Biomedical subjects

A Markham

Publications and source records attributed to A Markham.

At least 37 records · Page 2Linked to original sources

PubMed1999

Fluvastatin: a review of its use in lipid disorders.

UNLABELLED: Fluvastatin is an HMG-CoA reductase inhibitor used to treat patients with hypercholesterolaemia. Since fluvastatin was last reviewed in Drugs, trials have shown its efficacy in the secondary prevention of coronary heart disease (CHD) events and death and have expanded knowledge of its effects in primary CHD prevention and its mechanisms of activity. In addition to reducing total (TC) and low density lipoprotein (LDL-C) cholesterol, fluvastatin has antiatherogenic, antithrombotic and antioxidant effects, can improve vascular function, and may have immunomodulatory effects. Although fluvastatin interacts with bile acid sequestrants (requiring separation of doses), its pharmacokinetics permit oral administration to most patient groups. Fluvastatin is well tolerated, with adverse effects usually mild and transient. Use of fluvastatin to reduce lipids in patients with primary hypercholesterolaemia is well established. Its effects are similar in most patient groups, with 20 to 80 mg/day reducing LDL-C by 22 to 36%, triglycerides (TG) by 12 to 18% and apolipoprotein B by 19 to 28% and increasing high density lipoprotein cholesterol by 3.3 to 5.6%. Attempts to find fluvastatin dosages with efficacy equivalent to that of other HMG-CoA reductase inhibitors produce variable results, but larger per-milligram fluvastatin dosages are needed when patients switch from other HMG-CoA reductase inhibitors. Combinations of fluvastatin with fibric acid derivatives and bile acid sequestrants produce additive effects. Small noncomparative studies suggest fluvastatin reduces LDL-C in patients with hypercholesterolaemia secondary to kidney disorders by < or = 40.5% and with type 2 diabetes mellitus by < or = 32%. Three large randomised, double-blind trials show fluvastatin can help prevent CHD events or death and slow disease progression in patients with CHD with or without hypercholesterolaemia. In the Fluvastatin Angiographic Restenosis trial in patients undergoing balloon angioplasty, fluvastatin 80 mg/day for 40 weeks reduced the postangioplasty rate of deaths plus myocardial infarctions (1.5% vs 4% with placebo, p < 0.025) without altering vessel luminal diameters. In the Lipoprotein and Coronary Atherosclerosis Study in patients with coronary artery stenosis, luminal diameter reduced to a significantly lesser extent after fluvastatin 20 mg twice daily than placebo after 2.5 years (-0.028 vs -0.01 mm, p < 0.005). The Lescol in Symptomatic Angina study found reductions in all cardiac events or cardiac death in patients after 1 year of fluvastatin 40 mg/day (1.6% vs 5.6% for placebo, p < 0.05). CONCLUSIONS: An evolving pattern of data suggests that, in addition to its well established efficacy and cost effectiveness in reducing hypercholesterolaemia, fluvastatin may now also be considered for use in the secondary prevention of CHD.

Fatty Acids, Monounsaturated↗

PubMed1999

Mirtazapine: a review of its use in major depression.

UNLABELLED: Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA) which has predominantly been evaluated in the treatment of major depression. The drug had equivalent efficacy to tricyclic antidepressants and it was at least as effective as trazodone in the majority of available short term trials in patients with moderate or severe depression, including those with baseline anxiety symptoms or sleep disturbance and the elderly. A continuation study also showed that sustained remission rates were higher with mirtazapine than with amitriptyline and that the drugs had similar efficacy for the prevention of relapse. There is some evidence for a faster onset of action with mirtazapine than with the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). Mirtazapine was more effective than the SSRI fluoxetine at weeks 3 and 4 of therapy and it was also more effective than paroxetine and citalopram at weeks 1 and 2, respectively, in short term assessments (6 or 8 weeks). Preliminary data suggest that the drug may be effective as an augmentation or combination therapy in patients with refractory depression. Anticholinergic events and other events including tremor and dyspepsia are less common with mirtazapine than with tricyclic antidepressants. There was a greater tendency for SSRI-related adverse events with fluoxetine than with mirtazapine, but, overall, mirtazapine had a similar tolerability profile to the SSRIs. Increased appetite and bodyweight gain appear to be the only events that are reported more often with mirtazapine than with comparator antidepressants. In vitro and in vivo data have suggested that mirtazapine is unlikely to affect the metabolism of drugs metabolised by cytochrome P450 (CYP)2D6, although few formal drug interaction data are available. CONCLUSIONS: Mirtazapine is effective and well tolerated for the treatment of patients with moderate to severe major depression. Further research is required to define the comparative efficacy of mirtazapine in specific patient groups, including the elderly and those with severe depression. Clarification of its efficacy as an augmentation therapy and in patients with refractory depression and its role in improving the efficacy and reducing the extrapyramidal effects of antipsychotic drugs would also help to establish its clinical value. The low potential for interaction with drugs that are metabolised by CYP2D6, including antipsychotics, tricyclic antidepressants and some SSRIs, may also make mirtazapine an important option for the treatment of major depression in patients who require polytherapy. Mirtazapine also appears to be useful in patients with depression who present with anxiety symptoms and sleep disturbance.

