No lasting legacy: no change in reporting of women's sports in the British print media with the London 2012 Olympics and Paralympics.

BACKGROUND: The proportion of media sports coverage devoted to women is reported at between 1 and 6%. Our survey examines and compares reporting patterns before and after the 2012 Olympics and Paralympics. METHODS: We collected data on sports coverage in six national newspapers on 3 weekend days in February and March 2012, and in February 2013; ∼5 months before the opening of the 2012 Olympic Games and 5 months after the closing of the Paralympic Games. RESULTS: In 2012, 39 of 876 articles in national newspapers (4.5%) related to women's sports, compared with 22 of 755 (2.9%) in 2013; a non-significant reduction in coverage [difference 1.54%, 95% confidence interval (CI) -0.28 to 3.36). In 2012, 24 of 647 pictures (3.7%) related to women's activities, compared with 10 of 738 (1.4%) in 2013; a significant reduction in coverage (difference 2.35%; 95% CI 0.68-4.03). The median area per article was significantly greater for men in both years. CONCLUSIONS: We found a continuing bias towards men's sport in the media analysed and no evidence of improvement either before or after the 2012 Olympics and Paralympics. Increased support of women's sport in the print media could benefit individuals and influence the health of the population.

Tizanidine. A review of its pharmacology, clinical efficacy and tolerability in the management of spasticity associated with cerebral and spinal disorders.

The central alpha 2 adrenoceptor agonist tizanidine is a myotonolytic agent used in the treatment of spasticity in patients with cerebral or spinal injury. Wide interpatient variability in the effective plasma concentrations of tizanidine means that the optimal dosage must be titrated over 2 to 4 weeks for each patient (dosages of 2 to 36 mg/day have been used in clinical trials). Maximum effects occur within 2 hours of administration. Antispastic efficacy has been demonstrated for tizanidine in placebo-controlled trials, with reduction in mean muscle tone scores of 21 to 37% versus 4 to 9% for patients receiving placebo. Improvement in muscle tone occurred in 60 to 82% of tizanidine recipients, compared with 60 to 65% of baclofen and 60 to 83% of diazepam recipients. Spasm frequency and clonus are also reduced by tizanidine. The most common adverse effects associated with tizanidine are dry mouth and somnolence/drowsiness. Muscle strength, as assessed by objective means, appears not to be adversely affected by tizanidine and subjective muscle weakness is reported less often by tizanidine recipients than by those receiving baclofen or diazepam. Global tolerability was assessed as good to excellent in 44 to 100% of patients receiving tizanidine, compared with 38 to 90% of baclofen and 20 to 54% of diazepam recipients. In conclusion, tizanidine is an antispastic agent with similar efficacy to that of baclofen and a more favourable tolerability profile. While drowsiness is a frequently reported adverse effect with both agents, subjective muscle weakness appears to be less of a problem with tizanidine than with baclofen. Tizanidine, therefore, appears to be an attractive therapeutic alternative for patients with spasticity associated with cerebral or spinal damage.

Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification.

Acamprosate (calcium acetylhomotaurinate), a synthetic compound with a similar chemical structure to that of gamma-aminobutyric acid, is thought to act via several mechanisms affecting multiple neurotransmitter systems; inhibition of neuronal hyperexcitability by antagonism of excitatory amino acid activity and reduction of calcium ion fluxes has been suggested as its predominant mechanism of action. The drug is the first agent specifically designed to maintain abstinence in alcohol (ethanol)-dependent patients after detoxification. Voluntary oral ethanol consumption in ethanol-preferring or ethanol-dependent rats is dose-dependently reduced by acamprosate: total fluid intake and food consumption are not affected. The drug does not potentiate the acute or chronic toxic effects of ethanol and has no hypnotic, antidepressant, anxiolytic or muscle-relaxant effects in animals. There is no evidence of abuse potential with acamprosate. Oral acamprosate 1.3 or 2 g/day in 3 divided doses administered for 3 to 12 months to alcohol-dependent patients after detoxification was more effective than placebo in preventing alcohol relapse according to abstinence rates, duration of abstinence, gamma-glutamyl transferase levels and/or a variety of other clinical or biological end-points. Concomitant psychosocial/behavioural therapies were used in some trials. Compared with those with placebo, the superior abstinence rates and durations of abstinence with acamprosate were maintained during 6- to 12-month post-treatment follow-up periods, and greater abstinence rates with acamprosate were confirmed in a pooled analysis of data from 11 randomised placebo-controlled trials involving a total of 3338 patients with alcohol dependence. The efficacy of acamprosate appears to be dose dependent and enhanced by the addition of disulfiram. Acamprosate was generally well tolerated in placebo-controlled trials. The most common adverse events were gastrointestinal (especially diarrhoea) or dermatological and were mostly mild and transient. The percentage of patient withdrawals because of adverse events was similar in acamprosate and placebo groups. No trials have compared the efficacy or tolerability of acamprosate with those of other treatment approaches (including opiate antagonists or selective serotonin reuptake inhibitors) aimed at maintaining abstinence in detoxified alcohol-dependent patients. Thus, acamprosate, as an adjunct to psychosocial/behavioural therapies, represents a novel advance for the management of alcohol-dependent patients in the postdetoxification period. Longer term and comparative trials with other active therapies are required to confirm these promising results.

