Drugs

This article reviews a number of specific pharmacological considerations for patients with prosthetic heart valves. All patients with mechanical heart valves should be anticoagulated. In the past, an International Normalised Ratio (INR) of 2.5 to 4.5 has been recommended. Recent nonrandomised studies have suggested that a patient with a prosthetic valve who is at low risk for thromboembolic events could have an INR ranging from 1.8 to 3.5. The lower end of this range should only be used for patients at higher than average risk of haemorrhage, until randomised data show that levels below 2.5 may be applied universally. In high-risk patients (particularly those with previous thromboembolic events) low dose aspirin should be added. During noncardiac surgery, a patient at low risk for thromboembolic events could be managed by discontinuing anticoagulation 3 days before the operation, with warfarin recommenced as soon as possible afterwards. Perioperative heparinisation would be appropriate in a higher risk patient. Women with prosthetic heart valves wishing to become pregnant should be converted to the use of twice-daily subcutaneous heparin injections. Patients with bioprosthetic valves can be managed without anticoagulation unless they have some other reason to require it. Patients at high risk should be treated with aspirin or warfarin. Thrombolytic therapy for acute valve thrombosis should be used for those who are haemodynamically compromised and therefore have a high risk of mortality from operative intervention. All patients with prosthetic heart valves undergoing invasive procedures potentially causing bacteraemia should receive antibiotic prophylaxis for endocarditis. The actual drugs used depend on the likely nature of the bacteraemia, and any possible patient hypersensitivity.

Coronary heart disease (CHD) is a major cause of morbidity and mortality worldwide. Elevated low density lipoprotein-cholesterol (LDL-C) and reduced high density lipoprotein-cholesterol (HDL-C) levels are well recognised CHD risk factors, with recent evidence supporting the benefits of intensive LDL-C reduction on CHD risk. Such observations suggest that the most recent National Cholesterol Education Program Adult Treatment Panel III guidelines, with LDL-C targets of 2.6 mmol/L, may result in under-treatment of a significant number of patients and form the basis for the proposed new joint European Societies treatment targets of 2 and 4 mmol/L, respectively, for LDL and total cholesterol. HMG-CoA reductase inhibitors (statins) reduce LDL-C by inhibiting the rate-limiting step in cholesterol biosynthesis and reduced CHD event rates in primary and secondary prevention trials. The magnitude of this effect is not fully accounted for by LDL-C reduction alone and may relate to effects on other lipid parameters such as HDL-C and apolipoproteins B and A-I, as well as additional anti-inflammatory effects. With increasing focus on the benefits of intensive cholesterol reduction new, more efficacious statins are being developed. Rosuvastatin is a potent, hydrophilic enantiomeric statin producing reductions in LDL-C of up to 55%, with about 80% of patients reaching European LDL-C treatment targets at the 10 mg/day dosage. The Heart Protection Study (HPS) demonstrated that LDL-C reduction to levels as low as 1.7 mmol/L was associated with significant clinical benefit in a wide range of high-risk individuals, including patients with type 2 diabetes mellitus, or peripheral and cerebrovascular disease, irrespective of baseline cholesterol levels, with no apparent lower threshold for LDL-C with respect to risk. Various large endpoint trials, including Treating to New Targets (TNT) and Study of Effectiveness of Additional reductions in Cholesterol and Homocysteine (SEARCH) will attempt to further address the issue of optimal LDL-C reduction. At low LDL-C levels, HDL-C becomes an increasingly important risk factor and is the primary lipid abnormality in over half of CHD patients, with the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study set to assess the effect of raising HDL-C on cardiovascular events in patients with low HDL-C and LDL-C levels below 3 mmol/L. A variety of agents are being developed, which affect both LDL-C and HDL-C metabolism, including inhibitors of acyl-coenzyme A-cholesterol acyl transferase, microsomal transfer protein and cholesterol ester transfer protein, as well as specific receptor agonists. Ezetimibe is a selective cholesterol absorption inhibitor, which produces reductions in LDL-C of up to 25 and 60% reduction in chylomicron cholesterol content with a 10 mg/day dosage. A 1 mmol/L reduction in LDL-C results in a 25% reduction in cardiovascular risk, independent of baseline LDL-C levels. Growing evidence supports the concept that lower is better for LDL-C and that increasing HDL-C represents an important therapeutic target. Furthermore, there is growing appreciation of the role of inflammation in atherogenesis. Consequently, increasing numbers of people should receive lipid-regulating therapy with the development of newer agents offering potential mechanisms of optimising lipid profiles and thus risk reduction. In addition, the pleiotropic anti-inflammatory effects of lipid lowering therapy may provide further risk reduction.