Antidepressive Agents, Tricyclic↗

PubMed1999

Piperacillin/tazobactam: an updated review of its use in the treatment of bacterial infections.

UNLABELLED: Piperacillin/tazobactam is a beta-lactam/beta-lactamase inhibitor combination with a broad spectrum of antibacterial activity encompassing most Gram-positive and Gram-negative aerobic bacteria and anaerobic bacteria, including many pathogens producing beta-lactamases. Evidence from clinical trials in adults has shown that piperacillin/tazobactam, administered in an 8:1 ratio, is an effective treatment for patients with lower respiratory tract, intra-abdominal, urinary tract, gynaecological and skin/soft tissue infections, and for fever in patients with neutropenia. Combination regimens of piperacillin/tazobactam plus an aminoglycoside are used to treat patients with severe nosocomial (hospital-acquired) infections. In clinical trials, piperacillin/tazobactam was significantly more effective than ticarcillin/clavulanic acid in terms of clinical and microbiological outcome in patients with community-acquired pneumonia. In patients with intra-abdominal infections, clinical and bacteriological response rates were significantly higher with piperacillin/tazobactam than with imipenem/cilastatin (administered at a dosage lower than is recommended in countries outside Scandinavia). Piperacillin/tazobactam in combination with amikacin was at least as effective as ceftazidime plus amikacin in the treatment of ventilator-associated pneumonia and was significantly more effective than ceftazidime plus amikacin in the empirical treatment of febrile episodes in patients with neutropenia or granulocytopenia. In other trials, the efficacy of piperacillin/tazobactam was similar to that of standard aminoglycoside-containing and other treatment regimens in patients with intra-abdominal, skin/soft tissue or gynaecological infections. Piperacillin/tazobactam is generally well tolerated. The most frequent adverse events are gastrointestinal symptoms (most commonly diarrhoea) and skin reactions. The incidence of adverse events with piperacillin/tazobactam is higher when the combination is given in combination with an aminoglycoside than when given as monotherapy. CONCLUSION: Because of the broad spectrum of antibacterial activity provided by piperacillin/tazobactam, it is useful for the treatment of patients with polymicrobial infections caused by aerobic or anaerobic beta-lactamase-producing bacteria. Piperacillin/tazobactam appears to have a particularly useful role in the treatment of patients with intra-abdominal infections and, in combination with amikacin, in the treatment of patients with febrile neutropenia, especially given the current prevalence of Gram-positive infections in this group.

Bacterial Infections↗

PubMed1999

Sildenafil: a review of its use in erectile dysfunction.

