Showing papers in "Drugs in 1987"

Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy.

Abstract: Pentoxifylline (oxpentifylline) is an orally active haemorheological agent for the treatment of peripheral vascular disease, cerebrovascular disease and a number of other conditions involving a defective regional microcirculation. Pentoxifylline acts primarily by increasing red blood cell deformability, by reducing blood viscosity and by decreasing the potential for platelet aggregation and thrombus formation. Extensive open and placebo-controlled studies have shown that pentoxifylline 600 to 1200 mg/day for at least 6 weeks is associated with subjective and objective improvements in 60 to 100% of patients with peripheral vascular disease. The most commonly assessed clinical parameter, walking distance, is usually improved by about 100%, although much greater improvements have also been documented. Other parameters which have been clearly improved include lower limb rest pain, paraesthesia, muscle blood flow, cramps and leg ulcers. Pentoxifylline has produced consistently better results than placebo, and in those studies using comparative drugs, better results than nylidrin, adenosine and naftidrofuryl. In patients with cerebrovascular disorders, open studies with pentoxifylline, usually at a dosage of 600 to 1200 mg/day (300 to 600 mg/day in Japan), have shown marked overall clinical improvements in about 85% of patients. Symptomatic improvements in rehabilitation psychometric tests, neuromotor and speech deficits and other subjective symptoms have accompanied increased cerebral blood flow, particularly to ischaemic areas. Pentoxifylline would appear to be useful in most types of cerebrovascular disease including transient ischaemic attacks, sequelae of cerebral thrombosis and haemorrhage, and chronic ischaemic disorders. In patients with chronic cerebrovascular disease pentoxifylline 600 to 1200 mg/day conferred significant clinical benefit compared with placebo and in isolated studies proved to be superior to drugs such as co-dergocrine mesylate, adenosine and pyrithioxine. Preliminary studies indicate that pentoxifylline may also prove useful in vaso-occlusive crises of sickle cell disease, some hearing disorders, disorders of eye circulation, high altitude sickness and asthenozoospermia. Pentoxifylline is usually well tolerated when administered as the conventional controlled release formulation, gastrointestinal symptoms (about 3%) being the most common complaint, although these and other adverse effects have not occurred to a significantly greater extent than with placebo. Thus, pentoxifylline offers a well-tolerated and effective alternative to the treatment options available for patients with peripheral vascular disease.(ABSTRACT TRUNCATED AT 400 WORDS)

The retinoids. A review of their clinical pharmacology and therapeutic use.

Abstract: With the introduction of the synthetic retinoids, oral therapy with an acceptable risk/benefit ratio became possible for a variety of skin diseases including severe acne, psoriasis and numerous genodermatoses. This article reviews the clinical pharmacology, mechanisms of action and therapeutic use of the retinoids, particularly isotretinoin (13-cis-retinoic acid) and etretinate. The free aromatic acid of etretinate, etretin, and the new polyaromatic retinoid compounds (arotinoids) are also discussed. Isotretinoin is used clinically for oral therapy of severe acne, but is also recommended for severe Gram-negative folliculitis and rosacea not responding to traditional therapy. The results of several studies have established that acne therapy should be started with 1.0 mg/kg/day for 2 to 3 months after which the daily dosage should be lowered to 0.2 to 0.5 mg/kg/day for another 2 to 3 months. This therapeutic regimen of isotretinoin has proven to be the most successful in preventing relapses. Etretinate is particularly useful for oral therapy of widespread plaque-like, pustular and erythrodermic psoriasis, and of generalised lichen planus, Darier's disease and severe congenital ichthyoses. Whereas pustular forms of psoriasis require a high daily dosage of 1.0 mg/kg/day, erythrodermic psoriasis should be treated with a lower dosage of 0.25 to 0.35 mg/kg/day. In chronic plaque-like psoriasis, a mean daily dosage of 0.5 mg/kg/day over several weeks to months, usually combined with photo(chemo)therapy, tar or dithranol, is recommended. Other indications for oral etretinate therapy are adequately treated with a moderate dosage of 0.4 to 0.75 mg/kg/day. Etretin differs from etretinate in having a much shorter elimination half-life of 2 to 3 days, in contrast to 80 to 100 days after long term administration of etretinate. Moreover, it has not been shown to increase serum cholesterol levels. However, its clinical efficacy is not yet clearly established. Among the arotinoids, arotinoid ethylester (Ro 13-6298) has revealed the best anti-psoriatic and anti-inflammatory effects at extremely low dose levels. Furthermore, no significant elevations of serum lipids have been observed. Taking its prolonged elimination half-life and its efficacy/side effect ratio into account, the drug is comparable to etretinate. The free arotinoid carboxylic acid (Ro 13-7410) is currently undergoing clinical investigation. Another arotinoid, the parent compound Ro 15-0778, has not demonstrated any convincing clinical efficacy in acne or psoriasis, but topical anti-inflammatory effects were evident in some models.(ABSTRACT TRUNCATED AT 400 WORDS)

Ofloxacin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic use.

Abstract: Ofloxacin is one of a new generation of fluorinated quinolones structurally related to nalidixic acid. It is an orally administered broad spectrum antibacterial drug active against most Gram-negative bacteria, many Gram-positive bacteria and some anaerobes. Ciprofloxacin is the only other quinolone with superior in vitro antibacterial activity. However, the pharmacokinetic profile of ofloxacin is superior to that of ciprofloxacin, with more rapid absorption and a peak serum concentration several times higher. Moreover, ofloxacin achieves high concentrations in most tissues and body fluids. The results of clinical trials with ofloxacin have confirmed the potential for use in a wide range of infections, which was indicated by its in vitro antibacterial and pharmacokinetic profiles. It has proven effective against a high percentage of infections caused by Gram-negative organisms, slightly less effective against Gram-positive infections, and effective against some anaerobic infections. Clinical efficacy has also been confirmed in a variety of systemic infections as well as in acute and chronic urinary tract infections, and ofloxacin has generally appeared to be at least as effective as alternative orally administered antibacterial drugs. Ofloxacin is well tolerated and, although experience with the drug in clinical practice to date is limited, bacterial resistance does not appear to develop readily. Thus, ofloxacin is an orally active drug which offers a valuable alternative to other broad spectrum antibacterial drugs.

Nicardipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in the treatment of angina pectoris, hypertension and related cardiovascular disorders

Abstract: Nicardipine is an antagonist of calcium influx through the slow channel of the cell membrane and has been shown to be an effective and relatively well-tolerated treatment for stable effort angina and rest angina due to coronary artery spasm, and mild to moderate hypertension Although its exact mechanism of action in these disease states has not been precisely defined, the potent coronary and peripheral arterial dilator properties of nicardipine, with concomitant improvements in oxygen supply/demand and reductions in systemic vascular resistance, are of major importance Clinical studies have shown that nicardipine appears to be effective in the treatment of chronic stable exercise-induced angina pectoris and possibly in angina at rest due to coronary artery spasm In the treatment of stable angina, nicardipine has proved to be equally as effective as nifedipine However, haemodynamic and clinical studies indicate that nicardipine may have a further advantage of not depressing cardiac conduction or left ventricular function, even in patients with compromised cardiac pumping ability Nicardipine also appears to be useful as initial monotherapy or in combination with other antihypertensive drugs when used in the treatment of mild to moderate hypertension, and may have some advantages over other vasodilators in this regard in that it may not be as frequently associated with fluid retention or weight gain as other similar drugs In the treatment of hypertension nicardipine has been shown to be as effective as drugs such as hydrochlorothiazide, cyclopenthiazide, propranolol and verapamil in short term studies although confirmation of its long term usefulness in well-designed clinical trials is still required Similarly, although the use of nicardipine in other disorders such as congestive heart failure and cerebrovascular disease has provided encouraging preliminary results, more studies are needed to clarify its place in their treatment Side effects appear to be dose related and more frequent within the first few weeks of therapy Most of these effects are minor and transient in nature and include headache, flushing and peripheral oedema Thus, there is no doubt that nicardipine provides a suitable alternative to other drugs available for the treatment of angina and hypertension However, further well-designed comparative clinical trials are needed to clarify its relative place in the long term management of these disorders

Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states.

Abstract: Ticlopidine is an inhibitor of platelet action that has been used in the treatment of a variety of disease states in which platelets play a prominent role. Studies in animals and man have demonstrated that ticlopidine is a potent inhibitor of platelet aggregation induced by adenosine diphosphate (ADP), and variably inhibits aggregation due to collagen, adrenaline (epinephrine), arachidonic acid, thrombin, and platelet activating factor. Inhibition of platelet aggregation is both dose- and time-related, with its onset of activity being 24 to 48 hours, its maximal activity occurring after 3 to 5 days, and its activity still being present 72 hours after a final dose. Ticlopidine also inhibits the release reaction of platelets, prolongs bleeding time, reduces plasma levels of platelet factor 4 and beta-thromboglobulin in patients in whom these proteins are elevated, and may also inhibit platelet adhesion, increase red cell filtrability and decrease whole blood viscosity. In a large number of animal models, ticlopidine markedly inhibits thrombus formation or graft occlusion. Ticlopidine is well absorbed after oral administration. It is extensively metabolised and at least one of its metabolites is pharmacologically active. Therapeutic trials in patients with chronic arterial occlusion due to thrombangitis obliterans or arteriosclerosis obliterans, post-myocardial infarction, cerebrovascular thromboembolic disease, subarachnoid haemorrhage, vascular shunts or fistulas for haemodialysis, and sickle cell disease have shown promise for the use of ticlopidine. However, trials of patients with intermittent claudication, angina pectoris, diabetes mellitus with microvascular disease, aortocoronary bypass grafts, and vascular prostheses have had conflicting results or have shown an unfavourable side effect profile. Further studies are clearly required to establish the role of ticlopidine in many of these areas, some of which are already in progress. Overall, side effects occur in 10 to 15% of patients receiving ticlopidine. The most common side effects are gastrointestinal disturbances and skin rashes. Neither of these necessarily require discontinuation of therapy in most patients. Agranulocytosis, thrombocytopenia, and cholestatic jaundice have also been reported. Bleeding is infrequent except possibly in patients receiving ticlopidine prior to some surgical procedures.

The evolution of non-steroidal anti-inflammatory drugs and their mechanisms of action.

Abstract: The pro-inflammatory effects of prostaglandins have been clearly demonstrated with the use of various animal models of inflammation. Furthermore, the anti-inflammatory effects and some of the side effects of aspirin and other non-steroidal anti-inflammatory agents have been shown to depend on their ability to inhibit cyclo-oxygenase. These drugs, therefore, reduce the synthesis of prostaglandins, prostacyclin and thromboxane. They do not affect leukotriene production and there is no firm evidence to suggest that they alleviate inflammation through any other mechanism. In contrast, the corticosteroids facilitate the release of lipocortin which, through inhibition of phospholipase A2 reduces arachidonic acid release. These drugs possess potent anti-inflammatory properties and attempts have been made to develop non-steroidal drugs, such as BW755C, that display similar anti-inflammatory activity through inhibition of the 2 main pathways of the arachidonic acid cascade. Administration of low dose aspirin 40 mg/day selectively inhibits production of thromboxane A2 without affecting prostacyclin. This may be because, firstly, about 60% of an administered dose of aspirin is deacylated to salicylate during first-pass metabolism and, secondly, platelets cannot regenerate cyclo-oxygenase. Thus, absorbed aspirin irreversibly affects platelet thromboxane production in the pre-systemic circulation, but the systemic plasma aspirin concentration is likely to be too low to affect prostacyclin synthesis. Studies in experimental inflammation have shown that after the administration of aspirin, the concentration of salicylate in inflammatory exudate is considerably higher than that of aspirin. In addition, a comparison of prostaglandin synthesis inhibitory potencies shows that the concentration of salicylate, but not of aspirin, at the inflammatory site is high enough to substantially inhibit prostaglandin synthesis.

