Cefotaxime. A reappraisal of its antibacterial activity and pharmacokinetic properties, and a review of its therapeutic efficacy when administered twice daily for the treatment of mild to moderate infections.

Cefotaxime is well established as an effective and well tolerated antibacterial drug for 3 times daily parenteral treatment of a variety of moderate to severe infections in hospitalised patients. Its frequency of administration has recently been reassessed with a 12-hourly regimen. Comparative studies in hospitalised patients with nosocomial or community-acquired lower respiratory tract infections, demonstrate the similar clinical and bacteriological efficacy of twice daily cefotaxime 1 or 2 g and the same daily dose of ceftriaxone, usually administered once daily. Cefotaxime 2 g twice daily was also similar in efficacy to ceftriaxone 2 g once daily. Retrospective and post-marketing studies also reveal the similar efficacy of cefotaxime administered twice and 3 times daily, and pharmacoeconomic studies suggest that total direct costs of treatment with cefotaxime compared is similar to that with other third generation cephalosporins in currently used dosage regimens. When administered twice daily, cefotaxime is, thus, an effective antibacterial agent for the treatment of hospitalised patients outside the intensive care unit with a variety of mild to moderate non-CNS infections caused by susceptible organisms. When appropriately administered twice daily there is potential to lower the cost of antibacterial treatment without compromising efficacy.

Serenoa repens (Permixon). A review of its pharmacology and therapeutic efficacy in benign prostatic hyperplasia.

Serenoa repens (Permixon) has been available for several years for the treatment of men with benign prostatic hyperplasia (BPH). The drug is the n-hexane lipidosterolic extract of the dwarf American palm (also known as Serenoa repens) and is a complex mixture of various compounds. A number of pharmacodynamic effects have been demonstrated with the lipidosterolic extract of Serenoa repens (LSESR), suggesting multiple mechanisms of action including in vitro inhibition of both type 1 and type 2 isoenzymes of 5 alpha-reductase and interference with binding of dihydrotestosterone to cytosolic androgen receptors in prostate cells. In controlled clinical trials in men with BPH, oral administration of Serenoa repens 160 mg twice daily for 1 to 3 months was generally superior to placebo in improving subjective symptoms, such as dysuria, as well as objective parameters. The frequency of nocturia was reduced by 33 to 74%, while urinary frequency during the day decreased by 11 to 43% and peak urinary flow rate increased by 26 to 50% with Serenoa repens. Corresponding values for placebo were 13 to 39%, 1 to 29% and 2 to 35%. The only large comparative trial conducted to date, in which > 1000 men with moderate BPH were randomised to receive Serenoa repens 160 mg twice daily or finasteride 5 mg once daily for 6 months, demonstrated similar efficacy between the two drugs. No statistically significant difference was demonstrated between treatment groups for improvement in patient self-rated quality-of-life scores and the primary end-point of objective symptom score; International Prostate Symptom Score improved by 37% with Serenoa repens compared with 39% with finasteride. In much smaller comparative trials, few significant differences were demonstrated between Serenoa repens and alpha 1-receptor antagonists, and larger randomised trials of adequate duration are required to better compare the clinical efficacy of these drugs. The most frequently reported adverse events in clinical trials with Serenoa repens have been minor gastrointestinal problems (e.g. nausea and abdominal pain). In conclusion, Serenoa repens is well tolerated and has greater efficacy than placebo and similar efficacy to finasteride in improving symptoms in men with BPH. Although there is a need for further comparative studies, particularly with alpha 2-receptor antagonists, available data indicate that Serenoa repens is a useful alternative to alpha 1-receptor antagonists and finasteride in the treatment of men with BPH.

Cefuroxime axetil. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy.