Non-Q-wave myocardial infarction (MI) differs from Q-wave MI in 3 important respects: a smaller infarct size, possibly due to early reperfusion resulting from spontaneous thrombolysis, relief of spasm, or both; more frequent patency of the infarct-related artery; and a larger residual mass of viable but jeopardised myocardium within the perfusion zone of the infarct-related vessel. Left ventricular function is generally better unless impaired by previous MI. After the acute phase, the prognosis is worse when residual ischaemia is present, and reinfarction rates during hospitalisation and in the subsequent year of follow-up are higher. As myocardial ischaemia is potentially reversible, its presence should be actively sought in all patients with recognised non-Q-wave MI. On the basis of current knowledge and available data, the following guidelines for the management of non-Q-wave MI patients can be recommended: (1) diltiazem and aspirin should be administered to all patients as soon as the diagnosis is established, unless contraindications exist; (2) patients who develop early recurrent ischaemia on therapy (i.e. angina with associated ST-T-wave changes) should undergo prompt cardiac catheterisation and myocardial revascularisation; and (3) patients with entirely uncomplicated hospital histories who are asymptomatic should undergo exercise stress testing, preferably in conjunction with 201Tl perfusion scintigraphy, before hospital discharge. Only those patients with evidence of significant residual ischaemia need cardiac catheterisation and myocardial revascularisation.

Cefpirome is an injectable extended-spectrum or ‘fourth generation’ cephalosporin. Its antibacterial activity encompasses many of the pathogens involved in hospital-acquired infections such as Enterobacteriaceae, methicillin-susceptible Staphylococcus aureus, coagulase-negative staphylococci and viridans group streptococci. Cefpirome also has in vitro activity against Streptococcus pneumoniae regardless of penicillin susceptibility. It is stable against most plasmid- and chromosome-mediated β -lactamases, with the exception of the extended-spectrum plasmid-mediated SHV enzymes. Intravenous cefpirome 2g twice daily has shown clinical efficacy comparable to that of ceftazidime 2g 3 times daily in the treatment of hospitalised patients with moderate to severe infections. Clinical response and bacteriological eradication rates were similar in patients with severe pneumonia or septicaemia treated with either cefpirome or ceftazidime. Cefpirome appeared more effective than ceftazidime in the eradication of bacteria in patients with febrile neutropenia in 1 study; however, clinical response rates were similar in the 2 treatment groups. The tolerability of cefpirome appears similar to that of ceftazidime and other third generation cephalosporins, diarrhoea being the most frequently observed event. Thus, cefpirome is likely to be a valuable extended-spectrum agent for the treatment of severe infections. Cefpirome offers improved coverage against some Gram-positive pathogens and Enterobacteriaceae producing class I β-lactamases compared with the third generation cephalosporins, although this has yet to be demonstrated in clinical trials. Cefpirome has shown excellent antibacterial activity against Enterobacteriaceae, although its activity against Enterobacter cloacae is more variable. Its activity was at least 2-fold better than that of ceftazidime and cefotaxime against Citrobacter freundii, E. cloacae, Morganella morganii and Serratia marcescens but was similar to that of the other extended-spectrum agents cefepime and cefoselis. Cefpirome generally remained active against Enterobacteriaceae with reduced susceptibility or resistance to other agents (ceftazidime, cefotaxime, ceftriaxone and aminoglycosides), including Citrobacter spp., Enterobacter spp. and Klebsiella spp. Cefpirome has moderate activity against Pseudomonas aeruginosa, its potency being similar to or 2-fold less than that of ceftazidime, cefepime or cefoselis. Strains of P. aeruginosa resistant to ceftazidime or aminoglycosides were also resistant to cefpirome. β-Lactamase-producing and -nonproducing strains of Moraxella catarrhalis and Haemophilus influenzae are equally susceptible to cefpirome, whereas Acinetobacter