Pentamidine isethionate. A review of its antiprotozoal activity, pharmacokinetic properties and therapeutic use in Pneumocystis carinii pneumonia.

Abstract: Pentamidine isethionate, an aromatic diamidine, is an antiprotozoal agent proven to decrease mortality from Pneumocystis carinii pneumonia in debilitated infants and immunodeficient adults and children. Like the combination antimicrobial agent co-trimoxazole, pentamidine has been shown in retrospective studies to resolve episodes of pneumonia in approximately 41 to 87% of patients, including those with the acquired immunodeficiency syndrome (AIDS), when used alone or as sequential therapy. Although about 45% of all patients given pentamidine experience side effects--which may include nephrotoxicity, hypotension, hypoglycaemia or local reactions--in patients with AIDS the incidence of side effects is less with pentamidine than with co-trimoxazole. Thus, despite its profile of potentially severe side effects, pentamidine isethionate is a proven antimicrobial agent with a distinct place in the treatment of Pneumocystis carinii pneumonia in the growing population of AIDS patients.

Imipenem/cilastatin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy.

Abstract: Imipenem is the first available semisynthetic thienamycin and is administered intravenously in combination with cilastatin, a renal dipeptidase inhibitor that increases urinary excretion of active drug. In vitro studies have demonstrated that imipenem has an extremely wide spectrum of antibacterial activity against Gram-negative and Gram-positive aerobic and anaerobic bacteria, even against many multiresistant strains of bacteria. It is very potent against species which elaborate beta-lactamases. Imipenem in combination with equal doses of cilastatin has been shown to be generally well tolerated and an effective antimicrobial for the treatment of infections of various body systems. It is likely to be most valuable as empirical treatment of mixed aerobic and anaerobic infections, bacteraemia in non-neutropenic patients and serious hospital-acquired infections.

Pharmacokinetic Properties of the Cephalosporins

Abstract: Most cephalosporins can only be administered parenterally. Among agents that are absorbed from the gastrointestinal tract, those with bioavailabilities of 85 to 90% include cefroxadine, cefadroxil, cefsumide, cephalexin, cephradine, cephacetrile, and cefazaflur. Most cephalosporins are eliminated rapidly, with serum half-lives (t1/2s) of 1 to 2 hours. Exceptions are cefonicid with a t1/2 of 4.4 hours, cefpiramide with a t1/2 of 5.0 hours, and cefotetan with a t1/2 of 3.5 hours. The longest half-life is shown by ceftriaxone with a t1/2 of 8.5 hours. Cephalosporins are eliminated mostly by the kidneys, some with a substantial contribution from active tubular secretion, which is blocked by probenecid. The degree of metabolism varies. Only a few cephalosporins have a high biliary elimination. For example, with intravenously administered cefoperazone, about 70% appears in bile. High biliary elimination is also observed with cefmenoxime, ceftriaxone, cefbuperazone, and latamoxef (moxalactam). Because these are not appreciably absorbed from the gastrointestinal tract, the consequence is high intraintestinal concentrations of the drugs and a marked ensuing depression of the normal microflora with simultaneous emergence of resistant bacteria. The untoward ecological impact may even lead to Clostridium difficile-associated enterocolitis.

Side Effects of Cephalosporins

Abstract: Cephalosporins generally cause few side effects. Hypersensitivity reactions are less common than with the penicillins and modern studies have presented data contradicting a true cross-reactivity to cephalosporins in patients who have previously reacted to penicillins. Other hypersensitivity reactions to cephalosporins include fever, arthralgia and exanthema observed in two clusters of children who had been given cefaclor. Nephrotoxicity is not a problem with modern cephalosporins, although slight reductions of renal function have been seen when high doses of ceftazidime were used. Some of the new cephalosporins have a 3-methyl thiotetrazole side-chain, a moiety which confers a risk of reduced synthesis of prothrombin with subsequent risk of bleeding, and of disulfiram-like reactions in patients consuming alcohol following a cephalosporin dose. Other cephalosporins, e.g. ceftriaxone and cefoperazone, are excreted not only via the kidneys but also via the bile. This leads to high biliary concentrations of the active drug, increasing the risk of diarrhoea which may be caused by selection of cytotoxin-producing strains of Clostridium difficile. Laboratory adverse reactions to cephalosporins are rare. Eosinophilia and thrombocytosis are commonly reported, but are most probably not adverse reactions but signs of healing of the infections treated. Other haematological reactions have been reported in very few patients and have been rapidly reversible when treatment was stopped.

l-Carnitine. A preliminary review of its pharmacokinetics, and its therapeutic use in ischaemic cardiac disease and primary and secondary carnitine deficiencies in relationship to its role in fatty acid metabolism.

Abstract: l-Carnitine occurs naturally as an essential cofactor of fatty acid metabolism which is synthesised endogenously or obtained from dietary sources. In patients with primary carnitine deficiencies, which may be life-threatening, and some secondary deficiencies such as organic acidurias, the exogenously administered compound is clearly beneficial: by abolishing hypotonia, motor skills are improved, as are muscle weakness and wasting. In preliminary clinical trials in patients with ischaemic cardiac disease, therapy with l-carnitine has shown beneficial effects on myocardial function and metabolism and has improved exercise tolerance in patients with angina pectoris-findings which require further substantiation in larger controlled studies. Moreover, while some interesting evidence suggests that l-carnitine may find potential use in such diverse conditions as carnitine deficiencies secondary to prolonged total parenteral nutrition supplementation or chronic haemodialysis, hyperlipidaemias and the prevention of toxicity induced by anthracyclines and valproate, such findings must be regarded as preliminary. Exogenously administered l-carnitine is very well tolerated. Thus, while its role in primary deficiencies is established, with its profile of negligible toxicity l-carnitine is worthy of further investigation to more clearly define its therapeutic applications in a variety of conditions which may be indirectly related to alterations in fatty acid metabolism.

Bezafibrate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hyperlipidaemia.

