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Topiramate (Topamax) and epilepsy

| Filed under Antiepileptics

Epilepsy is a group of disorders of the brain characterized by recurring episodes of convulsive seizures, sensory disturbances, abnormal behaviour, loss of consciousness, or all of these. In all types of epilepsy, an uncontrolled electrical discharge from the nerve cells in the cerebral cortex of the brain is evident. While the cause of most types of epilepsy is unknown, it can be associated with head injury, infection, brain tumour, intoxication, or chemical imbalance.

Topiramate is a new drug that has shown promise in the treatment of epilepsy. Since preliminary evaluation has been encouraging, double-blind, placebo-controlled trials were established in an effort to better define the effectiveness, safety and appropriate dose range of topiramate for refractory partial epilepsy. The objective of this study was to evaluate a medium-to-high dose range consisting of daily dosages of 600, 800, and 1,000 mg of topiramate.

A total of 190 patients with epilepsy, aged from 18 to 68, were enrolled in the study. Over 90% of the patients had a history of complex partial seizures, and over 60% also had secondary generalized seizures. Patients were randomly assigned to one of four groups: placebo (47 patients), 600 (48 patients), 800 (48 patients), or 1,000 (47 patients) mg topiramate (Topamax) per day.

During the 18-week treatment period, the rate of reduction in average monthly seizure rates was 1% for placebo, 41% for 600 mg/day and 800 mg/day topiramate, and 38% for 1,000 mg/day topiramate. Patients who experienced a 50% or greater reduction in the frequency of seizures included 9% of those in the placebo group, 44% in the 600 mg/day topiramate group, 40% in the 800 mg/day topiramate group, and 38% in the 1,000 mg/day topiramate group. While none of the patients in the placebo group experienced improvement of 75% to 100% in the frequency of seizures, 20% of the patients given topiramate were improved to this extent. Topiramate therapy was discontinued in 16% of patients because of side effects, the most common of which were dizziness, headache, fatigue and confusion.

The results of this study indicate that topiramate is highly effective and generally well tolerated in the treatment of refractory partial epilepsy. Dosages of topiramate greater than 600 mg/day do not appear to result in significantly greater effectiveness and may result in more side effects. However, individuals who are able to tolerate higher dosages may receive additional benefit. The investigators suggest that future studies should be aimed at better characterization of the adverse effects of topiramate. Evaluations of the safety and effectiveness of smaller doses and smaller dosage increments are also indicated.

1. Would topiramate be effective in the treatment of other forms of epilepsy, or only refractory partial epilepsy?

The primary studies that have been completed and were submitted to the U.S. FDA for approval were conducted in patients with refractory partial epilepsy. Open-label studies of this medication included patients who had other types of epilepsy and anecdotal experience suggests the drug may be effective in other seizure types. There are currently ongoing studies looking at other seizure types such as generalized epilepsies and the Lennox-Gastaut Syndrome. The Lennox-Gastaut syndrome is a severe form of epilepsy typically seen in childhood and is considered one of the most difficult epileptic syndromes to treat. Results of these studies may be presented at national meetings in the next year or two.

2. Is topiramate synthetic or derived from a natural substance? How was it discovered?

Topiramate is a synthetic compound developed by the Johnson & Johnson Pharmaceutical Research Institute. Its effectiveness in epilepsy was discovered through the collaborative program of the National Institutes for Health Epilepsy Branch. The Epilepsy Branch program allows corporations to submit compounds that might be effective in epilepsy to be evaluated in a series of animal tests and compared to standard antiepileptic drugs. This program has screened thousands of compounds over the last two decades. Topiramate was one of the compounds found to be highly effective in animal models and so was moved on to testing in humans with epilepsy.

3. Are there any trials planned to compare the efficacy and safety of topiramate with other similar drugs?

Most experts in the field feel that such trials are definitely necessary in order to compare the efficacy and tolerability of these medications. Unfortunately, these comparative trials require large numbers of patients, a tremendous effort to organize, and are extremely costly. It is my understanding that several companies have preliminary plans for such comparative trials. At the present time I am not involved in any of these trials and do not believe that any comparative trials are ongoing in the United States.

