Frovatriptan.

black triangle Frovatriptan, a new serotonin receptor agonist developed for the acute treatment of migraine, has high affinity for serotonin 5-HT1B and 5-HT1D receptor subtypes and is a potent stimulator of contraction in human basilar arteries. black triangle A long terminal elimination half-life (approximately 26 hours) is a distinctive pharmacokinetic feature of frovatriptan which appears to be independent of dose, age, gender and renal function. black triangle A single oral dose of frovatriptan 2.5mg was effective in the acute treatment of migraine providing meaningful relief within 2 hours to approximately twice as many recipients as placebo in clinical trials. black triangle Consistent relief of migraine symptoms was achieved in patients who treated a number of consecutive attacks with frovatriptan and the incidence of 24-hour migraine recurrence was reduced. black triangle Frovatriptan was well tolerated in clinical trials, with the overall incidence of adverse events occurring with frovatriptan 2.5mg only slightly higher than that reported with placebo. Mild to moderate fatigue, nausea and paraesthesia were the most commonly reported drug-related adverse events.

Darbepoetin alfa.

Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for the treatment of anaemia associated with chronic kidney disease. In single-dose studies in patients undergoing dialysis, the mean terminal half-life for intravenous darbepoetin alfa was approximately 3-fold longer than for intravenous recombinant human erythropoitin (r-HuEPO, epoetin alfa; 25.3 vs 8.5 hours). The mean terminal half-life after subcutaneous administration of darbepoetin alfa was 48.8 hours. In randomised nonblind trials in patients undergoing dialysis, darbepoetin alfa (0.45 pg/kg) given once weekly for the correction of anaemia increased haemoglobin (Hb) levels to a similar extent as darbepoetin alfa three times weekly or r-HuEPO two or three times weekly. A double-blind, randomised clinical trial reported that switching patients from a three-times weekly regimen of r-HuEPO to once weekly darbepoetin alfa with additional placebo twice weekly (all intravenously) maintained Hb levels between 9.0 and 13.0 g/dl to a similar extent as continued treatment with r-HuEPO three times weekly. In a randomised nonblind study, r-HuEPO-naive patients with chronic renal insufficiency received either subcutaneous darbepoetin alfa once weekly or r-HuEPO twice weekly. 93% of patients receiving darbepoetin alfa and 92% of patients receiving r-HuEPO achieved a Hb increase of > or = 1.0 g/dl from baseline and the mean increase in Hb level over the initial 4 weeks was similar for both treatments. The number and frequency of adverse events, withdrawals and deaths reported in clinical trials did not differ between patients receiving darbepoetin alfa and patients receiving r-HuEPO. There have been no reports of immune responses to darbepoetin alfa in 1534 patients receiving treatment for up to 2 years.

Atorvastatin: an updated review of its pharmacological properties and use in dyslipidaemia.

UNLABELLED: Atorvastatin is a synthetic hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. In dosages of 10 to 80 mg/day, atorvastatin reduces levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglyceride and very low-density lipoprotein (VLDL)-cholesterol and increases high-density lipoprotein (HDL)-cholesterol in patients with a wide variety of dyslipidaemias. In large long-term trials in patients with primary hypercholesterolaemia. atorvastatin produced greater reductions in total cholesterol. LDL-cholesterol and triglyceride levels than other HMG-CoA reductase inhibitors. In patients with coronary heart disease (CHD), atorvastatin was more efficacious than lovastatin, pravastatin. fluvastatin and simvastatin in achieving target LDL-cholesterol levels and, in high doses, produced very low LDL-cholesterol levels. Aggressive reduction of serum LDL-cholesterol to 1.9 mmol/L with atorvastatin 80 mg/day for 16 weeks in patients with acute coronary syndromes significantly reduced the incidence of the combined primary end-point events and the secondary end-point of recurrent ischaemic events requiring rehospitalisation in the large. well-designed MIRACL trial. In the AVERT trial, aggressive lipid-lowering therapy with atorvastatin 80 mg/ day for 18 months was at least as effective as coronary angioplasty and usual care in reducing the incidence of ischaemic events in low-risk patients with stable CHD. Long-term studies are currently investigating the effects of atorvastatin on serious cardiac events and mortality in patients with CHD. Pharmacoeconomic studies have shown lipid-lowering with atorvastatin to be cost effective in patients with CHD, men with at least one risk factor for CHD and women with multiple risk factors for CHD. In available studies atorvastatin was more cost effective than most other HMG-CoA reductase inhibitors in achieving target LDL-cholesterol levels. Atorvastatin is well tolerated and adverse events are usually mild and transient. The tolerability profile of atorvastatin is similar to that of other available HMG-CoA reductase inhibitors and to placebo. Elevations of liver transaminases and creatine phosphokinase are infrequent. There have been rare case reports of rhabdomyolysis occurring with concomitant use of atorvastatin and other drugs. CONCLUSION: Atorvastatin is an appropriate first-line lipid-lowering therapy in numerous groups of patients at low to high risk of CHD. Additionally it has a definite role in treating patients requiring greater decreases in LDL-cholesterol levels. Long-term studies are under way to determine whether achieving very low LDL-cholesterol levels with atorvastatin is likely to show additional benefits on morbidity and mortality in patients with CHD.

Calcipotriol ointment. A review of its use in the management of psoriasis.

