Catastrophic antiphospholipid syndrome complicating orthotopic liver transplantation.

Catastrophic antiphospholipid syndrome (CAPS) is an acutely devastating situation characterized by widespread thrombotic microangiopathy in the presence of elevated titers of antiphospholipid antibodies. We describe a 57-year old woman who underwent liver transplantation for primary sclerosing cholangitis and developed this malignant variant of the antiphospholipid syndrome.

Cilostazol.

Cilostazol is an antiplatelet agent with vasodilating properties that has been used in the treatment of patients with peripheral ischaemia such as intermittent claudication. The drug inhibits platelet aggregation induced by ADP, collagen and arachidonic acid. Unlike aspirin (acetylsalicylic acid), cilostazol inhibits both primary and secondary aggregation. It also acts as a vascular vasodilator by inhibiting calcium-induced contractions while having no direct effect on contractile proteins. In double-blind randomised trials, patients with intermittent claudication receiving cilostazol showed significant improvements versus placebo in terms of time to initial pain and maximal walking or absolute claudication distance; these findings were confirmed by cilostazol patients' positive responses on subscales measuring physical functioning and quality of life. In a 24-week randomised double-blind trial in patients with intermittent claudication, cilostazol 100mg twice daily produced significant improvements in pain-free and maximum walking distances, compared with pentoxifylline (oxpentifylline) 400mg 3 times daily and placebo. Cilostazol has been well tolerated, with the most common adverse events being headache, diarrhoea, abnormal stools and dizziness.

Insuficiencia renal en pacientes con trasplante hepatico: incidencia y factores predisponentes / Renal failure in patients with liver transplat: incidence and predisposing factors

En los pacientes que son sometidos a un trasplante hepático se desarrolla con frecuencia insuficiencia renal. Sin embargo, su incidencia y los factores predisponentes al desarrollo de esta complicación no han sido bien establecidos. Por tanto, nuestro estudio ha sido dirigido a clarificar ambos aspectos en pacientes que han sido sometidos a un trasplante hepático en el Hospital Italiano de Buenos Aires. Para ello, se evaluaron em forma retrospectiva 38 pacientes adulltos receptores de un trasplante hepático durante su estadía en el hospital (40 + 10 días) (media + DS). En el an lisis final se excluyeron 3 pacientes (1 hepatitis fulminante y 2 con sobrevida menor a 72 hs). El tratamiento inmunosupresor se basó en el triple esquema: ciclosporina, corticoides y azatioprina. La presencia de insuficiencia renal se definió como la existencia de una creatinina sérica > 1.5 mg/dl y/o urea > 80 mg/dl. La insuficiencia renal se clasificó cronológicamente como precoz (días 0-6) y tardia (luego del día 6). Los siguientes par metros fueron evaluados en relación a la insuficiencia hepática: preoperatoria (función hepatocelular mediante la clasificación de Chil-Pugh y renal), intraoperatorios (cantidad de hemoderivados transfundidos, episodios de hipotensión, "by-pass" venovenoso, duración de la cirugía y de la fase anhepática) y postoperatorios (sepsis, rechazo, niveles plasm ticos de ciclosporina y uso de drogas nefrotóxicas). En veintiuno de los 35 pacientes (60 por ciento) con trasplante hepático se desarrolló insuficiencia renal. En 6 pacientes fue precoz y en 15 tardía. En la serie global, los pacientes con insuficiencia renal presentaron un mayor deterioro de la función hepática en el preoperatorio (8.6 + 0.3 vs 7.8 + 0.4, p<0.05), en el intraoperatorio un mayor requerimiento de hemoderivados (13.1 + 4.3 vs 10.1 + 3.8 unidades, p<0.05) y en el postoperatorio in nivel más elevado de ciclosporina (624 + 60 vs 430 + 30 ng/ml, p<0.05) que aquellos pacientes en quienes no se desarrolló complicación. Asimismo, en los pacientes que presentaron la insuficiencia renal en forma precoz se observó un mayor deterioro de la función hepatocelular y un mayor requerimiento de hemoderivados durante la cirugía. De otra parte, en los pacientes que la desarrollaron en forma tardía, la etiopatogenia de esta complicación fue multifactorial (falla del injerto, uso de drogas nefrotóxicas y ciclosporina). En 1 paciente hubo necesidad de realizar hemodiálisis y en otro hemofiltración...(AU)

