of seizure types, including drug- induced, electroshock-induced, light-induced, amygdala-kindled, and audiogenic. It is well tolerated and does not cause withdrawal effects, displace other drugs, or induce hepatic enzymes (although it is a target for enzyme inducers). It is rapidly and completely absorbed, with a half-life of 5 to 8 hours. Because tiagabine is highly effective for partial- onset seizures, it will be approved initially for the adjunctive treatment of partial seizures, with or without secondarily generalized seizures.

Other new antiepileptic drugs on the market or under investigation include valproate (Divalproex/Abbott), topiramate (Topamax/Ortho-McNeil), gabapentin (Neurontin/Warner Lambert), lamotrigine (Lamictal/Glaxo Wellcome), vigabatrin, oxcarbazepine, and levetiracetam. Valproic acid decreases the activity of the enzyme that degrades gamma-aminobutyric acid and increases the activity of the enzyme that generates GABA; topiramate enhances gamma-aminobutyric acid and inhibits glutamate; and gabapentin, which is structurally related to GABA, has a unique (and as yet poorly understood) influence on gamma-aminobutyric acid neurotransmission. Vigabatrin acts through the selective, irreversible inhibition of GABA transaminase, the enzyme responsible for the metabolism of gamma-aminobutyric acid. Oxcarbazepine was developed by modifying the chemical formula of carbamazepine to improve tolerability; it is at least as effective as its parent, but is better tolerated, has fewer drug interaction problems, induces fewer enzymes, and causes less skin allergy. Levetiracetam is an interesting new compound in clinical trial that appears to bind a specific receptor on nerve cell membranes. It shows a broad spectrum of anticonvulsant activity and has been particularly effective for partial seizures. It has a high therapeutic index and does not appear to interact with other antiepileptic drugs.

Lamotrigine is the first antiepileptic drug that was designed specifically to inhibit glutamate and its close cousin, aspartate. It blocks sodium channels and stabilizes the presynaptic neuronal membrane, inhibiting the release of glutamate and aspartate. It has a wide spectrum of antiepileptic activity, including partial-onset and primary generalized tonic-clonic seizures, and is particularly useful for mentally retarded patients. It is very well tolerated and does not alter concentrations of concomitant antiepileptic drugs or induce hepatic enzymes although it is a target for enzyme induction. It interacts with both valproic acid (which approximately doubles the plasma elimination half-life of lamotrigine) and carbamazepine (concomitant lamotrigine/carbamazepine therapy can cause a potentially dangerous cerebellar toxic syndrome).

The understanding of epilepsy has advanced substantially in the past decade, and new antiepileptic drugs with novel mechanisms of action are continually being developed. Monotherapy is the goal-that is, the admInistration of one drug with a mechanism of action specific for the form of epilepsy being treated-but in clinical practice, polytherapy is often used. Using multiple drugs increases the risis of adverse effects and drug interactions, but the new GABAergics have such good safety profiles that “rational polytherapy” is a workable solution to what is often a very complex neurologic problem.

Trileptal: Introduction

More than 2 million people in the US have some form of epilepsy. Seventy percent of them are adults. Although contemporary treatment approaches can provide full or partial control of seizures in about 85% of patients, some 15% of patients do not achieve this control, and many patients are virtually resistant to available drug therapies. Some patients with partial onset seizures – those that originate in one hemisphere of the brain, often without loss of consciousness – resort to surgery to remove the affected area of the brain, ideally without affecting personality or function.

Novartis Pharmaceuticals Corporation recently received FDA approval to market Trileptal (oxcarbazepine), a new drug for both adults and children with partial seizures. The recommended daily doses range from 1200 mg/day as adjunctive therapy and 2400 mg/day as monotherapy in adults (given as two daily doses), and 30-46 mg/kg/day as adjunctive therapy for children ages 4-16.

Trileptal: How It Works

The activity of Trileptal is primarily exerted through its metabolite, monohydroxy metabolite (MHD). The precise mechanism by which Trileptal and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the brain.

