Health and Pills

Posts Tagged ‘Medications’

Arthrotec is a new product that combines the NSAID diclofenac and the prostaglandin analog misoprostol. The diclofenac component of Arthrotec is responsible for the relief of the symptoms of arthritis. The misoprostol component is responsible for the mucoprotective properties. Arthrotec has the dual purpose of relieving the signs and symptoms of arthritis and protecting patients from the development of gastric and duodenal ulcers.

It is available in two strengths. One formulation (Arthrotec 50) contains 50 mg of diclofenac and 200 mcg of misoprostol while the other (Arthrotec 75) contains 75 mg of diclofenac and 200 mcg of misoprostol. The usual dose of Arthrotec in the management of osteoarthritis is 50 TID and for rheumatoid arthritis is 50 TID or QID; BID dosing can be used.

How it works:

Diclofenac sodium:

Diclofenac sodium is an NSAID that exhibits classical anti-inflammatory, antipyretic, as well as analgesic properties. As with other NSAIDs, its exact mechanism is not completely understood but it is believed that diclofenac, like other NSAIDs, works in part by inhibiting prostaglandin synthetase.

Misoprostol:

Misoprostol is a synthetic prostaglandin E1 analog. In animals, misoprostol inhibits gastric acid secretion and promotes mucosal protective properties. Misoprostol can increase bicarbonate and mucus production and decrease the secretion of gastric acid. The exact reason for protection against ulcers has not be determined.

Clinical Tips

Diclofenac:

Diclofenac is completely absorbed through the gastrointestinal tract following oral administration. The diclofenac portion of Arthrotec is stable in the acidic environment of the stomach. However, it is rapidly released from the formulation once it enters the more basic environment of the duodenum. Peak plasma levels of this portion are reached in about 2 hours. Because of the extensive first pass effect, only 50% of the dose is available for absorption. The diclofenac portion of Arthrotec is metabolized by the liver and cleared by the urine (65%) and the biliary route (35%).

Misoprostol:

Misoprostol is rapidly absorbed following oral administration, but must undergo metabolic activation into misoprostol acid before it can exerts it pharmacologic actions. The misoprostol acid that is present in Arthrotec reaches peak plasma levels in about 20 minutes and is rapidly eliminated with an approximate half-life of 30 minutes.

Arthrotec follows similar pharmacokinetic parameters as the individual components. The amount of absorption of the two components from the preparation of Arthrotec is comparable to the amount of absorption of the two individual components separately. Importantly, food tends to decrease the bioavailability of the two components of Arthrotec. The pharmacokinetic profile of the diclofenac component in Arthrotec is unchanged in elderly patients and in patients who are renally and hepatically challenged. The pharmacokinetics of misoprostol is influenced by age as well as renal and hepatic impairment; the levels of misoprostol in these individual may double. Hence, it is necessary to adjust the dose in elderly patients and in patients who have renal and hepatic problems.

Clinical studies have shown that diclofenac alone, or in combination with misoprostol, is effective in the treatment of the signs and symptoms of osteoarthritis and rheumatoid arthritis. When given alone, misoprostol has been shown to reduce the occurrence of gastric and duodenal ulcers in patients who were receiving a variety of NSAIDs for the management of arthritic conditions. When Arthrotec was compared to diclofenac alone in patients who had osteoarthritis, the incidence of drug-induced ulcers was lower in patients who were receiving Arthrotec than those who were receiving diclofenac. Even though the incidence of gastric and duodenal ulcers was lower with Arthrotec, only the incidence of gastric ulcers was significantly lower in patients who were receiving Arthrotec than those who were receiving diclofenac.

Abdominal pain, diarrhea, upset stomach, and nausea are among the most common side effects with Arthrotec. Diarrhea may be reduced if this medication is taken with meals. Most adverse effects that occur with misoprostol are mild to moderate and generally resolve following a few days of treatment.

Instructions for the Patient

Arthrotec should not be given to patients who are allergic to aspirin, who have pre-existing asthma, and who have severe renal failure. It should not be given to patients who are pregnant or who are planning to become pregnant because it is believed the misoprostol component can cause fetal death.

Patients should also be advised to swallow Arthrotec whole; they should not chew, crush or dissolve this medication. In addition, patients should be advised to report any signs and symptoms of liver failure (jaundice, itching, nausea) to their physician.

Now finally, let us grant that all the claims made for a new drug are true, that with it we can do this or that, as alleged. There still remains the question: do we want to do all these things? Shall we tranquilize the patient merely because the means are at hand, or alert and stimulate him, willy-nilly, when he is deluded or obsessed? Do we really want to lose control of all our mild elderly diabetics through a fistful of pills? Are we to go on creating more resistant infections through giving each new antibiotic a whirl? Shall we blindly accept the asseveration that two drugs with opposing types of action invariably give a nice blended effect when used together in fixed proportions ? Do we need to risk orthostatic hypotension, ileus, visual disturbances, palpitation, paresthesias, etc., merely to obtain blood pressure reduction in a mildly hypertensive patient? How frequently is intravenous iron administration advisable? Do we want often to replace thyroid substance with a quicker-acting compound whose omission may cause distressing withdrawal symptoms? And so on and on.