UNLABELLED: Calcipotriol, a vitamin D3 analog, acts not only to inhibit cell proliferation and enhance cell differentiation in the skin of patients with psoriasis, but also appears to have effects on immunologic markers that are thought to play a role in the etiology of the disease. In several well designed, short term studies in adults, calcipotriol ointment 50 micrograms/g twice daily provided similar or superior efficacy to several other antipsoriatic agents in adult patients with mild to moderate psoriasis. In patients with nonscalp psoriasis, the drug provided superior efficacy to twice daily placebo (vehicle ointment), twice daily fluocinonide 500 micrograms/g, once daily tacalcitol 4 micrograms/g and twice daily coal tar 5% plus allantoin 2% and hydrocortisone 0.5%. Furthermore, calcipotriol therapy generally provided superior efficacy to twice daily betamethasone valerate 1 to 1.2 mg/g or once daily dithranol 1 to 20 mg/g, and similar efficacy to twice daily betamethasone dipropionate plus salicylic acid or once daily maxacalcitol 6 to 50 micrograms/g. Limited data indicated that calcipotriol ointment 50 micrograms/g also improved overall disease severity in children. In combination with other antipsoriatic agents [acitretin, cyclosporine, betamethasone valerate, halobetasol (ulobetasol)], ultraviolet B or psoralen ultraviolet A (PUVA) phototherapy, calcipotriol ointment 50 micrograms/g twice daily improved the beneficial effects of these drugs on overall disease severity in adult patients with moderate to severe psoriasis. Furthermore, in separate trials, calcipotriol combination therapy reduced the dosage of acitretin required to achieve clearance of psoriasis and the duration of PUVA and dosage of UVA phototherapy, potentially improving the benefit/risk ratio for these other antipsoriatic treatments. Calcipotriol was generally well tolerated in short and long term studies in adult patients, with the majority of adverse events being mild to moderate in intensity and transient. The most common adverse events associated with calcipotriol therapy were dermatologic in nature and included lesional or perilesional irritations, face and scalp irritations, worsening of psoriasis and miscellaneous dermatologic events. Notably, there have been very few reports of patients developing hypercalcemia or hypercalciuria during calcipotriol therapy, with most occurring in patients who exceeded the recommended dosage of 100 g/week. Although data in children are limited, the drug was well tolerated with the nature and incidence of adverse effects similar to those observed in adult patients. CONCLUSIONS: Extensive clinical experience, along with several short and long term clinical trials, has shown calcipotriol ointment to be an effective and well tolerated topical agent in adult patients with psoriasis. In addition, calcipotriol ointment proved beneficial in combination with other topical, phototherapy or systemic antipsoriatic treatments, reducing the dosage and/or duration of some of these treatments and potentially improving their benefit/risk ratio. Calcipotriol ointment is valuable as a first- or second-line therapy option for the management of mild to moderate psoriasis and in combination with other antipsoriatic agents for more severe psoriasis.

Cyclosporin: an updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (neoral)1 in organ transplantation.

UNLABELLED: Cyclosporin is a lipophilic cyclic polypeptide immunosuppressant that interferes with the activity of T cells chiefly via calcineurin inhibition. The original oil-based oral formulation of this drug (Sandimmun)l was characterised by high intra- and interpatient pharmacokinetic variability, with poor bioavailability in many patients; a novel microemulsion formulation (Neoral)1 was therefore developed to circumvent these problems. Studies show increases, attributable chiefly to improved absorption in patients who absorb the drug only poorly from the original formulation, in mean systemic exposure to cyclosporin with the microemulsion, with no clinically significant differences in tolerability or drug interaction profiles. Cyclosporin microemulsion is at least as effective as the oil-based formulation in renal, liver and heart transplant recipients, with trends towards decreased incidence of acute rejection with the microemulsion formulation in some (statistically significant in a few) trials. Cyclosporin microemulsion and tacrolimus appear to have similar efficacy in preventing acute rejection episodes in most renal, pancreas-kidney, liver and heart transplant recipients. However, there are indications of superior efficacy for tacrolimus in some trials, particularly in the prevention of severe acute rejection and in Black transplant recipients. Current 12-month data also indicate equivalent efficacy of sirolimus in renal transplantation. Conversion from the oil-based to microemulsion formulation in stable renal, liver and heart transplant recipients is achievable with no change in acute rejection rates. The addition of an anti-interleukin-2 receptor monoclonal antibody and/or mycophenolate mofetil to cyclosporin microemulsion plus corticosteroids decreases rates of acute rejection; corticosteroid withdrawal without increased acute rejection rates was also achieved on the addition of these agents in some trials. Pharmacoeconomic analyses have shown savings in direct healthcare costs in kidney or liver transplantation when cyclosporin microemulsion is used in preference to the oil-based formulation, although studies incorporating indirect costs or expressing costs in terms of therapeutic outcomes are currently unavailable. CONCLUSIONS: The introduction of cyclosporin microemulsion has consolidated the place of the drug as a mainstay of therapy in all types of solid organ transplantation; research into optimisation of outcomes through more effective therapeutic monitoring in patients receiving this formulation is ongoing. Several novel immunosuppressants have been introduced in recent years: further clinical and pharmacoeconomic research will be needed to clarify the relative positioning of these agents, particularly with respect to specific patient groups. Other new drugs (basiliximab/daclizumab and mycophenolate mofetil) offer particular advantages when used in combination with cyclosporin.

