Formation of active metabolites of psychotropic drugs. An updated review of their significance

Most of the currently available psychotropic drugs form 1 or more active metabolites during in vivo biotransformation in humans and/or animals. In some cases these metabolites are rapidly conjugated and excreted, but in others they attain blood and/or brain concentrations within the same range as, or even higher than, those of the parent drug, thus being potential biologically active compounds. The formation of metabolites with their own biological activity in addition to that of the parent compound may result in a complex situation where different chemical species participate in the final effects. These chemical species may have different pharmacokinetic properties of distribution and clearance. They may act by similar mechanisms, by different mechanisms or even antagonistically. The formation of active metabolites may be important not only for the therapeutic outcome but also for explaining the toxicity of particular drugs. The examples given, although limited, provide evidence that studies on drug metabolites are essential for an understanding of the mechanism of action of psychotropic drugs, and for extrapolating pharmacological and toxicological findings from animals to humans. The development of any new psychotropic agent requires knowledge of the pharmacology and toxicology of all active species as well as their pharmacokinetic profile, including the extent to which they reach the central nervous system.     

Metabolites of antihypertensive drugs. An updated review of their clinical pharmacokinetic and therapeutic implications.

Many antihypertensive drugs are extensively metabolised in humans. Since some metabolites are active and may therefore contribute to the pharmacological activity of the parent drugs, knowledge of the pharmacokinetic properties of active metabolites is important for understanding the overall effects of drugs. Four categories of antihypertensive drugs with active metabolites are dealt with, with selected examples described in some detail. First, drugs with effects relying totally on active metabolites include agents such as methyldopa, cadralazine and many angiotensin converting enzyme (ACE) inhibitors. Secondly, those with effects primarily due to active metabolites include drugs such as triamterene and spironolactone. Thirdly, agents with effects primarily due to the parent drug, but with active metabolites providing significant contributions to the overall pharmacological effect, include drugs such as indoramin, alprenolol, acebutolol, diltiazem and verapamil. Lastly, agents with pharmacological effects with only minor (if any) contributions from active metabolites include drugs such as propranolol, metoprolol, carteolol and others.     

Conformational analysis of clinically active anticonvulsant drugs

A series of ureides active against grand mal epilepsy have been studied by using classical potential energy calculations. The series includes phenyl ethyl and diphenyl derivatives of hydantoins, succinimides, glutarimides, oxazolidine-2,4-diones, pyrimidine-2,6-diones, barbituric acids, and phenacemide. A thorough examination of the conformational possibilities did not reveal an exclusive conformation that could account for their activity. However, comparisons with diazepam and other benzodiazepines known to have the ability to competitively bind with drugs such as diphenylhydantoin at some sites show that there is a distinct conformational preference that may well account for their activity against grand mal epilepsy. The conformational studies led to the proposal of a general model for anticonvulsant activity comprising two aromatic rings or their equivalent in a favored orientation and a third region, usually a cyclic ureide, comprising a number of hydrogen-bond-forming functional groups. The specific placement of hydrogen-bonding groups in this region appears to be of less importance than the correct conformational arrangement of the hydrophobic elements.     

Bopindolol. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy.

Bopindolol is a nonselective beta-adrenoceptor antagonist [corrected] with partial agonist activity which is used in the treatment of hypertension. The drug is rapidly metabolised to an active hydrolysed form. The antihypertensive effects of bopindolol 0.5 to 4 mg are sustained for more than 24 hours after once daily dosing, and the drug appears similar in efficacy to propranolol, metoprolol, atenolol, pindolol and slow release nifedipine in the treatment of mild to moderate forms of this disease. In limited trials bopindolol has also successfully reduced symptoms in patients with angina pectoris, anxiety and essential tremor. Thus, bopindolol is an effective and well-tolerated beta-adrenoceptor antagonist.     

Xipamide. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy

Xipamide is a diuretic derived from salicylic acid and has a structural resemblance to chlorthalidone. Its pharmacodynamic profile shows a diuretic efficacy is similar to that of frusemide (furosemide) at doses up to 40 mg, but the onset and duration of action are comparable to those of hydrochlorothiazide. Xipamide has been studied mostly in the treatment of mild to moderate essential hypertension, with few controlled studies of its use in oedematous states. The efficacy of xipamide 20 to 40 mg once daily in patients with mild to moderate hypertension is comparable to that of bendrofluazide 5 mg, bumetanide 1 mg or hydrochlorothiazide 50 mg when used alone in newly treated or previously treated patients. The addition of xipamide 20 to 40 mg daily to regimens containing beta-blockers, adrenergic neuron-blocking drugs and/or methyldopa has resulted in a further reduction in blood pressure. A few studies in oedematous states suggest that xipamide 40 to 80 mg is comparable in efficacy to equal doses of frusemide, and that the side effects of hypokalaemia, hyperuricaemia and increased blood glucose in diabetics or latent diabetics are similar to those of other diuretics. Thus, xipamide is a suitable alternative to other diuretics in the treatment of mild to moderate hypertension and combines the efficacy of frusemide with a less abrupt action in the treatment of oedema.     

