Non-steroidal anti-inflammatory analgesics other than salicylates.

The largest group of non-narcotic analgesics are the arylalkanoic acid derivatives, comprising derivatives of arylacetic acid, propionic acid, heteraryl acetic acid and indole acetic acid. Common to all of these drugs is their inhibition of prostaglandin biosynthesis, which contributes to their analgesic and other pharmacological properties as well as to their principal side effect, gastrointestinal irritation. Although these drugs all cause some gastric microbleeding, they do so to a lesser extent than aspirin. The arylalkanoic acid derivatives, as well as the anthranilic acid and oxicam derivatives, are peripherally acting as evidenced by their lack of activity in classical tests of central analgesic activity. After oral administration of these drugs, their peak plasma concentrations are generally attained in 1 to 3 hours; absorption is not generally influenced by food. Volume of distribution is mostly low (less than 0.2 L/kg) and protein binding is high (usually 95 to 99%). Elimination is by glucuronide formation for several of the propionic acid derivatives and generally by biotransformation for derivatives of arylacetic acid, indole and indene acetic acid, and the oxicams. The elimination half-life of the arylalkanoic acid derivatives is in most instances about 2 to 5 hours, although notable exceptions include carprofen (approximately equal to 20 h), fenbufen (10 h), naproxen (12-15 h) and sulindac (16 h for the active metabolite). The elimination half-life of indomethacin varies considerably between and within individuals. Piroxicam has the longest half-life, averaging 45 hours. The pharmacokinetic properties of the anthranilic acid derivatives (fenamates, glafenine) generally resemble those of the arylacetic acids. Few clinically significant drug interactions are associated with concomitant administration of the arylalkanoic acids or piroxicam and other drugs. Since the arylalkanoic acids are highly bound to plasma proteins (mainly albumin) there is a theoretical potential for displacement reactions with drugs that are used at plasma concentrations high enough to exceed the binding capacity of their own primary binding sites. However, such reactions have rarely been reported. Although the concomitant administration of aspirin and several of the propionic acid derivatives results in a significant decrease in the plasma concentration of the latter, the clinical significance of such interactions is uncertain and probably minimal.(ABSTRACT TRUNCATED AT 250 WORDS)

Pyrazolone derivatives.

In many countries, the pyrazolone derivatives, which include dipyrone, antipyrine, aminopyrine and propyphenazone, are widely used analgesics. Dipyrone, the most widely used pyrazolone, has been the most studied. The pyrazolidine derivatives, phenylbutazone and oxyphenbutazone, which are not generally used for analgesia since they differ from the pyrazolones in terms of efficacy and tolerance, are not discussed in this article. Dipyrone is an inhibitor of cyclo-oxygenase but, unlike aspirin, its effect is rapidly reversible. The inhibition of prostaglandin biosynthesis contributes to the analgesic activity of the pyrazolone derivatives. Peak plasma concentrations of the pyrazolone derivatives generally occur 1 to 1.5 hours after oral administration. Half-lives vary from 1 to 2 hours with propyphenazone, to about 7 hours with dipyrone (2 hours for the active metabolite of dipyrone, 4-methylaminoantipyrine, MAA). Half-life of antipyrine varies considerably between individuals (5 to 35 hours). Unlike the NSAIDs generally, the pyrazolone derivatives antipyrine, aminopyrine and propyphenazone are minimally bound to plasma proteins. The pyrazolones undergo extensive biotransformation, aminopyrine and dipyrone being converted to active metabolites. Dipyrone is the only drug for which results of recent double-blind trials are available. Oral dipyrone has been shown to be more effective than an equal dose of aspirin or paracetamol in alleviating postoperative pain, and intravenous dipyrone 2.5g was similar in efficacy to pethidine 50 mg. In patients with acute ureteral or biliary colic, dipyrone 2.5g intravenously was similar in efficacy to indomethacin 50 mg or pethidine 50 mg. The most frequently reported side effects of the pyrazolone derivatives are skin rashes. Gastrointestinal side effects are rare. Blood dyscrasias, mostly associated with aminopyrine, have received wide attention in the medical literature, but their true incidence with dipyrone is considerably lower than the often quoted incidence for amidopyrine reported more than 30 years ago.

