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

-

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

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

Too often, illnesses in older people are misdiagnosed, overlooked, or dismissed as part of the normal aging process, simply because health professionals are not trained to recognize how diseases and drugs affect seniors. Developing the knowledge, skills and resources to provide pharmaceutical care to the nation’s seniors is our professional responsibility and will be the focus of future articles in this series.

The ever-increasing elderly population emphasizes the need to better understand drug therapy in the context of the aging process and the unique problems that ensue. Twenty-eight percent of hospitalizations of the elderly are due to adverse drug reactions (17%) and medication noncompliance (11%).

Adverse drug events (ADE) are among the top five greatest and most preventable threats to the health of the elderly (after CHF, breast cancer, hypertension, and pneumonia), and approximately 95% of ADEs are predictable. It has been suggested by some that any symptom experienced by an elderly patient should be considered a drug side effect until proven otherwise.

Ensuring the appropriateness of a senior patient’s drug therapy is paramount. Potentially inappropriate medications put seniors at risk for ADEs that could lead to unnecessary morbidity and mortality based on polypharmacy, pharmacokinetics, pharmacodynamics and compliance factors.

Polypharmacy significantly increases the risk of drug-drug interactions. Changes in pharmacokinetic processes, namely absorption, distribution, metabolism and elimination, are associated with age and further altered by disease states. Data also support phamacodynamic changes in the elderly. These changes have been noted in the central nervous system, cardiovascular system, and in various receptors (beta-adrenergic, cholinergic, and dopaminergic) resulting in an altered response to many drugs in the older patient. Existing pathology may further complicate the presentation of disease and drug effects. Compliance becomes more of an issue in the elderly when polypharmacy exists due to the complexity of disease states and regimens.

A solid understanding of these issues is necessary to comprehensively evaluate drug regimens in this population and recommend dosage modifications where appropriate. Tailoring a drug regimen based on the individual’s clinical response requires ongoing assessment. There are many factors to consider.

Falls

Pharmacokinetic and pharmacodynamic changes associated with aging may contribute to the increased risk of falls caused by medications. The rate of falls increases with age. In the community, about one third of people over 65 years old fall at least once a year and the rate is higher in patients living in long-term care facilities.Psychotropic medications have been consistently and significantly associated with an increased risk of falls in the elderly. The tricyclic antidepressants, serotonin reuptake inhibitor antidepressants, benzodiazepines, and antipsychotics need to be monitored closely in the geriatric population with regard to falls. Studies have consistently shown a significant association between multiple medication use and risk of falling in the elderly.

When these medications are necessary, they should be started at low doses and slowly titrated upward. Orthostatic blood pressure should be monitored and assessment should be ongoing. Anti-hypertensives may lead to falls secondary to postural/orthostatic hypotension or a reduction in cerebral blood flow.

Crushing Medications

Discomfort, pain or difficulty swallowing medication is a problem faced by many elderly patients. Dysphagia is seen in patients with Parkinson’s disease, altered mental status, or as a result of a cerebral vascular accident. When a solid dosage form is reduced to a powder (crushed or opened), the surface area is greater and the substance usually dissolves more readily making it more easily absorbed. This may result in an increase in the rate of side effects or toxicity. This is especially true in the elderly with impaired renal or hepatic function. Information to help in determining whether a particular tablet or capsule can be safely altered, tips for crushing tablets and administering the powder, and whether it is available in an alternative dosage form may be obtained through resources 7 and 8 listed above.

Mechanism of action of Lipitor (atorvastatin)

Although a number of “statins” are now available, atorvastatin is the only drug in this class indicated as an adjunct to diet in the reduction of elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (apo-B), and triglyceride (TG) levels in patients with primary hypercholesterolemia and mixed dyslipidemia. It is the first drug of its class specifically indicated for lowering both low-density lipoprotein cholesterol and triglyceride levels. It is also the only statin indicated for the reduction of total cholesterol and low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia, a rare, serious, life-threatening, autosomal dominant, inherited disorder of lipid metabolism.