UNLABELLED: Sildenafil is an oral therapy for erectile dysfunction of a broad range of causes. By selectively inhibiting phosphodiesterase type 5, it allows corpus cavernosum smooth muscle to relax, potentiating erections during sexual stimulation. Blood pressure is reduced transiently by sildenafil, but more marked hypotension may occur during concurrent administration of sildenafil and organic nitrates; this combination is contraindicated. Sildenafil is rapidly absorbed, with dose-proportional peak plasma concentrations within 1 hour of administration. The elimination half-life is 3 to 5 hours. Dosages usually begin at 50mg taken when needed =1 hour before sexual activity no more than once daily. The maximum dose is 100mg when needed once daily and lower doses (e.g. 25mg) may be used in elderly patients and those with hepatic or renal impairment or receiving cytochrome P450 enzyme CYP3A4 inhibitors, such as ritonavir, saquinavir, ketoconazole, erythromycin or cimetidine. More than 3000 patients with erectile dysfunction of organic (e.g. diabetes or spinal cord injury), psychogenic or mixed origin received sildenafil 5 to 100mg or placebo in fixed- or titrated-dose trials. Sildenafil was associated with dose-related improvements in the frequency, hardness and duration of erections and in patients' abilities to achieve and maintain erections adequate for successful sexual intercourse. In titrated-dose trials, the most commonly effective doses were 50 or 100mg, although lower doses were effective in some patients. Sildenafil was significantly more effective than placebo in erectile dysfunction of all tested causes. The efficacy of sildenafil was not affected by patient age (> or < or =65 years) or by antihypertensive or antidepressant medications. The drug was effective in patients with severe erectile dysfunction. Efficacy was maintained in long term (1-year) studies. Sildenafil also appears to improve the quality of life of both patients and their sexual partners. Common adverse events associated with sildenafil were transient and mild or moderate and included headache, flushing, dyspepsia, nasal congestion and abnormal vision. Tolerability was maintained in long term (< or =1 year) studies. No serious sildenafil-related adverse events occurred in clinical trials; cardiovascular events seen in postmarketing surveillance generally occurred in patients with other known risk factors. CONCLUSIONS: Sildenafil is an effective oral treatment in men with erectile dysfunction. It was significantly superior to placebo in improving erections and allowing successful penetrative sexual intercourse. Although its place in disease management is still emerging and there are contraindications to its use, if preliminary positive reports are confirmed, sildenafil will be the pre-eminent first-line therapy for erectile dysfunction.

Clinical Trials as Topic↗

PubMed1999

Terbinafine. An update of its use in superficial mycoses.

UNLABELLED: Terbinafine is an allylamine antifungal agent which has fungicidal activity against a wide variety of dermatophytes, moulds and certain dimorphic fungi, and fungistatic activity against Candida albicans. Oral terbinafine 250 mg/day is effective in the treatment of superficial dermatophyte infections such as onychomycosis, tinea pedis and tinea corporis/cruris, generally achieving mycological cure in > 80% of patients. The drug is also effective in children with tinea capitis when administered orally in the dosage range 62.5 to 250 mg/day for 4 weeks. Comparative data indicate that oral terbinafine is more effective than continuous or intermittent intraconazole in dermatophyte onychomycosis, and is as effective as itraconazole 400 mg/day in tinea pedis. The drug has shown greater efficacy than griseofulvin in dermatophyte onychomycosis, tinea pedis and tinea corporis/cruris, and comparable efficacy in children with tinea capitis. Additionally, oral terbinafine is more effective than ketoconazole 200 mg/day in tinea corporis/cruris. Topical terbinafine 1% formulations are effective when applied once or twice daily for up to 2 weeks, achieving mycological cure in > 80% of patients with tinea pedis, tinea corporis/cruris, cutaneous candidiasis and pityriasis versicolor. Its formulations are at least as effective as miconazole 2% cream and naftifine 1% gel in tinea pedis, and more effective than clotrimazole 1% cream, bifonazole 1% cream and oxiconazole 1% lotion. Mycological cure rates achieved with terbinafine generally improve after treatment cessation, reflecting the drug's fungicidal mechanism of action and its residual effect in tissue. Terbinafine is well tolerated after oral or topical administration and has a relatively low potential for drug interactions. Pharmacoeconomic data support the use of terbinafine in dermatophyte infections of the skin or nails. CONCLUSIONS: Evidence suggests that oral terbinafine is the treatment of choice for dermatophyte onychomycosis, as it achieves high rates of mycological and clinical cure, is generally well tolerated and has a relatively low potential for drug interactions. It must also be considered a first-line treatment option, along with itraconazole, in cutaneous mycoses which warrant systemic treatment; topical terbinafine is a treatment of choice in less extensive mycoses. The use of terbinafine in non-dermatophyte or mixed infections has not been fully defined.