Insuficiencia renal en pacientes con trasplante hepatico: incidencia y factores predisponentes / Renal failure in patients with liver transplat: incidence and predisposing factors

En los pacientes que son sometidos a un trasplante hepático se desarrolla con frecuencia insuficiencia renal. Sin embargo, su incidencia y los factores predisponentes al desarrollo de esta complicación no han sido bien establecidos. Por tanto, nuestro estudio ha sido dirigido a clarificar ambos aspectos en pacientes que han sido sometidos a un trasplante hepático en el Hospital Italiano de Buenos Aires. Para ello, se evaluaron em forma retrospectiva 38 pacientes adulltos receptores de un trasplante hepático durante su estadía en el hospital (40 + 10 días) (media + DS). En el an lisis final se excluyeron 3 pacientes (1 hepatitis fulminante y 2 con sobrevida menor a 72 hs). El tratamiento inmunosupresor se basó en el triple esquema: ciclosporina, corticoides y azatioprina. La presencia de insuficiencia renal se definió como la existencia de una creatinina sérica > 1.5 mg/dl y/o urea > 80 mg/dl. La insuficiencia renal se clasificó cronológicamente como precoz (días 0-6) y tardia (luego del día 6). Los siguientes par metros fueron evaluados en relación a la insuficiencia hepática: preoperatoria (función hepatocelular mediante la clasificación de Chil-Pugh y renal), intraoperatorios (cantidad de hemoderivados transfundidos, episodios de hipotensión, "by-pass" venovenoso, duración de la cirugía y de la fase anhepática) y postoperatorios (sepsis, rechazo, niveles plasm ticos de ciclosporina y uso de drogas nefrotóxicas). En veintiuno de los 35 pacientes (60 por ciento) con trasplante hepático se desarrolló insuficiencia renal. En 6 pacientes fue precoz y en 15 tardía. En la serie global, los pacientes con insuficiencia renal presentaron un mayor deterioro de la función hepática en el preoperatorio (8.6 + 0.3 vs 7.8 + 0.4, p<0.05), en el intraoperatorio un mayor requerimiento de hemoderivados (13.1 + 4.3 vs 10.1 + 3.8 unidades, p<0.05) y en el postoperatorio in nivel más elevado de ciclosporina (624 + 60 vs 430 + 30 ng/ml, p<0.05) que aquellos pacientes en quienes no se desarrolló complicación. Asimismo, en los pacientes que presentaron la insuficiencia renal en forma precoz se observó un mayor deterioro de la función hepatocelular y un mayor requerimiento de hemoderivados durante la cirugía. De otra parte, en los pacientes que la desarrollaron en forma tardía, la etiopatogenia de esta complicación fue multifactorial (falla del injerto, uso de drogas nefrotóxicas y ciclosporina). En 1 paciente hubo necesidad de realizar hemodiálisis y en otro hemofiltración...

[Renal failure in patients with liver transplant: incidence and predisposing factors]. / Insuficiencia renal en pacientes con trasplante hepático: incidencia y factores predisponentes.