Clinical Tips

In head-to-head clinical trials when starting doses were compared, atorvastatin was superior to lovastatin, pravastatin, and simvastatin in reducing elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides. In two placebo-controlled, dose-response studies in hypercholesterolemic patients, once-daily administration of atorvastatin significantly reduced low-density lipoprotein cholesterol by 39% to 60% across the dose range of 10 mg to 80 mg. In addition, atorvastatin reduced triglyceride levels by 19% to 37% across the dose range. In a large clinical study, the number of patients meeting the National Cholesterol Education Program – Adult Treatment Panel II target levels, while taking daily 10-mg doses of Lipitor, was assessed. After 16 weeks, 93% of patients with fewer than two risk factors for coronary heart disease and a baseline low-density lipoprotein cholesterol of 190 mg/dL or lower reached a target of 160 mg/dL or lower, and 19% of those with coronary heart disease and an low-density lipoprotein cholesterol of 130 mg/dL or more reached a target of 100 mg/dL low-density lipoprotein cholesterol or lower.

The most frequent treatment-related adverse events are constipation, flatulence, dyspepsia, and abdominal pain. Fewer than 2% of patients treated with Lipitor in controlled studies discontinued treatment because of drug-related adverse events. Elevations of serum transaminases occurred in fewer than 1% of patients, but it is recommended that liver function tests be performed before the start of treatment, after 6 and 12 weeks, and periodically thereafter. As with other statins, the risk of myopathy is increased when the drug is taken with cyclosporine, fibric acid derivatives, niacin, erythromycin, or azole antifungals. Patients should be advised to report unexplained muscle pain, tenderness, or weakness, especially if accompanied by malaise or fever.

There are five HMG-CoA reductase inhibitors available on prescription in the US — lovastatin (Mevacor/Merck), simvastatin (Zocor/Merck), pravastatin (Pravachol/Bristol- Myers Squibb), and fluvastatin (Lescol/Sandoz) — and there are several more under clinical investigation, including one in late-stage trials at Warner-Lambert. Also known as “statins,” these agents slow the progression of coronary artery disease (CAD) and have actually been shown to induce regression of atherosclerotic lesions in CAD patients. They reduce the incidence of death from coronary causes and death from any cause in men with established coronary artery disease. There is also evidence that the statins may affect coronary vasculopathy by a mechanism independent of cholesterol lowering, possibly associated with the immune system. The more lipophilic (fat loving) statins have been associated with some skeletal muscle complaints (myositis, rhabdomyolysis), but most of the side effects reported in clinical trials have been mild and tolerable (headache, abdominal pain, constipation, flatulence, and diarrhea).

Cardiovascular disease afflicts nearly 60 million Americans and leads to almost half of all deaths, yet only about a quarter of patients with angina or a previous myocardial infarction (MI) are taking a drug to reduce cholesterol levels. With annual sales worldwide of more than $4 billion and an enormous potential market, HMG-CoA reductase inhibitors could become one of the most successful classes of pharmaceuticals ever developed.

Preventing Second Heart Attacks with Simvastatin

The first of the major clinical trials to document the beneficial effects of the statins on mortality from heart disease was the Scandinavian Simvastatin Survival Study. In this five-year, multicenter trial involving 4,444 middle aged men with hypercholesterolemia and established CAD, simvastatin in a dose of 20-40 mg per day reduced the overall risk of heart attack (fatal and nonfatal) by 37%. Benefits were apparent within about one year of initiation of therapy, and by two years the risk of coronary artery disease death was reduced by 46%. Although the study focused on preventing second heart attacks, the investigators noted that simvastatin also reduced the risk of undergoing myocardial revascularization procedures by 37% and slightly reduced fatal and nonfatal cerebrovascular events. (Scandinavian Simvastatin Survival Study Group (4S).

According to Merck, the cost of the drug administered to study participants ($11.5 million) was only partially offset by the savings in hospitalization ($8 million) — but there are 75 more people alive today who would otherwise have succumbed to heart disease.