Flunarizine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use

Flunarizine is a 'selective' calcium entry blocker with a similar chemical structure and pharmacological profile to the related compound, cinnarizine. However, in contrast to cinnarizine it has a long plasma half-life and need only be given once a day. The majority of therapeutic trials in the prophylaxis of migraine, occlusive peripheral vascular disease and vertigo of central or peripheral origin have been placebo-controlled, and have shown that the drug produces significantly greater beneficial effects than placebo as evaluated by subjective and objective criteria. A small number of comparative studies have shown flunarizine to be at least as effective as pizotifen in migraine prophylaxis, and in a longer term study as effective as cinnarizine in vertigo of central origin. However, it has not been compared with other drugs which may be useful in these areas, such as methysergide in migraine prophylaxis, some antihistamines or phenothiazines in vertigo, or (understandably at this stage of its evolution) with surgical revascularisation in severe occlusive peripheral vascular disease. In preliminary placebo-controlled studies there was some evidence that flunarizine may improve impaired cognitive function in patients with cerebrovascular disorders, but such findings need further confirmation in additional carefully conducted studies. With a very long half-life, flunarizine may be given once daily; and drowsiness, the main side effect, can be minimised by taking the daily dose in the evening. Thus, it appears that flunarizine will offer a useful alternative in some therapeutic areas that can be difficult to manage with previously available therapy. However, a definitive statement on its relative place in therapy of such conditions must await a few well-controlled comparative studies.     

Bumetanide. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use

Bumetanide is a potent 'loop' diuretic for the treatment of oedema associated with congestive heart failure, hepatic and renal diseases, acute pulmonary congestion and premenstrual syndrome and in forced diuresis during and after surgery. Bumetanide may be given orally, intravenously or intramuscularly and produces a rapid and marked diuresis, and increased urinary excretion of sodium, chloride and other electrolytes (within 30 minutes) which persists for 3 to 6 hours. Its principal site of action is on the ascending limb of the loop of Henle, with a secondary action on the proximal tubule. Pharmacologically, bumetanide is about 40-fold more potent than frusemide (furosemide), with the exception of its effects on urinary potassium excretion where its potency is lower. Studies in patients with oedema due to congestive heart failure, pulmonary oedema or hepatic disease show that oral or intravenous bumetanide 0.5 to 2 mg/day produces results comparable to those with frusemide 20 to 80 mg/day. In acute pulmonary oedema, intravenous bumetanide produces a very rapid diuresis. Higher doses of bumetanide may be required (up to 15 mg/day) in patients with chronic renal failure or nephrotic syndrome. In these patients muscle cramps are not uncommon with bumetanide, but glomerular filtration rates are unaffected. In most studies, diuretic effects were accompanied by decreased bodyweight, abdominal girth and improvements in a variety of haemodynamic parameters. Comparison of bumetanide with frusemide at a dose ratio of 1 : 40 reveals no significant differences in clinical response with the exception of renal disease, where patients with oedema appear to respond better to bumetanide. Combination with thiazide diuretics enhances the clinical response to bumetanide. Potassium supplements and spironolactone may be beneficial additions to bumetanide where patients at risk of hypokalaemia can be identified. Clinically important side effects are infrequent, with audiological impairment occurring to a lesser extent than with frusemide. Bumetanide thus offers an important alternative to frusemide when a 'loop' diuretic is indicated.     

Meptazinol. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy

Meptazinol is a new opioid-type analgesic with mixed agonist/antagonist properties. It may be given orally, intravenously or intramuscularly. In studies in patients with moderate to severe pain of various aetiologies, usually following surgery or in obstetrics, the characteristics of analgesia with meptazinol were comparable to those seen with equianalgesic doses of pentazocine, pethidine or a combination of dextropropoxyphene and paracetamol. Preoperative use and use as a component of anaesthesia require further investigation before conclusions may be drawn on its effectiveness in these areas. Onset of action, recorded in a few studies, was faster than that with the other analgesics but duration was shorter than that of morphine, buprenorphine and pentazocine. Only a small number of patients with chronic pain have received long term therapy with meptazinol; in such patients there was no need for increased doses as treatment progressed. Respiratory depression has only been observed in patients receiving meptazinol as a premedication or while undergoing anaesthesia. Similarly any haemodynamic changes have been limited to preoperative patients or patients undergoing anaesthesia. Like other agonist/antagonist analgesic drugs, the abuse potential of meptazinol seems relatively low, but only wider clinical use for longer periods can establish this with certainty. The most commonly reported side effects have been gastrointestinal in nature, and although the incidence of central nervous system side effects has been relatively low, drowsiness and dizziness have caused occasional problems. Thus, meptazinol is a relatively potent but safe addition to the analgesics available for treatment of the patient with moderate to severe pain.     