Leuprorelin. A review of its pharmacology and therapeutic use in prostatic cancer, endometriosis and other sex hormone-related disorders.

Leuprorelin (leuprolide acetate) is a gonadotrophin-releasing hormone (GnRH) analogue used to treat a wide range of sex hormone-related disorders including advanced prostatic cancer, endometriosis and precocious puberty. It acts primarily on the anterior pituitary, inducing a transient early rise in gonadotrophin release. With continued use, leuprorelin causes pituitary desensitisation and/or down-regulation, leading to suppressed circulating levels of gonadotrophins and sex hormones. Clinical trials in men with advanced prostatic cancer demonstrate that leuprorelin (usually monthly depot injections of 3.75 or 7.5 mg) is less likely to cause serious adverse cardiovascular effects than diethylstilbestrol, and has comparable efficacy to bilateral orchiectomy or other GnRH analogues. Therefore, the choice between leuprorelin and orchiectomy may be made on the basis of the patient's treatment preference, along with specific patient characteristics and cost implications. Monthly intramuscular or subcutaneous administration of depot leuprorelin 3.75 mg was superior to placebo, and comparable to oral danazol 800 mg/day or intranasal buserelin 900 micrograms/day, in achieving objective and subjective responses in women with endometriosis. Thus, leuprorelin is an effective alternative to other treatments for women with endometriosis, but the recommended duration of its use in this clinical setting is limited to 6 months because it reduces bone mineral density. In children with central precocious puberty, leuprorelin (usually monthly intramuscular or subcutaneous injections of depot leuprorelin 3.75 to 15mg) decreases mean growth velocity and signs of sexual maturation and increases predicted adult height compared with baseline measurements. Although effects on final adult height are predicted from available data and require confirmation in long term follow-up studies, the absence of effective alternatives to GnRH analogues makes leuprorelin a first-line therapy for children with this rare disease. In women with uterine leiomyomata, monthly intramuscular administration of depot leuprorelin 3.75 mg for 6 months markedly reduces uterine volume and fibroid-related symptoms, but, as with other GnRH analogues, these effects dissipate following discontinuation of the drug. As adjuvant therapy in women undergoing in vitro fertilisation or gamete intrafallopian transfer, leuprorelin (usually 0.5 to 1 mg/day subcutaneously) reduces the risk of cancelled cycles for oocyte retrieval by preventing premature luteinisation. While some studies demonstrate an improvement in intermediate end-points such as increased number of mature oocytes retrieved and embryos available for transfer, a significant effect has not been demonstrated on the rate of live births per stimulated cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Isradipine. An update of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of mild to moderate hypertension.

Since the earlier review in Drugs substantial additional data have accumulated regarding the antihypertensive efficacy of isradipine in various clinical situations, as well as data on its clinical effects in atherosclerosis. Recent therapeutic trials confirm that the efficacy of isradipine in the treatment of patients with mainly mild to moderate hypertension, when administered orally as a conventional or modified release preparation, is similar to that of titrated dosages of amlodipine, felodipine, nifedipine, diltiazem, captopril, methyldopa, metoprolol, prazosin and hydrochlorothiazide. A further decrease in blood pressure can be expected when isradipine is combined with another antihypertensive drug in patients who have not responded adequately to monotherapy. Initial studies have shown that intravenous isradipine is effective in controlling hypertension following coronary artery bypass graft surgery and that it appears useful in the treatment of intraoperative hypertension and hypertensive crisis, and in hypertensive disorders in pregnancy, when administered orally or intravenously. A large study, the Multicentre Isradipine Diuretic Atherosclerosis Study (MIDAS), was designed to compare the efficacy of isradipine and hydrochlorothiazide in reducing the rate of progression of carotid artery wall thickness, measured by B-mode ultrasound, as a surrogate for early atherosclerosis. Results indicated that wall thickness increased significantly less with isradipine than hydrochlorothiazide after 6 months of therapy. Thereafter the rate of progression remained parallel for the remainder of the 3-year trial. The confirmation of its antihypertensive efficacy, along with its favourable haemodynamic profile and reversal of left ventricular hypertrophy, minimal effect on glucose and lipid metabolism, preservation of quality of life and good tolerability, makes isradipine a suitable drug for the treatment of most patients with mild to moderate hypertension.