Insulin glargine: a review of its therapeutic use as a long-acting agent for the management of type 1 and 2 diabetes mellitus.

UNLABELLED: Insulin glargine is a recombinant human insulin analogue produced by DNA technology using a nonpathogenic strain of Escherichia coli. Two modifications of human insulin result in a stable molecule which is soluble in slightly acidic conditions (pH 4.0) and precipitates in the neutral pH of subcutaneous tissue. Because of these properties, absorption of insulin glargine is delayed and the analogue provides a fairly constant, basal insulin supply without peaks in plasma insulin levels for approximately 24 hours, similar to that achieved by a continuous subcutaneous insulin infusion. Insulin glargine is indicated as a once daily subcutaneous injection to provide basal glycaemic control in adults and children aged >6 years with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Fasting plasma glucose and fasting blood glucose levels generally improved to a greater extent in patients with type 1 diabetes mellitus receiving insulin glargine than patients who administered Neutral Protamine Hagedorn (NPH) insulin. In patients with type 1 or 2 disease, glycosylated haemoglobin levels were slightly reduced and to a similar extent with insulin glargine and NPH insulin. Most clinical trials in patients with type 1 or 2 diabetes mellitus demonstrated a lower incidence of hypoglycaemia, especially nocturnal hypoglycaemia, compared with NPH insulin. One of the most common adverse events with insulin glargine treatment was injection site pain which, in some studies, occurred more frequently than in patients receiving NPH insulin. In all cases the symptoms were mild and treatment discontinuation was not required. Otherwise, the drug is well tolerated and does not appear to be immunogenic. CONCLUSIONS: Insulin glargine once a day provides basal control of glycaemia for approximately 24 hours without inducing peaks in plasma insulin levels in patients with type 1 or 2 diabetes mellitus. In long term, well designed trials insulin glargine once daily improved glycaemic control at least as effectively as NPH insulin given once or twice daily. The drug was well tolerated and in most studies the incidence of nocturnal hypoglycaemia was significantly less in patients treated with insulin glargine compared with patients receiving NPH insulin. Therefore, insulin glargine is likely to be a useful addition to the armamentarium of insulin therapy by establishing basal glycaemic control with once daily administration and a reduced risk of nocturnal hypoglycaemia.

Telmisartan: a review of its use in hypertension.

UNLABELLED: Telmisartan is an angiotensin II receptor antagonist that is highly selective for type 1 angiotensin II receptors. It was significantly more effective than placebo in large (n >100), double-blind, randomised, multicentre clinical trials in patients with mild to moderate hypertension. Telmisartan 20 to 160 mg once daily produced mean reductions in supine trough systolic blood pressure and diastolic blood pressure of up to 15.5 and 10.5 mm Hg, respectively. Maximum blood pressure reduction occurred with a dosage of 40 to 80 mg/day. Telmisartan 40 to 120 mg/day was as effective as amlodipine 5 to 10 mg/day or atenolol 50 to 100 mg/day in dose-titration studies. Telmisartan 20 to 160 mg/day was generally similar in efficacy to enalapril 5 to 20 mg/day or lisinopril 10 to 40 mg/day in both titration-to-response and other studies. Hydrochlorothiazide was coadministered in most of the titration-to-response studies if patients remained hypertensive. Telmisartan 80 mg/day was more effective than submaximal dosages of losartan (50 mg/day) or valsartan (80 mg/day) and was as effective as a fixed-dose combination of losartan 50 mg plus hydrochlorothiazide 12.5 mg over the last 6 hours of the dosage interval and the whole 24-hour postdose interval. In patients with severe hypertension, telmisartan 80 to 160 mg/day was as effective as enalapril 20 to 40 mg/day (both agents could be titrated and combined sequentially with hydrochlorothiazide 25 mg and amlodipine 5 mg). The addition of hydrochlorothiazide to telmisartan was more effective than each agent alone at lowering blood pressure in patients with hypertension. Telmisartan was well tolerated in patients with mild to moderate hypertension and was significantly less likely to cause persistent, dry cough than lisinopril. CONCLUSION: Telmisartan is an effective antihypertensive agent with a tolerability profile similar to that of placebo. Comparative data have shown telmisartan to be as effective as other major classes of antihypertensive agents at lowering blood pressure. Compared with lisinopril, telmisartan is associated with a significantly lower incidence of dry, persistent cough. Therefore, telmisartan is a useful therapeutic option in the management of patients with hypertension.

Cefuroxime axetil: an updated review of its use in the management of bacterial infections.