Animals↗

PubMed1999

Perindopril 2mg/indapamide 0.625mg. Fixed low-dose combination.

Low-dose drug combinations have been proposed in International Guidelines for use in patients with hypertension. The fixed low-dose combination of perindopril 2mg with indapamide 0.625mg combines an angiotensin converting enzyme (ACE) inhibitor with a non-thiazide diuretic. Coadministration of perindopril and indapamide did not have any clinically significant effects on the pharmacokinetic profile of either agent in healthy volunteers. In experimental models of hypertension, perindopril/indapamide restored endothelial function, improved microvascular density, reduced left ventricular and aortic hypertrophy, and reversed renal end-organ damage. Once daily oral perindopril 2mg/indapamide 0.625mg normalised blood pressure (BP) in 83.6% of elderly patients with essential hypertension (diastolic BP was reduced to < or =90mm Hg) and 81.7% of those with isolated systolic hypertension (systolic BP was reduced to <160mm Hg) after approximately 1 year of treatment. BP normalisation was sustained in 79.8% of patients throughout the study. Fixed low-dose perindopril/indapamide had a tolerability profile similar to that of placebo in clinical trials; most adverse events were of mild to moderate severity. Coadministration of the 2 agents reduced the incidence of hypokalaemia seen with indapamide alone.

Animals↗

PubMed1999

Ofloxacin otic solution: a review of its use in the management of ear infections.

UNLABELLED: Ofloxacin is a synthetic fluoroquinolone antibacterial agent that inhibits the supercoiling activity of bacterial DNA gyrase, halting DNA replication. Ofloxacin has been formulated as a 0.3% otic solution for the treatment of ear infections. Topical administration of ofloxacin otic solution 0.3% produces very high concentrations of drug in the ear, thus broadening the spectrum of activity of ofloxacin greatly, to cover most common ear pathogens. Results of clinical trials indicate that ofloxacin otic solution 0.3% is as effective as topical neomycin/polymixin B/hydrocortisone preparations in the treatment of otitis externa (clinical cure rate >80% in adults and >95% in children for both treatments) and oral amoxicillin/clavulanic acid in the treatment of otitis media in the presence of tympanostomy tubes in children (clinical cure rates 76 and 69% for ofloxacin and amoxicillin/clavulanic acid, respectively). It is also effective in the treatment of chronic suppurative otitis media in adolescents and adults with perforated tympanic membranes (75 to 91% clinical cure rate). Because of the limited systemic absorption after topical administration, ofloxacin otic solution 0.3% is well tolerated. Adverse events were usually classed as mild to moderate, with < or =2% considered severe. The most frequent adverse events were bitter taste (5%), primarily in patients with non-intact tympanic membranes, and pruritus (2%). The incidence of adverse events with ofloxacin otic solution 0.3% was similar to that with other ototopical preparations and significantly less than that with oral amoxicillin/clavulanic acid. Unlike comparative ototopical antibacterials, ofloxacin was not ototoxic or chondrotoxic in animal studies. In addition, no ototoxicity was detected in clinical studies in humans. CONCLUSIONS: Ofloxacin otic solution 0.3% is clinically effective in the treatment of otitis externa and otitis media in patients with tympanic membrane perforations or tympanostomy tubes. The high concentrations achieved with this ototopical solution render it active against a broad spectrum of organisms. It is well tolerated, avoiding many systemic adverse events, and is not associated with ototoxicity. As the first ototopical agent approved for use in patients with non-intact tympanic membranes, ofloxacin otic solution 0.3% provides a valuable advantage over current treatment alternatives.

Anti-Infective Agents↗

PubMed1999

Rabeprazole: a review of its use in acid-related gastrointestinal disorders.