Cefuroxime axetil is an oral cephalosporin which is rapidly hydrolysed to the active parent compound, cefuroxime. Cefuroxime has a broad spectrum of in vitro antibacterial activity which encompasses methicillin-sensitive staphylococci and the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis and group A beta-haemolytic streptococci. Cefuroxime has broad spectrum activity against the beta-lactamase positive respiratory pathogens H. influenzae and M. catarrhalis; it is also active against penicillin-susceptible and -intermediate strains of S. pneumoniae. In clinical trials, cefuroxime axetil (administered twice daily) has been evaluated in the treatment of upper and lower respiratory tract infections and has demonstrated similar efficacy to established antibacterial agents, including amoxicillin/clavulanic acid and cefaclor. Five days' treatment with cefuroxime axetil was recently shown to be as effective as 10 days' treatment with either cefuroxime axetil or amoxicillin/clavulanic acid in patients with acute otitis media or acute bronchitis. Cefuroxime axetil was at least as effective as phenoxymethylpenicillin (penicillin V) in the treatment of patients with group A beta-haemolytic streptococcal tonsillopharyngitis. A number of studies have evaluated the efficacy of cefuroxime axetil as the oral component of intravenous to oral sequential therapy in hospitalised patients with lower respiratory tract infection. In each study patients received parenteral cefuroxime for approximately 2 days followed by cefuroxime axetil for 5 to 10 days. In comparative studies, cefuroxime sequential therapy was as effective as amoxicillin/ clavulanic acid sequential therapy and full courses of parenteral cefuroxime, cefotiam or cefoperazone. Adults with urinary tract infections and skin infections were also effectively treated with cefuroxime axetil, as were adults and adolescents with early stage lyme disease. Cefuroxime axetil is associated with a low incidence of adverse events, with gastrointestinal disturbances being the most frequently observed. Thus, cefuroxime axetil is an effective and convenient treatment for a wide range of infections and may be considered a therapeutic option when empirical treatment of community-acquired infections is required. Moreover, given the promising results of several intravenous/oral sequential treatment studies, cefuroxime axetil may also become established as an oral component of sequential treatment regimens.

Goserelin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in benign gynaecological disorders.

Goserelin is a gonadotrophin-releasing hormone (GnRH) analogue which, during continuous administration, down-regulates the pituitary-ovarian gonadal axis and reduces levels of the gonadotrophins, luteinising hormone and follicle-stimulating hormone. In women, this results in suppression of ovarian steroidogenesis and a decline in estrogen to levels similar to those observed after menopause or following surgical oophorectomy. Thus, goserelin has a useful role in the management of some benign estrogen-dependent gynaecological disorders. Goserelin is available as a biodegradable sustained release depot 3.6mg injection which is administered every 28 days. In women with endometriosis, monthly injections of depot goserelin were effective in achieving resolution of endometriotic implants and in improving pelvic symptoms, including pain and dyspareunia. Randomised clinical comparisons of depot goserelin with danazol indicate that goserelin is at least as effective as danazol and is better tolerated in the treatment of endometriosis. In the management of uterine leiomyomata (fibroids), goserelin depot injections reduce uterine size and the size of uterine leiomyomata, with maximum clinical benefit achieved approximately 3 to 4 months after initiation of treatment. When used as an adjunctive pretreatment for women undergoing surgical removal of uterine leiomyomata, goserelin was associated with technically easier surgical procedures, reduced intraoperative blood loss and reduced transfusion requirements around the time of surgery. As an alternative to surgery, therapeutic use of goserelin is limited by the rapid regrowth of leiomyomata following cessation of treatment. However, goserelin may be a useful treatment for women approaching menopause, in whom uterine leiomyomata shrink naturally as endogenous estrogen levels decline. In women with dysfunctional uterine bleeding, treatment with depot goserelin before surgery facilitates resection and ablative procedures by suppressing endometrial growth and thinning the endometrial mucosa. Goserelin is also an effective alternative to surgery in this patient group. As adjuvant therapy for women undergoing assisted reproduction procedures, goserelin is associated with reduced cycle cancellation rates and with an increase in the rate of oocyte retrieval. The tolerability profile of goserelin is characterised by adverse effects typical of hypoestrogenism, including hot flushes, loss of libido and loss of bone mineral density. However, concomitant 'add-back' hormone replacement therapy appears to effectively reduce these hypoestrogenic symptoms. In summary, the availability of depot goserelin has broadened the spectrum of effective treatments for benign estrogen-dependent gynaecological disorders. As goserelin is effective as a sustained release depot formulation suitable for administration on a monthly basis, it is also a convenient and practical treatment choice.

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.

Cefixime. A review of its therapeutic efficacy in lower respiratory tract infections.