UNLABELLED: Cefuroxime axetil, a prodrug of the cephalosporin cefuroxime, has proven in vitro antibacterial activity against several gram-positive and gram-negative organisms, including those most frequently associated with various common community-acquired infections. In numerous randomised, controlled trials, 5 to 10 days' treatment with oral cefuroxime axetil (250 or 500 mg twice daily) was an effective treatment in patients with upper (URTI) and lower respiratory tract infections (LRTI) as assessed by clinical and bacteriological criteria. The drug was as effective as several other cephalosporins, quinolones, macrolides and amoxicillin/clavulanic acid. Shorter courses (5 to 10 days') of cefuroxime axetil were at least as effective as a 10 day course. Furthermore, sequential therapy with intravenous cefuroxime (750 mg 2 or 3 times daily for 2 to 5 days) followed by oral cefuroxime axetil (500 mg twice daily for 3 to 8 days) proved an effective treatment in adult patients with community-acquired pneumonia (CAP). This approach provided similar efficacy to intravenous ampicillin/sulbactam followed by oral amoxicillin/clavulanic acid, a full parenteral course of cefuroxime, or intravenous then oral azithromycin or clarithromycin. Additionally, cefuroxime axetil was an effective treatment in patients with genitourinary, skin and soft-tissue infections, and erythema migrans associated with early stage Lyme disease. The drug is well tolerated by adult and paediatric patients, with adverse effects that are consistent with those of other cephalosporins. The majority of adverse events (primarily gastrointestinal disturbances) were mild to moderate in intensity and reversible upon discontinuation of treatment, with very few serious adverse events reported. CONCLUSIONS: Cefuroxime axetil is a broad spectrum antibacterial agent with a pharmacokinetic profile that permits convenient twice-daily administration. The drug is an effective and well tolerated treatment in patients with various infections, including otitis media, pharyngitis, sinusitis, CAP and acute exacerbations of chronic bronchitis. Cefuroxime axetil proved effective as a component of intravenous/oral sequential therapy in the treatment of CAP, although there are currently no dosage recommendations available for this regimen in some countries. Cefuroxime axetil may be considered as an empirical therapy for a range of community-acquired infections, including those in which beta-lactamase-producing strains of common respiratory pathogens are identified as the causative organisms. In an era of rapidly emerging bacterial resistance, empirical treatment with bacterial agents, potentially preventing the emergence of bacterial resistance to agents such as cefuroxime axetil may ensure the appropriate use of newer antibacterial agents, potentially preventing the emergence of bacterial resistance to these newer drugs.

Oxcarbazepine: an update of its efficacy in the management of epilepsy.

UNLABELLED: Oxcarbazepine (10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide) is a 10-keto analogue of carbamazepine with anticonvulsant activity. In newly diagnosed adult patients, oxcarbazepine monotherapy is as effective as phenytoin and vaiproic acid at reducing generalised tonic-clonic and partial seizure frequency. Furthermore, oxcarbazepine 2400 mg/day as monotherapy has also proved effective in the treatment of refractory partial seizures in adult patients. Oxcarbazepine 600, 1200 and 2400 mg/day as adjunctive therapy significantly reduced seizure frequency compared with placebo in 692 patients with refractory partial seizures. The efficacy of oxcarbazepine monotherapy is similar to that of phenytoin in the treatment of children and adolescents with newly diagnosed partial or generalised tonic-clonic seizures. Additionally, adjunctive therapy with oxcarbazepine was significantly more effective than placebo at reducing seizure frequency in children and adolescents with refractory partial seizures. The most commonly reported adverse events associated with oxcarbazepine monotherapy and/or adjunctive therapy in adults and/or children are somnolence, dizziness, headache, nausea and vomiting. Oxcarbazepine monotherapy is better tolerated than phenytoin (in both adults and children) and valproic acid (in adults), and although 75 to 90% of adult patients in 5 recent monotherapy studies reported adverse events while receiving oxcarbazepine, <8% withdrew from treatment because of them. Acute hyponatraemia, although usually asymptomatic, develops in 2.7% of patients treated with oxcarbazepine. Adverse events most likely to resolve upon switching to oxcarbazepine therapy from treatment with carbamazepine are undetermined skin reactions (rashes, pruritus, eczema), allergic reactions and a combination of malaise, dizziness and headache. Although oxcarbazepine does have a clinically significant interaction with some drugs (e.g. phenytoin and oral contraceptives), it has a lower propensity for interactions than older antiepileptic drugs (AEDs) because its major metabolic pathway is mediated by noninducible enzymes. CONCLUSION: Oxcarbazepine as monotherapy is a viable alternative to established AEDs in the treatment of partial and generalised tonic-clonic seizures in adults and children. Furthermore, it is also effective as adjunctive therapy in the treatment of refractory partial seizures in both age groups. In addition, the drug is tolerated better than the older, established AEDs, and has a lower potential for drug interactions. These attributes make oxcarbazepine an effective component in the initial treatment of newly diagnosed partial and generalised tonic-clonic seizures, and also as an adjunct for medically intractable partial seizures in both adults and children.

Parecoxib (parecoxib sodium).