Nifedipine gastrointestinal therapeutic system (GITS). A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in hypertension and angina pectoris.

Nifedipine 'gastrointestinal therapeutic system' (GITS) is a recently developed formulation that slowly releases the drug into the intestinal tract over a 24-hour period. When administered once daily, it is of similar efficacy to sustained release formulations of felodipine, verapamil, and diltiazem and at least as effective as standard formulations of lisinopril and enalapril, and long-acting propranolol and atenolol in the treatment of patients with mild to moderate essential hypertension. Substitution of nifedipine GITS for conventional formulations of nifedipine, diltiazem or verapamil, maintained adequate control of anginal symptoms in patients with stable angina pectoris. Nifedipine GITS appears to maintain quality of life and is apparently better tolerated than those formulations of nifedipine which require 2 or 3 times daily administration in both elderly and younger patients. In addition, it has minimal effect on lipid and glucose metabolism and reverses left ventricular hypertrophy, and is thus suitable for treatment of the majority of patients with mild to moderate hypertension or angina pectoris.

Rifaximin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential in conditions mediated by gastrointestinal bacteria.

Rifaximin is a derivative of rifamycin which acts by inhibiting bacterial ribonucleic acid (RNA) synthesis. It is virtually unabsorbed after oral administration; thus it is used primarily to treat local conditions within the gastrointestinal tract. In vitro data indicate rifaximin possesses good activity against species of Staphylococcus, Streptococcus and Enterococcus but lesser activity against species of Enterobacteriaceae. Bacterial resistance during exposure to rifaximin has been reported but its clinical importance remains to be fully defined. Results of comparative trials demonstrate that rifaximin is similar in efficacy to neomycin and lactulose in patients with hepatic encephalopathy and appears to be better tolerated. In 1 study, cyclical administration of rifaximin for 15 days per month was associated with progressive improvement over a 3-month period. In patients with infectious diarrhoea, rifaximin induces more rapid improvement in stool consistency and decreased frequency of faecal evacuations when compared with placebo, and is similar in efficacy to neomycin. Available data suggest rifaximin may be of some use in acute diverticulitis, but its use for the prevention of inflammatory complications or for control of common symptoms of diverticulosis requires further study. Preoperative treatment with rifaximin as antibacterial prophylaxis in colorectal surgery shows some potential but should be further investigated. Overall, rifaximin may be useful as an alternative therapy in hepatic encephalopathy but more data are needed to better define its clinical potential in infectious diarrhoea, diverticular disease and as antibacterial prophylaxis prior to colorectal surgery.

Nedocromil sodium. An updated review of its pharmacological properties and therapeutic efficacy in asthma.

Nedocromil sodium, the disodium salt of a pyranoquinoline dicarboxylic acid, has anti-inflammatory properties in vitro, in animal models of asthma, and in humans, as evidenced by inhibition of inflammatory cell activation and mediator release, early and late allergen-induced bronchoconstriction and airway hyperresponsiveness. Recent therapeutic trials confirm the safety and efficacy of inhaled nedocromil sodium as adjunctive therapy in adult patients whose asthma is not adequately controlled by beta-agonists alone. Nedocromil sodium has also been shown to improve symptoms when added to existing treatment with methylxanthines and corticosteroids. Some studies show nedocromil sodium to be successful replacement therapy for methylxanthines, in addition to enabling a modest reduction in inhaled corticosteroids in some patients. Thus, nedocromil sodium may be suitable in patients with asthma as an adjunct to existing therapy, as an alternative to regularly administered oral and inhaled beta-agonists and oral methyl-xanthines, and potentially, to low dose inhaled corticosteroids as maintenance therapy in patients with mild to moderate asthma being considered for corticosteroid therapy.

Loracarbef. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacy.