Grepafloxacin.

Grepafloxacin (OPC-17116) is a new once-daily fluoroquinolone antimicrobial agent which appears to have high tissue penetration and the wide spectrum of antimicrobial activity typical of this class of agents, but with improved activity against Gram-positive organisms, notably Streptococcus pneumoniae. The in vitro activity of grepafloxacin was similar to or slightly lower than that of ciprofloxacin against Enterobacteriaceae but better than that of ciprofloxacin against most Gram-positive organisms. In particular, grepafloxacin showed good activity against pathogens implicated in community-acquired pneumonia, with 4-fold higher potency than ciprofloxacin against S. pneumoniae, including penicillin-resistant strains. In animal studies, grepafloxacin did not induce convulsions when administered at high doses in conjunction with nonsteroidal anti-inflammatory agents. Grepafloxacin has a weak propensity for causing phototoxicity, similar to that of ciprofloxacin. In comparative clinical trials, grepafloxacin demonstrated similar efficacy to amoxicillin in community-acquired pneumonia, ofloxacin in pneumonia and chronic respiratory tract infection, and cefixime in uncomplicated gonococcal urethritis and gonococcal cervicitis. Grepafloxacin has also shown clinical efficacy in preliminary studies in patients with chlamydial endocervical infection or bacillary dysentery.

Once-weekly fluoxetine.

The relatively long half-life of the selective serotonin reuptake inhibitor fluoxetine has allowed the development of a delayed-release (enteric-coated) formulation containing 90 mg fluoxetine per capsule for once-weekly oral administration. The cumulative relapse rate in patients switched to once-weekly fluoxetine 90 mg for 25 weeks (after responding to 13 weeks of fluoxetine 20 mg/day) was similar to that in patients continuing to receive fluoxetine 20 mg/day and significantly lower than seen in patients switched to placebo. The efficacy of the once-weekly formulation was also similar to that of the daily formulation in other assessment parameters (modified 17-item Hamilton Rating Scale for Depression, Clinical Global Impressions - Severity of Illness Scale). Patient compliance (measured using an electronically monitored tablet bottle) was maintained at 87.5% in evaluable patients receiving once-weekly fluoxetine 90 mg for 12 weeks from a baseline of 85.4% after responding to 4 weeks of fluoxetine 20 mg/day; in contrast, compliance declined significantly (from 87.3% at baseline to 79.4%; p < 0.001) in patients continuing to receive 20 mg/day for 12 weeks. Once-weekly fluoxetine is well tolerated, with a tolerability profile similar to that of the immediate-release formulation.

Transdermal fentanyl: an updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control.

UNLABELLED: Fentanyl is a synthetic opioid agonist which interacts primarily with the mu-opioid receptor. The low molecular weight, high potency and lipid solubility of fentanyl make it suitable for delivery by the transdermal therapeutic system. These patches are designed to deliver fentanyl at a constant rate (25, 50, 75 and 100 microg/h), and require replacement every 3 days. Data from randomised, nonblind trials suggest that transdermal fentanyl is as effective as sustained-release oral morphine in the treatment of chronic cancer pain, as reported by patients using visual and numerical analogue scales as well as verbal description scales. No obvious differences in health-related quality of life were found in patients with chronic cancer pain when comparing transdermal fentanyl with sustained-release oral morphine. Nevertheless, significantly more patients expressed a preference for transdermal fentanyl than for sustained-release oral morphine after a randomised, nonblind, crossover trial. Because of the formation of a fentanyl depot in the skin tissue, serum fentanyl concentrations increase gradually following initial application, generally levelling off between 12 and 24 hours. Thereafter, they remain relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Once achieved, steady-state plasma fentanyl concentrations can be maintained for as long as the patches are renewed. The most frequently observed adverse events during transdermal fentanyl administration (as with other opioid agonists) included vomiting, nausea and constipation. Data from a nonblind, randomised trials suggest that constipation occurs less frequently in patients receiving transdermal fentanyl than in those given sustained-release oral morphine. The most serious adverse event reported in US premarketing trials was hypoventilation, which occurred with an incidence of approximately 2%. Adverse reactions related to skin and appendages (i.e. rash and application site reactions - erythema, papules, itching and oedema) were reported in 153 patients with cancer at a frequency between 1 and 3%. CONCLUSION: Transdermal fentanyl is a useful opioid-agonist for the treatment of moderate to severe chronic cancer pain. The advantages of transdermal fentanyl include ease of administration and the 3-day application interval. These factors coupled with a lower incidence of constipation are likely to contribute to the reported patient preference of transdermal fentanyl over sustained-release oral morphine.