Preventing First Heart Attacks with Pravastatin

If reducing cholesterol levels can increase survival in patients with coronary artery disease, will cholesterol reduction increase survival in hypercholesterolemic subjects without any signs of CAD? Scottish researchers have reported that reducing cholesterol levels in otherwise healthy men with hypercholesterolemia can indeed reduce mortality from coronary artery disease. In the West of Scotland Coronary Prevention Study, the HMG-CoA reductase inhibitor pravastatin (Pravachol/Bristol-Myers Squibb) was found to be effective for preventing first heart attacks in men apparently free of coronary disease. Participants in this placebo-controlled trial were 6,595 middle-aged men (45-64 years old) in apparent good health but with LDL cholesterol levels of 155-232 mg/dL (4.0-6.0 mmol/L), the highest quartile of the range found in the British population. (In the US, approximately 25% of the adult male population has LDL cholesterol levels above 155 mg/dL.)

Compared with placebo, pravastatin 40 mg/day lowered plasma cholesterol levels by 20%, low-density lipoprotein cholesterol by 26%, and triglycerides by 12%, and increased levels of HDL cholesterol by 5%. During five-year follow-up, pravastatin significantly reduced the rate of fatal and nonfatal coronary events (by 31%), death from all cardiovascular causes (by 32%), and overall mortality (by 22%). Risk reduction was independent of age and smoking status, and beneficial effects were seen within six months of initiation of therapy. As in the simvastatin study, coronary angiography and revascularization were significantly reduced in the treated group. When subjects were grouped based on lipid levels at baseline, coronary risk was related to higher plasma LDL cholesterol and triglyceride levels (levels above the median values) and lower HDL cholesterol levels (below the median value). Plasma cholesterol was not a significant factor.

Pravastatin is unique among the HMG-CoA inhibitors in that it is hydrophilic and so skeletal muscle side effects are not the problem they are with lipophilic agents. As with other studies, pravastatin did not cause myopathy and had no effect on liver function. Therapy was well tolerated and withdrawals from the pravastatin group were no more frequent than from the placebo group. According to the investigators, “reducing cholesterol levels with pravastatin reduces the risk of coronary events in asymptomatic subjects with hypercholesterolemia.” They estimated that if 1000 men with hypercholesterolemia and no evidence of previous myocardial infarction were treated with pravastatin for five years, there would be 20 fewer nonfatal MIs, seven fewer deaths from cardiovascular causes and two fewer deaths from other causes than would be expected in the absence of statin therapy.  Bristol-Myers spent $30 million on the study, but it remains to be seen how the cost of treatment balances the cost of disease.

Heart Transplantation: Adding Pravastatin to the Drug Regimen

Survival following heart transplantation has increased dramatically in recent years. For patients today who can afford the high cost of transplantation and are lucky enough to obtain a donor heart, survival rates following surgery are about 85% after one year and 70% after five years. The three factors limiting survival are rejection and infection during the first year after transplantation, and accelerated CAD. Rejection is controlled primarily with the immunosuppressant cyclosporine, infection with a range of antimicrobials, and CAD with drugs to reduce hypercholesterolemia.

Cyclosporine by itself deserves much of the credit for prolonging post-transplantation survival. According to editorialists Valantine and Schroeder in New England Journal of Medicine, at least 60% of patients can be maintained on cyclosporine plus a second immunosuppressant (azathioprine), with corticosteroids added when rejection occurs. For patients resistant to corticosteroids, antilymphocyte antibodies can be administered, although this will increase the risk of infection and lymphoma. The most promising drugs under investigation for preventing transplant rejection are those that inhibit the metabolism, proliferation, or activity of the T-lymphocytes involved in the rejection mechanism.

To reduce the risks associated with cyclosporine therapy (the drug is nephrotoxic), investigators are coadministering the drug with an agent that delays the metabolism of cyclosporine, effectively extending the half-life and reducing the dose of cyclosporine required to maintain therapeutic blood levels. Two cyclosporine-sparing agents under investigation — diltiazem and ketoconazole — are known to bind hepatic cytochrome oxidase and inhibit cyclosporine metabolism. In a study of diltiazem coadministered with cyclosporine after heart transplantation, Valantine et al found that patients in the diltiazem group had reduced rates of coronary artery narrowing during the first year, a decrease in the number of patients dying from coronary artery disease in the transplants, and a marked improvement in overall survival. Diltiazem also reduced systemic blood pressure, improved renal function, and slowed the development of hypercholesterolemia.