Loracarbef is an orally administered member of a new synthetic class of beta-lactam antibiotics, the carbacephems, which is characterised by enhanced chemical stability. At low concentrations (< 2 mg/L) in vitro, it inhibits Streptococcus pneumoniae, S. pyogenes, beta-haemolytic streptococci groups B, C and G. Proteus mirabilis and Moraxella catarrhalis, including beta-lactamase-producing strains. At therapeutic plasma concentrations it is also active in vitro against most strains of Staphylococcus aureus, S. saprophyticus, Escherichia coli and beta-lactamase-positive and -negative strains of Haemophilus influenzae. Like other beta-lactams, loracarbef is inactive against methicillin-resistant strains of S. aureus. When administered at dosages of 200 to 400 mg twice daily, the clinical and bacteriological efficacy of loracarbef is comparable with that of amoxicillin and amoxicillin/clavulanic acid in patients with upper or lower respiratory tract infections, and comparable with that of cefaclor in treating infections of the lower respiratory tract, skin and skin structures and urinary tract. Loracarbef and phenoxymethylpenicillin (penicillin V) were equally effective in treating streptococcal pharyngitis and tonsillitis. Loracarbef is generally well tolerated by all age groups and causes less diarrhoea than amoxicillin/clavulanic acid. It is administered twice daily. It offers a suitable alternative to other orally administered antibiotics for the treatment of mild to moderate infections caused by susceptible organisms.

Rifabutin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacy.

Rifabutin is a derivative of rifamycin S with activity against mycobacteria including atypical organisms such as Mycobacterium avium and M. intracellulare, also referred to as Mycobacterium avium-intracellulare complex (MAC). To date, rifabutin is the only drug to have been studied in large prospective placebo-controlled trials that has been shown to significantly reduce the incidence of disseminated MAC infection when administered prophylactically as a single agent to patients with acquired immune deficiency syndrome (AIDS). Initial studies also indicate that rifabutin may be a useful component of multiple drug regimens for the treatment of MAC infection, although further studies combining rifabutin with other recently available antimycobacterial drugs are required to determine the most effective regimens. When rifabutin is combined with at least two other antimycobacterial drugs, the combination appears to be of similar efficacy to rifampicin (rifampin)-containing regimens in patients with newly diagnosed pulmonary tuberculosis. Since available therapy for MAC infection in patients with AIDS is still suboptimal, rifabutin, at present the only first-line agent for prophylaxis against disseminated MAC infection in patients with advanced human immunodeficiency virus (HIV) infection, has the potential to make a valuable contribution to the continuing attempts to preserve the quality of life of patients with AIDS.

Naftifine. A review of its antimicrobial activity and therapeutic use in superficial dermatomycoses.

Naftifine is an allylamine derivative for topical administration with a mechanism of action distinct from that of other classes of antifungal agents. It inhibits squalene epoxidase and may have certain anti-inflammatory properties, but its precise mechanism of action is as yet unclear. In vitro, naftifine has potent fungistatic and fungicidal activity against dermatophytes. This correlates well with its clinical and mycological activity in patients with dermatophytoses. There is improvement in clinical symptoms and overall therapeutic success after a 2- to 5-week course of therapy in a high percentage of patients (usually over 80%) with tinea cruris or corporis, and in a slightly smaller percentage of those with tinea pedis. Naftifine is moderately active in vitro against moulds, but is generally less active against yeasts, including Candida albicans. However, it has proved reasonably effective in the treatment of patients with cutaneous candidiasis, although further studies are necessary to establish its place in therapy for this indication. In view of its good local tolerability, absence of systemic adverse effects, novel mechanism of action and effectiveness with once-daily application, naftifine offers a useful addition to available pharmaceutical options in patients with dermatomycoses.

Salmeterol xinafoate. A review of its pharmacological properties and therapeutic potential in reversible obstructive airways disease.

Salmeterol xinafoate, like salbutamol (albuterol), is a saligenin derivative, and a selective beta 2-adrenoceptor agonist. It produces bronchodilation for at least 12 hours following inhalation of a single 50 micrograms dose. Salmeterol is intended for regular twice-daily treatment of reversible airways obstruction and not for immediate symptomatic relief, and when used in this manner, 50 micrograms twice daily is more effective than salbutamol 200 micrograms or terbutaline 500 micrograms administered 4 times daily, or individually titrated oral doses of theophylline in improving objective and subjective criteria of efficacy in patients with mild to moderate asthma. Salmeterol 100 micrograms inhaled twice daily may provide better control than the lower dose in patients with severe asthma. The long duration of effect of salmeterol makes it particularly suitable for treating patients with nocturnal asthma in whom it improves sleep quality. The place of salmeterol, like that of other beta 2-adrenoceptor agonists used regularly in the treatment of asthma, is being debated. Patients in need of regular beta 2-agonist therapy should also be regarded as candidates for inhaled corticosteroids to counteract underlying inflammation. Thus, salmeterol may be particularly useful in patients requiring regular treatment with beta 2-agonists for nocturnal asthma and results of trials in progress involving large numbers of patients are awaited with interest.