Zolpidem. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential

Zolpidem is an imidazopyridine, a chemically novel nonbenzodiazepine hypnotic agent which acts at the benzodiazepine omega 1-receptor subtype in the brain. With a rapid onset of action and short elimination half-life, it reduces the latency to and prolongs the duration of sleep in patients with insomnia, yet has no major effects on sleep stages when given in dosages of 5 to 20 mg nightly. Rebound effects on withdrawal of the drug have not been observed. Unlike benzodiazepines, zolpidem has no myorelaxant or anticonvulsant effects and its effects on anxiety appear to be minor. While zolpidem aids sedation, and may reduce memory or psychomotor function within the first 2 hours after administration of single oral doses, its use as a surgical premedicant remains to be established. Adverse effects are predominantly CNS and gastrointestinal in nature. Altered pharmacokinetics may lead to an increase in dose-proportionate adverse effects in the elderly and in patients with renal dysfunction. Limited evidence to date suggests that the dependence liability of zolpidem is minimal. Thus, zolpidem is an interesting alternative to benzodiazepines in the treatment of insomnia, with properties that potentially offer worthwhile advantages in this therapeutic area if they are confirmed with wider clinical experience.     

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

Zidovudine (azidothymidine) is a thymidine analogue antiretroviral drug active against human immunodeficiency virus (HIV). In acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) patients, orally and intravenously administered zidovudine is effective in reducing the incidence of opportunistic infections and neoplasms, increasing helper T lymphocyte numbers, and improving survival rates and quality of life. Adverse effects include serious haematological abnormalities and severe headache, abdominal discomfort, nausea, myalgia and insomnia. In addition, neutropenia and other anaemias frequently limit zidovudine therapy and may result in a need for multiple blood transfusions, dose reductions or withdrawal of the drug. However, despite these problems and the lack of information about some aspects of zidovudine use, zidovudine provides a major hope for HIV-infected patients, and it has rapidly become the standard therapy for improving the quality and duration of the lives of AIDS and ARC patients.     

Azelastine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential

Azelastine is an antiallergic agent which demonstrates histamine H1-receptor antagonist activity and also inhibits histamine release from mast cells following antigen and non-antigen stimuli. Azelastine antagonises histamine- and leukotriene-induced bronchospasm in animal studies and reduces airway responsiveness to inhaled antigen or distilled water, and exercise challenge. In comparative studies, orally administered azelastine in doses up to 4 mg/day consistently relieved symptoms in patients with seasonal or perennial rhinitis - comparable to inhaled sodium cromoglycate (cromolyn sodium) 80 mg/day, oral chlorpheniramine (chlorphenamine) and oral terfenadine 120 mg/day. In addition, azelastine administered as an intranasal spray was as effective as oral terfenadine 120 mg/day and intranasal budesonide 0.4 mg/day in alleviating symptoms of rhinitis. Azelastine is also a potent antiasthmatic agent which produces significant and long lasting bronchodilation in patients with bronchial asthma. The drug is superior to placebo and comparable to oral ketotifen 2 mg/day and sustained release theophylline 700 mg/day when administered as a twice daily oral 4 mg dose. Azelastine is generally well tolerated: the most common adverse effects are altered taste perception and drowsiness. Adverse effects are mild and transient and result in withdrawal of treatment in less than 2% of patients. In a comparative study oral azelastine 2 or 4 mg/day produced no more sedation than terfenadine 120 mg/day. Thus, barring unexpected findings with wider clinical use, azelastine offers an effective and well tolerated choice of treatment for patients with allergic rhinitis and/or bronchial asthma, which may be particularly beneficial in patients in whom inhaled drug treatment is contraindicated.     