Abstract: Bezafibrate is a lipid-lowering drug, chemically related to clofibrate. At its recommended dosage of 200 mg 3 times daily, or alternatively 400 mg once daily as a sustained-release preparation, it produces substantial reductions in plasma triglyceride and cholesterol concentrations in patients with hypertriglyceridaemia and hypercholesterolaemia, respectively. Preliminary investigations indicate that a single daily dose of 400 mg in a sustained-release preparation is as effective as 200 mg 3 times daily. In patients with any type of hyperlipoproteinaemia bezafibrate also increases the plasma HDL-cholesterol concentration. These effects are equivalent in patients with primary hyperlipoproteinaemia or hyperlipoproteinaemia secondary to diabetes or renal disease, although dosage adjustment is important in the latter group. During long term therapy (2 to 4 years) the influence of bezafibrate on the lipid profile is sustained. The lipid-lowering effects of bezafibrate are at least equivalent to those of clofibrate, fenofibrate, colestipol, probucol or sustained release etofibrate. In addition, the increase in HDL-cholesterol tends to be at least as great as with all alternative treatments studied. Bezafibrate is rapidly eliminated, and thus does not accumulate during prolonged administration in patients with normal renal function. Experimental studies have shown bezafibrate to have a complex range of effects on lipoproteins and on the enzymes and receptors involved in lipid metabolism. However, its exact mechanism of lipid-lowering action is unclear. Bezafibrate enhances anticoagulation in hyperlipoproteinaemic patients requiring anticoagulant therapy, and preliminary investigations indicate that it reduces the plasma fibrinogen concentration, especially in patients with hyperfibrinogenaemia. These properties of bezafibrate could contribute to an antiatherogenic effect of the drug, but further investigation is required to establish the drug's potential as chronic therapy in patients with hyperfibrinogenaemic atherosclerosis. Adverse reactions to bezafibrate have largely been restricted to gastrointestinal disturbances, with some cutaneous reactions and central nervous system effects. The incidence of side effects has been no greater than with comparative lipid-lowering drugs. In patients with renal disease, a few cases of marked elevation of serum creatine phosphokinase and myoglobin, and associated muscle cramps, have been reported (diagnosed as rhabdomyolysis). Hepatic enzyme induction by bezafibrate in rats results in hepatomegaly, but there has been no case of significant hepatotoxicity in man.(ABSTRACT TRUNCATED AT 400 WORDS)

Nitrendipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension.

Abstract: Nitrendipine is a calcium entry blocker shown to inhibit the movement of calcium through the 'slow channel' of cardiac and vascular smooth muscle, thus inducing peripheral vasodilation with consequent reductions in elevated blood pressure. As evidenced by clinical trials, nitrendipine promptly lowers blood pressure in patients with mild to moderate hypertension, and sustains this effect during long term administration. Combining nitrendipine with other antihypertensive agents such as diuretics or beta-blockers often results in successful treatment in patients unresponsive to nitrendipine monotherapy. Headache, oedema, flushing and palpitations commonly occurring during treatment with nitrendipine are generally mild, usually subsiding with continued therapy. Thus, although additional long term studies are required to properly assess the relative merits of the drug compared with other antihypertensives, by providing the clinician with an effective and safe alternative to traditional therapies, nitrendipine represents a step forward in the treatment of mild to moderate hypertension.

Sulbactam/ampicillin. A review of its antibacterial activity, pharmacokinetic properties, and therapeutic use.

Abstract: Sulbactam is a semisynthetic beta-lactamase inhibitor which when combined with certain beta-lactam antibacterials extends their activity against bacteria that are normally resistant to the antibiotic due to production of beta-lactamases. In combination with ampicillin it extends the antibacterial activity of ampicillin to include beta-lactamase-producing strains which are otherwise resistant, including Bacteroides fragilis, and increases the susceptibility of many sensitive strains. Sulbactam is poorly absorbed after oral administration and sulbactam/ampicillin is therefore administered parenterally, although another linked sulbactam-ampicillin compound, sultamicillin, has been developed which is well absorbed after oral administration. The basic pharmacokinetic characteristics of sulbactam after parenteral administration are similar to those of ampicillin. Multiple-dose therapy with sulbactam/ampicillin is clinically and bacteriologically effective in infections of the urinary tract, skin and soft tissue, bones and joints, respiratory tract, ears, nose and throat, as well as intra-abdominal and obstetric and gynaecological infections and septicaemia. In addition, single intramuscular doses of sulbactam/ampicillin administered with oral probenecid are therapeutically effective in gonorrhoea, including infections due to penicillinase-producing and/or ampicillin-resistant Neisseria gonorrhoeae. In the prophylaxis of infectious complications of surgery sulbactam/ampicillin is superior to placebo and appears to be similar in efficacy to several alternative antibacterial regimens. Further studies involving larger numbers of patients are needed to clarify the comparative therapeutic and prophylactic efficacy of sulbactam/ampicillin and alternative antibacterial drugs. Nonetheless, sulbactam/ampicillin improves the therapeutic and prophylactic efficacy of an antibacterial of familiar safety, and must be seen as a worthwhile advance.

An elucidation of the arachidonic acid cascade. Discovery of prostaglandins, thromboxane and leukotrienes

Abstract: Arachidonic acid is normally stored in membrane-bound phospholipids and released by the action of phospholipases. Enzymatic conversion of released arachidonic acid into biologically active derivatives proceeds through one of several routes. Cyclo-oxygenase converts arachidonic acid to unstable cyclic endoperoxides from which prostaglandins, prostacyclin and thromboxanes are derived. Formation of the leukotrienes from arachidonic acid is initiated by the action of 5-lipoxygenase producing leukotriene A4. Hydrolysis of leukotriene A4, or the incorporation of glutathione results in the formation of leukotriene B4 and C4, respectively. In addition, 12- and 15-lipoxygenase can catalyse arachidonic acid conversion and lipoxins A and B are amongst the possible products. Many of these metabolites of arachidonic acid feature prominently in the development of inflammation. Prostaglandin E2 and prostacyclin are potent vasodilators, while leukotriene D4 causes cellular adhesion, chemotaxis of neutrophils and degranulation. Leukotrienes C4, D4 and E4 contribute to inflammation by increasing vascular permeability. Leukotrienes are also believed to play an important pathophysiological role in allergic broncho-constriction of asthma. Through pharmacological intervention in the arachidonic acid cascade various anti-inflammatory agents have been developed. These include aspirin-like drugs, which inhibit cyclo-oxygenase. Corticosteroids appear to indirectly inhibit phospholipases thus preventing release of arachidonic acid. Future progress in this field is likely to produce drugs which antagonise arachidonic acid derivatives or inhibit the enzymes involved in their synthesis with greater specificity.