Acrivastine. A review of its pharmacological properties and therapeutic efficacy in allergic rhinitis, urticaria and related disorders.

Acrivastine is a short acting histamine H1-receptor antagonist with a rapid onset of action. Double-blind clinical trials have shown acrivastine (usually 8mg three times daily) to be an effective and well tolerated antihistamine in the treatment of chronic urticaria and allergic rhinitis. Acrivastine was more effective than placebo and similar in efficacy to clemastine or terfenadine in the treatment of seasonal allergic rhinitis. In the treatment of dermatoses in which histamine has a pathogenetic role, the efficacy of acrivastine was superior to that of placebo and similar to that of usual dosages of clemastine, hydroxyzine, chlorpheniramine, cyproheptadine or terfenadine. Acrivastine caused less drowsiness than clemastine, the incidence of adverse effects being indistinguishable from that with placebo or terfenadine. Thus, acrivastine is an effective addition to drugs currently available for the treatment of patients with allergic diseases in whom a histamine H1-receptor antagonist is indicated. Because of its rapid onset of action acrivastine will be particularly useful for 'on demand' therapy in patients with intermittent symptoms.

Zalcitabine. A review of its pharmacology and clinical potential in acquired immunodeficiency syndrome (AIDS).

Zalcitabine is an analogue of the nucleoside deoxycytidine which, when intracellularly converted to an active triphosphate metabolite, inhibits replication of human immunodeficiency virus (HIV). Zalcitabine is thought to act in the early phase of HIV replication by inhibiting reverse transcriptase and terminating the viral DNA chain. In vitro, zalcitabine is one of the more effective nucleoside analogues currently in clinical use for HIV infection, with 0.5 mumol/L concentrations completely inhibiting HIV replication in human T lymphocyte cell lines. In clinical trials, p24 antigen levels decreased and CD4 cell counts increased in patients with acquired immunodeficiency syndrome (AIDS) receiving zalcitabine > or = 0.03 mg/kg/day as monotherapy. Dose-dependent adverse effects that include peripheral neuropathy, stomatitis and rash, restrict long term use at higher dosages, and it is unclear whether zalcitabine monotherapy is as effective as zidovudine in extending survival in HIV-infected patients. Alternating or concomitant therapy with zalcitabine and zidovudine provides effective inhibition of viral replication and disease progression (as measured by improvements in CD4 cell counts) with lower and less toxic dosage regimens. At present, therefore, zalcitabine has a place in AIDS therapy both in combination with zidovudine, and as monotherapy for patients unable to tolerate zidovudine.

Bitolterol. A preliminary review of its pharmacological properties and therapeutic efficacy in reversible obstructive airways disease.

Bitolterol is a beta-adrenoceptor agonist which is hydrolysed to colterol by tissue esterases present at high concentrations in the lung. Animal studies indicate that bitolterol has significant beta 2-selectivity. In initial clinical trials transient cardiovascular effects have occurred in about 5% of patients. The spectrum of other adverse reactions with bitolterol is similar to that found with other beta-adrenoceptor agonists. Preliminary therapeutic trials of bitolterol administered by aerosol or nebuliser in adult patients with asthma have shown variable but significant improvements in forced expiratory volume in 1 second (FEV1) and a duration of action of up to 8 hours in some patients. Bitolterol has been shown to provide similar maximum increases in FEV1 to isoprenaline (isoproterenol) and to be significantly longer acting in long term comparative trials. Either alone or in combination with oral theophylline, bitolterol aerosol produces greater and more prolonged bronchodilation than oral theophylline alone but more consistently in non-steroid-dependent patients. Duration of bronchodilation with bitolterol in patients receiving steroids is less than in those who are not steroid dependent, perhaps due to more severe disease in the former group. More long term trials in larger groups of patients are clearly needed to assess the efficacy and safety of bitolterol in comparison with other long acting beta-adrenoceptor agents, and to define the role of bitolterol in the combination regimens of antiasthmatic agents which are becoming increasingly popular. Nevertheless, bitolterol appears to be a well tolerated and relatively long acting alternative to other beta-adrenoceptor agonists in the treatment of reversible obstructive airways disease.