Rabeprazole is an inhibitor of the gastric proton pump. It causes dose-dependent inhibition of acid secretion and has a more rapid onset of action than omeprazole. Duodenal ulcers healed faster after treatment with rabeprazole 20 or 40 mg/day than placebo or ranitidine 150 mg 4 times daily and at a generally similar rate to omeprazole 20 mg/day in patients with duodenal ulcers; rabeprazole was similar or superior to these agents in relieving symptoms. Rabeprazole 20 and 40 mg/day healed gastric ulcers faster than placebo, and rabeprazole 20 mg/day healed ulcers at a similar healing rate, to omeprazole 20 mg/day in well controlled 6-week studies. Gastric ulcer symptom relief with rabeprazole was similar or superior to that provided by omeprazole or placebo. In 8-week studies in patients with gastro-oesophageal reflux disease (GERD), rabeprazole 10, 20 and 40 mg/day were more effective than placebo, rabeprazole 20 mg/day was more effective than ranitidine 150 mg twice daily, and rabeprazole 20 mg/day was similar in efficacy to omeprazole 20 mg/day. Symptom relief with rabeprazole in 8-week trials in patients with GERD was superior to that provided by placebo, and similar to ranitidine or omeprazole. Rabeprazole was similar to omeprazole and superior to placebo in both maintenance of healing and prevention of symptoms in patients with healed GERD in 1-year studies. One-week triple therapy with rabeprazole 20 mg twice daily plus 2 antibacterial agents achieved > or = 90% Helicobacter pylori eradication, but, as would be expected, a regimen of rabeprazole 20 mg twice daily plus 1 antibacterial agent was less successful. The drug was as effective as omeprazole and lansoprazole as part of triple therapy for H. pylori eradication. Rabeprazole successfully reduced acid output to target levels and prevented further pathological changes in 10 patients with Zollinger-Ellison syndrome. Usual dosages of rabeprazole are 20 mg/day for 4 weeks to treat duodenal ulcers, 6 weeks for gastric ulcers and 8 weeks for GERD, although some patients with duodenal ulcer may respond to a 10 mg/day dosage. For long term maintenance of GERD healing, 10 or 20 mg daily doses are adequate. Patients with hypersecretory states may need individualised dosages starting at 60 mg/day. The drug was well tolerated in clinical trials, with headache, rash, infection, diarrhoea and flu syndrome as the most common adverse events. In conclusion, rabeprazole appears to be a well tolerated proton pump inhibitor with a rapid onset of action and a low potential for drug interactions. The drug may be used to achieve healing and the relief of symptoms of duodenal ulcer, gastric ulcer and GERD, maintain GERD healing, and can form part of effective regimens to eradicate H. pylori.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1999

Orlistat: a review of its use in the management of obesity.

UNLABELLED: Orlistat is a novel non-systemic treatment for obesity. The drug inhibits lipases in the gastrointestinal tract, preventing the absorption of approximately 30% of dietary fat. Pharmacodynamic and dose-finding studies have established that a 120 mg dose of orlistat 3 times daily (with each main meal) is optimal. Controlled studies have established that orlistat 120 mg 3 times daily for 1 year, in conjunction with a hypocaloric diet, enables weight reduction of 7.9 to 10.2% in obese non-diabetic individuals. In 1 study the reduction was 6.2% in obese patients with type 2 diabetes. Orlistat 120 mg 3 times daily was significantly more effective than placebo (also given in conjunction with a hypocaloric diet) in these studies. The drug was also significantly more effective than placebo in 2-year randomised double-blind studies involving >2000 patients. During the second year of treatment, when patients were switched from a hypocaloric diet to a eucaloric diet, orlistat recipients regained significantly less weight than placebo recipients. Orlistat appears to improve lipid profiles in non-diabetic obese patients, reducing levels of total cholesterol and low density lipoprotein cholesterol. In a study of patients with obesity associated with type 2 diabetes, patients treated with orlistat lost more weight and had improved serum lipid profiles compared with placebo recipients. In addition, orlistat-treated patients achieved significant improvements in glycaemic control, enabling dosages of antidiabetic drugs to be reduced. Long term (1 to 2 years) tolerability data from 2038 patients in placebo-controlled trials revealed that the drug was generally well tolerated. The most commonly reported adverse events were related to decreased fat absorption and included oily faecal spotting, flatus with discharge, faecal urgency and oily stool. Systemic adverse events attributable to orlistat were negligible. CONCLUSION: Orlistat in conjunction with a hypocaloric diet has been shown to induce clinically significant weight loss in keeping with current guidelines for the management of obesity. This, together with its acceptable tolerability profile and lack of systemic adverse events, make it an attractive option in the treatment of obesity. The drug may have a positive effect on obesity-associated cardiovascular risk factors and type 2 diabetes.