Cefixime is an orally active third generation cephalosporin with in vitro antibacterial activity against most important lower respiratory pathogens. The drug is active against Haemophilus influenzae, Moraxella catarrhalis and penicillin-susceptible Streptococcus pneumoniae but not Staphylococcus aureus. Cefixime has a long elimination half-life (3 hours compared with 0.5 hours for cefaclor and 1.5 hours for cefalexin), which allows once daily administration. Several trials have established the clinical efficacy of the drug in patients with lower respiratory tract infection (LRTI). In comparative studies cefixime had similar efficacy to amoxicillin +/- clavulanic acid, cefaclor, cefalexin, cefuroxime axetil and clarithromycin. Trials evaluating the efficacy of cefixime as the oral component of intravenous to oral switch therapy have produced promising preliminary results although further carefully designed trials are needed in this area. As with certain other drugs of its class, gastrointestinal disturbances are the most frequently reported adverse events in patients taking cefixime and cases of pseudomembranous colitis have been reported. Thus, cefixime is an effective treatment for mild to moderate LRTI and may have a role as the oral component of intravenous to oral switch therapy although further well designed studies are needed to confirm initial favourable results in this important emerging area of antibacterial therapy.

Nilvadipine. A review of its pharmacodynamic and pharmacokinetic properties, therapeutic use in hypertension and potential in cerebrovascular disease and angina.

Nilvadipine, a calcium antagonist of the dihydropyridine class, selectively blocks calcium channels in vascular smooth muscle. Compared with nifedipine, the prototype of the dihydropyridines, nilvadipine has a longer duration of action. The antihypertensive efficacy of nilvadipine appears to be comparable with that of nicardipine and nitrendipine, enalapril and captopril and hydrochlorothiazide/triamterene, although further clinical experience is required to establish the claimed advantages nilvadipine may have over the other dihydropyridine derivatives currently used to treat hypertension. Preliminary studies suggest that nilvadipine may also be useful in the treatment of patients with stable exertional or variant angina. Studies conducted in Japan indicate that nilvadipine improves symptoms resulting from cerebral infarction in some patients, but further comparative studies are required to confirm these results. The tolerability of nilvadipine appears to be comparable with that of nicardipine and better than that of nifedipine with respect to flushes, oedema and liver function abnormalities. As is typical of calcium antagonists, there is no evidence of tolerance to the antihypertensive effects of nilvadipine. The drug is equally effective in treating hypertension in elderly and younger patients and does not appear to adversely affect glucose or lipid metabolism. Thus, provided its apparently good tolerability is confirmed by wider clinical experience, it should be a suitable alternative to other calcium antagonists when used alone or in conjunction with other drugs for the majority of patients with mild to moderate hypertension.

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)

Teicoplanin. A reappraisal of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacy.

Since an earlier review in the Journal substantial additional data have accumulated, further clarifying the in vitro activity, pharmacokinetic profile, clinical efficacy and tolerability of teicoplanin. Recent therapeutic trials confirm the efficacy of teicoplanin in the treatment of microbiologically confirmed Gram-positive infections, including septicaemia, endocarditis, and infections of skin and soft tissue, bone and joints, and the lower respiratory tract. As teicoplanin can be administered once daily intramuscularly as well as intravenously, it has potential for outpatient treatment of severe Gram-positive infections. Teicoplanin is appropriate as treatment of patients with fever and neutropenia, but there is still controversy over the timing for introduction of glycopeptide antibiotics into therapeutic regimens. Teicoplanin is generally reserved for secondary therapy of patients with documented bacteraemia who fail to respond to initial empirical antibiotic regimens, but probably should be part of the initial empirical regimen in the setting of a high incidence of methicillin-resistant staphylococci. Teicoplanin has a lower propensity than vancomycin to impair renal function when either drug is combined with an aminoglycoside, causes fewer anaphylactoid reactions, and appears to be of comparable efficacy. Thus, teicoplanin may be preferred to vancomycin in the treatment of Gram-positive infections, and where a glycopeptide antibiotic is deemed a necessary inclusion in a regimen for empirical treatment in patients with fever and neutropenia.

Piperacillin/tazobactam. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential.