Do we really need all the time all the things that all the new drugs will give us? With full realization of the probable absurdity of the comparison, I am nevertheless going to liken political man’s possession of his new military weaponry with medical man’s acquisition of his new pharmaceutical arsenal. The time is not yet here when the decision will have to be made whether to drop the hydrogen bomb or not to drop it, but all the world is quivering with fear that such a moment is imminent, and men of good will everywhere are agitating for restriction of the use of this dreadful new power to those activities only of mankind wherein his best survival interests can be selectively aided. To use or not to use the new drugs for all they can do, that too is a question, our peculiar and particular medical question, and ours the solemn responsibility to answer it. For progress in this field will not be halted, and we are only now crossing the threshold into the vast drug sales room of the near future, whose walls and floors and counters and chests and racks and shelves will be loaded with bottles crying out “Use me! Or me! Or me! Or all of us together!” Shall we do it, always in all cases, all of it? Money in immense amounts is invested in the effort to tell us that this is our duty; the symptom is there, the drug is or soon will be available; the two must meet head-on invariably. “Treat your patient with these new drugs, Doctor, treat him, each one of him, or else a new kind of physician will be created who will do it.” In such exaggeration there is truth. Investigations now under way, may bestow power through drugs over metabolic processes as will make nuclear fission seem puny in potentiality for control of the world.

We doctors, while we can, must make the decision whether to give up and merely hand out the pills, or not. No individual can dictate that decision, but remember: all drugs, even the very best, are psychologically or physically potentially toxic agents — and none should be used unless unavoidable.

Publish date: 1959

Progress has been made with such giant strides in recent decades that one is tempted at times to bemoan the smallness of the territories still to be conquered. But for the pharmacologist at least, whatever the feeling may be in other circles, there exists a sufficient and powerful antidote for his ego in the large list of areas in which drugs are still badly needed. The things we might expect from these drugs, drugs that are not yet found or devised, are shown in Tables 3 and 4.

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This is a wonderful list, is it not? All this still left for the pharmacologist to do. And of course he will eventually do most of it, but there is something between him and the practitioner — a great vested interest which must sell to live. This vast pharmaceutical industry has become a familiar and essential ingredient of medical practice, and we should all generously and gladly attempt to be useful to it in recognition of a mutual interest and a shared desire. But this must not be done through yielding independence or sacrificing the intelligent approach!

Do not, I implore you, gain all the accretions to your pharmacologic knowledge from the paid sales representative, whose training is necessarily not comparable with yours, or accept the receipt of his sample as a mandate to use it. And do not believe the bromide that no one can keep up with medical advances today, for there are numerous existing abstract, year book, review and other services which make it quite possible to do so sufficiently well for practical and satisfying purposes. The expenditure of only a minimal amount of time is required too, if one’s time slices are adequately cut with this in mind. Most of you are keeping up better than you are told that you are.

And then there are the advertisements, the gorgeously colored spreads that make it difficult to find the reading matter in many of our journals. Please, if you must study the more gaudy of them at all, do so with a sour skepticism and a jaundiced and cynical eye. Be advised and aware that in some instances the journal references embodied in these advertisements are to preliminary findings that do not apply at all directly to the clinical claims that are made, and that in other instances the references are to publications that have actually been written by the pharmaceutical house staff itself for the inexperienced investigators who have made the clinical trials. The fact is that there are not enough existing facilities, and fully qualified clinical research workers, to perform the kind of studies that every new drug should have before it is made available for uncontrolled use in practice.

Publish date: 1959

During each of the past ten years the pharmaceutical industry has produced an average of approximately 400 new products. In the most recent year of record, 1957, the number is said to have been precisely 400, and 51 of these were single new chemicals. Many of the agents are produced in refined form in amounts that are absurdly small in relation to the bulk of the crude materials from which they are processed. Some typical yields of useful and familiar materials of different sorts are shown in Table 1. Add to the comparisons afforded in this table the fact that many entirely synthetic compounds are obtained through even more exhausting and expensive manipulations than are required in refining crude materials; and consider in addition the huge sums expended in research and promotion in order to make available, and to bring into the physician’s awareness, the packaged drugs awaiting his prescription — think of these things and it will easily be realized that the pharmaceutical manufacturers are obliged to interest themselves vitally in what it is that makes a new product acceptable to the doctor. To supply one observer’s version of what the requirements are, is the purpose of this presentation.