Anti-Obesity Agents↗

PubMed1999

Dofetilide: a review of its use in atrial fibrillation and atrial flutter.

UNLABELLED: Dofetilide is a 'pure' class III antiarrhythmic agent which has demonstrated efficacy in the conversion of atrial fibrillation or flutter to sinus rhythm and the maintenance of sinus rhythm. By blocking the rapid component of the cardiac delayed rectifier potassium current (I(Kr)), dofetilide prolongs the cardiac action potential duration and the effective refractory period. This is thought to increase the likelihood of a re-entrant wavefront encountering refractory tissue and terminating the arrhythmia. Preliminary findings from the EMERALD (European and Australian Multicenter Evaluative Research on Atrial Fibrillation Dofetilide) and SAFIRE-D (Symptomatic Atrial Fibrillation Investigation and Randomized Evaluation of Dofetilide) studies suggest that oral dofetilide is effective in the conversion of atrial fibrillation or flutter to sinus rhythm. Both studies have yet to be published in full. In SAFIRE-D, dofetilide 500microg twice daily for 3 days achieved a conversion rate of 32% compared with a 1% rate for placebo. A similar conversion rate was achieved after 3 days in EMERALD with dofetilide 500microg twice daily (29%) which was significantly greater than that achieved with sotalol 80mg twice daily (6%; p < 0.05). Oral dofetilide also appears to be effective in the maintenance of sinus rhythm. An abstract report of EMERALD participants who had been converted to sinus rhythm showed that 71% of patients who received oral dofetilide remained in sinus rhythm after 6 months (compared with 26% of placebo and 59% of sotalol recipients: both p < 0.05). Restoration of sinus rhythm using intravenous dofetilide is more likely in patients with recent-onset versus prolonged-duration arrhythmia, and in those with atrial flutter rather than atrial fibrillation. Limitations of comparative data for intravenous dofetilide are such that few conclusions can be drawn. Although generally well tolerated in clinical trials, dofetilide has proarrhythmic potential. Torsade de pointes ventricular tachycardia was reported in up to 3.3% of patients who received oral dofetilide in the DIAMOND (Diamond Investigations of Arrhythmia and Mortality on Dofetilide) studies, although only a small proportion of patients in these studies had atrial fibrillation; most episodes occurred within the first 3 days. Whether the propensity of dofetilide for this life-threatening arrhythmia is similar to that of other class III antiarrhythmic agents has yet to be determined. Importantly, the long term use of oral dofetilide in patients at high risk for sudden cardiac death is not associated with an increased risk of mortality, although these DIAMOND findings cannot necessarily be extrapolated to patients with atrial fibrillation. CONCLUSIONS: Dofetilide offers an alternative to currently available antiarrhythmic agents for the pharmacological conversion of atrial fibrillation or atrial flutter to sinus rhythm and for the maintenance of sinus rhythm after cardioversion. However, further comparative data are necessary before its definitive place can be determined.

Animals↗

PubMed1998

Cytogenetics and the surgeon: an invaluable tool in diagnosis, prognosis and counselling of patients with solid tumours.

BACKGROUND: Cytogenetic studies have become an important part of tumour characterization. In a minority of tumours cytogenetic and/or molecular studies may be of help for diagnosis, selection of treatment protocols and predicting outcome. METHODS: This article reviews the literature on solid tumour translocations and established family cancer syndromes. In addition, the potential importance of genetics in management of patients with breast, ovarian and pancreatic carcinoma is reviewed. RESULTS AND CONCLUSION: Cytogenetic analysis of tumours may help confirm the diagnosis when conventional histology demonstrates no evidence of differentiation along a particular tissue pathway. For patients with well defined cancer syndromes, cytogenetic and molecular analysis offers the prospect of screening to reduce the risk of malignant disease. For many malignancies the underlying genetic anomalies are gradually being elucidated. Further studies designed to demonstrate the significance of these findings can only be undertaken if tumour material is collected and stored in optimal conditions for cytogenetic and/or molecular biological studies.