spp. are only moderately susceptible or resistant to the drug. Cefpirome demonstrated 2- to 16-fold greater activity than ceftazidime and cefotaxime against methicillin-sensitive Staphylococcus aureus [MSSA; minimum inhibitory concentration required to inhibit 90% of strains (MIC90) values ≤1.56 mg/L] and coagulase-negative staphylococci (MIC90 values ≤4 mg/L). In common with other cephalosporins, it showed little activity against methicillin-resistant staphylococci. Streptococcus pneumoniae are highly susceptible to cefpirome (MIC90 values ≤0.06 mg/L); strains with intermediate and high resistance to penicillin are susceptible to cefpirome, although with increased MIC90 values (≤2 mg/L). S. agalactiae, S. pyogenes and viridans group streptococci are also susceptible to cefpirome, although penicillin-resistant viridans group streptococci showed varying susceptibility to the drug. Enterococcus faecalis are generally resistant to cefpirome. Among anaerobic organisms, Clostridium perfringens and Peptostreptococcus spp. were susceptible, whereas Bacteroides spp. and C. difficile were resistant to cefpirome. Cefpirome permeates faster through the outer bacterial membrane of E. cloacae than ceftriaxone and cefotaxime. It binds with high affinity to penicillin binding protein (PBP) 3 in E. coli, PBPs 3 and la in P. aeruginosa, PBP1b in S. pneumoniae and PBPs 1 and 2 in S. aureus. Cefpirome showed stability against broad-spectrum and some extended-spectrum plasmid-mediated β-lactamases including TEM-1 to -10, TEM-12, SHV-1 and -6, OXA-1, -2 and -3, and CAZ-2, but had no activity against bacteria producing SHV-2 to -5. Cefpirome has a low affinity for chromosomal β-lactamases and is stable against hydrolysis by most chromosomally mediated cephalosporinases. Peak plasma concentrations (Cmax) and the area under the plasma concentration-time curve (AUC0-∞) increased in a dose-dependent manner after intravenous or intramuscular administration of cefpirome 0.25 to 2g in healthy male volunteers. Cmax values were between 86.7 and 97.4 mg/L after a single intravenous injection of cefpirome 1g and were between 23.2 and 30.6 mg/L about 2 hours after intramuscular administration of the same dose. Estimates of relative bioavailability of cefpirome after intramuscular administration were 91.6 and 97.6%. No drug accumulation was evident after administration of cefpirome 1 or 2g every 12 hours for up to 5.5 days. The apparent volume of distribution at steady-state was between 15.3 and 21.3L and approximately 8 to 12% of the drug was bound to plasma proteins. About 80% of an administered dose of cefpirome is recovered unchanged in the urine of healthy volunteers over 48 hours. Total and renal clearance rates ranged from 6.6 to 10.6 L/h and 4.9 to 6.7 L/h, respectively. The mean elimination half-life (t½β) of cefpirome ranged from 1.7 to 2.3 hours. Total body and renal clearance were significantly reduced, and AUC0-∞ and t½β significantly increased in patients with moderate to severe renal impairment [creatinine clearance (CLcr) ≤3 L/h] compared with healthy volunteers and patients with mild impairment. Haemodialysis removed about 48% of the drug from the body during a 4-hour session, and the elimination of cefpirome was significantly prolonged during continuous ambulatory peritoneal dialysis (CAPD). In the elderly, t½β correlated with the degree of renal impairment. Intravenous cefpirome 2g twice daily has shown similar efficacy to intravenous ceftazidime 2g 3 times daily in the treatment of moderate to severe infections in hospitalised patients in large randomised multicentre studies. Satisfactory responses occurred in 57% of patients with severe (mostly nosocomial) pneumonia treated with either cefpirome or ceftazidime and the bacteriological eradication rate was 68%. Clinical failure was reported in 34 and 36% of cefpirome and ceftazidime recipients, respectively. A large retrospective analysis of the efficacy of these 2 drugs in patients with severe pneumonia revealed clinical response rates of 82 and 74.5% in cefpirome and ceftazidime treatment groups. In the empirical treatment of suspected bacteraemia and/or sepsis, cefpirome achieved a satisfactory clinical response in 76% of patients compared with 80% of ceftazidime recipients 1 to 5 days after completion