Combining tazobactam, a beta-lactamase inhibitor, with the ureidopenicillin, piperacillin, successfully restores the activity of piperacillin against beta-lactamase-producing bacteria. Tazobactam has inhibitory activity, and therefore protects piperacillin against Richmond and Sykes types II, III, IV and V beta-lactamases, staphylococcal penicillinase and extended-spectrum beta-lactamases. However, tazobactam has only species-specific activity against class I chromosomally-mediated enzymes. Resistant organisms include some Citrobacter spp., Enterobacter spp., Serratia spp., Xanthomonas maltophilia and Enterococcus faecium. Consistent with its in vitro activity, preliminary clinical data indicate that the fixed combination of piperacillin/tazobactam (dose ratio 8:1) is effective in the treatment of moderate to severe polymicrobial infections, including intra-abdominal, skin and soft-tissue and lower respiratory tract infections. In limited comparative trials, piperacillin/tazobactam demonstrated equivalent or better efficacy than standard comparator regimens in these infections. Piperacillin/tazobactam in combination with an aminoglycoside was effective in the empirical treatment of fever in patients with neutropenia and compared favourably with ceftazidime in combination with an aminoglycoside, although second-line therapy with a glycopeptide antibiotic may be indicated in unresponsive episodes. Data from phase III trials indicate that piperacillin/tazobactam has a tolerability profile typical of a penicillin agent. Piperacillin/tazobactam provides a broad spectrum of antibacterial activity in a convenient single formulation suitable for use in the treatment of polymicrobial infections. Possible limitations concern its restricted activity against class I beta-lactamases, enzymes that are becoming increasingly important in the nosocomial environment. Combined therapy with an aminoglycoside may be necessary in more serious infections.

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.

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

Cefodizime is a third generation cephalosporin with a broad spectrum of antibacterial activity. Administered intravenously or intramuscularly, cefodizime 1 to 4 g daily for an average of 7 to 10 days produced clinical cure in 80 to 100% of patients (adults, elderly or children) with upper or lower respiratory tract infections or urinary tract infections, and in comparative trials cefodizime was as effective as other third generation cephalosporins. A single dose of cefodizime 1 or 2 g is also useful in treating lower urinary tract infections, particularly uncomplicated infections, with a rate of clinical success of 72 to 88%. Urogenital gonorrhoea, whether caused by beta-lactamase producing or non-beta-lactamase producing Neisseria gonorrhoeae, is very effectively treated by single dose therapy with intramuscular cefodizime 0.25 to 1 g (virtually 100% cured). Preliminary data from a small number of patients indicate that cefodizime may also be useful in the treatment of otitis media, sinusitis and gynaecological infections, and for the prophylaxis or treatment of surgical infections. The clinical efficacy of cefodizime in comparison with other third generation cephalosporins is superior to that predicted from in vitro results. This superior activity of cefodizime may be related to the relatively long elimination half-life of the drug or its ability to modify some functions of the immune system--a potentially important finding awaiting further investigation. Cefodizime is well tolerated and has a tolerability profile similar to other members of its class with systemic adverse events being primarily gastrointestinal or dermatological. Thus, limited comparative studies indicate cefodizime has the potential to become a useful alternative to current antimicrobial therapy for the treatment of a variety of infections. Cefodizime may be more convenient to administer than some other agents of its class as it may be given once or twice daily. While there are no trials comparing cefodizime to other third generation cephalosporins in immunosuppressed populations, preliminary information indicates cefodizime may be useful in this group.

Cefpodoxime proxetil. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential.

Cefpodoxime proxetil is an orally administered prodrug which is absorbed and de-esterified by the intestinal mucosa to release the third generation cephalosporin, cefpodoxime. Cefpodoxime is stable towards the most commonly found plasmid-mediated beta-lactamases and the drug has a broad spectrum of antibacterial activity encompassing both Gram-negative and Gram-positive bacteria, rendering it a possible option for empirical use in a wide range of community acquired infections in both adult and paediatric patients. The extended plasma half-life of cefpodoxime (1.9 to 3.7 h) permits twice daily administration. In comparative trials, twice daily cefpodoxime proxetil (dose equivalent cefpodoxime 100 to 400 mg) was as effective as a 3- to 4-times daily regimen of phenoxymethylpenicillin in pharyngotonsillitis, as well as thrice daily amoxicillin (with or without clavulanic acid) or cefaclor against infections of the ear, the upper and lower respiratory tract, the urinary tract and those of the skin and soft tissues. The latter reflects the enhanced antistaphylococcal activity of cefpodoxime, which distinguishes it from other orally active third generation cephalosporins such as cefixime. Most notably, an oral regimen of cefpodoxime proxetil was as efficacious as parenterally administered ceftriaxone for the treatment of bronchopneumonia in hospitalised patients at risk due to the presence of underlying diseases, addictions or advancing age. A single oral dose of cefpodoxime was also as efficacious as ceftriaxone in uncomplicated anogenital gonococcal infections. Cefpodoxime proxetil is generally well tolerated, with mild to moderate gastrointestinal disturbances occurring in 4 to 15% of patients treated with therapeutic doses. Thus, a convenient twice daily oral regimen of cefpodoxime proxetil can be prescribed as an effective alternative to established beta-lactam therapies in the empirical outpatient treatment of infections of the respiratory and urinary tracts as well as those of the skin and soft tissues.