Renal failure is a common finding in patients undergoing orthotopic liver transplantation. The aim of the present study was to evaluate the incidence, prognostic value of pre, intra and postoperative factors and severity of renal dysfunction in patients who undergo liver transplantation. Therefore, the records of 38 consecutive adult patients were reviewed. Renal failure was defined arbitrarily as an increase in creatinine (> 1.5 mg/dl) and/or blood urea (> 80 mg/dl). Three patients were excluded of the final analysis (1 acute liver failure and 2 with a survival lower than 72 hs.) Twenty one of the 35 patients has renal failure after orthotopic liver transplantation. Six of these episodes developed early, having occurred within the first 6 days. Late renal impairment occurred in 15 patients within the hospitalization (40 +/- 10 days) (Mean +/- SD). In he overall series, liver function, evaluated by Child-Pugh classification, a higher blood-related requirements and cyclosporine levels were observed more in those who experienced renal failure than those who did not (p < 0.05). Early renal failure was related with preoperative (liver function) and intraoperative (blood requirements) factors and several causes (nephrotoxic drugs and graft failure) other than cyclosporine were present in patients who developed late renal impairment. No mortality. No mortality was associated with renal failure. We conclude that renal failure a) is a common finding after liver transplantation, b) the pathogenesis of this complication is multifactorial and, c) in not related with a poor outcome.

Dalteparin sodium. A review of its pharmacology and clinical use in the prevention and treatment of thromboembolic disorders.

The low molecular weight heparin (LMWH) dalteparin sodium is notable for its improved pharmacokinetic characteristics (chiefly increased bioavailability and plasma elimination half-life) compared with unfractionated heparin (UFH). These properties enable the drug to be given subcutaneously as a single daily dose, compared with the 8- to 12-hourly regimens necessary with UFH. Dalteparin sodium also appears to exert a greater inhibitory effect than UFH on plasma activity of coagulation factor Xa relative to its effects on clotting times [usually expressed as activated partial thromboplastin time (APTT)] and activity of factor IIa. It is not associated with any clinically significant effects on the fibrinolytic system and may have less lipolytic activity than UFH. Extensive clinical studies have been conducted to compare the antithrombotic efficacy of dalteparin sodium with that of UFH in surgical thromboprophylaxis, treatment of established deep vein thrombosis (DVT) and the anticoagulation of patients undergoing haemodialysis and haemofiltration. The majority of trails of patients receiving thromboprophylactic heparin perioperatively have shown similar efficacy of dalteparin sodium and UFH in the prevention of DVT and pulmonary embolism (PE), although 2 groups of investigators reported superior antithrombotic potency for dalteparin sodium. The two types of heparin appear similarly effective in the management of established DVT and the maintenance of the extracorporeal circulation in haemodialysis circuits. Dalteparin sodium has also shown clinical benefit in the management of patients with unstable angina or non-Q-wave myocardial infarction. The overall incidence of haemorrhagic complications observed with daltparin sodium therapy is no greater than that associated with UFH, and data suggest that perioperative transfusion requirements and frequency of bleeding are lower after dalteparin sodium. The antithrombotic efficacy of dalteparin sodium is at least equivalent to that of UFH, although further clinical comparisons with other LMWHs are required. Further studies are also needed to clearly define any advantages of dalteparin sodium over UFH (and other antithrombotics) with regard to the incidence of haemorrhagic complications. The drug has also shown clinical efficacy in the prevention of myocardial infarction and death in patients with unstable coronary artery disease. In addition, there may be cost advantages attached to the once-daily subcutaneous regimen of dalteparin sodium, but this requires further examination. Thus, dalteparin sodium is an effective antithrombotic agent for perioperative thromboprophylaxis, the management of established DVT, and the anticoagulation of patients undergoing haemodialysis.

Propofol. An overview of its pharmacology and a review of its clinical efficacy in intensive care sedation.