Nimesulide. A preliminary review of its pharmacological properties and therapeutic efficacy in inflammation and pain states.

Nimesulide is a new non-steroidal anti-inflammatory analgesic agent given orally or rectally on a twice daily basis in a number of inflammatory and pain states. Although still at an early stage of clinical assessment, preliminary evidence suggests that nimesulide 200 to 400mg daily is significantly more effective than placebo in reducing the pain, fever and inflammatory symptoms of chronic rheumatoid arthritis or osteoarthritis, respiratory tract infections, otorhinolaryngological diseases, soft tissue and oral cavity inflammation, dysmenorrhoea, phlebitis/thrombosis, urogenital disease and postoperative pain states. In a number of comparative studies, nimesulide has also been shown to be more effective than piroxicam (in osteoarthritis), paracetamol (acetaminophen) [in respiratory tract inflammation], benzydamine or naproxen (in otorhinolaryngological disease), phenylprenazone (in laryngotracheitis/bronchitis, respiratory inflammation and otorhinolaryngological disease), Serratia peptidases (in postoperative or dental pain, trauma and phlebitis), ketoprofen (in postoperative dental pain) and mefenamic acid (in dysmenorrhoea). In addition, the efficacy of nimesulide has been observed to be comparable with that of aspirin, with or without vitamin C, and mefenamic acid (in respiratory tract infection), ibuprofen (in soft tissue disease), naproxen (in respiratory tract inflammation, dysmenorrhoea and postoperative pain states), suprofen and paracetamol (in postoperative pain states), benzydamine (in genitourinary tract inflammation) and dipyrone, paracetamol or diclofenac (in fever). The safety profile of nimesulide has yet to be fully established, although initial evidence suggests the usual adverse effects associated with non-steroidal anti-inflammatory drugs occur, possibly with a lower incidence of gastrointestinal problems than with other members in its therapeutic class. Nimesulide, therefore, appears to offer a useful alternative to other non-steroidal anti-inflammatory drugs in the treatment of patients with inflammatory conditions and/or pain and fever states. However, further definition of its efficacy and tolerability is clearly required, particularly in comparison with established or other new drugs in its therapeutic class.

Flumazenil. A preliminary review of its benzodiazepine antagonist properties, intrinsic activity and therapeutic use.

Flumazenil, a 1,4-imidazobenzodiazepine, is a specific benzodiazepine antagonist which is indicated for use when the effect of a benzodiazepine must be quickly attenuated or terminated. Following intravenous administration, the onset of clinically apparent benzodiazepine antagonism usually occurs within 1 to 5 minutes. Although flumazenil has a short elimination half-life of about 1 hour, a single intravenous dose of up to 1 mg is usually sufficient to attain and maintain for about 2 hours the desired level of consciousness after general anaesthesia or conscious to moderate sedation induced by benzodiazepines. After intoxication with high doses of benzodiazepines the initial single dose of flumazenil will require supplementing with repeated low intravenous doses or an infusion (0.1 mg/h) to maintain a state of wakefulness. Flumazenil is well tolerated, and since it reliably attenuates or reverses the central effects of benzodiazepines and is specific for these drugs, it facilitates diagnosis by eliminating benzodiazepine intoxication in patients in whom the cause of unconsciousness is unknown. While results of some studies suggested that flumazanil may have intrinsic benzodiazepine partial agonist or inverse agonist activity, this is unlikely to be clinically important with usual doses. Thus, flumazenil is a very promising, effective, short acting benzodiazepine antagonist which is well tolerated by most patients. Undoubtedly, its full clinical potential has yet to be realised.