Sustained release nifedipine formulations. An appraisal of their current uses and prospective roles in the treatment of hypertension, ischaemic heart disease and peripheral vascular disorders.

Nifedipine antagonises influx of calcium through cell membrane slow channels, and sustained release formulations of the calcium channel blocker have been shown to be effective in the treatment of mild to moderate hypertension and both stable and variant angina pectoris. Preliminary findings also indicate that these formulations are effective in the treatment of Raynaud's phenomenon and hypertension in pregnancy, and that they reduce the frequency of ischaemic episodes in some patients with silent myocardial ischaemia. The exact mechanism of action of nifedipine in all of these disorders has not been defined. However, its potent peripheral and coronary arterial dilator properties, together with improvements in oxygen supply/demand, are of particular importance. A major goal of sustained release therapy is to permit reductions in the frequency of nifedipine administration, preferably to once daily, and thus improve patient compliance. Two new once-daily formulations--the nifedipine gastrointestinal therapeutic system (GITS) and a fixed combination capsule comprising sustained release nifedipine 20 mg and atenolol 50 mg--have exhibited marked antihypertensive efficacy. The GITS preparation has also been used effectively in the treatment of stable angina pectoris, and both formulations appear to be well tolerated. Sustained release nifedipine formulations are generally better tolerated than their conventionally formulated counterparts, particularly with regard to reflex tachycardia. Adverse effects seem to be dose related, are mainly associated with the drug's potent vasodilatory action, and include headache, flushing and dizziness. Generally, these effects are mild to moderate in severity and transient, usually diminishing with continued treatment. Thus, sustained release nifedipine formulations are useful and established cardiovascular therapeutic agents which have demonstrable efficacy in various forms of angina, mild to moderate hypertension and Raynaud's phenomenon. Further, promising results shown by the nifedipine GITS formulation, with its advantage of once daily administration suggest that it is likely to become one of the preferred nifedipine formulations for the treatment of hypertension and the various forms of angina.

Teicoplanin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential.

Teicoplanin is a glycopeptide antibiotic with a molecular structure which is related to that of vancomycin. Gram-positive bacteria such as staphylococci (including methicillin-resistant strains), streptococci, enterococci and many anaerobic Gram-positive bacteria are susceptible to teicoplanin in vitro. Teicoplanin has an exceptionally long half-life, allowing once-daily intramuscular or intravenous administration. Teicoplanin is clinically and bacteriologically effective against a wide variety of Gram-positive infections such as septicaemia, endocarditis, skin and soft tissue infections and infections associated with venous catheters. The drug is equally efficacious against methicillin-resistant and -susceptible staphylococci. Adverse effects with teicoplanin are generally limited to local effects or hypersensitivity reactions. While teicoplanin has the potential for ototoxicity and nephrotoxicity, the incidence appears to be quite low when recommended serum concentrations are maintained. Teicoplanin is a valuable alternative to vancomycin, and providing controlled comparative studies prove equivalent safety and efficacy between the 2 glycopeptides the more easily administered teicoplanin should become the preferred antibacterial agent.

Buserelin. A review of its pharmacodynamic and pharmacokinetic properties, and clinical profile.