Propofol is a phenolic derivative that is structurally unrelated to other sedative hypnotic agents. It has been used extensively as an anaesthetic agent, particularly in procedures of short duration. More recently it has been investigated as a sedative in the intensive care unit (ICU) where it produces sedation and hypnosis in a dose-dependent manner. Propofol also provides control of stress responses and has anticonvulsant and amnesic properties. Importantly, its pharmacokinetic properties are characterised by a rapid onset and short duration of action. Noncomparative and comparative trials have evaluated the use of propofol for the sedation of mechanically ventilated patients in the ICU (postsurgical, general medical, trauma). Overall, propofol provides satisfactory sedation and is associated with good haemodynamic stability. It produces results similar to or better than those seen with midazolam or other comparator agents when the quality of sedation and/or the amount of time that patients were at adequate levels of sedation are measured. Patients sedated with propofol also tend to have a faster recovery (time to spontaneous ventilation or extubation) than patients sedated with midazolam. Although most studies did not measure time to discharge from the ICU, propofol tended to be superior to midazolam in this respect. In a few small trials in patients with head trauma or following neurosurgery, propofol was associated with adequate sedation and control of cerebral haemodynamics. The rapid recovery of patients after stopping propofol makes it an attractive option in the ICU, particularly for patients requiring only short term sedation. In short term sedation, propofol, despite its generally higher acquisition costs, has the potential to reduce overall medical costs if patients are able to be extubated and discharged from the ICU sooner. Because of the potential for hyperlipidaemia and the development of tolerance to its sedative effects, and because of the reduced need for rapid reversal of drug effects in long term sedation, the usefulness of propofol in long term situations is less well established. While experience with propofol for the sedation of patients in the ICU is extensive, there are still areas requiring further investigation. These include studies in children, trials examining cerebral and haemodynamic outcomes following long term administration and in patients with head trauma and, importantly, pharmacoeconomic investigations to determine those situations where propofol is cost effective. In the meantime, propofol is a well established treatment native to benzodiazepines and/or other hypnotics or analgesics when sedation of patients in the ICU is required. In particular, propofol possesses unique advantages over these agents in patients requiring only short term sedation.

Spirapril. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertension.

Spirapril is a non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor prodrug which is converted to the active metabolite spiraprilat following oral administration, and which has been evaluated primarily for the treatment of hypertension. In dose-finding studies of patients with mild to severe hypertension, spirapril > or = 6 mg once daily produced reductions in blood pressure of approximately 10 to 18 mm Hg (systolic) and 7 to 13 mm Hg (diastolic) [24-hour postdose trough readings at the end of the treatment period]. Blood pressure normalisation (trough diastolic blood pressure < or = 90 mm Hg) had occurred in 29 to 50% of patients at the end of these investigations. The dose-response curve for spirapril appears to be flat for doses of 6 to 24 mg once daily. Comparisons with other ACE inhibitors are limited in number, and further studies are required before the relative antihypertensive efficacy of spirapril can be fully evaluated. However, in single, well controlled clinical trials, spirapril produced similar reductions in blood pressure to those seen with enalapril or captopril. When given as monotherapy or in combination with hydrochlorothiazide, spirapril may offer potential advantages over the calcium antagonist nitrendipine. Spirapril is generally well tolerated and produces an adverse event profile similar to that of other ACE inhibitors. Data from small studies suggest that spirapril can be used without dosage adjustment in patients with renal impairment, as a consequence of its dual renal and hepatic clearance mechanisms. This is in contrast to most ACE inhibitors, which are eliminated by a predominantly renal mechanism that results in accumulation of the active metabolite when renal function is impaired. However, the utility of spirapril in this patient group has yet to be fully determined because of conflicting data regarding its effects on renal function. Thus, spirapril is an effective antihypertensive agent which is well tolerated. Further comparative trials are needed to fully determine its efficacy with respect to other ACE inhibitors, and a better understanding of its effects on renal function will clarify its role in hypertensive patients with renal failure.

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

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

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)

Dornase alfa. A review of its pharmacological properties and therapeutic potential in cystic fibrosis.