'Second generation' dihydropyridine calcium antagonists. Greater vascular selectivity and some unique applications.

Abstract: The newer dihydropyridine calcium antagonists are structurally related to nifedipine, but may provide greater vascular selectivity and wider clinical utility. Five new dihydropyridines — nisoldipine, nicardipine, nimodipine, felodipine and nitrendipine — are reviewed with regard to their preclinical pharmacology, haemodynamic effects and clinical indications.

Sotalol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use.

Abstract: Sotalol is a beta-adrenoceptor blocking agent devoid of intrinsic sympathomimetic activity, membrane stabilising actions and cardioselectivity. It lengthens repolarisation and the effective refractory period in all cardiac tissues independently of its antiadrenergic properties. Combining Class II and Class III antiarrhythmic properties, sotalol can be given either intravenously or orally and its pharmacokinetic properties permit long dosing (once or twice daily) intervals. Controlled and uncontrolled studies have established the efficacy of sotalol in mild-to-moderate essential hypertension and in angina of effort. Sotalol reduces anginal frequency and glyceryl trinitrate (nitroglycerin) consumption and increases exercise capacity during treadmill stress tests. In addition, although there is evidence that the drug reduces reinfarction rate in survivors of acute infarction, the data for reduction in sudden death rates in these patients are not as compelling as for other beta-blockers. However, comparative and additional long term studies are required before an accurate assessment of the use of sotalol in these disorders can be made. When used in the treatment of mild-to-moderate hypertension sotalol is more effective than placebo and comparable to other beta-blockers in reducing elevated blood pressures. In addition, a synergistic antihypertensive response is achieved when sotalol is combined with hydrochlorothiazide. Still, additional well-controlled comparative studies are required before the value of sotalol relative to other drug treatment regimens in the management of hypertension can be made. In preliminary studies sotalol appeared effective in most forms of supraventricular tachyarrhythmias with its effects being similar to those of other beta-blockers. However, preliminary data indicate that sotalol is likely to be more effective than than conventional beta-blockers in converting atrial flutter and fibrillation to sinus rhythm and maintaining stability post-conversion. Sotalol also appears to be a promising agent in the control of ventricular arrhythmias. In suppressing premature ventricular contractions it is at least as effective as procainamide. In ventricular tachycardia and fibrillation, intravenous sotalol (1.5 mg/kg), prevents reinduction by programmed electrical stimulation in 40 to 50% of cases if double stimuli are used. Both prevention of reinducible arrhythmia and the suppression of spontaneous arrhythmias on Holter recordings are predictive of a long term favourable clinical outcome. In patients with reduced ejection fractions, sotalol depresses ventricular function less than conventional beta-blockers.(ABSTRACT TRUNCATED AT 400 WORDS)

Lipid-lowering drugs. An overview of indications and optimum therapeutic use.

Abstract: Drug treatment of patients with hyperlipoproteinaemia is indicated to reduce the risk of atherosclerosis in patients with increased concentrations of atherogenic lipoproteins, and to lower the plasma concentrations of triglyceride-rich lipoproteins in patients with severe hypertriglyceridaemia who are at risk of abdominal pain and pancreatitis. Such therapy should be initiated only after satisfactory exclusion of secondary causes of hyperlipoproteinaemia, and should be regarded as an adjunct to rather than a substitute for appropriate dietary therapy. Drug therapy should be strongly considered in those patients with concentrations of atherogenic lipoproteins which exceed the 90th to 95th percentile for age. In patients with increased plasma concentrations of low density lipoproteins (LDL), agents which enhance the rate of LDL catabolism (cholestyramine and colestipol) or reduce the rate of LDL synthesis [e.g. nicotinic acid (niacin)] are the 'drugs of choice'. For those patients with concurrent hypertriglyceridaemia, nicotinic acid is the preferred initial drug, and in both patient groups combined drug therapy is often necessary to attain optimal reductions in LDL cholesterol concentrations. Clofibrate remains the 'drug of choice' for the rare patient with type III hyperlipoproteinaemia, whereas the newer agent gemfibrozil should be used in patients with plasma triglyceride concentrations above 1000 mg/dl who are at increased risk of abdominal pain and pancreatitis. Although currently limited to investigational use, mevinolin and related compounds, which are specific inhibitors of the rate-limiting enzyme in cholesterol biosynthesis (HMG Co-A reductase), offer considerable promise in the therapy of patients with primary hypercholesterolaemia due to elevated levels of LDL cholesterol.

Nedocromil sodium. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of reversible obstructive airways disease.

Abstract: Nedocromil sodium is a sodium cromoglycate-like drug which inhibits activation and mediator release from inflammatory cells such as eosinophils, neutrophils, macrophages, monocytes, mast cells and platelets. Non-comparative and placebo-controlled therapeutic studies in adult patients of up to 52 weeks duration have demonstrated the tolerability and efficacy of nedocromil 4 mg twice or 4 times daily in the management of reversible obstructive airways disease producing significant improvements in asthma symptom scores and pulmonary function tests. When added to existing therapy, nedocromil sodium permits reductions of 20 to 70% in concomitant bronchodilator use and appears to have a moderate steroid sparing effect in patients receiving inhaled corticosteroids. To date no controlled studies have been published comparing nedocromil sodium with sodium cromoglycate and other established therapies in adult reversible obstructive airways disease or asthma, which limits the overall conclusions which can be drawn about the position of nedocromil sodium relative to other treatments. However, preliminary clinical data suggest that although nedocromil sodium cannot substitute completely for bronchodilators or inhaled corticosteroids, with its additive and dose-sparing effects and the convenience of a twice daily dosage it is a promising prophylactic adjunctive agent for the management of reversible obstructive airways disease.