Parecoxib (parecoxib sodium) is an injectable pro drug of valdecoxib, which is a potent and selective inhibitor of cyclo-oxygenase-2. Intravenous (IV) or intramuscular (IM) parecoxib >20 mg has analgesic activity superior to that of placebo and similar to that of IV or IM ketorolac 30 or 60 mg well controlled trials in patients with postoperative dental pain (n = 304 to 457). In a well controlled trial (n = 202), IV parecoxib 20 or 40mg showed analgesic activity greater than that of placebo and IV morphine 4mg and similar to that of IV ketorolac 30 mg following gynaecological surgery Following orthopaedic surgery, the analgesic activity of IV parecoxib 20 or 40mg was similar to that of IV ketorolac 30 mg and superior to that of IV morphine 4 mg or placebo in well controlled trials (n = 175 and 208). IV parecoxib (40 mg twice daily for 7 days) produced significantly fewer gastrointestinal erosions and/or ulcers than ketorolac (15 mg 4 times a day for 5 days) in healthy volunteers in a well controlled trial; effects on upper gastrointestinal mucosa were similar for parecoxib and placebo. Parecoxib is well tolerated after dental, gynaecological or orthopaedic surgery. The most common adverse events irrespective of treatment (parecoxib, ketorolac or placebo) after dental surgery were nausea, alveolar osteitis, dizziness and headache. Nausea, abdominal pain, headache, abdominal fullness, dizziness, back pain, fever, hypoactive bowel sounds, vomiting, tachycardia, somnolence, abnor mal breath sounds and pruritus occurred in > or = 10% of parecoxib recipients after gynaecological surgery. Similar results were seen in placebo recipients.

Ganciclovir: an update of its use in the prevention of cytomegalovirus infection and disease in transplant recipients.

Ganciclovir is a nucleoside guanosine analogue which incorporates ganciclovir triphosphate (the active moiety) into DNA during elongation, thereby inhibiting viral replication. Comparative studies of pre-emptive and prophylactic ganciclovir therapies in bone marrow transplant (BMT) recipients have shown similar rates of cytomegalovirus (CMV) infection, disease and patient mortality. Long term prophylaxis with either oral, or sequential intravenous/oral, ganciclovir has shown efficacy in renal allograft recipients, including high risk patients or those receiving antilymphocyte antibody therapy. A preliminary study indicates that ganciclovir is more efficacious than aciclovir in paediatric patients. Both oral and intravenous prophylactic ganciclovir regimens have shown efficacy compared with no antiviral treatment in lung transplant recipients; initial reports have shown similar efficacy between pre-emptive and prophylactic ganciclovir. Oral ganciclovir monotherapy is as efficacious as sequential intravenous/oral ganciclovir therapy in liver transplant recipients. Pre-emptive treatment was equally as effective as long term ganciclovir prophylaxis in high risk patients. Ganciclovir prophylaxis for 4 weeks appears ineffective in heart allograft recipients treated with antithymocyte globulin. Long term sequential intravenous/ oral ganciclovir therapy has shown greater efficacy in preventing CMV disease than sequential ganciclovir/aciclovir therapy. in these patients. Initial reports indicate that pre-emptive therapy may be beneficial in this patient group. although this remains to be determined. Ganciclovir in therapeutic dosage regimens generally has acceptable tolerability with adverse effects usually of a haematological or neurological nature. Neutropenia, thrombocytopenia and anaemia are the primary dose-limiting toxicities associated with ganciclovir therapy. Overall, neutropenia occurs less frequently with administration of oral ganciclovir than with intravenous ganciclovir. Monitoring of renal function is recommended as serum creatinine levels may rise during ganciclovir therapy. In addition, ganciclovir prophylaxis appears more cost effective than the majority of other currently available therapies for CMV with oral ganciclovir more cost effective than intravenous ganciclovir. In conclusion, it is unlikely that a single strategy will be able to be applied to all transplant patients for the prevention of CMV disease. An optimal strategy will probably be arisk-adapted approach. Prophylactic treatment with ganciclovir appears the best strategy to implement in high risk patients: oral ganciclovir formulations may be best employed where lower toxicity is required. Pre-emptive treatment with ganciclovir appears most efficacious in patients identified as lower risk or, in the case of BMT recipients, where lower toxicity may be desirable. Ganciclovir remains an important therapeutic option for the prevention and treatment of CMV disease in transplant recipients.

Perindopril/indapamide 2/0.625 mg/day: a review of its place in the management of hypertension.

The fixed low-dose combination of the ACE inhibitor perindopril and the non-thiazide diuretic indapamide has been evaluated in the management of patients with mild to moderate hypertension. Combination therapy aims to improve overall therapeutic efficacy while minimising adverse effects. In well-designed multicentre clinical trials, perindopril/indapamide at doses ranging from 2/0.625 to 8/2.5 mg/day was significantly more effective than placebo in achieving adequate blood pressure (BP) control. A similar reduction in supine BP was observed when combined perindopril/indapamide 2/0.625 mg/day was compared with losartan 50 mg/day or atenolol 50 mg/day. Similar reductions in 24-hour ambulatory BP were also seen with perindopril/indapamide 2/0.625 mg/day and irbesartan 150 mg/day. However, response and normalisation rates were significantly higher with combination therapy than with losartan or irbesartan monotherapy. Combined perindopril/indapamide 2/0.625 mg/day therapy effectively reduced BP in elderly patients aged 65 to 85 years to a significantly greater extent than either atenolol 50 mg/day or placebo. Supine BP was also normalised in approximately two-thirds of patients in a small noncomparative trial in patients with hypertension and renal impairment. Low-dose perindopril/indapamide 2/0.625 mg/day was well tolerated in clinical trials; the most common adverse events were headache and cough. Hypokalaemia, associated with the use of diuretics, occurred with a higher incidence with combined perindopril/indapamide 2/0.625 mg/day therapy than with either atenolol 50 mg/day or placebo. Perindopril/indapamide 2/0.625 mg/day has shown efficacy in well designed comparative trials with atenolol, losartan and irbesartan including elderly patients and patients with renal impairment. Studies comparing this dosage of perindopril/ indapamide with other combination therapies would be beneficial in allowing the place of perindopril/indapamide to be more accurately determined. The fixed-low dose combination of perindopril/indapamide provides a promising and well tolerated treatment option in the management of patients with mild to moderate hypertension.