By cleaving neutrophil-derived DNA present in the infected lungs of patients with cystic fibrosis (CF), dornase alfa (recombinant human deoxyribonuclease I) reduces the adhesiveness and viscoelasticity of CF sputum. Well designed clinical studies performed in patients with CF and mild to moderate pulmonary disease [forced vital capacity (FVC) > or = 40% of predicted value] show that aerosolised dornase alfa improves lung function, achieving a 6 to 7% increase from baseline in forced expiratory volume in 1 second (FEV1) after 6 months' therapy. Improvements in general well-being and CF-related symptoms were also noted by patients. Importantly, dornase alfa reduced the relative risk of respiratory exacerbations requiring parenteral antibiotics by 22 to 34% compared with placebo. Short term studies with dornase alfa in patients with more severe pulmonary disease (FVC < 40% of predicted value) and in those with acute infectious exacerbations did not reveal any significant improvements in pulmonary function, although long term studies are required to fully determine efficacy. Voice alteration, laryngitis or rash may develop with dornase alfa therapy, although more clinical experience with the agent is required to define its tolerability profile. Anaphylaxis has not been reported with dornase alfa to date. In summary, aerosolised dornase alfa offers modest improvements in lung function and, importantly, a reduced risk of respiratory exacerbations in patients with CF and an FVC > or = 40% of the predicted value, thus representing an important adjunct agent in this patient group.

Etidronic acid. A review of its pharmacological properties and therapeutic efficacy in resorptive bone disease.

Etidronic acid is an orally and intravenously active bisphosphonate, which is believed to inhibit resorption of bone via a number of cellular mechanisms, including alteration of osteoclastic activity. In studies of patients with symptomatic Paget's disease, etidronic acid 5 to 20 mg/kg/day administered orally rapidly decreased the biochemical indices of bone turnover. Mineralisation defects in forming bone may be avoided by the use of an initial dosage of 5 mg/kg/day for up to 6 months; dosages above 10 mg/kg/day should be limited to 3 months' duration, and dosages greater than 20 mg/kg/day should be avoided. Although 3-day intravenous therapy with etidronic acid 7.5 mg/kg/day has shown superior efficacy to rehydration and forced diuresis in the management of hypercalcaemia of malignancy, the efficacy of the drug is lower than that of the newer bisphosphonates, pamidronic acid and clodronic acid. Clinical studies involving postmenopausal women with established osteoporosis have indicated that oral etidronic acid 400 mg/day for 14 days as part of a 90-day cycle, repeated for up to 3 years, increases the bone mineral density (BMD) of the lumbar vertebrae and appears to reduce the incidence of vertebral fracture. Published data suggest that etidronic acid shows similar efficacy to hormone replacement therapy (HRT) in these respects. The above dosage also appears to be effective in preventing corticosteroid-induced osteoporosis when administered as part of an intermittent, cyclical regimen. Etidronic acid in higher dosages (10 to 20 mg/kg/day orally) is effective in reducing the incidence of heterotopic ossification and its ensuing complications in both neurological and post-surgical patients. Etidronic acid is well tolerated by the majority of patients, with gastrointestinal complaints reported most commonly, but tends to delay the normal mineralisation of forming bone when administered continuously at higher dosages for prolonged periods. This is of little consequence where short term treatment is involved, but may be detrimental to those patients receiving longer courses of therapy. This effect may be minimised or avoided by using the lowest effective dosage for as short a time as possible (as in the above recommendations for Paget's disease), or by the use of intermittent cyclical therapy (as in the management of osteoporosis). Etidronic acid therefore retains a role in the management of resorptive bone disease, particularly in the treatment of Paget's disease, the prevention of heterotopic ossification, and as a second-line option in postmenopausal osteoporosis. However, the development of newer bisphosphonates requires that these compounds be continually compared and re-evaluated.

Abciximab (c7E3 Fab). A review of its pharmacology and therapeutic potential in ischaemic heart disease.

Abciximab (c7E3 Fab) is a chimaeric human-murine monoclonal antibody Fab (fragment antigen binding) fragment. It binds to the platelet glycoprotein IIb/IIIa receptor and inhibits platelet aggregation. In two double-blind placebo-controlled trials, abciximab therapy reduced the incidence of ischaemic complications during the initial postoperative period (30 days or until hospital discharge) in high-risk patients undergoing percutaneous coronary angioplasty or directional atherectomy. It also reduced the incidence of clinical restenosis compared with placebo during longer term (6 months) follow-up of these patients. Although abciximab delayed the need for coronary artery bypass graft surgery, it did not reduce the proportion of patients ultimately requiring this procedure. The drug was generally well tolerated in clinical trials, with bleeding complications being the major adverse event. Abciximab is at an early stage of its clinical introduction and, not surprisingly, some aspects of its use remain to be further assessed. Nevertheless, results show the addition of abciximab to standard aspirin plus heparin therapy during coronary angioplasty or directional atherectomy improves the outcome of the revascularisation procedure in patients with a high risk of subsequent acute ischaemic complications. The results of further trials defining the optimum dosage of heparin when administered with abciximab, and evaluating the role of abciximab in a wider range of patients, are eagerly awaited.