4. What is known about the long-term effects of topiramate (Topamax)?

In the database submitted to the FDA consisting of approximately 3,000 patients, there did not seem to be any consistent abnormalities of the function of the liver or bone marrow as seen with some other medications. Some patients at the University of Cincinnati Epilepsy Treatment Center have been on the medication for over eight years without significant problems.

5. Has its safety in children been evaluated?

Trials evaluating topiramate’s safety and effectiveness in children are currently underway. Preliminary data are encouraging; however, we must wait for the final results of these efficacy and safety trials in order to fully determine its role in the treatment of children.

Epilepsy is a group of disorders of the brain characterized by recurring episodes of convulsive seizures, sensory disturbances, abnormal behaviour, loss of consciousness, or all of these. In all types of epilepsy, an uncontrolled electrical discharge from the nerve cells in the cerebral cortex of the brain is evident. While the cause of most types of epilepsy is unknown, it can be associated with head injury, infection, brain tumour, intoxication, or chemical imbalance.

Topiramate is a new drug that has shown promise in the treatment of epilepsy. Since preliminary evaluation has been encouraging, double-blind, placebo-controlled trials were established in an effort to better define the effectiveness, safety and appropriate dose range of topiramate for refractory partial epilepsy. The objective of this study was to evaluate a medium-to-high dose range consisting of daily dosages of 600, 800, and 1,000 mg of topiramate.

A total of 190 patients with epilepsy, aged from 18 to 68, were enrolled in the study. Over 90% of the patients had a history of complex partial seizures, and over 60% also had secondary generalized seizures. Patients were randomly assigned to one of four groups: placebo (47 patients), 600 (48 patients), 800 (48 patients), or 1,000 (47 patients) mg topiramate per day.

During the 18-week treatment period, the rate of reduction in average monthly seizure rates was 1% for placebo, 41% for 600 mg/day and 800 mg/day topiramate, and 38% for 1,000 mg/day topiramate. Patients who experienced a 50% or greater reduction in the frequency of seizures included 9% of those in the placebo group, 44% in the 600 mg/day topiramate group, 40% in the 800 mg/day topiramate group, and 38% in the 1,000 mg/day topiramate group. While none of the patients in the placebo group experienced improvement of 75% to 100% in the frequency of seizures, 20% of the patients given topiramate were improved to this extent. Topiramate therapy was discontinued in 16% of patients because of side effects, the most common of which were dizziness, headache, fatigue and confusion.

The results of this study indicate that topiramate is highly effective and generally well tolerated in the treatment of refractory partial epilepsy. Dosages of topiramate greater than 600 mg/day do not appear to result in significantly greater effectiveness and may result in more side effects. However, individuals who are able to tolerate higher dosages may receive additional benefit. The investigators suggest that future studies should be aimed at better characterization of the adverse effects of topiramate. Evaluations of the safety and effectiveness of smaller doses and smaller dosage increments are also indicated.

Questions for Dr. Privitera:

1. Would topiramate be effective in the treatment of other forms of epilepsy, or only refractory partial epilepsy?

The primary studies that have been completed and were submitted to the U.S. FDA for approval were conducted in patients with refractory partial epilepsy. Open-label studies of this medication included patients who had other types of epilepsy and anecdotal experience suggests the drug may be effective in other seizure types. There are currently ongoing studies looking at other seizure types such as generalized epilepsies and the Lennox-Gastaut Syndrome. The Lennox-Gastaut syndrome is a severe form of epilepsy typically seen in childhood and is considered one of the most difficult epileptic syndromes to treat. Results of these studies may be presented at national meetings in the next year or two.

2. Is topiramate synthetic or derived from a natural substance? How was it discovered?

Topiramate is a synthetic compound developed by the Johnson & Johnson Pharmaceutical Research Institute. Its effectiveness in epilepsy was discovered through the collaborative program of the National Institutes for Health Epilepsy Branch. The Epilepsy Branch program allows corporations to submit compounds that might be effective in epilepsy to be evaluated in a series of animal tests and compared to standard antiepileptic drugs. This program has screened thousands of compounds over the last two decades. Topiramate was one of the compounds found to be highly effective in animal models and so was moved on to testing in humans with epilepsy.