Domperidone. A review of its use in diabetic gastropathy.

UNLABELLED: Domperidone is a selective antagonist at peripheral dopamine D2 receptors, with gastroprokinetic and antiemetic properties. It increases the frequency and duration of antral and duodenal contractions, thus decreasing/improving transit time of food through the gastrointestinal tract. Gastric emptying of liquids and solids is significantly improved with oral domperidone 40 to 120 mg/day in patients with diabetic gastropathy. Oral domperidone 40 to 80 mg/day significantly decreased the severity of symptoms of gastropathy from baseline values in 66 to 88% of patients with type 1 (insulin-dependent) or insulin-requiring diabetes mellitus. Double-blind withdrawal of domperidone from patients who had responded previously led to greater deterioration of symptoms in patients with delayed gastric emptying than in those who continued receiving the drug. Quality of life was significantly improved in patients who showed a symptomatic response to domperidone. The administration of domperidone 40 to 120 mg/day significantly reduced hospitalisation rates in patients with gastropathy. The symptomatic improvement with domperidone 80 mg/day was similar to that seen with cisapride 40 mg/day or metoclopramide 40 mg/day, and therapeutic benefits seen in symptoms of gastropathy were maintained with domperidone for up to 12 years. Domperidone 40 to 80 mg/day may be effective in patients who are refractory to metoclopramide, and a combination of domperidone 80 mg/day with cisapride 80 mg/day may improve some symptoms in patients who do not respond to either agent alone. Domperidone 40 to 120 mg/day was well tolerated for periods up to 12 years in trials in patients with diabetic gastropathy. Adverse events with domperidone 80 mg/day were similar to those seen in placebo recipients and significantly fewer than in patients receiving metoclopramide 40 mg/day. Although significant elevation of plasma prolactin levels (unrelated to dosage and duration of treatment) occurred in all domperidone recipients, prolactin-related adverse events were observed in only 10 to 20% of patients. CONCLUSIONS: The available data suggest that domperidone 40 to 80 mg/day is an effective agent for the management of symptoms of gastropathy in patients with type 1 diabetes mellitus. In addition, it may provide symptom improvement in patients with gastropathy refractory to other gastroprokinetic agents. Domperidone maintains efficacy in the long term (up to 12 years) and appears to have a better tolerability profile than metoclopramide 40 mg/day.

Fluvastatin: a review of its pharmacology and use in the management of hypercholesterolaemia.

Fluvastatin, a member of the group of drugs known as HMG-CoA reductase inhibitors, is used in the treatment of patients with hypercholesterolaemia. In clinical trials in patients with primary hypercholesterolaemia, fluvastatin 20 or 40 mg/day achieved marked reductions from baseline in serum levels of low density lipoprotein (LDL)-cholesterol (19 to 31%) and total cholesterol (15 to 21%), along with modest declines in serum triglyceride levels (1 to 12%) and small increases in high density lipoprotein (HDL)-cholesterol levels (2 to 10%). These beneficial effects on the serum lipid profile were similar to those demonstrated with other HMG-CoA reductase inhibitors, although direct comparative trials are limited. Concomitant administration of fluvastatin plus another lipid-lowering agent, such as a bile acid sequestrant, a fibrate or nicotinic acid, usually reduced serum levels of total cholesterol and LDL-cholesterol by at least a further 5 to 10% from baseline compared with fluvastatin monotherapy. Fluvastatin has a similar tolerability profile to that of other HMG-CoA reductase inhibitors. Gastrointestinal disturbances, which are usually mild and transient, were the most frequently reported adverse events with fluvastatin in clinical trials. Persistent elevation of serum transaminase levels occurred in approximately 1% of fluvastatin recipients, which is similar to the rate for other HMG-CoA reductase inhibitors. Unlike other HMG-CoA reductase inhibitors, which have been infrequently associated with myopathy and rarely with rhabdomyolysis, these events have not been associated with fluvastatin to date, although fluvastatin has not been used as extensively as agents such as lovastatin. HMG-CoA reductase inhibitors other than fluvastatin, when given in combination with drugs such as fibrates, nicotinic acid, cyclosporin or erythromycin, can increase the risk of these potentially serious adverse events. Thus far, myopathy or rhabdomyolysis have not been reported among patients receiving fluvastatin concomitantly with any of these drugs. Therefore, fluvastatin can be given with caution in combination with fibrates, nicotinic acid, cyclosporin or erythromycin. In conclusion, fluvastatin has similar efficacy and tolerability profiles to other HMG-CoA reductase inhibitors, which are among the most effective agents available for treating patients with hypercholesterolaemia. Pharmacoeconomic studies performed to date suggest an advantage for fluvastatin over other HMG-CoA reductase inhibitors, predominantly because of its relatively low acquisition costs (at least in those countries in which the evaluations were conducted). Thus, fluvastatin is effective and well tolerated in patients with hypercholesterolaemia and appears to have an economic advantage over other HMG-CoA reductase inhibitors, primarily as a result of its relatively low acquisition costs.