Quinapril. A reappraisal of its pharmacology and therapeutic efficacy in cardiovascular disorders.

Following systemic absorption, quinapril is converted by de-esterification to quinaprilat (the active diacid metabolite), an inhibitor of angiotensin converting enzyme (ACE). Pharmacodynamic studies in animals indicate inhibition of ACE both in plasma and at tissue sites, such as the arterial wall and heart, following administration of quinapril. Tissue ACE inhibition may be an important component of the mechanism of action of quinapril (and other ACE inhibitors) in achieving favourable effects in cardiovascular disorders. Quinaprilat has a short elimination half-life (approximately 2 hours), but binds potently to and dissociates slowly from ACE, thus allowing once or twice daily administration of quinapril in the treatment of patients with hypertension or congestive heart failure. Quinapril 10 to 40 mg/day has achieved adequate control of blood pressure in most patients with essential hypertension in clinical trials. Some patients required quinapril dosages up to 80 mg/day and/or concomitant diuretic therapy. Titrating quinapril dosages from 10 to 40 mg/day increased response rates without increasing the incidence or severity of adverse events. Addition of hydrochlorothiazide to quinapril therapy improved response rates by approximately 10 to 20% in patients with hypertension. In general, blood pressure control with quinapril monotherapy was similar to that achieved with enalapril or other standard antihypertensive agents in comparative trials. Quinapril < or = 40 mg/day improved exercise tolerance, reduced the severity and frequency of symptoms, and improved functional (New York Heart Association) class in most clinical studies of patients with congestive heart failure. In addition, beneficial haemodynamic and echocardiographic changes achieved with quinapril were maintained for up to 1 year with continued administration to such patients, but its effect on survival in patients with congestive heart failure has not been reported. The tolerability profile of quinapril is broadly similar to that of other ACE inhibitors; pooled data from clinical trials indicated that 12% of patients with hypertension or congestive heart failure receiving quinapril experienced a treatment-related adverse effects compared with 15% of enalapril recipients and 16% of captopril recipients. Thus, quinapril has clearly established a role as an effective and well tolerated alternative to other ACE inhibitors for the treatment of hypertension and congestive heart failure. While effects of quinapril on survival of patients with congestive heart failure have not been determined, large intervention studies have demonstrated improved mortality rates with other ACE inhibitors. Further studies, including a large ongoing trial of normotensive patients with coronary artery disease but normal left ventricular function, may also establish a role for quinapril in treating patients with ischaemic heart disease.

Inhaled fluticasone propionate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma.

Fluticasone propionate is an androstane carbothioate glucocorticosteroid with almost twice the topical anti-inflammatory potency of beclomethasone dipropionate. Importantly, it is not appreciably absorbed from the gastrointestinal tract. However, the fraction of active drug absorbed from the lungs after inhalation, and therefore total systemic availability, has yet to be determined. Inhaled fluticasone propionate administered at dosages of 1500 micrograms/day for 1 year or 2000 micrograms/day for 6 weeks did not cause clinically significant pituitary-adrenal suppression. Preliminary data from 2 published trials also indicate no significant effect on growth in children. However, wider clinical experience is needed to clarify the effects of long term administration on pituitary-adrenal function, bone metabolism and attainment of adult height in children. In clinical studies, inhaled fluticasone propionate was at least as effective as beclomethasone dipropionate or budesonide when administered at half the dosage of the comparators in patients with mild to moderate or severe asthma. Limited data suggest that fluticasone propionate also has considerable potential in the management of childhood asthma. In trials of up to 1 year in duration, fluticasone propionate appeared to be well tolerated by both adults and children. Whether an improved tolerability profile compared with other corticosteroids is a major clinical benefit of the extremely low oral bioavailability of inhaled fluticasone propionate requires confirmation. Nevertheless, on the basis of available data from initial clinical trials of mostly limited duration, inhaled fluticasone propionate offers an effective treatment option for the management of asthma, with the potential of an enhanced safety profile.