3. Are there any trials planned to compare the efficacy and safety of topiramate with other similar drugs?

Most experts in the field feel that such trials are definitely necessary in order to compare the efficacy and tolerability of these medications. Unfortunately, these comparative trials require large numbers of patients, a tremendous effort to organize, and are extremely costly. It is my understanding that several companies have preliminary plans for such comparative trials. At the present time I am not involved in any of these trials and do not believe that any comparative trials are ongoing in the United States.

4. What is known about the long-term effects of topiramate?

In the database submitted to the FDA consisting of approximately 3,000 patients, there did not seem to be any consistent abnormalities of the function of the liver or bone marrow as seen with some other medications. Some patients at the University of Cincinnati Epilepsy Treatment Center have been on the medication for over eight years without significant problems.

5. Has its safety in children been evaluated?

Trials evaluating topiramate’s safety and effectiveness in children are currently underway. Preliminary data are encouraging; however, we must wait for the final results of these efficacy and safety trials in order to fully determine its role in the treatment of children.

Opioid overdose

| Filed under Drugs

An 18-year-old man is brought into the emergency department after being found on the street unresponsive. He is lethargic and does not answer questions. He has been given 1 ampule of Dextrose intravenously without result. On examination, his heart rate is 60 beats per minute, and respiratory rate is 8 per minute and shallow. His pupils are pinpoint and not reactive. There are multiple intravenous track marks on his arms bilaterally. The emergency physician concludes that the patient has had a drug overdose.

What is the most likely diagnosis?

What is the most appropriate medication for this condition?

In addition to its therapeutic actions, what other effects might this medication produce?

Answers to case: Opioid overdose

Summary: An 18-year-old unresponsive man presents with pinpoint pupils, shallow respirations, and multiple intravenous track marks on his arms bilaterally.

Most likely diagnosis: Opioid overdose, likely heroin.

Most appropriate medication for this condition: Naloxone.

Additional effects this medication might produce: Symptoms of precipitated withdrawal that may include lacrimation, rhinorrhea, sweating, dilated pupils, diarrhea, abdominal cramping, and tremor.

Clinical correlation

Opioids are drugs with morphine-like activity that reduce pain and induce tolerance and physical dependence. Certain individuals seek the euphoria obtained from the intravenous injection of opioids such as heroin. There are three different cell receptors specific for opioids: mu, kappa, and delta (µ, k, δ), all of which exist as multiple subtypes. This patient has the classic signs of opioid overdose: somnolence, respiratory depression, and miosis. Stimulation of the mu receptor results in analgesia (supraspinal and spinal), respiratory depression, euphoria, and physical dependence. Continuous, heavy use of opioids can result in tolerance, where more drug is required to obtain the same euphoric “high,” and also to physical dependence. Naloxone, a competitive antagonist of opioids, is used to treat opioid overdose. Its intravenous administration leads to an almost immediate reversal of all effects of the opioids.

In individuals who are physically dependent, administration of naloxone will immediately precipitate opioid withdrawal, which consists of a constellation of signs and symptoms that include nausea and vomiting, muscle aches, lacrimation or rhinorrhea, diarrhea, fever, and dilated pupils. Likewise, when someone physically dependent on opioids ceases its administration there is a more slowly developing (hours or days) constellation of symptoms of opioid withdrawal that includes sensitivity to touch and light, goose flesh, auto-nomic hyperactivity, GI distress, joint and muscle aches, yawning, salivation, lacrimation, urination, defecation, and a depressed or anxious mood. In general, physical dependence induced by opioids with a short half-life tend to result in a rapid severe withdrawal, while physical dependence induced by opioids with a long half-life tends to be associated with a less severe and more gradual course of withdrawal. Although very uncomfortable, opioid withdrawal is generally not life-threatening.