Trileptal: Clinical Study Results

The efficacy of Trileptal in adults and children was established in six multicenter randomized double-blind controlled trials. Four of these studies demonstrated Trileptal’s effectiveness as monotherapy. One trial was conducted in 102 adult patients with refractory partial seizures who had been withdrawn from other antiepileptic drugs (AEDs) and received either placebo or Trileptal. Trileptal was given as 1500 mg/day on day 1 and 2400 mg/day thereafter for an additional 9 days. During the 10-day study period, patients who took Trileptal experienced significantly fewer partial seizures than those on placebo.

Similar results in favor of Trileptal were observed in a study of 67 untreated patients with newly diagnosed and recent-onset partial seizures who began treatment with either placebo or 300 mg Trileptal twice daily. Trileptal was titrated to 1200 mg/day (600 mg twice daily) in 6 days, followed by maintenance treatment for 84 days.

A third study substituted Trileptal monotherapy 2400 mg/day for carbamazepine in 143 patients whose seizures were inadequately controlled by carbamazepine at a stable dose of 800 to 1600 mg/day. The Trileptal dose was maintained for 56 days. Patients who were able to tolerate 2400 mg/day of Trileptal during carbamazepine withdrawal were randomized to receive either 300 mg/day or stay on the 2400 mg/day dose. After an observation period of 126 days, patients who received 2400 mg/day of Trileptal experienced significantly fewer seizures than those on the 300 mg/day dose.

Similar results in favor of the 2400 mg/day dose of Trileptal were observed in a fourth monotherapy trial conducted in 87 patients whose seizures were inadequately controlled on 1 or 2 AEDs. Patients were randomized to receive either 2400 mg/day or 300 mg/day Trileptal while eliminating their standard AED regimen over a 6-week period. Seizure frequency was evaluated over an additional 84 days.

Two studies assessed the efficacy of Trileptal as adjunctive therapy for partial seizures in 692 adults and 264 children (3-17 years of age). In both trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients were randomized to receive either placebo or a specific dose of Trileptal in addition to their other AEDs. Adults were followed for 24 weeks while children were observed for 14 weeks. The adults received fixed Trileptal doses of 600, 1200, or 2400 mg/day, while the children received 30-46 mg/kg/day. Trileptal significantly reduced seizure frequency at all doses tested. In the group of adults receiving 2400 mg/day Trileptal, however, more than 65% of the adults discontinued treatment because of adverse events.

Trileptal: What the Patient Should Know

Trileptal may render hormonal contraceptives less effective, so other non-hormonal forms of contraception are recommended in women taking Trileptal (particularly since Trileptal may have the potential to result in birth defects). Caution should be exercised if alcohol is consumed by patients who are taking Trileptal, since an additive sedative effect may result. Trileptal may also result in dizziness or drowsiness, so patients should avoid driving or operating machinery until they have adequately gauged the effects of Trileptal on their ability to perform these tasks.

The most common adverse reactions reported with Trileptal include dizziness, drowsiness, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, abdominal pain, tremor, dyspepsia, and abnormal gait. Hyponatremia may develop during Trileptal use. Patients with a known sensitivity to carbamazepine should be aware that 25-30% of them may experience hypersensitivity to Trileptal, and if so, should immediately discontinue using Trileptal. Patients should inform their physicians of other medications they may be taking, since Trileptal may interact with certain drugs (such as felodipine and verapamil).

Keppra: Introduction

More than 2 million people in the US have some form of epilepsy. Seventy percent of them are adults. Although contemporary treatment approaches can provide full or partial control of seizures in about 85% of patients, some 15% of patients do not achieve this control, and many patients are virtually resistant to available drug therapies. Some patients with partial onset seizures – those that originate in one hemisphere of the brain, often without loss of consciousness – resort to surgery to remove the affected area of the brain, ideally without affecting personality or function.