Losartan potassium: a review of its pharmacology, clinical efficacy and tolerability in the management of hypertension.

Losartan potassium is an orally active, nonpeptide angiotensin II (AII) receptor antagonist. It is the first of a new class of drugs to be introduced for clinical use in hypertension. This novel agent binds competitively and selectively to the AII subtype 1 (AT(1)) receptor, thereby blocking AII-induced physiological effects. An active metabolite, E3174, contributes substantially to its antihypertensive effect, which persists throughout 24 hours after once-daily administration. In patients with mild to moderate hypertension, losartan potassium 50 to 100mg once daily as monotherapy lowers blood pressure to a similar degree to enalapril, atenolol and felodipine extended release (ER). Losartan potassium combined with hydrochlorothiazide reduces blood pressure further than either drug given separately. About one-third of patients with severe hypertension have responded to the combination product. Losartan potassium appears to be effective in elderly patients. Losartan potassium is very well tolerated. In clinical trials, dizziness was the only drug-related event reported more frequently with losartan potassium monotherapy than with placebo. First-dose hypotension is uncommon. An aspect of the drug's tolerability profile which may prove to be particularly advantageous is that it is associated with a similar incidence of cough to placebo in patients with a history of ACE inhibitor-related cough. Additionally, clinically relevant adverse metabolic effects or laboratory abnormalities have not been documented during losartan potassium therapy and renal function is preserved in patients with or without renal insufficiency. The adverse effect profile of the losartan potassium-hydrochlorothiazide combination resembles those for losartan potassium monotherapy and placebo. Long term tolerability data are limited (<2 years) but support the very good tolerability profile in shorter studies. Elements of the drug's profile yet to be assessed or reported fully in the literature include long term efficacy; potential to favourably influence cardiovascular and renovascular systems (and ultimately mortality) in patients with hypertension and, lastly, cost effectiveness and influence on quality of life. In summary, losartan potassium is the first AT(1)+ receptor antagonist to become available for the management of hypertension and, as such, it is an important new antihypertensive agent. Pending long term data as outlined above, it is likely to find initial use in patients with mild to severe hypertension who are unresponsive to, or intolerant of their current therapy. However, with its novel mechanism of action, good efficacy and favourable tolerability profile, losartan potassium is well placed to claim a prominent position in the management of patients with essential hypertension in the future.

A cellular pertussis vaccine (Infanrix-DTPa; SB-3). A review of its immunogenicity, protective efficacy and tolerability in the prevention of Bordetella pertussis infection.

SB-3 (Infanrix-DTPa) is one of a new generation of vaccines for immunisation against pertussis (whooping cough), diphtheria and tetanus. It is a 3-component (pertussis toxin, filamentous haemagglutinin and pertactin) chemically inactivated acellular pertussis pertussis-diphtheria-tetanus toxoid (DTaP) vaccine, and it differs from conventional whole-cell pertussis-diphtheria-tetanus toxoid (DTwP) vaccines in that it comprises inactivated purified Bordetella pertussis antigens rather than whole cells of the bacillus. SB-3, like a number of other DTaP vaccines, elicits a similar or more often, a significantly greater immune response than various DTwP vaccines in healthy infants and young children. initial data from comparative studies indicate that SB-3 also remains immunogenic when given in combination with hepatitis B vaccine or concurrently administered with Haemophilus influenzae type b (HbOC) conjugate vaccine. A combination of SB-3 and H. influenzae type b tetanus (PRP-T) conjugate vaccine results in lower anti-PRP antibody response than when both vaccines are administered concurrently. Data from two large, multicentre, German and Italian studies in infants indicate that the protective efficacy of SB-3 against pertussis was significantly better than one DTwP (DTwP-CON) but similar to another one (DTwP-BW) under investigation. Compared with another DTaP vaccine (BIO-3), SB-3 was just as protective. Overall, the data from these 2 studies indicate that primary vaccination with SB-3 provides effective protection against pertussis, even under the stringent conditions of a household contact with typical pertussis. As the other DTaP vaccines, SB-3 is better tolerated than DTwP vaccines, with a significantly lower incidence of common adverse events such as local reactions (swelling, pain and a erythema), irritability, fever, persistent crying and local tenderness. Clinical experience with SB-3 thus far indicates that, like other DTaP vaccines, it is associated with significantly fewer common (non-serious) adverse events than DTwP vaccines. Less clear is whether it has any advantage over DTwP vaccines with respect to protective efficacy or over other DTaP vaccines with respect to tolerability and protective efficacy. Nevertheless, the available data support the use of SB-3 for infant immunisation, as well as providing a suitable basis for the development of new combination vaccines.