Source Of The Drug

I should say that if the new drug proposed for your use is, or is derived from, an old folk remedy the chances are good that it is worth paying attention to — not trying at once, willy-nilly, but at least watching to the extent of asking to see the records of its unbiased and controlled trials in specialized clinics. For the record of such agents is impressive, as is shown in the listing in Table 2 of valuable drugs obtained from folk medicine.

If a drug is offered because it has been discovered by search among the chemically close relatives of an active drug for another one of the same sort, you will be well advised to be hesitant in accepting it until full trials have been made by others better placed for such trials than yourself. Good drugs have often been developed through such approaches admittedly, but since these searches are usually begun merely to turn up for competitive reasons another drug as good as the one of established value, there is no obligation to believe a priori that the new agent is better than the old. It may be just as good and no more toxic, and this in itself may sometimes assure it a place in the armamentarium since there are instances in which there is advantage in having two strings to one’s bow — but let the qualified investigators determine the facts of the case while you continue to use the agent whose worth you know. Now, if the new drug has been evolved in attempting to improve an original compound through chemical modification, I should advise again to delay transferring patients to it until its clinical status has been proved by investigators qualified to make the controlled trials. There is a tendency among sales representatives of some pharmaceutical houses to maintain that certain chemical configurations reliably confer specific pharmacologic attributes upon compounds in which they are incorporated. But the actual fact is that invariability and predictability have not yet been achieved in this field of structure-activity relationships. One wants to know in each instance, first, whether the chemical configuration in question has really been shown by disinterested investigators to possess the attributes claimed for it; second, whether the structure to which it has been attached is one that is likely thereby to have the desired pharmacologic action conferred upon it or strengthened in it; and, third, whether the attachment has been made at a point that will potentiate or may actually weaken and possibly even pervert the action of the basic structure. These things the individual practitioner surely will not know.

Publish date: 1959

Studies have shown that the most commonly used antiepileptic drugs (AEDs) reduce blood levels of oral contraceptives (OCs) by about 40%. But how many physicians know this? After seeing five epileptic patients in two years at Johns Hopkins Hospital with unexpected and inconvenient pregnancies that occurred during OC and AED therapies, Krauss et al decided to conduct a national survey to see how aware physicians are of the interactions between antiepileptic drugs and oral contraceptives. They were interested to find out how many physicians know that hepatic enzyme-inducing AEDs increase the metabolism of oral contraceptives, thus reducing blood levels. They also wanted to find out if physicians know that antiepileptic drugs increase the risk of birth defects two- to threefold (or more in high-risk patients).

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).

The FDA has approved a novel antiepileptic agent – topiramate (Topamax/Ortho-McNeil)-for the adjunctive treatment of adults with partial-onset seizures. Topiramate was identified by scientists at the National Institutes of Health during random screening of promising drug candidates, and was developed by the R.W. Johnson Pharmaceutical Research Institute. The drug blocks voltage-sensitive sodium channels, enhances the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and blocks the action of the excitatory neurotransmitter glutamate. It also inhibits carbonic anhydrase, although this may not contribute to anticonvulsant activity.

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.

Status epilepticus is a persistent, generalized tonic-clonic seizure that occurs in some 60,000 Americans each year, primarily children but also frequently people over age 60. One third of patients are known epileptics and one third have no history of epilepsy (in half of these, the seizures are a first manifestation of epilepsy). Seizures can also be nonepileptic; origins can be toxic, metabolic, traumatic, hypoxic, electrolytic, pharmacologic, hemorrhagic, neoplastic, infectious, or febrile; seizures can also result from substance abuse or withdrawal.

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).

Question. How many double blind studies have been done on the use of antiepileptics for rapid cyclers? If anxiety is a factor, what other drugs should be used with them?

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.

Epilepsy is a chronic neurologic disorder that may result from brain injury, developmental malformation, or a genetic abnormality. It is characterized by recurrent seizures caused by sudden, excessive electrical activity in the brain. Seizures are classified as generalized, in which the electrical discharge occurs throughout the brain, and partial onset, wherein the electrical activity is localized (in simple partial-onset seizures, consciousness is maintained; in complex partial, consciousness is altered). Epilepsy affects up to 1% of the population in industrialized countries, with the highest rates occurring in children and adolescents. Most seizures (60%) are complex partial or secondarily generalized, and 25 to 30% of these seizures are refractory to available therapy. But for every refractory patient, there is another patient who goes into remission on antiepileptic drug (AED) therapy and then, after a seizure-free period, remains in remission when antiepileptic drugs are withdrawn. This shows that epilepsy is not always a lifelong condition.

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 risks 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.

Brand Name: Trileptal
Active Ingredient: oxcarbazepine
Indication: Treatment of partial epileptic seizures as monotherapy in adults or adjunctive therapy in adults and children as young as age 4
Company Name: Novartis Pharmaceuticals Corporation
Availability: Approved by FDA January 10, 2000

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).