Efavirenz: a pharmacoeconomic review of its use in HIV infection.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of patients with HIV infection. Both US and British treatment guidelines for HIV infection recommend NNRTI- or protease inhibitor-based combinations [i.e. with nucleoside reverse transcriptase inhibitors (NRTIs)] as first-line treatmentoptions in the management of HIV disease. Results of a pivotal randomised study (DMP 266-006) comparing efavirenz- versus indinavir-based triple combination therapy in patients with HIV infection (the majority of whom were antiretroviral therapy-naive) showed the efavirenz-based regimen was better tolerated and had greater success in achieving reductions in viral load below the limit of detection. These and other clinical data were incorporated into economic models in 2 analyses, one conducted in the US and the other in Canada. The US analysis examined long term clinical and economic outcomes predicted on the basis of response (viral load and CD4+ cell counts), tolerability and willingness to adhere to therapy. The efavirenz-based regimen was the dominant treatment strategy as it was predicted to improve survival and reduce direct medical costs in the US healthcare system. Compared with the indinavir-containing regimen, survival was increased by 11% (absolute difference) and cumulative costs were reduced by $US10,326 per patient (1998 discounted costs) at 5 years after starting treatment with efavirenz-based therapy. The Canadian analysis was conducted from the perspective of the Ontario healthcare system. This study did not consider differences in clinical efficacy between treatment groups, costs of study medication or outcomes beyond 1 year--all factors that would have favoured the efavirenz-based regimen. Of the 2 treatment options, the efavirenz-based regimen was associated with 7.4% lower average annual medical care costs, primarily because of greater costs associated with adverse clinical events with the indinavir-based regimen. In conclusion, current treatment guidelines for HIV infection recognise efavirenz-based combination regimens as a first-line treatment option. A pivotal comparative clinical trial (DMP 266-006) showed a significantly greater virological response to efavirenz- than indinavir-based triple combination therapy, and the efavirenz-based regimen was better tolerated. These clinical data are supported by pharmacoeconomic analyses conducted in the US and Canada, both of which showed lower medical care costs with the efavirenz-based regimen. The US analysis also predicted long term health benefits, such as improved survival, with efavirenz- versus indinavir-based triple combination therapy. These results must be weighed against the inherent difficulties of predicting long term treatment failure rates from short term data, and the limited number of pharmacoeconomic analyses conducted with efavirenz to date.

Levosimendan.

Levosimendan, a pyridazinone-dinitrile derivative, is a calcium sensitiser with additional action on adenosine triphosphate (ATP)-sensitive potassium channels. It is used intravenously (IV) for the treatment of decompensated cardiac failure. At therapeutic doses, levosimendan exhibits enhanced contractility with no increase in oxygen demands. It also produces antistunning effects without increasing myocardial intracellular calcium concentrations or prolonging myocardial relaxation. Levosimendan also causes coronary and systemic vasodilation. In patients with decompensated congestive heart failure (CHF), IV levosimendan significantly reduced the incidence of worsening CHF or death. IV levosimendan significantly increased cardiac output or cardiac index and decreased filling pressure in the acute treatment of stable or decompensated CHF in large, double-blind, randomised trials and after cardiac surgery in smaller trials. Levosimendan is well tolerated, with the most common adverse events (headache, hypotension, nausea) being secondary to vasodilation. It has not been shown to be arrhythmogenic. Levosimendan has shown no clinically important pharmacokinetic interactions with captopril, felodipine, beta-blockers, digoxin, warfarin, isosorbide-5-mononitrate, carvedilol, alcohol (ethanol) or itraconazole.

Bendamustine.

Bendamustine is a bifunctional alkylating agent with cytotoxic activity against human ovarian and breast cancers in vitro. It shows only partial in vitro cross-resistance with cyclophosphamide, melphalan, carmustine and cisplatin. Bendamustine as monotherapy or as part of combination chemotherapy protocols for first-line or subsequent treatment produced objective response rates of 61 to 97% in patients with Hodgkin's disease or non-Hodgkin's lymphoma (NHL) [41 to 48% in high grade NHL]. In patients with multiple myeloma, a bendamustine/prednisone regimen produced a higher rate of complete response (32 vs 11%) and more durable responses than a melphalan/prednisone regimen. Substitution of bendamustine for cyclophosphamide in a standard first-line COP regimen (cyclophosphamide, vincristine and prednisolone) yielded similar response rates in patients with advanced low grade NHL. Substituting bendamustine for cyclophosphamide in the CMF protocol (cyclophosphamide, methotrexate and fluorouracil) prolonged remission from 6.2 to 15.2 months in patients with metastatic breast cancer. The most common adverse events in patients receiving bendamustine are haematological events and gastrointestinal disturbances. Bendamustine has a relatively low propensity to induce alopecia.

Risedronate: a review of its pharmacological properties and clinical use in resorptive bone disease.