Tenoxicam. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy.

Abstract: Tenoxicam is a new non-steroidal anti-inflammatory and analgesic agent of the oxicam class, and therefore closely related to piroxicam. It possesses a long half-life which enables it to be administered once daily. Clinical trials in patients with rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gout and non-articular rheumatism suggest that tenoxicam 20mg daily is an equally effective anti-inflammatory and analgesic agent compared with piroxicam 20mg daily, and that it is at least as well tolerated. Additionally, a few small studies in rheumatoid arthritis and osteoarthritis suggest that tenoxicam 20mg daily is as effective and as well tolerated as usual therapeutic dosages of diclofenac, ibuprofen, indomethacin and naproxen. Transient mild or moderate gastrointestinal symptoms, in 8% of patients at a dosage of 20mg daily, are the most frequently reported side effects. If further studies confirm the initially favourable efficacy and tolerability findings, particularly the relatively low incidence of adverse effects, tenoxicam can be considered a useful new agent for the symptomatic treatment of rheumatic and inflammatory diseases, and a worthwhile alternative to other non-steroidal anti-inflammatory drugs.

Haloperidol decanoate. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis.

Abstract: Haloperidol decanoate is a depot preparation of haloperidol, a commonly used butyrophenone derivative with antipsychotic activity. Haloperidol decanoate has no intrinsic activity: its pharmacodynamic actions are those of haloperidol--primarily that of central antidopamine activity. The monthly administered depot formulation has several clinical and practical advantages over oral haloperidol: better compliance and more predictable absorption; more controlled plasma concentrations; fewer extrapyramidal side effects; less frequent reminders of condition; and reduced medical workload. In open and controlled studies, haloperidol decanoate has produced adequate maintenance or improvement of the condition of patients with psychoses (mainly schizophrenia) when an abrupt change from orally administered haloperidol or other antipsychotic drugs has been instituted. Limited comparative studies indicate that the depot and oral forms of haloperidol are equally effective, and that haloperidol decanoate is at least as effective as depot forms of fluphenazine, pipothiazine, flupenthixol and perphenazine in controlling the symptoms of psychosis. Extrapyramidal side effects and the need for concomitant anti-Parkinsonian drugs may be a problem, but may be less frequent than with oral haloperidol or other depot antipsychotics. Thus, haloperidol decanoate offers a useful alternative in the treatment of psychoses to orally administered haloperidol or to other depot antipsychotic drugs.

Propafenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias.

Abstract: Propafenone is a Class I antiarrhythmic agent with weak beta-adrenoceptor antagonist activity which can be given both intravenously and orally. Dosage must be individualised because of dose-dependent pharmacokinetics, a wide range of clinically effective plasma concentrations (64 to 3271 micrograms/L) after comparable doses, the presence of an active metabolite (5-hydroxy-propafenone) and genetically determined metabolic oxidation. In non-comparative studies propafenone 450 and 900 mg/day orally significantly suppressed premature ventricular complexes and couplets in 96% and 75% of patients, respectively, and abolished ventricular tachycardia in 75% of patients. Efficacy was confirmed in placebo-controlled studies in which propafenone 300 to 900mg daily suppressed premature ventricular complexes (greater than 80%) in 77% of patients; 87% of patients had significant reductions in couplets and abolition of ventricular tachycardia. In patients with ventricular arrhythmias refractory to other antiarrhythmic agents, propafenone 450 to 1200 mg/day suppressed arrhythmias in 63% of patients (in long term therapy 66%). Electrically induced arrhythmias were prevented by intravenously administered propafenone in 12 to 23% of patients. However, long term oral therapy was effective in 77% of patients selected using programmed electrical stimulation. Propafenone was also effective in suppressing atrial and AV nodal/junctional re-entrant tachycardias and Wolff-Parkinson-White tachycardias involving accessory pathways. A limited number of comparisons with other antiarrhythmic drugs indicate that the antiarrhythmic efficacy of propafenone is superior or similar to that of quinidine, disopyramide and tocainide, and comparable to that of lignocaine (lidocaine), flecainide and metoprolol against ventricular arrhythmias and a smaller number of atrial arrhythmias. Cardiovascular side effects indicate a proarrhythmic effect similar to that with other Class I drugs, occasional precipitation of congestive heart failure and conduction abnormalities; the latter two occur more often in patients with underlying ventricular dysfunction. Non-cardiovascular side effects (neurological, gastrointestinal) are well tolerated and generally resolve with continued therapy or dosage reduction. Thus, propafenone is an effective antiarrhythmic agent, and is a useful addition to currently available drugs, although further studies will be required to determine clearly its place in therapy compared with more established antiarrhythmic drugs.

Clinical pharmacokinetics of felodipine. A summary.