Tiaprofenic acid. A reappraisal of its pharmacological properties and use in the management of rheumatic diseases.

Tiaprofenic acid is a nonsteroidal anti-inflammatory drug (NSAID) used in the treatment of patients with rheumatic diseases and other clinical conditions of pain and inflammation. Like other propionic acid derivatives, tiaprofenic acid is effective and generally well tolerated. Comparative studies in patients with rheumatoid arthritis or osteoarthritis receiving tiaprofenic acid 600 mg/day demonstrated improvements in pain intensity, duration of morning stiffness, articular index and other clinical variables which were similar to those achieved with alternative NSAIDs. Tolerability was also comparable between tiaprofenic acid and other NSAIDs in most trials; the most frequently reported adverse events involved the gastrointestinal tract. Some studies showed a trend towards fewer patient withdrawals because of adverse events with tiaprofenic acid than with NSAIDs such as indomethacin. Current evidence suggests that nonbacterial cystitis is more likely to be associated with tiaprofenic acid than with other NSAIDs. This reaction should, however, be considered in the perspective of its infrequent occurrence and its typical reversibility, and against the wider background of the established usage of tiaprofenic acid and its overall tolerability profile which is similar to that of other NSAIDs. Unlike indomethacin, tiaprofenic acid was not associated with increased cartilage degradation in a recently completed large clinical trial known as LINK, which evaluated the effects of long term administration in patients with osteoarthritis of the knee. Thus, tiaprofenic acid is an established option among the range of NSAIDs used in the treatment of patients with rheumatic diseases, with efficacy and tolerability profiles that are relatively well characterised. The availability of a sustained release dosage form of tiaprofenic acid, which has a similar efficacy and tolerability profile to the standard formulation, provides a convenient once daily dosage regimen.

Famciclovir. A review of its pharmacological properties and therapeutic efficacy in herpesvirus infections.

Famciclovir, a synthetic acyclic guanine derivative, is a prodrug which, after oral administration, is rapidly metabolised to the highly bioavailable antiviral compound penciclovir. Penciclovir is active in vitro against the herpesviruses herpes simplex virus (HSV)-1, HSV-2 and varicella zoster virus (VZV). Famciclovir is an effective treatment of immunocompetent patients with acute herpes zoster (shingles) caused by VZV. Comparative studies have demonstrated that famciclovir has therapeutic efficacy similar to that of oral aciclovir (acyclovir) in attenuating the acute signs and symptoms of infection (including pain during the acute phase of infection). In a placebo-controlled study, famciclovir significantly reduced the duration of postherpetic neuralgia; this effect was more pronounced (almost a 3-fold reduction) in patients aged > or = 50 years. In immunocompetent patients with recurrent genital herpes infection, suppressive treatment with oral famciclovir effectively prolonged the time to recurrence of symptomatic episodes of infection compared with placebo. In addition, famciclovir significantly reduced the duration of viral shedding, accelerated healing of genital herpes lesions and reduced the duration of symptoms. Famciclovir is reported to be the first antiviral agent to significantly reduce symptoms associated with multiple genital herpes lesions. Famciclovir is a well-tolerated drug with a tolerability profile similar to that of placebo and aciclovir. Thus, famciclovir is now established as an effective treatment of immunocompetent patients with herpes zoster or genital herpes infection, particularly as famciclovir is administered in a convenient dosage regimen that may improve compliance compared with aciclovir.

Amlodipine. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disease.

Amlodipine belongs to the dihydropyridine class of calcium channel blockers. Both short and long term studies indicate that amlodipine effectively lowers mild to moderately elevated blood pressure and relieves symptoms of angina pectoris. In comparative studies, its antihypertensive efficacy is similar to that of other established agents such as beta-blockers, diuretics, ACE inhibitors and other calcium channel blockers (including the dihydropyridines); limited comparative data are, however, available in patients with angina pectoris. Amlodipine may offer potential in patients with congestive heart failure. Vasodilator adverse events such as oedema, headaches, and flushing are commonly observed with amlodipine. The drug does not appear to cause postural hypotension, reflex tachycardia or cardiac conduction disturbances. Comparative studies suggest that amlodipine is at least as well tolerated as other standard agents. Thus, amlodipine provides an attractive therapeutic option for the treatment of hypertension, and offers potential for patients with angina pectoris. Its beneficial effects in patients with congestive heart failure require confirmation in future studies.