UNLABELLED: Risedronate is a novel orally administered pyridinyl bisphosphonate indicated for the prevention or treatment of postmenopausal and glucocorticoid-induced osteoporosis and Paget's disease. The drug reduces bone turnover and decreases resorption chiefly through osteoclastic effects, with no undesirable effects on cortical porosity or thickness or on cancellous bone volume. Four randomised, double-blind trials have been carried out in 4873 patients with postmenopausal osteoporosis. In 2 of these studies, the primary end-point of vertebral fracture incidence was reduced by risedronate 5mg once daily by up to 65 and 49% relative to placebo after 1 and 3 years, respectively. Across all 4 trials, risedronate improved lumbar spine, femoral neck and femoral trochanter bone mineral density (BMD) statistically significantly relative to placebo. The drug also prevented bone loss in a study in 383 women with recent menopause, and reduced the risk of hip fracture in elderly women with confirmed osteoporosis in a trial involving a total of 9331 patients. Risedronate 5 mg/day plus estrogen has been shown to be superior to estrogen alone in a 12-month double-blind study in 524 women with at least 1-year's history of menopause. Two randomised, double-blind and placebo-controlled 12-month studies in a total of 518 patients have shown risedronate 5 mg/day to prevent or reverse bone loss in patients receiving glucocorticoid therapy. Risedronate 30 mg/day was associated with statistically significant reductions in mean serum levels of alkaline phosphatase (ALP) in noncomparative studies in patients with Paget's disease. ALP normalisation rates ranged from 53.8 to 65% across two 84-day treatment cycles in 2 of these trials in 180 patients. In a randomised, double-blind study in 123 patients, risedronate 30 mg/day for 2 months evoked significantly greater serum ALP responses than etidronate 400 mg/day for 6 months. The overall tolerability profile of risedronate was similar to that of placebo in clinical studies, with no evidence of acute-phase reactions or mineralisation defects, or excess incidence of upper GI lesions, in patients receiving the drug. CONCLUSIONS: Risedronate is an effective and well tolerated novel bisphosphonate that is suitable for first-line therapy in Paget's disease. The rapid and sustained reductions in vertebral fracture incidence and BMD changes seen in patients with postmenopausal and glucocorticoid-induced osteoporosis indicate the drug to be a valuable treatment option with first-line potential, particularly in patients for whom hormonal therapy is inappropriate. The effects of the drug on hip fracture incidence in elderly women with confirmed osteoporosis point to a particular role in older patients, or those with more advanced disease.

Rivastigmine. A pharmacoeconomic review of its use in Alzheimer's disease.

UNLABELLED: Alzheimer's disease is associated with a large cost burden, of which institutionalised care constitutes a major component. Therefore, the decision to move a patient from the community to institutionalised care is associated with a significant increase in direct costs. About three-quarters of patients with Alzheimer's disease are admitted to a nursing home within 5 years of diagnosis. Unpaid or informal caregiver time is another large cost in Alzheimer's disease, especially for patients cared for in the community; informal care can account for up to three-quarters of healthcare costs in non-institutionalised patients. Several cholinesterase inhibitors, of which rivastigmine is one, are available for the treatment of patients with mild to moderate Alzheimer's disease. By improving cognitive function and slowing the rate of cognitive decline, cholinesterase inhibitor therapy may reduce a significant part of the economic burden of the disease by delaying the move to institutionalised care. In the absence of prospective long term data which focus on pharmacoeconomic end-points, modelling techniques have been used to extrapolate clinical data available for some cholinesterase inhibitors, including rivastigmine. Four economic analyses, based on a single model of cognitive decline, have been performed with rivastigmine from the perspective of the provider or society. All show that rivastigmine therapy (excluding drug-related costs) is associated with cost savings in patients with mild to moderate Alzheimer's disease by delaying the time to institutionalisation. If the acquisition cost of the drug was factored in, the cost savings completely or partially offset treatment costs. The magnitude of the cost savings increased as the time horizon increased (up to 2 years). The largest savings were realised in patients with mild disease over a 2-year time-frame, suggesting that treatment should be initiated early from an economic viewpoint. Pharmacoeonomic data comparing different cholinesterase inhibitors are, as yet, unavailable. CONCLUSION: Pharmacoeconomic analyses, based on modelled data excluding drug costs, indicate that rivastigmine completely or partially offsets the costs of treatment by delaying cognitive decline and the time to institutionalisation in patients with mild to moderate Alzheimer's disease. From a societal perspective, cost savings are realised if the drug is introduced early in the disease. Additional benefits offered by rivastigmine on behavioural symptoms, which may reduce caregiver burden, have yet to be investigated from a pharmacoeconomic perspective.

Zafirlukast: an update of its pharmacology and therapeutic efficacy in asthma.