The gonadotrophin releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH); gonadorelin] agonist buserelin is a promising new agent in the treatment of a variety of disorders in gynaecology and andrology, paediatrics and oncology. While a single dose of buserelin stimulates the release of pituitary gonadotrophins, multiple doses produce reversible pituitary desensitisation, and this specific blockade of gonadotrophin support to the gonads provides the basis for the drug's efficacy in conditions dependent on sex hormone secretion. Thus, buserelin provides comparable efficacy to orchidectomy or high dose estrogens in the treatment of hormone-sensitive prostate cancer and exhibits a lower incidence of adverse effects. During the early phase of treatment it may be particularly useful in combination with antiandrogens. Buserelin also appears promising in hormone-sensitive premenopausal breast cancer. Extensive studies have proven the value of buserelin in endometriosis, where it produces a transient remission with gradual recurrence of the disease on cessation of treatment. Surgical intervention is necessary in severe disease after buserelin-induced involution of the lesions. In patients with uterine leiomyoma, preliminary data suggest that buserelin may be beneficial in rendering surgery more conservative by reducing fibroid size, although it appears unlikely to preclude surgical intervention. The use of buserelin to induce a state of reversible hypogonadotrophism before administration of exogenous gonadotrophins is a promising strategy in the treatment of infertility associated with polycystic ovary syndrome and other conditions of infertility with underlying ovarian dysfunction; such a strategy also clearly enhances the efficiency of in vitro fertilisation programmes. Initial studies suggest its potential usefulness as a female contraceptive when administered intermittently in conjunction with a progestogen. Buserelin represents a first-line treatment of central precocious puberty. In endometriosis the adverse effect profile of buserelin is generally favourable, with hypoestrogenic effects such as hot flushes and vaginal dryness, and decreased libido, predominating. There is no apparent detrimental effect on lipid metabolism. The potential for adverse hypoestrogenic effects on bone mineral content with long term administration remains to be clarified. Thus, the GnRH agonist buserelin represents an advance in the treatment of a variety of gynaecological and andrological as well as paediatric and oncological conditions, infertility and other sex-hormone dependent conditions, with a low incidence of adverse treatment effects.

Mesalazine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in chronic inflammatory bowel disease.

Mesalazine (5-aminosalicylic acid; mesalamine), the active moiety of sulphasalazine (salazosulfapyridine), is available in specially formulated oral and rectal forms for the treatment of active ulcerative colitis of mild to moderate severity and for maintenance therapy during disease remission. Tablets or capsules coated with acrylic-based resin and tablets containing microgranules coated with ethylcellulose deliver mesalazine to the distal small intestine and colon, thus avoiding the need for the carrier, sulphapyridine, which is responsible for many of the adverse effects associated with sulphasalazine. Since mesalazine is released in the small intestine from some coated preparations in contrast to sulphasalazine, these oral formulations have therapeutic potential in Crohn's disease. A limited number of therapeutic trials suggest that orally administered mesalazine 1.5 to 2.4g daily is of similar efficacy to sulphasalazine 2 to 3g daily in patients with mild to moderate ulcerative colitis. The efficacy of mesalazine enemas has been more widely investigated, a dose of 1 to 4g once daily being consistently more effective than placebo and apparently similar to enemas of prednisone 25mg or oral sulphasalazine 3g. Initial results suggest that mesalazine 4g enemas may be more effective than those containing hydrocortisone 100mg. Mesalazine and sulphasalazine in approximately equivalent oral dosages are similarly effective in maintaining remission in ulcerative colitis. Orally administered coated mesalazine is generally well tolerated by about 85% of patients allergic to or intolerant of sulphasalazine, the remainder experiencing similar reactions to both drugs. Adverse effects of mesalazine enemas are confined to local irritation and effects resulting from enema-tip insertion. Thus, orally administered coated mesalazine is a suitable alternative to sulphasalazine in the treatment of patients with mild to moderate active distal ulcerative colitis and for maintaining remission particularly in patients allergic to or intolerant of sulphasalazine. In patients who find enema therapy acceptable, mesalazine enemas are effective and well tolerated.

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.

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.

Astemizole. A review of its pharmacodynamic properties and therapeutic efficacy.

Astemizole is an H1-histamine receptor antagonist with a long duration of action permitting once daily administration. Its efficacy in seasonal and perennial allergic rhinitis has been convincingly demonstrated, and several comparative studies suggest that astemizole is at least as effective as some other H1-histamine receptor antagonists. A few smaller studies have shown beneficial effects on the symptoms of allergic conjunctivitis and chronic urticaria (but not atopic dermatitis). While astemizole appears to share with other H1-histamine receptor antagonists a tendency to increase appetite and cause weight gain after prolonged use, it offers the important advantage of an absence of significant central nervous system depression or anticholinergic effects with usual doses. Thus, astemizole offers a worthwhile improvement in side effect profile over 'traditional' H1-histamine receptor antagonists, especially in patients bothered by the sedative effects of these drugs.