Foscarnet. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections.

The DNA polymerase of human herpes viruses, including cytomegalovirus (CMV), and the reverse transcriptase of human immunodeficiency virus (HIV) are selectively inhibited in vitro by the pyrophosphate analogue foscarnet. Inhibition is reversible on withdrawal of foscarnet and additive or synergistic effects have been demonstrated in vitro with other antiviral drugs, including ganciclovir and zidovudine. Foscarnet appears to have negligible effects on host enzymes and cells. Complete or partial clinical resolution of ocular symptoms is obtained in more than 89% of patients with acquired immunodeficiency syndrome (AIDS) and CMV retinitis during foscarnet induction therapy, but relapse occurs soon after ceasing treatment. Maintenance treatment given daily can extend the period of remission considerably. Foscarnet and ganciclovir monotherapy had similar efficacy in the treatment of CMV retinitis in patients with AIDS in several studies, and have been used concomitantly in immunocompromised patients with recalcitrant CMV infections. In 1 trial, patients receiving foscarnet survived for significantly longer than those receiving ganciclovir. Foscarnet has been used successfully in the treatment of limited numbers of immunocompromised patients with CMV-associated gastrointestinal (improvement in over 67% of patients) and other infections. Aciclovir-resistant herpes simplex infections in immunocompromised patients have also been treated successfully with foscarnet. Almost 90% of a foscarnet dose is excreted in the urine. Reversible nephrotoxicity is common during foscarnet therapy, but may be reduced by dosage adjustment and adequate hydration. Anaemia, nausea and vomiting, disturbances in electrolyte levels and genital ulceration have also been associated with administration of the drug. The different tolerability profiles of foscarnet and zidovudine facilitate the use of these agents in combination in patients with AIDS and CMV infection; whereas ganciclovir, like zidovudine, is associated with dose-limiting haematological toxicity. The apparent survival benefits seen in these patients when receiving foscarnet and zidovudine (possibly linked to synergy between zidovudine and foscarnet and/or the inherent anti-HIV activity of foscarnet), appear to offer potentially important advantages for foscarnet over ganciclovir in the treatment of selected patients with AIDS and CMV infections.

Fexofenadine.

The nonsedating histamine H1 receptor antagonist fexofenadine is the active metabolite of terfenadine. It reduced the allergic response in animal models of allergy and did not prolong the QT interval (QTc) in dogs or rabbits at plasma concentrations many times higher than those seen after administration of therapeutic dosages. Similarly, relative to placebo, fexofenadine did not affect mean QTc in patients given dosages of up to 480 mg/day for 2 weeks or in volunteers who received up to 800 mg/day for 6 days or 240 mg/day for 12 months. In a double-blind clinical trial, oral fexofenadine 120 or 180mg once daily controlled symptoms in patients with seasonal allergic rhinitis as effectively as cetirizine. Other double-blind clinical trials showed that fexofenadine 40 to 240mg twice daily was significantly more effective than placebo. Fexofenadine 180 or 240mg once daily was significantly more effective than placebo in patients with chronic idiopathic urticaria. The drug was well tolerated in these clinical trials, with an adverse event profile similar to that seen with placebo. The most common adverse events were headache, throat irritation, viral infection, nausea, dysmenorrhoea, drowsiness, dyspepsia and fatigue.

Colloidal bismuth subcitrate. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in peptic ulcer disease.