Cladribine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies.

Cladribine (2-chloro-2'-deoxyadenosine) is an adenosine deaminase-resistant analogue of deoxyadenosine. In the treatment of hairy cell leukaemia, cladribine has demonstrated excellent efficacy (complete response in 33 to 92% of patients) in noncomparative studies. Cladribine appears to compare favourably with other systemic agents in this indication as it achieves a high degree of efficacy after a single 7-day course, with an acceptable tolerability profile. However, long term data and direct comparative studies with interferon-alpha and pentostatin (deoxycoformycin) are required to confirm the finite advantages offered by cladribine. Preliminary results obtained in other indications including chronic lymphocytic leukaemia, non-Hodgkin's lymphoma, cutaneous T cell lymphoma, Waldenström's macroglobinaemia and acute myeloid leukaemia in children have been sufficiently encouraging to warrant further study. Early pharmacokinetic data suggest that cladribine may be administered by oral and subcutaneous routes, both of which permit convenient outpatient therapy. Myelosuppression, the dose-limiting toxicity of cladribine, and culture-negative fever are the most common adverse effects associated with therapy. However, cladribine appears to be only rarely associated with many of the other adverse effects that characterise antineoplastic therapy. In the weeks post-treatment, there is a small but definite risk of serious infection; infections with a fatal outcome have been reported in a number of studies with cladribine. In conclusion, preliminary data concerning cladribine have been extremely encouraging. Should early response rates in patients with hairy cell leukaemia be sustained, the efficacy of the drug, together with a short treatment regimen, a favourable tolerability profile, and the possibility of oral therapy, suggest that cladribine is likely to supersede other agents available for this indication.

Pentostatin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in lymphoproliferative disorders.

Pentostatin, a potent inhibitor of adenosine deaminase, is an antineoplastic agent which has been studied in the treatment of a variety of lymphoproliferative disorders. It is particularly effective in the treatment of hairy cell leukaemia, achieving complete remissions in 33 to 92% of patients, and has useful activity in treating B cell chronic lymphocytic leukaemia, prolymphocytic leukaemia, adult T cell leukaemia/lymphoma and cutaneous T cell lymphoma refractory to conventional chemotherapy. Initial results suggest that in the treatment of hairy cell leukaemia pentostatin achieves a more rapid response and higher frequency of complete remission with longer duration than interferon-alpha 2a, although it is still not known if some patients experiencing complete remission have been cured. The drug has yet to be directly compared with other promising purine analogues such as cladribine and fludarabine, and results of such comparisons are required before the ultimate role of pentostatin in the treatment of hairy cell leukaemia can be clearly established. However, pentostatin does produce a substantial response in a difficult therapeutic area and should be considered for initial treatment of hairy cell leukaemia.

Sotalol. An updated review of its pharmacological properties and therapeutic use in cardiac arrhythmias.