Abstract: Felodipine is completely absorbed from the gastrointestinal tract. However, the amount reaching the systemic circulation is reduced to about 15% because of first-pass degradation. The bioavailability is constant within the dose interval of 5 to 40mg orally. The frequency histogram of the area under the plasma concentration-time curve (AUC) seems to be normally distributed. The disposition of felodipine is independent of the administered dose over the intravenous dose interval (1-3 mg). The plasma concentration-time curve declines in 3 distinct phases. The mean elimination half-life of felodipine is approximately 25h. Felodipine is extensively distributed to extravascular tissues. The volume of distribution of felodipine is about 10 L/kg, implying that less than 1% of the amount of drug in the body is localised in the blood. Felodipine is more than 99% bound to plasma proteins. Mean total clearance from the blood is 1 to 1.5 L/min and, therefore, felodipine is considered a high clearance drug. Felodipine is metabolised completely and no unchanged drug is eliminated in the urine. The first step in the metabolism involves oxidation to the corresponding pyridine derivative by the cytochrome P-450 system. Identified metabolites in plasma and urine are devoid of vasodilating activity. Long term treatment, and the presence of hypertension and impaired renal function do not affect the disposition of felodipine. Elderly people may have higher plasma levels than the young and middle-aged. Impaired liver function significantly decreases systemic clearance. Cimetidine and food affect felodipine kinetics, but with negligible clinical implications. Therapeutic concentrations of felodipine do not interact with highly protein-bound drugs and these drugs have no effect on the binding of felodipine to human plasma proteins in vitro. Plasma levels of digoxin and metoprolol tended to increase during felodipine treatment. There is a significant correlation between plasma concentrations of felodipine and haemodynamic effects in both healthy subjects and hypertensive patients during short term as well as during long term treatment.

Antiviral therapy in AIDS. Clinical pharmacological properties and therapeutic experience to date.

Abstract: The rapid spread of human immunodeficiency virus (HIV) infections and the grim outcome of these infections have focused interest on the possibilities for medical intervention. The end- stage of these infections, acquired immune deficiency syndrome (AIDS), was first recognised in 1981, and the causative agent isolated in 1983. Already several antiviral drugs have been investigated. One initially promising drug, suramin, was found to have a net harmful effect but another, zidovudine (azidothymidine) has been shown to prolong life in AIDS patients. The properties of these and several other antiviral drugs such as antimoniotungstate (HPA- 23), foscarnet (phosphonoformate) ribavirin, dideoxynucleotides, and interferons, are reviewed. The role of immunomodulating modalities such as plasmapheresis, bone marrow transplantation, thymosin, interleukin- 2, inosine pranobex (isoprinosine), and cyclosporin are also discussed.

Buflomedil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in peripheral and cerebral vascular diseases.

Abstract: Buflomedil hydrochloride is a vasoactive drug with a variety of pharmacodynamic properties. Importantly, it seems to improve nutritional blood flow in ischaemic tissue of patients with peripheral and/or cerebral vascular disease by a combination of pharmacological effects: inhibition of alpha-adrenoceptors, inhibition of platelet aggregation, improved erythrocyte deformability, nonspecific and weak calcium antagonistic effects, and oxygen sparing activity. Therapeutic trials with buflomedil in patients with peripheral vascular diseases have shown that it increases walking distances in those with intermittent claudication and heals trophic lesions and reduces rest pain in many patients with more severe vasculopathies. In open clinical trials a good to very good clinical response was achieved in 57 to 87% of those treated. In comparative studies buflomedil 600 mg/day orally was shown to be significantly superior to placebo and comparable in efficacy to pentoxifylline (oxpentifylline) and naftidrofuryl. In patients with symptoms presumed to be due to cerebrovascular insufficiencies and elderly patients with senile dementia, buflomedil 450 to 600 mg/day alleviated symptoms associated with impairment of cognitive and psychometric function and was significantly superior to placebo and slightly more effective than drugs such as cinnarizine, flunarizine and co-dergocrine mesylate. Overall, buflomedil at dosages of up to 600 mg/day has been very well tolerated and discontinuation of therapy has rarely been necessary. Thus, buflomedil would seem to be a useful adjunct to conservative treatment in patients with mild-to-moderate peripheral vascular disease and/or cerebrovascular insufficiency, and well worth a try in patients with more severe peripheral disease unable to undergo surgery. However, a few well-designed long term studies are needed to fully define its overall place in therapy.

Misoprostol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of peptic ulcer disease.

Abstract: Misoprostol is an analogue of prostaglandin E1 and is the first synthetic prostaglandin analogue to be made available for the treatment of peptic ulcer disease. It inhibits gastric acid secretion in man, and there is also some evidence that it limits the extent of gastrointestinal damage induced by ulcerogenic agents in animals and healthy volunteers at doses lower than those required to inhibit acid secretion. This 'cytoprotective' activity has been explained by several mechanisms, but its contribution to the clinical efficacy of misoprostol in healing established ulcers is doubtful since the drug does not appear to be effective in healing peptic ulcers at non-antisecretory dosages. In clinical trials, ulcer healing has been reported in 60 to 85% of patients with duodenal ulcers and 32 to 54% with gastric ulcers receiving misoprostol 200 micrograms 4 times daily for 4 weeks--the recommended dosage. In comparative studies, the percentage of patients with healed ulcers after misoprostol (800 micrograms daily) was not significantly different from that with cimetidine (1200 mg daily), although there was greater pain relief with cimetidine. No study has yet been published concerning the use of misoprostol as maintenance therapy for the prevention of ulcer recurrence, and no long term tolerability data are available. However, in acute ulcer healing studies (2 to 12 weeks in duration) misoprostol has been well tolerated. Diarrhoea was the most commonly reported symptom, and this was only rarely of sufficient severity to interfere with treatment. No evidence of histopathological changes in the gastric mucosa induced by misoprostol have been reported in man. Evidence of uterine stimulant effects in women receiving misoprostol during the first trimester of pregnancy has resulted in the drug being contraindicated during pregnancy. Thus, misoprostol is a new type of antiulcer drug, providing an alternative approach to the therapy of peptic ulcer disease. It has been shown to be effective and well tolerated in the healing of both gastric and duodenal ulcers. Future studies need to identify the specific types of patients likely to obtain most benefit from treatment, in order to define more clearly the place of misoprostol in the treatment of these indications, as well as addressing the possibility of ulcer prevention with lower doses of misoprostol.

Human insulin. A review of its biological activity, pharmacokinetics and therapeutic use.