Ketoconazole is another cyclosporine-sparing agent that can reduce the dose required to maintain adequate immunosuppression. In their study of 43 cardiac transplant patients, Keogh et al found that early administration of low-dose ketoconazole (200 mg per day) reduced the cyclosporine dose by 62% at one week and 80% at one year (as compared with controls). Moreover, ketoconazole reduced the rate of rejection and the incidence of infection. Since ketoconazole is an antifungal, the dramatic reduction in fungal infections observed in treated patients was expected. But treated patients showed reductions in all types of infection. Since ketoconazole also has some activity against certain bacteria and viruses (for example, Staphylococcus epidermidis, Nocardia, and herpes simplex viruses 1 and 2), the overall reduction in infectious disease is probably due to ketoconazole’s broad antimicrobial action. The reduction in infection could also reflect reduced immunosuppression because of the lower dose of cyclosporine needed. The investigators estimated that ketoconazole therapy resulted in cost savings per patient of $5,200 in the first year of therapy and about $3,920 in each subsequent year. This estimate represents only the cost of drugs, not the savings from reduced rates of rejection and infection.

Another important cause of morbidity following heart transplantation is accelerated coronary artery disease. Hypercholesterolemia is common after transplantation, affecting 60-80% of recipients and causing coronary vasculopathy in the transplants. Kobashigawa et al reported that early use of pravastatin after cardiac transplantation safely lowers cholesterol levels, reduces the incidence of CAD, decreases the incidence of major rejection (accompanied by hemodynamic compromise), improves one-year survival, and reduces the development of coronary vasculopathy (as diagnosed by coronary angiography, intracoronary ultrasonography, or at autopsy). The investigators followed 47 transplant patients given pravastatin 20-40 mg/day and 50 transplant patients who did not receive pravastatin (to serve as controls). Although pravastatin did not prevent rejection, it delayed the onset of rejection and thus improved first-year survival. The beneficial effects may result directly from the reduction in cholesterol levels, or may be due to the effects of pravastatin on the immune system (the drug suppresses natural killer cells). There may be a synergistic effect between pravastatin and cyclosporine, since pravastatin does not cause immunosuppression in the absence of cyclosporine (i.e. in patients who do not have transplants).

Infection, rejection, and accelerated CAD in the transplanted heart are all interrelated. For example, the most common cause of infection following transplantation is cytomegalovirus, and this virus not only increases morbidity but also predisposes patients to rejection and coronary artery disease of their transplants. The antiviral ganciclovir in combination with cytomegalovirus hyperimmune globulin provides the best prophylaxis against cytomegalovirus infection, and also prevents fungal infections, reduces the incidence of acute rejection, and has the potential to protect against CAD in transplants. Ketoconazole protects against a broad range of fungal, bacterial and viral infections, and reduces the incidence of transplant rejection. And pravastatin reduces coronary artery disease and protects against rejection. The optimal drug regimen following heart transplantation may turn out to be cyclosporine, ketoconazole, and pravastatin, with ganciclovir plus cytomegalovirus hyperimmune globulin for preventing viral infection. What remains to be seen is what adverse effects these drugs have on each other and on the patient.

(Source: http://www.imshealth.com)

US$: Sales and rank are in US$ with quarterly exchange rates.

LC$: Growth is in constant $ to normalize for exchange rate fluctuations.

Growth rates in US$ are not recommended due to extreme fluctuations in the value of the dollar.

Product names shown are IMS International Product names.

Products marketed around the world with different names or marketing companies are grouped together.

The names generally reflect the name in the country where the product was lauched first.

A match on two of three criteria (local brand name, marketing corporation and active ingredient) will be grouped together.