of treatment. A satisfactory bacteriological outcome was evident in 90 and 86% of patients, respectively. In the treatment of febrile episodes in patients with neutropenia, cefpirome and ceftazidime each achieved satisfactory clinical responses in 72% of patients. However, the bacteriological success rate was higher in cefpirome recipients (89 vs 74%). Cefpirome in combination with gentamicin also demonstrated similar efficacy to piperacillin and gentamicin in the empirical treatment of febrile patients with neutropenia; a satisfactory response was observed in 58 and 47% of episodes, respectively, after 72 hours according to an intention-to-treat analysis. Cefpirome is well tolerated by the majority of patients. The incidence of adverse events in an analysis of 3103 patients receiving cefpirome in phase II and III clinical trials was 12.5%, similar to that reported for a combined group treated with comparator agents (predominantly ceftazidime; 13.7%). Diarrhoea was the most common adverse event (occurring in 1.6% of patients) followed by rash (1.4%) and nausea (1.3%). Treatment was withdrawn because of adverse events in 5.1 and 5.0% of patients treated with cefpirome or comparator agents. In clinical studies in patients with severe infections, the incidence of adverse events in patients treated with cefpirome ranged between 4 and 30% and was similar to that reported for ceftazidime. The recommended dosage of cefpirome for the treatment of hospitalised patients with severe infections (pneumonia and septicaemia) and febrile episodes in patients with neutropenia is 2g administered by intravenous injection or infusion every 12 hours. As the main route of elimination of cefpirome is renal, dosage reduction is necessary in patients with moderate to severe renal impairment (CLcr ≤3 L/h) and patients undergoing CAPD. A supplementary dose is required at the end of haemodialysis.

The principal symptoms and signs of endometriosis are tissue lesions and pelvic pain. These occur to varying degrees, with a chronic pattern and a tendency for deterioration with time. Patients with endometriosis often also have fertility problems, but the relationship between this and the signs and symptoms of the disease is inconsequent; the basic pathophysiology is not exactly known. Although an immunological defect resulting in an inflammatory reaction around discharged menstrual debris in the pelvic cavity has been shown, no treatments based on this process are available. Estrogen often plays an important role in the progression of lesions and pain. Therefore, the aim of treatment usually has been to downregulate the ovaries and/or give antiestrogenic drugs as an alternative to surgical removal. As complete downregulation of the ovaries and hypoestrogenaemia does not seem to be crucial, achievement of amenorrhoea seems to be sufficient. This means that women may continue to have circulating estrogen levels so that severe hypoestrogenic adverse effects such as bone déminéralisation, dry vagina, psychiatric symptoms or anabolic/androgenic effects of gestagens can be avoided. However, as both symptoms and the dependence of hormones may vary between and within women, the treatment needs to be individualised. There are a number of available treatments for endometriosis on the market and it is important for the doctor to know how to reach the therapeutic window of these treatments for each woman. It is also important to inform the patient about the different possibilities so that the treatment with the least impact on her quality of life can be chosen. When the therapeutic window has been identified, the treatment may then either be continued for a long period of time or be repeated when needed.

Satraplatin is the first orally administered platinum drug to be evaluated in the clinic. Oral satraplatin plus prednisone improved progression free survival significantly relative to prednisone alone in patients with hormone-refractory prostate cancer in a randomised study. Furthermore, single-agent satraplatin has demonstrated activity in ovarian cancer and small cell lung cancer similar to that observed with single-agent cisplatin or carboplatin. In >600 treated patients, satraplatin was generally well tolerated and the most common adverse event was non-cumulative myelosuppression.