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

Pirprofen is a non-steroidal anti-inflammatory drug, related structurally to drugs such as ibuprofen, ketoprofen and naproxen. Published clinical trials indicate that pirprofen 600 to 1200 mg/day as 2 or 3 divided doses is a suitable alternative to usual therapeutic dosages of aspirin, flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam and sulindac in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, musculoskeletal disorders and non-articular rheumatism. More studies are required to evaluate its potential relative to other commonly used drugs in the treatment of gout, juvenile rheumatoid arthritis and dysmenorrhoea. In patients with acute postsurgical, trauma or cancer pain, single oral or intramuscular doses of pirprofen 200 to 400mg provide equivalent analgesic activity to usual therapeutic doses of aspirin, diflunisal, ketoprofen, noramidopyrine, paracetamol and pentazocine. As with other non-steroidal anti-inflammatory drugs, gastrointestinal complaints are the most frequently reported side effects. At equivalent analgesic or anti-inflammatory dosages, pirprofen probably causes fewer side effects than aspirin and appears to be as well tolerated as the other agents with which it has been compared. Long term tolerability, particularly compared with some of the newer, purportedly less gastrotoxic agents or formulations, needs to be investigated further. Pirprofen does not appear likely to offer any particular advantage with respect to efficacy and tolerability over other non-steroidal anti-inflammatory drugs, except aspirin. However, as no one agent is the most suitable drug for all patients requiring such therapy, pirprofen may be considered along with other drugs of this type in the therapy of arthritic conditions and acute pain states.     

Minocycline: A review of its antibacterial and pharmacokinetic properties and therapeutic use.

Minocycline is a semi-synthetic tetracycline derivative which is well absorbed and distributed in body tissues and is suitable for twice daily administration. It appears to be as generally effective as other tetracyclines and analogues, but also to be effective in infections due to tetracycline-resistant staphylococci. Side-effects are typical of those of other tetracyclines, but minocycline has been associated with a high incidence of vertigo in some studies. On the other hand, minocycline appears to have little or no photosensitising potential. It is not yet clear whether minocycline can be safely used in patients with moderate or severe impairment of renal function, but if used in renal failure, the plasma urea concentration should be monitored.     

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

Ibopamine is an orally active derivative of dopamine which undergoes hydrolysis to the active moiety epinine. In single-dose and short term studies ibopamine demonstrated inotropic and vasodilating properties. It improved cardiac and systemic haemodynamics by increasing cardiac output and reducing afterload, both at rest and during exercise. In non-comparative clinical studies ibopamine produced benefits in functional class and clinical symptoms for up to 1 year in patients with moderate to severe congestive heart failure. Similarly, short term comparative studies with placebo have indicated ibopamine as a useful adjunct in the treatment of patients maintained on conventional therapy with digoxin, diuretics and vasodilators. Preliminary evidence also suggests that ibopamine is as effective as digoxin in the treatment of patients with moderate congestive heart failure. Should the results of long term comparative studies confirm these encouraging findings, ibopamine will be a useful addition to the drugs available or as an alternative to digoxin for the treatment of congestive heart failure.     

Ketorolac. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential

Ketorolac is a non-steroidal agent with potent analgesic and moderate anti-inflammatory activity. It is administered as the tromethamine salt orally, intramuscularly, intravenously, and as a topical ophthalmic solution. Clinical studies indicate single-dose efficacy greater than that of morphine, pethidine (meperidine) and pentazocine in moderate to severe postoperative pain, with some evidence of a more favourable adverse effect profile than morphine or pethidine. In single-dose studies ketorolac has also compared favourably with aspirin, paracetamol (acetaminophen) and a few other non-steroidal anti-inflammatory drugs. If further investigation confirms the initially favourable findings regarding efficacy and tolerability, ketorolac will be a useful alternative to opioid agents in postsurgical pain. It may well also find use in acute musculoskeletal pain, where it appears at least as effective as other agents with which it has been compared. From the limited clinical data available, ketorolac also seems promising in the treatment of ocular inflammatory conditions. Additional multiple-dose studies are required to evaluate fully the potential of ketorolac in the management of chronic pain states where it has shown superior efficacy to aspirin. In summary, ketorolac offers promise as an alternative to opioid and to other nonsteroidal analgesics in ameliorating moderate to severe postsurgical pain, and with wider clinical experience may find a place in the treatment of acute musculoskeletal and other pain states, and ocular inflammatory conditions.     

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

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)     

Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential.