UNLABELLED: Zafirlukast is a selective and competitive orally administered inhibitor of the cysteinyl leukotrienes LTC4, LTD4 and LTE4. The drug is indicated for the prophylaxis and treatment of chronic asthma, and has been developed in response to mounting evidence indicating the importance of the cysteinyl leukotrienes in the pathogenesis of this disorder. The efficacy of zafirlukast 20 mg twice daily has been shown in double-blind placebo-controlled studies of up to 13 weeks' duration in patients aged > or = 12 years. Zafirlukast was consistently superior to placebo in improving objective measures of lung function and subjective measures such as symptom scores and use of as-required bronchodilator therapy. This dosage is also as effective when added to low-dosage inhaled corticosteroid therapy as doubling of corticosteroid dosages. Recent studies indicate superior efficacy over zafirlukast of twice-daily inhaled fluticasone propionate 88 microg or salmeterol 42 microg, although zafirlukast was nevertheless associated with clinical improvement. Data also show zafirlukast 40 mg to be of similar efficacy to pranlukast 225 mg (both twice daily). Overall, preliminary pharmacoeconomic data suggest that healthcare costs are reduced by zafirlukast therapy, although superior cost effectiveness has been reported with inhaled fluticasone propionate. and further studies are needed. Data are available to show improvements in patient-rated quality of life, and preference for and high rates of compliance with zafirlukast. In clinical trials, zafirlukast has shown an adverse event profile similar to that of placebo. Isolated reports of hepatic dysfunction in a small number of individuals receiving the drug have been received, and recommendations for monitoring of patients are in place. Although no causal relationship has been established between zafirlukast and Churg-Strauss Syndrome, patients undergoing corticosteroid dosage reductions require careful surveillance. CONCLUSIONS: zafirlukast is an effective and well tolerated agent for preventive monotherapy in mild to moderate persistent asthma. Emerging data indicate benefit of the drug when added to low-dosage inhaled corticosteroids and show that it may be a viable alternative to inhaled adjunctive treatments and increased corticosteroid dosages in some patients. Although inhaled fluticasone propionate and salmeterol have been associated with greater clinical improvement than zafirlukast in clinical studies, compliance considerations and the confirmed clinical efficacy relative to placebo of the drug denote zafirlukast as an effective alternative in treatment programmes based on individualised therapy. As experience with zafirlukast accumulates, it is expected that the drug will be positioned more definitively in national and international treatment guidelines.

Inhaled budesonide/formoterol combination.

Current evidence suggests that the addition of the long acting inhaled beta2-agonist formoterol to low or moderate doses of the inhaled corticosteroid budesonide is effective in improving lung function and reducing the incidence of asthma exacerbations. Concurrent use of budesonide with formoterol does not result in any untoward interaction that affects the pharmacodynamic or pharmacokinetic profiles of the individual drugs, or their adverse effect profiles. The administration of combined budesonide/formoterol is effective in improving morning and evening peak expiratory flow rates in adults with persistent asthma. Control of asthma symptoms is also significantly improved. In children aged 4 to 17 years, combined budesonide/formoterol is effective in increasing both morning and evening peak expiratory flow rates and significantly improving forced expiratory volume in 1 second (FEV1). The most commonly encountered adverse effects in clinical trials with combination budesonide/formoterol therapy have been respiratory infection, pharyngitis and coughing. No adverse effects on pulse rate, blood pressure or serum potassium have been reported with combination therapy.

Fluoxetine: a review of its therapeutic potential in the treatment of depression associated with physical illness.

UNLABELLED: Fluoxetine is a potent and selective inhibitor of neuronal serotonin (5-hydroxytryptamine) reuptake. Fluoxetine reduces food, energy and carbohydrate intake and increases resting energy expenditure, which may account for the moderate and transient bodyweight loss observed with its use. Glucose tolerance and/or hypoglycaemia in patients with type 2 diabetes mellitus improve with fluoxetine therapy. The ability of fluoxetine to inhibit cytochrome P450 (CYP) isoenzymes (CYP2D6, CYP2C and CYP3A4), is potentially important for patients with physical illness who may be taking multiple concomitant medications. Fluoxetine was more effective than placebo in 2 double-blind, randomised trials, and according to limited data appears to be equally effective compared with other SSRIs and tricyclic antidepressants (TCAs), in the treatment of depression in patients with HIV/AIDS. The efficacy of fluoxetine is also superior to that of placebo in the treatment of depression in patients with diabetes mellitus and stroke as shown in double-blind randomised trials, although its efficacy relative to that of nortriptyline in stroke is uncertain. Fluoxetine had similar efficacy to that of desipramine in patients with cancer, with improved Hamilton Depression Rating Scale and quality-of-life scores from baseline; however, the drug was not more effective than placebo in a double-blind randomised trial. Medically healthy individuals tolerate fluoxetine well. Like other SSRIs, fluoxetine lacks the anticholinergic, cardiovascular, sedative and weight-increasing properties of TCAs, and is safer in overdose than TCAs and monoamine oxidase inhibitors. Rates of sexual dysfunction and suicidal ideation with fluoxetine appear similar to those seen with other SSRIs. CONCLUSION: Fluoxetine has shown superior efficacy compared with placebo in the treatment of depression in patients with HIV/AIDS, diabetes mellitus or stroke; however, it has not significantly improved depressive symptoms versus placebo in patients with cancer. The efficacy of fluoxetine appears similar to that of desipramine in patients with stroke, cancer or HIV, and is similar to that of sertraline or paroxetine in patients with HIV/AIDS; comparisons with nortriptyline give equivocal results. The potential for drug interactions with fluoxetine use should be carefully considered because most patients with comorbid physical illness will be receiving multiple comedications. Although fluoxetine has proved effective as an antidepressant in this population in several clinical trials, its drug interaction profile and long half-life are a potential limitation, and these properties should be carefully considered in relation to the status of each patient.