The fundamental abnormality in asthma is bronchial reactivity. Airways obstruction and flow limitation arise as a result of viscid bronchial secretions, oedema of the walls of airways and some bronchial muscle contraction. During attacks, patients breathe at increased lung volume, as airways closure occurs within the normal tidal range. In severe asthma, total lung capacity is increased and there is a loss of elastic recoil of the lungs. Ventilation is poorly distributed so that it becomes mismatched with pulmonary blood flow. This mismatching results in arterial hypoxaemia, even in mild attacks. Despite increased work of breathing, patients most commonly maintain a normal or even increased alveolar ventilation. The arterial carbon dioxide tension is thus frequently low or normal, despite a marked reduction in forced expired volume. Hypercapnia usually indicates that airways obstruction is extremely severe. When carbon dioxide retention occurs during mild asthma, patients will usually be found to have impaired ventilatory control even in symptom-free periods. As the essential feature of an asthmatic attack is airways obstruction or flow limitation, tests such as forced expired volume in one second and maximum midexpiratory flow rate are sensitive indices of the degree of abnormality present and are essential in the proper continued management of patients with asthma. Control of airways calibre is maintained by an interplay between autonomic balance, local gas tensions and humoral factors. The humoral factors, including slow reacting substance of anaphylaxis, kinins, prostaglandins and histamine, are released from sensitised or damaged mast cells. There are two types of bronchodilator drug: the sympathomimetic amines, which stimulate β-adrenergic receptors, by activating the enzyme adenyl cyclase to bring about increased concentrations of intracellular cyclic AMP; and the xanthine derivatives, which also increase levels of cyclic AMP by competitively inhibiting the enzyme cyclic nucleotide phosphodiesterase which breaks down cyclic AMP. Sympathomimetic amines stimulate both β1-adrenergic (myocardium) and β2 -adrenergic receptor sites (bronchial smooth muscle). Modification of the chemical structure of isoprenaline has produced substances which have more ‘specific’ β2 -receptor (bronchial) activity. Sodium cromoglycate stabilises airways against a variety of insults without any known influence on the adenyl cyclase cyclic AMP system. It is most effective in preventing allergic asthma, inhibiting the release of histamine and slow reacting substance of anaphylaxis after antigen-reagin combination. The corticosteroids exert most of their effect in asthma by their anti-inflammatory activity, but they also act on airways to enhance the release of adenyl cyclase induced by catecholamines, and so increase the responsiveness of β-adrenergic receptors to sympathomimetic amines. Corticosteroids are carried in plasma both protein bound and in a free form: this has important clinical implications if serum albumin levels are reduced, when it is advisable to use lower than normal doses. On the other hand, larger than normal doses are necessary in severe attacks of asthma in steroid-treated patients because of the increased metabolic clearance rate of cortisol; perhaps due to hypoxaemia stimulating hepatic microsomal enzymes, a phenomenon which does seem to account for the reduced effectiveness of

Although migraine is a highly disabling disorder, it remains underdiagnosed. Its relevance is often minimized by both patients and physicians, and the presence of concomitant diseases such as depression can interfere with diagnosis. Migraine is often inappropriately treated by patients who often self-administer over-the-counter analgesics or do not follow physician prescriptions, and by physicians who do not always prescribe migraine-specific treatments when they are indicated. These factors can lead to patient dissatisfaction with migraine therapy. Surveys show that migraine patients consider complete pain relief to be the most important attribute of an acute migraine treatment. Other important attributes are rapid onset, lack of recurrence, restoration of function, and the absence of side-effects. Medical professionals treating migraine need up-to-date clinical information to diagnose this disorder effectively, to understand the breadth of treatments available, and to choose the most appropriate treatment. Physician-patient communication is also a key factor in migraine management and allows physicians to gain the trust of their patients. Educating patients about migraine and involving them in treatment decisions are likely to improve patient satisfaction with therapy. Education and involvement will also help patients to understand their disorder better, to identify and avoid migraine triggers, and to improve their understanding of and compliance with drug therapy. Such an approach may also help physicians to manage patient expectations.