Colloidal bismuth subcitrate (CBS) possesses at least equal efficacy with histamine H2-receptor antagonist drugs in the treatment of peptic ulcer disease. However, CBS has the advantage of slower ulcer relapse rates than those seen after initial healing with the H2-antagonists. It has been postulated that this effect may be partly due to the antibacterial properties of CBS against Campylobacter pylori, a bacterium found in the gastric mucosa and gastric metaplasia within the duodenum of most patients with peptic ulcer and closely associated with gastritis. However, the role of C. pylori in the aetiology of peptic disease is far from clear. The mechanism by which CBS heals ulcers has not been fully elucidated, but several actions may be involved. CBS and mucus form a glycoprotein-bismuth complex in vitro. This provides a diffusion barrier to HCl and may, therefore, provide a protective coating in the ulcer crater which allows healing of the lesion to occur. Prostaglandin E2 production is also stimulated by CBS with subsequent secretion of alkali into the mucus layer. In addition, CBS has a direct inhibitory effect on C. pylori. Administration of CBS results in low levels of bismuth absorption. Most of the ingested bismuth is excreted as bismuth sulphide, causing blackening of the faeces, and the small amount absorbed is excreted in the urine. Bismuth intoxication (encephalopathy) has been reported with prolonged administration of bismuth salts, and there has been 1 report of similar intoxication in a patient receiving unusually high doses of CBS for a prolonged period. However, no such intoxication has been reported with CBS used at its recommended dosage in the acute treatment of peptic ulcer disease, and no other serious adverse effects have been associated with CBS. Tissue accumulation during prolonged therapy seems likely, and the safety of CBS during long term maintenance therapy has not been established. The lack of effect on gastric acid secretion is seen as an added advantage for CBS, since prolonged drug-induced hypochlorhydria has been postulated to have potentially detrimental effects. Thus, while the role of C. pylori in peptic ulceration requires further clarification, CBS would appear to have an important place in the treatment of peptic ulcer disease with the advantage of relatively slow relapse rates after initial healing and treatment discontinuation.

Doxazosin. An update of its clinical pharmacology and therapeutic applications in hypertension and benign prostatic hyperplasia.

Doxazosin is a long-acting alpha 1-adrenoceptor antagonist structurally related to prazosin and terazosin. Its antihypertensive effect is produced by a reduction in the smooth muscle tone of peripheral vascular beds resulting in a decrease in total peripheral resistance without significant effect on cardiac output or heart rate. In benign prostatic hyperplasia, doxazosin's effect of relieving bladder outflow obstruction is produced through a reduction in prostatic tone mediated via alpha 1-adrenoceptor blockade. In most comparative trials doxazosin has proven to be equally effective as the comparator drug in the treatment of mild to moderate hypertension. It has been used in a variety of patient populations including the elderly, Blacks, smokers, and patients with concomitant disease states such as renal dysfunction, hypercholesterolaemia, non-insulin dependent diabetes mellitus (NIDDM) and respiratory disease. Doxazosin has also been used successfully in combination with beta-adrenoceptor antagonists, diuretics, calcium channel antagonists, and angiotensin-converting enzyme inhibitors in patients with hypertension that is uncontrolled with monotherapy. Doxazosin has a beneficial effect on some of the risk factors associated with coronary heart disease including elevated serum lipid levels, impaired glucose metabolism, insulin resistance and left ventricular hypertrophy. Modest decreases in total cholesterol, low density lipoprotein cholesterol and triglycerides are seen with doxazosin therapy while small increases in high density lipoprotein cholesterol and the high density lipoprotein cholesterol/total cholesterol ratio are consistently reported. Some studies have reported an improvement in glucose tolerance although this effect has been more consistently seen in nondiabetic patients than in patients with NIDDM. Additionally, doxazosin produces a similar reduction in left ventricular hypertrophy to other antihypertensive agents. Modelling-based calculations suggest that doxazosin significantly reduces the risk of developing coronary heart disease in patients with mild to moderate hypertension, although this remains to be confirmed in long term prospective studies. Doxazosin appears to be a promising agent in the treatment of urinary symptoms associated with benign prostatic hyperplasia. Similar to other alpha 1-adrenoceptor antagonists, doxazosin treatment produces increases in peak and mean urinary flow rates and improves other objective and symptomatic measures.(ABSTRACT TRUNCATED AT 400 WORDS)

Fosinopril: a reappraisal of its pharmacology and therapeutic efficacy in essential hypertension.

Fosinopril is a phosphinic acid derivative which undergoes rapid hydrolysis after oral administration to the active diacid ACE inhibitor fosinoprilat. Cardiotropic effects have been associated with the drug, and the compensatory dual elimination route of fosinopril via renal and hepatic systems offers an opportunity for ACE inhibitor treatment of hypertension in patients with renal or hepatic impairment. Comparative trials of monotherapy with fosinopril 10 to 40 mg/day have demonstrated antihypertensive efficacy equivalent to that of sustained release nifedipine 40 mg/day, hydrochlorothiazide 25 to 50 mg/day, enalapril 5 to 10 mg/day amlodipine 5 to 10 mg/day and sustained release verapamil 240 to 480 mg/day, and superior to that of isradipine 5 mg/day. The efficacy of combination therapy with fosinopril 10 to 20 mg/day and hydrochlorothiazide 12.5 mg/day was significantly superior to that of hydrochlorothiazide alone, tended to be superior to that of fosinopril 20 mg/day alone and was similar to that of sustained release nifedipine 40 mg/day alone. The combination of fosinopril/chlorthalidone 20 to 40/25 mg/day was as effective as propranolol/chlorthalidone 80 to 160/25 mg/day. The incidence of adverse effects associated with fosinopril is low, and cough may possibly occur less often with this drug than with other ACE inhibitors. Fosinopril thus offers an effective and well tolerated option for the treatment of hypertension in adult and elderly patients, including those with renal or hepatic impairment.