The opioid methadone may be administered in a daily dose to individuals physically dependent on opioids, most notably heroin, as a “maintenance therapy” or to ameliorate the symptoms of opioid withdrawal.

Approach to pharmacology of the opioids

Objectives

1. Describe the mechanism of action of opioids as analgesics.

2. Explain how opioids reduce pain.

3. List the major opioid agonists and antagonists, their therapeutic uses, and their important pharmacokinetic properties.

4. Describe the adverse effects of opioids.

Definitions

Endogenous opioid peptides: Class of natural endogenous peptides that bind to human mu, delta, and kappa opioid receptors. Four classes of such peptides have been described: (1) the pentapeptide enkephalins (met and leu), (2) the endorphins (β-endorphin), (3) the dynorphins (A, B, C), all of which are proteolytically released from larger precursor molecules, and (4) the endomorphins. Together, they may modulate a number of important functions of the body (e.g., pain, reactions to stress and anxiety).

Fasciculation: Muscular twitching of contiguous groups of muscle fibers

Lacrimation: Secretion of tears from the eyes

Rhinorrhea: Mucous-like material that comes out of the nose

Continuation:

Opioid overdose: Class

Opioid overdose: Questions – Answers

Acute Mountain Sickness

| Filed under Drug Therapy

Rapid ascension and exposure to altitudes greater than 8,000 feet without appropriate acclimatization is an environmental malady risked by many outdoors enthusiasts. Initiating within 1 to 2 days, this spectrum of symptoms has collectively been termed Altitude Sickness (AS) or Acute Mountain Sickness (AMS). As elevation increases, the partial pressure of oxygen decreases, causing climbers to experience hypoxemia. At 11,500 feet, the oxygen in the air is about 65% of the amount available at sea level, which forces the body to struggle to maintain normal levels of oxygenation. Ventilation may decrease further as one sleeps, potentiating the hypoxemia (Table 1).

Table 1: Acclimatization to High Altitude
Response Mechanism Time
Ventilation Stimulation by hypoxia Immediate and ongoing
Gas exchange in the lung Better matching of ventilation and perfusion to optimize O2 transport from the air to the blood Immediate
Blood Increase in RBCs to increase oxygen-carrying capacity
Shift of the O2-Hgb dissociation curve		 Days to weeks
Tissues Increase in capillary density
Increase in mitochondrial density		 Probably weeks

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.

Table 2: Drug Therapy for Acute Mountain Sickness
Drug Dose Mechanism of Action Adverse Effects Comments
Acetazolamide

(Diamox)

 Prevention:
125-250 mg PO BID 24 hr before ascent and first 2 days at high altitude

Treatment:
125-250 mg PO BID until symptoms resolve

 Carbonic anhydrase inhibitor; causes HCO3diuresis and respiratory stimulation; increases PaO2; promotes ion transport across blood brain barrier Paresthesias; diuresis; potential dehydration; alters taste of carbonated beverages Sulfa reactions possible; no rebound effect; can be taken episodically; pregnancy category C
Dexamethasone

(Decadron )

 Prevention:
2-4 mg PO Q6H or 4 mg PO Q12H

Treatment: 4 mg Q6H, PO, IM

 Unknown; may reduce brain blood volume; may reduce capillary leak; may block lipid peroxidation Hyperglycemia; mood changes; dyspepsia rebound effect on withdrawal Can be lifesaving; effects evident in 2-8 hr; no effect on acclimatization; pregnant women should not take if possible
Furosemide

(Lasix )

 80 mg PO Q12H for a total of 2 doses* Loop diuretic; decreases ECV; decreases pulmonary congestion Hypovolemia; hypotension; hypokalemia; hypomagnesemia Not recommended for prevention; evidence is scant
Aspirin 325 mg PO Q4H x 3 doses Prostaglandin inhibition Dyspepsia; GI bleeding For HA prevention; no clinical trials
Ibuprofen

(Advil, Motrin, Nuprin)

 400-600 mg PO x 1, MR Prostaglandin inhibition Dyspepsia; GI bleeding For HA prevention; no clinical trials
Prochlorperazine