Sotalol is a nonselective beta-adrenoceptor antagonist which prolongs cardiac repolarisation independently of its antiadrenergic action (class III antiarrhythmic properties). The antiarrhythmic action of sotalol appears to arise predominantly from its class III properties, and the drug exhibits a broader antiarrhythmic profile than the conventional beta-blockers. Sotalol is effective in controlling paroxysmal supraventricular tachycardias and the ventricular response to atrial fibrillation/flutter in Wolff-Parkinson-White syndrome, in maintaining sinus rhythm after cardioversion of atrial fibrillation/flutter, and in preventing initiation of supraventricular tachyarrhythmias following coronary artery bypass surgery. Sotalol shows promise in the control of nonmalignant and life-threatening ventricular arrhythmias, particularly those associated with ischaemic heart disease. It is effective in suppressing complex forms of ventricular ectopy, displaying superior antiectopic activity to propranolol and metoprolol. The acute efficacy of sotalol in preventing reinduction of sustained ventricular tachyarrhythmias and suppressing spontaneous episodes of these arrhythmias on Holter monitoring is translated into long term prophylactic efficacy against arrhythmia recurrence in approximately 55 to 85% of patients with refractory life-threatening ventricular arrhythmias. In addition, sotalol offers the advantage over the class I agents of reducing cardiac and all-cause mortality in the high risk population with life-threatening ventricular arrhythmias. The adverse effects of sotalol are primarily related to its beta-blocking activity and its class III property of prolonging cardiac repolarisation. Sotalol is devoid of overt cardiodepressant activity in patients with mild or moderate left ventricular dysfunction. The overall arrhythmogenic potential is moderately low, but torsade de pointes may develop in conjunction with excessive prolongation of the QT interval due to bradycardia, hypokalaemia or high plasma concentrations of the drug. In summary, sotalol displays a broad spectrum of antiarrhythmic activity, is haemodynamically well tolerated, and confers a relatively low proarrhythmic risk. It is likely to prove particularly appropriate in the treatment and prophylaxis of life-threatening ventricular tachyarrhythmias.

Tiapride. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in geriatric agitation.

Tiapride is a substituted benzamide derivative with selective dopamine D2-receptor antagonist properties which appears to have preferential affinity for extrastriatal dopamine receptors. Animal and clinical studies show that tiapride has anxiolytic properties but the mechanism of action is uncertain. Results from limited studies indicate that the clinical efficacy of tiapride in the treatment of agitation, aggressiveness, anxiety and sleep disorders in the elderly appears superior to that of placebo, chlorpromazine, lorazepam and meprobamate. Tiapride also exerts a beneficial effect on vigilance and alertness in elderly patients and causes less sedation than chlorpromazine. Tiapride is well tolerated at the dosages recommended for elderly patients. Further well designed comparative studies with newer drugs are needed to determine the relative place of tiapride in the treatment of geriatric agitation, and such studies should also address the quality-of-life benefits for the patient. Additional clinical experience to determine the efficacy of tiapride in elderly patients with more than one disease condition, receiving concomitant medications, and/or with renal impairment is also required. However, despite these current limitations, tiapride may have potentially important applications in this difficult area of clinical medicine.

Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states.

Tramadol is a centrally acting analgesic which possesses opioid agonist properties and activates monoaminergic spinal inhibition of pain. It may be administered orally, rectally, intravenously or intramuscularly. In patients with moderate to severe postoperative pain, intravenous or intramuscular tramadol has generally proved to be of equivalent potency to pethidine (meperidine) and one-fifth as potent as nalbuphine. Intravenous tramadol 50 to 150mg was equivalent in analgesic efficacy to morphine 5 to 15mg in patients with moderate pain following surgery; however, when administered epidurally tramadol was one-thirtieth as potent as morphine. Tramadol has demonstrated efficacy in a few studies in the short term treatment of chronic pain of various origins. Orally administered tramadol was found to be an effective analgesic in step 2 of the World Health Organization's guidelines for the treatment of patients with cancer pain. Tramadol is well tolerated in short term use with dizziness, nausea, sedation, dry mouth and sweating being the principal adverse effects. Respiratory depression has been observed in only a few patients after tramadol infusion anaesthesia. When used for pain relief during childbirth, intravenously administered tramadol did not cause respiratory depression in neonates. The tolerance and dependence potential of tramadol during treatment for up to 6 months appears to be low, although the possibility of dependence with long term use cannot be entirely excluded. Thus, evidence to date of the analgesic effectiveness of tramadol combined with a low respiratory depressant effect and low dependence potential in short term use, suggests that the drug may become a useful alternative to the opioid analgesics currently available for the treatment of patients with moderately severe acute or chronic pain.