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

Oxaprozin is a newer non-steroidal anti-inflammatory drug advocated for use in painful rheumatic and inflammatory conditions. As is the case with some other newer non-steroidal anti-inflammatory drugs, oxaprozin offers the convenience of once-daily administration. Published data suggest that oxaprozin 1200 mg once daily is comparable in effectiveness with usual dosages of aspirin, ibuprofen, indomethacin, naproxen, piroxicam and sulindac in the treatment of rheumatoid arthritis and osteoarthritis. More controlled clinical trials in adequate numbers of patients are necessary to evaluate its potential in other rheumatic and inflammatory conditions. Oxaprozin produced fewer gastrointestinal side effects than aspirin, and the short term tolerability of oxaprozin was similar to that of other non-steroidal anti-inflammatory drugs. If further definition of its efficacy and tolerability compared with other non-steroidal anti-inflammatory drugs during long term therapy confirms these initially favourable results, then oxaprozin would appear to offer a useful and convenient alternative in the treatment of painful rheumatic and inflammatory conditions.

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

Aztreonam (azthreonam; SQ 26,776) is the first member of a new class of beta-lactam antibiotics, the monobactams. Aztreonam is selectively active against Gram-negative aerobic bacteria and inactive against Gram-positive bacteria. Thus, in vitro, aztreonam is inhibitory at low concentrations (MIC90 less than or equal to 1.6 mg/L) against Enterobacteriaceae except Enterobacter species, and is active against Pseudomonas aeruginosa, 90% of pseudomonads being inhibited by 12 to 32 mg/L. Aztreonam is inactive against Gram-positive aerobic bacteria and anaerobes, including Bacteroides fragilis. Therefore, when administered alone, aztreonam has minimal effect on indigenous faecal anaerobes. Aztreonam must be administered intravenously or intramuscularly when used to treat systemic infections, since absolute bioavailability is very low (about 1%) after oral administration. Since elimination half-life is less than 2 hours, 6- or 8-hourly administration is used in the treatment of moderately severe or severe infections, although 12-hourly injection is adequate in less severe systemic and some urinary tract infections. Therapeutic trials have shown aztreonam to be effective in Gram-negative infections including complicated infections of the urinary tract, in lower respiratory tract infections and in gynaecological and obstetric, intra-abdominal, joint and bone, skin and soft tissue infections, uncomplicated gonorrhoea and septicaemia. In comparisons with other antibiotics, aztreonam has been at least as effective or more effective than cefamandole in urinary tract infections and similar in efficacy to tobramycin or gentamicin. Where necessary, aztreonam and the standard drug have both been combined with another antibiotic active against Gram-positive and/or anaerobic bacteria. Aztreonam has been effective in eradicating pseudomonal infections in most patients (except in patients with cystic fibrosis), but the inevitably limited number of pseudomonal infections available for study prevents any conclusions as to the relative efficacy of aztreonam compared with other appropriate regimens against these infections. Thus, with an antibacterial spectrum which differs from that of other antibiotics, aztreonam should be a useful alternative to aminoglycosides or 'third generation' cephalosporins in patients with proven or suspected serious Gram-negative infections.

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

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.

Cefonicid. A review of its antibacterial activity, pharmacological properties and therapeutic use.

Cefonicid is a 'second generation' cephalosporin administered intravenously or intramuscularly. It is similar to cefamandole in its superiority to first generation cephalosporins against several enterobacteriaceae as well as its activity against Haemophilus influenzae, including beta-lactamase-producing strains. Its activity against Staphylococcus aureus is similar to that of cefoxitin and inferior to cefamandole and first generation cephalosporins. It has excellent in vitro activity against Neisseria gonorrhoeae, but is inactive against Pseudomonas, Acinetobacter, Serratia, and Bacteroides fragilis. Due to high achievable plasma concentrations and a relatively long half-life, in most clinical trials cefonicid has been administered once daily. It was comparable in efficacy with cefamandole or cefazolin in the treatment of patients with urinary tract, lower respiratory tract, and soft tissue and bone infections. It has also been compared with penicillin in the treatment of uncomplicated gonorrhoea. Results from a small series of patients with endocarditis appear to indicate that cefonicid should not be used in patients with serious staphylococcal infections. Single doses of cefonicid given preoperatively appear to offer a similar degree of protection against post-surgical infection as multiple doses of other antibiotics, but further data from studies involving larger numbers of patients are needed to confirm these impressions. Patients who require prolonged antibiotic therapy, such as those with osteomyelitis being treated as outpatients after a relatively short inpatient course, could benefit from the once daily dose regimen of cefonicid.