Trimetrexate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the treatment of Pneumocystis carinii pneumonia.

Trimetrexate is a folinic acid analogue structurally related to methotrexate, whose primary mechanism of action is believed to be inhibition of dihydrofolate reductase. This reduces the production of DNA and RNA precursors and leads to cell death. Trimetrexate is lipophilic and can passively diffuse across cell membranes including those of Pneumocystis carinii and its mammalian host. To minimise toxicity, trimetrexate must be coadministered with calcium folinate (leucovorin calcium), a reduced folate coenzyme, which is transported into, and protects, mammalian host cells but not P. carinii cells. In noncomparative trials trimetrexate was effective in the treatment of P. carinii pneumonia (PCP) in patients with AIDS who were intolerant of or refractory to cotrimoxazole (trimethoprim/sulfamethoxazole) and pentamidine treatment. In these patients, 2- to 4-week survival rates of 48 to 69% were reported. In a comparative trial in the initial therapy of PCP, trimetrexate was less effective than cotrimoxazole in moderate to severe disease as evidenced by a significantly higher failure rate. Trimetrexate was better tolerated than cotrimoxazole when used in this setting, however. Significantly fewer patients receiving trimetrexate plus calcium folinate discontinued treatment because of adverse events than did patients receiving cotrimoxazole. The most common adverse effect associated with trimetrexate is myelosuppression (neutropenia and thrombocytopenia); this is mitigated by coadministration of calcium folinate and is generally reversible upon dosage reduction or discontinuation. Other adverse effects include increases in serum aminotransferase levels, anaemia, fever, rash/pruritus, and increased alkaline phosphatase or serum creatinine levels. Further research into the use of trimetrexate, including its efficacy as prophylaxis, in combination with other agents and as an oral formulation, is needed to clearly define its role in the treatment of PCP and to identify patients most likely to benefit. Currently, trimetrexate should be considered as an alternative treatment option in immunocompromised patients with moderate to severe PCP who have not responded to or are intolerant of first-line therapy.

Aciclovir. A reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic efficacy.

Aciclovir (acyclovir) is a nucleoside analogue with antiviral activity in vitro against the herpes simplex viruses (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpesvirus 6 (HHV-6). Topical, oral or intravenous aciclovir is well established in the treatment of ophthalmic, mucocutaneous and other HSV infections, with intravenous aciclovir the accepted treatment of choice in herpes simplex encephalitis. The efficacy of aciclovir is increased with early (preferably during the prodromal period) initiation of treatment but, despite significant clinical benefit, viral latency is not eradicated, and pretreatment frequencies of recurrence usually continue after episodic acute treatment is completed. Intravenous administration has also shown benefit in the treatment of severe complications of HSV infection in pregnancy, and neonatal HSV infections. Recurrence of HSV has been completely prevented or significantly reduced during suppressive therapy with oral aciclovir in immunocompetent patients. Use of oral aciclovir is effective but controversial in the treatment of otherwise healthy individuals with varicella (chickenpox), and in some countries it has been recommended for use only in cases which may be potentially severe. The development of rash and pain associated with herpes zoster (shingles) is attenuated with oral or intravenous aciclovir therapy, ocular involvement is prevented, and post-herpetic neuralgia appears to be decreased. Similarly, in a few patients with zoster ophthalmicus, oral aciclovir has reduced the frequency and severity of long term ocular complications and post-herpetic neuralgia, and herpes zoster oticus is improved with intravenous aciclovir. Oral aciclovir has prevented recurrence of HSV genital or orofacial infections during suppressive therapy in > 70% of immunocompetent patients in most clinical trials. Suppression of latent HSV, VZV and CMV infections has been achieved in many immunocompromised patients receiving the oral or intravenous formulations. Aciclovir also appears to offer partial protection from invasive CMV disease in CMV-seropositive bone marrow transplant recipients. The few comparative trials published have shown aciclovir to be at least as effective as other investigated antivirals in the treatment of HSV infections in immunocompetent patients, and more effective than inosine pranobex in the prophylaxis of genital herpes. Similarly, in isolated clinical trials, oral aciclovir appears as effective as topical idoxuridine and oral brivudine in some parameters in immunocompetent patients with VZV infections, and the intravenous formulation appears at least as effective as oral brivudine and intravenous vidarabine in treating these infections in immunocompromised patients.(ABSTRACT TRUNCATED AT 400 WORDS)