(Compazine)

 10 mg PO or IM

Q6-8H PRN

 CTZ inhibitor EPS; sedation Preg cat C; use diphenhydramine IM for EPS; for nausea/vomit
Promethazine

(Phenergan)

 25-50 mg PO, IM, PR

Q6H PRN

 CTZ inhibitor EPS; sedation Preg cat C; use diphenhydramine IM for EPS; for nausea/vomit
Zolpidem

(Ambien )

 10 mg PO HS PRN Non–BZP modulator of gamma-aminobutyric acid receptors Rare For insomnia; does not depress ventilation at high altitude; preg cat B
ECV = extracellular volume; GI = gastrointestinal; HA = headache; CTZ = chemoreceptor trigger zone;
BZP = benzodiazepine; EPS = extrapyramidal symptoms; IM = Intramuscular;
* Only dose studied in clinical trials; many favor using lower doses to minimize adverse effects

Arthrotec (Diclofenac and Misoprostol) for Inflammatory Rheumatic Diseases

| Filed under Drugs

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.

Drugs: To Use or Not to Use. Must All Drugs Be Used?

| Filed under Old Publications

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

Drugs: To Use or Not to Use. Weighing The Evidence Offered

| Filed under Old Publications

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.

Table 3. Drugs Are Still Needed To Provide Prophylaxis Or Cure In:
common cold trichomoniasis infertility
virus influenza fluke infestations threatened abortion
brucellosis pneumonoconioses hyperemesis gravidarum
virus encephalitides renal disease eclampsia
foot-and-mouth disease portal cirrhosis endometriosis
leptospirosis peptic ulcer menstrual disturbances
rabies ulcerative colitis cataracts
trypanosomiasis many of the psychoses glaucoma
yellow fever parkinsonism impaired hearing
infectious mononucleosis cerebral palsy infantile colic
virus hepatitis migraine urolithiasis
smallpox Bell’s palsy anuna
tetanus Meniere’s disease obesity
schistosomiasis Sydenham’s chorea alcoholism malignancy
the mycoses multiple sclerosis and the muscular atrophies and dystrophies and syringomyelia burns
poliomyelitis shock of irreversible degree
dengue

-

Table 4. Drugs Are Still Needed To:
prevent atherosclerosis replace blood-letting in polycythemia vera and blood transfusion in shock
prevent hypertension
prevent development, check progress, even cause retrogression of valvular lesions correct the defects in hemophilia and in purpura
combat the circulatory and respiratory dissolution associated with pulmonary embolism
act more selectively in the autonomic nervous system
combat rheumatic carditis and rheumatoid arthritis specifically
restore circulation in the peripheral vascular diseases
end the disturbed uric acid metabolism in gout
attack dermatologic lesions effectively systemically separate the pharmacologic (useful) from thephysiologic (harmful) actions of ACTH
combat anemias other than the simple iron deficiency and pernicious types
combat intractable pain with non-addicting agents

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

Drugs: To Use or Not to Use

| Filed under Old Publications

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.

Table 1. Refined Yields From Crude Materials

Product

Source

Recovery per 1,000,000 parts of crude material
Copper Ore

10,000
Magnesium Sea water

1,270
Uranium Ore

700
Reserpine Plant root

500
Typical antibiotic Fermentation broth

100
Vitamin B12 Fermentation broth

1

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.

Table 2. Drugs Derived From Folk Medicine
atropine ergonovine pilocarpine
caffeine ergotamine quinidine
cocaine ipecac quinine
codeine iron salts reserpine
colchicine morphine salicylates
digitalis papaverine scopolamine
emetine physostigmine theophylline
ephedrine tubocurarine

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

Drug interactions: OCs, AEDs, and the risk of pregnancy

| Filed under Antiepileptics

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).

Med Topiramate (Topamax) in Epilepsy

| Filed under Antiepileptics

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.

Parenteral fosphenytoin, diazepam rectal gel for refractory seizures, status epilepticus

| Filed under Antiepileptics

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).