Abstract: Human insulin, whether produced by recombinant DNA techniques (biosynthetic, insulin crb) or enzymatic modification of porcine insulin (semisynthetic, insulin emp) is equivalent in biological activity to porcine insulin following intravenous administration. Slight differences between human and porcine insulin in hypoglycaemic activity after subcutaneous injection appear to be related to differences in absorption, and are unlikely to be of major clinical importance. Similarly, reported minor differences in counterregulator hormone response to human insulin compared with porcine insulin need further study, but they are unlikely to have important clinical implications. In clinical use the therapeutic efficacy of human insulin is similar to that of porcine insulin. The lower antigenicity with human insulin relative to purified porcine insulin is of potential therapeutic value, and it is logical to use human insulin in newly diagnosed diabetics, in patients treated intermittently with insulin, in cases of immunological insulin resistance, and in patients with allergy and local reaction against animal insulin. Thus, human insulin seems to have no disadvantages compared with purified porcine insulin and may have some advantages. While there appears to be no compelling reason to change patients whose diabetes is presently well controlled with purified porcine insulin to human insulin, the availability of human insulin at a price equal to or less than that of animal origin makes such a change logical. In the meantime, human insulin should be considered the insulin of 'first choice' for newly diagnosed diabetics requiring insulin therapy and in carbohydrate intolerance and diabetes occurring during pregnancy.

Enprostil. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of peptic ulcer disease.

Abstract: Enprostil, a synthetic analogue of prostaglandin E2, is effective in the treatment of patients with duodenal or gastric ulcers. As demonstrated in pharmacological studies in healthy volunteers and in patients with inactive ulcer disease, gastric acid secretion is suppressed by up to 80% for almost 12 hours after single doses of enprostil. The drug also reduces the secretion of pepsin, another 'aggressive' factor in peptic ulcer disease. Interestingly, in contrast to the H2-receptor antagonists, which either increase or have no effect on serum gastrin concentrations, enprostil inhibits basal and postprandial gastrin release. Although the possible effects of enprostil on 'defensive' factors in peptic ulcer disease-which are thought to protect the mucosa-require much further clarification, some evidence obtained in man indicates that bicarbonate secretion is enhanced by enprostil. Further, data from animal studies suggest that microvascular integrity may be preserved by a direct action of enprostil on the gastric mucosa. In healthy volunteers, the administration of enprostil in antisecretory doses protects the gastric mucosa against of enprostil in antisecretory doses protects the gastric mucosa against aspirin-induced injury. Cumulative rates of ulcer healing observed in patients with duodenal ulcers after 4 weeks' treatment with enprostil 35 micrograms twice daily were about 50 to 80%, which were similar to those seen in comparative trials with usual therapeutic doses of cimetidine or pirenzepine, but less than occurred with ranitidine. Moreover, enprostil has been shown to relieve daytime pain in a similar percentage of patients as do these H2-receptor antagonists, but night-time pain appears to respond less well to therapy with the prostaglandin. As evidenced by a few controlled trials in patients with gastric ulcers, treatment with enprostil 35 micrograms twice daily for 6 weeks provides ulcer healing in parallel with pain relief as effectively as cimetidine and ranitidine in a high percentage of patients (about 80% after 6 weeks). Prophylactic treatment with enprostil after initial ulcer healing has reduced the rate of duodenal ulcer relapse in patients 'at risk', but to a lesser extent than has ranitidine. Gastrointestinal symptoms-abdominal cramping and pain, flatulence, nausea and notably, diarrhoea-are the most frequently reported side effects during therapy with enprostil. Diarrhoea occurs in about 10% of patients, but is rarely of a severity necessitating treatment discontinuation.(ABSTRACT TRUNCATED AT 400 WORDS)

Side Effects of Ofloxacin in Clinical Trials and in Postmarketing Surveillance

Abstract: Data derived from clinical trials of ofloxacin in 15,962 patients show that the incidence rate of adverse drug events was 4.27 per 100 patients. Symptoms were generally mild and related to the gastrointestinal tract, nervous system or hypersensitivity reactions in rank order. On the other hand, spontaneous reports obtained during postmarketing surveillance involving 1.5 million patients showed that the most frequent adverse drug events were related to the nervous system; next in order of frequency were hypersensitivity reactions and gastrointestinal symptoms. A comparison of the data obtained from clinical trials and postmarketing surveillance revealed no change in the favourable overall benefit:risk ratio of ofloxacin. Possible reasons for the different patterns of adverse drug events are discussed.

Mechanisms of Resistance to Cephalosporin Antibiotics

Abstract: Cephalosporins, like other β-lactams, bind to the bacterial penicillin-binding proteins (PBPs). These correspond to the D-ala- D-ala trans-, carboxy- and endo-peptidases responsible for catalysing the cross-linking of newly formed peptidoglycan. Resistance arises when the PBPs — and particularly the transpeptidases — are modified, or when they are protected by β-lactamases or ‘permeability barriers’. Target-mediated cephalosporin resistance can involve either reduced affinity of an existing PBP component, or the acquisition of a supplementary β-lactam-insensitive PBP. β-lactamases are produced widely by bacteria and may be determined by chromosomal or plasmid DNA. The chromosomal β-lactamases are species-specific, but can be classified into a few broad groups. The plasmid-mediated enzymes cross interspecific and intergeneric boundaries. The level of β-lactamase-mediated resistance relates to the amount of enzyme produced with or without induction; to the location of the enzyme (extracellular for Gram-positive organisms and periplasmic in Gram-negative ones); and to the kinetics of the enzyme’s activity. In Gram-positive organisms the PBPs are located on the outer aspect of the cytoplasmic membrane and so shielding by permeability barriers is minimal. In Gram-negative cells, however, the PBPs are protected by the outer membrane, which most β-lactams cross by diffusion through aqueous pores composed of ‘porin’ proteins. In enterobacteria, a clear correlation exists between porin quantity and cephalosporin resistance, suggesting that the outer membrane is the sole barrier to drug entry. Such relationships are less clear for Pseudomonas aeruginosa, where the cell may contain additional barriers between the outer membrane and the PBPs. Although elevated cephalosporin resistance often is attributed to a single factor (PBP-modification, β-lactamase action or impermeability) an organism’s response to a drug often reflects the interplay of several factors. Mathematical models can be proposed to describe this interplay.