Now a new drug manufactured by UCB Pharma, Inc. – Keppra (levetiracetam) – may help patients with partial onset epileptic seizures when administered with other antiepileptic drugs (AEDs). Keppra’s approval within ten months of NDA submission to the FDA makes it the fastest AED approval to date. Keppra has several features that make it a valuable antiseizure medication: Clinicians can initiate treatment with an effective 500 mg daily dose, rather than begin with a subtherapeutic dose and titrate upward. Moreover, Keppra displays a favorable safety profile and does not interact with concomitantly administered AEDs or other drugs (such as oral contraceptives, digoxin, warfarin, and probenecid).

Keppra is approved for use in adults and is available in 250 mg, 500 mg, and 750 mg tablets for oral administration with or without food.

Keppra: How It Works

The exact mechanism by which Keppra exerts its antiepileptic effect is not known and does not appear to derive from any interaction with mechanisms known to be involved in inhibitory and excitatory neurotransmission. In vitro studies show that a stereoselective binding site for Keppra exists exclusively in the synaptic plasma membranes of the central nervous system, but not in peripheral tissues. Both in vitro and in vivo recordings of epileptiform activity from the hippocampus show that Keppra inhibits burst firing without affecting normal neuronal excitability. This finding suggests that Keppra may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity.

Keppra: Clinical Study Results

The efficacy of Keppra was demonstrated in three multicenter, randomized, double-blind, placebo-controlled studies in 904 patients with refractory partial onset seizures with or without secondary generalization. At the time of the study, patients were taking a stable dose of 1 to 2 AEDs and were required to have experienced at least four partial onset seizures during each 4-week period during the 12-week baseline period.

Each of the three studies consisted of the 12-week baseline period followed by an 18-week treatment period. The treatment period included a 6-week titration period followed by a 12-week fixed-dose evaluation period, during which concomitant AED regimens were continued. The primary measure of effectiveness was the percent reduction in weekly partial seizure frequency relative to placebo during the entire 18-week treatment period. Responder rate (the incidence of patients with a seizure reduction of 50% or more) was measured as a secondary outcome.

Study 1 was conducted at 41 sites in the US and compared Keppra 1000 mg/day (97 patients), Keppra 3000 mg/day (101 patients), and placebo (95 patients) given in equally divided doses twice daily. The reduction in weekly seizure frequency was 26.1% in the Keppra 1000 mg group and 30.1% in the Keppra 3000 mg group, a significant reduction compared to placebo. Responder rates were 7.4% for placebo, 37.1% for patients who received 1000 mg Keppra, and 39.6% for the 3000 mg Keppra group – a significant difference.

Study 2 was conducted at 62 centers in Europe and compared Keppra 1000 mg/day (106 patients), Keppra 2000 mg/day (105 patients), and placebo (111 patients) given in equally divided doses twice daily. The reduction in weekly seizure frequency was 17.1% in the Keppra 1000 mg group and 21.4% in the Keppra 2000 mg group, a significant reduction compared to placebo. Responder rates were 6.3% for placebo, 20.8% for patients who received 1000 mg Keppra, and 35.2% for the 3000 mg Keppra group – a significant difference between Keppra and placebo and between the two doses of Keppra.

Study 3 was conducted at 47 centers in Europe and compared Keppra 3000 mg/day (180 patients) and placebo (104 patients). The patients who received Keppra experienced a 23.0% reduction in weekly seizure frequency and achieved a 39.4% responder rate (compared to 14.4% in the placebo group).

Keppra: What the Patient Should Know

Adverse effects associated with Keppra include somnolence and fatigue, dizziness, coordination difficulties (ataxia, abnormal gait, or incoordination), and asthenia. Keppra may also be associated with behavioral symptoms, such as agitation, hostility, anxiety, and depression. These effects occurred primarily during the first four weeks of treatment. Because of associated dizziness and somnolence, patients should be advised to avoid driving or operating heavy machinery until they have gauged the effect of Keppra on their performance. Keppra is also substantially excreted by the kidney, so caution should be taken in administering the proper dose to patients with moderate to severe renal impairment and patients undergoing hemodialysis.