Clarithromycin is an acid-stable orally administered macrolide antimicrobial drug, structurally related to erythromycin. It has a broad spectrum of antimicrobial activity, similar to that of erythromycin and inhibits a range of Gram-positive and Gram-negative organisms, atypical pathogens and some anaerobes. Significantly, clarithromycin demonstrates greater in vitro activity than erythromycin against certain pathogens including Bacteroides melaninogenicus, Chlamydia pneumoniae, Chlamydia trachomatis, Mycobacterium chelonae subspecies--chelonae and--abscessus, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium avium complex, Legionella spp. and, when combined with its 14-hydroxy metabolite, against Haemophilus influenzae. However, bacterial strains resistant to erythromycin are also generally resistant to clarithromycin. The antimicrobial activity of clarithromycin appears to be enhanced by the formation in vivo of the microbiologically active 14-hydroxy metabolite. In combination, additive or synergistic activity against a variety of pathogens including Haemophilus influenzae, Moraxella catarrhalis, Legionella species (principally Legionella pneumophila) and various staphylococci and streptococci has been demonstrated. Clarithromycin has a superior pharmacokinetic profile to that of erythromycin, allowing the benefits of twice daily administration with the potential for increased compliance among outpatients where a more frequent regimen for erythromycin might otherwise be indicated. The clinical efficacy of clarithromycin has been confirmed in the treatment of infections of the lower and upper respiratory tracts (including those associated with atypical pathogens), skin/soft tissues, and in paediatrics. Clarithromycin was as effective as erythromycin and other appropriate drugs including beta-lactams (penicillins and cephalosporins) in some of the above infections. A most promising indication for clarithromycin appears to be in the treatment of immunocompromised patients infected with M. avium complex, M. chelonae sp. and Toxoplasma sp. Small initial trials in this setting reveal clarithromycin alone or in combination with other antimicrobials to be effective in the eradication or amelioration of these infections. Noncomparative studies have provided preliminary evidence for the effectiveness of clarithromycin in the treatment of infections of the urogenital tract, oromaxillofacial and ophthalmic areas. However, the promising in vitro and preliminary in vivo activity of clarithromycin against Mycobacterium leprae and Helicobacter pylori warrant further clinical trials to assess its efficacy in patients with these infections. Despite the improved pharmacokinetic profile and in vitro antimicrobial activity of clarithromycin over erythromycin, comparative studies of patients with community-acquired infections reveal the 2 drugs to be of equivalent efficacy. However, clarithromycin demonstrates greater tolerability, principally by inducing fewer gastrointestinal disturbances.(ABSTRACT TRUNCATED AT 400 WORDS)     

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

The antibacterial efficacy of oral lomefloxacin has been investigated in a wide variety of infections, including respiratory and uncomplicated and complicated urinary tract infections, obstetric, gynaecological, joint, skin, oral, ear, nose, throat and eye infections. It has also been used as an otic solution in patients with otitis media and as an ophthalmic solution in the treatment of eye infections. In clinical trials its efficacy is equivalent to that of other quinolones and it is at least as effective as other antibacterial drugs ordinarily used in these infections. Lomefloxacin offers certain advantages compared with other quinolone antibacterial drugs in that it may be conveniently administered once daily and theophylline dosage adjustment does not appear to be necessary in patients receiving this bronchodilator concomitantly. Thus, orally administered lomefloxacin should prove a useful broad spectrum antibacterial drug for a wide variety of clinical infections.     

Halofantrine. A review of its antimalarial activity, pharmacokinetic properties and therapeutic potential.

Halofantrine is an orally administered blood schizontocide which is active against both chloroquine-sensitive and chloroquine-resistant plasmodia. Dose-finding and noncomparative clinical trials have confirmed the efficacy of halofantrine in the treatment of falciparum malaria in areas of chloroquine- and sulfonamide/pyrimethamine-resistant malaria and vivax malaria. However, poor results obtained in patients who failed mefloquine prophylaxis suggest that the efficacy of halofantrine may not extend to mefloquine-resistant P. falciparum, although more studies are needed to confirm this. Data concerning halofantrine in the treatment of P. ovale and P. malariae infections are still limited. One comparative study indicates that halofantrine has an efficacy equivalent to that of mefloquine and may be better tolerated. Halofantrine is generally well tolerated in both adults and children, the most common drug-associated effects being abdominal pain, pruritus, vomiting, diarrhoea, headache and rash, although it is difficult to distinguish between disease- and treatment-related events. The development of parasite resistance to halofantrine, like other blood schizontocides, is inevitable. Poor absorption resulting in variable peak plasma halofantrine concentrations, and possible cross-resistance with mefloquine, may accelerate the emergence of resistance to halofantrine. Thus, it is of primary importance that halofantrine is used only in areas where chloroquine- and sulfonamide/pyrimethamine-resistance are established in order to preserve and sustain its efficacy. If used with care, halofantrine will provide an important treatment option for falciparum malaria, a widespread parasitic disease associated with considerable morbidity against which the number of effective drugs available is being increasingly compromised by the spread of resistance.