Age of Onset↗

PubMed1998

Pamidronate. A review of its use in the management of osteolytic bone metastases, tumour-induced hypercalcaemia and Paget's disease of bone.

Pamidronate (APD) is a potent inhibitor of bone resorption that is useful in the management of patients with osteolytic bone metastases from breast cancer or multiple myeloma, tumour-induced hypercalcaemia or Paget's disease of bone. After intravenous administration, the drug is extensively taken up in bone, where it binds with hydroxyapatite crystals in the bone matrix. Matrix-bound pamidronate inhibits osteoclast activity by a variety of mechanisms, the most important of which appears to be prevention of the attachment of osteoclast precursor cells to bone. In patients with osteolytic bone metastases associated with either breast cancer or multiple myeloma, administration of pamidronate together with systemic antitumour therapy reduces and delays skeletal events, including pathological fracture, hypercalcaemia and the requirement for radiation treatment or surgery to bone. Pamidronate generally improves pain control. Quality-of-life and performance status scores in pamidronate recipients were generally as good as, or better than, those in patients who did not receive the drug. Overall survival does not appear to be affected by pamidronate therapy. Tumour-induced hypercalcaemia also responds well to pamidronate therapy: 70 to 100% of patients achieve normocalcaemia, generally 3 to 5 days after treatment. Response durations vary, but are commonly 3 weeks or longer, In comparative studies, pamidronate produced higher rates of normocalcaemia and longer normocalcaemic durations than other available osteoclast inhibitors, including intravenous etidronate, clodronate and plicamycin (mithramycin). In most patients with Paget's disease of bone, intravenous pamidronate reduces bone pain and produces biochemical response. Serum alkaline phosphatase levels generally fall 50 to 70% from baseline 3 to 4 months after pamidronate treatment. Biochemical response may be prolonged. Pamidronate is well tolerated by most patients. Transient febrile reactions, sometimes accompanied by myalgias and lymphopenia, occur commonly after the first infusion of pamidronate. Other reported adverse events include transient neutropenia, mild thrombophlebitis, asymptomatic hypocalcaemia and, rarely, ocular complications (uveitis and scleritis). Pamidronate should be considered for routine use together with systemic hormonal or cytotoxic therapy in patients with breast cancer or multiple myeloma and osteolytic metastases. At present, pamidronate is the drug of choice for first-line use in the management of patients with tumour-induced hypercalcaemia. It is an effective treatment for Paget's disease and is the treatment of choice where oral bisphosphonates are not an option.

Antineoplastic Agents↗

PubMed1998

Pramipexole. A review of its use in the management of early and advanced Parkinson's disease.

UNLABELLED: Pramipexole is an orally active non-ergoline dopamine agonist with selective activity at dopamine receptors belonging to the D2 receptor subfamily (D2, D3, D4 receptor subtypes) and with preferential affinity for the D3 receptor subtype. It is approved as monotherapy in early Parkinson's disease and as adjunctive therapy to levodopa in patients with advanced disease experiencing motor effects because of diminished response to levodopa. The potential neuroprotective effects of pramipexole have been shown in animal and in vitro studies. Data from relatively long term (10- or 31-week) studies suggest that pramipexole monotherapy (0.375 to 6.0 mg/day) can improve activities of daily living and motor symptoms in patients with early Parkinson's disease. Pramipexole (0.375 to 4.5 mg/day for 31 or 36 weeks), as an adjunct to levodopa in advanced disease, improved activities of daily living and motor symptoms, reduced the duration and severity of 'off' periods and allowed a reduction in levodopa dosage. Mentation, behaviour and mood [Unified Parkinson's Disease Rating Scale (UPDRS) part I], and timed walking test were not significantly improved. The extent of disability improved according to the UPDRS parts II and III but, when assessed by secondary efficacy parameters, it is unclear whether disability or the severity of disease improved. No significant differences were observed in patients randomised to pramipexole or bromocriptine according to a secondary hypothesis in a prospective study in which both drugs were better than placebo. Some quality-of-life measures improved with active treatment relative to placebo. Further studies comparing pramipexole with other dopamine agonists and levodopa in patients with early and advanced Parkinson's disease would be useful. In pramipexole recipients with early disease, the most commonly experienced adverse events were nausea, dizziness, somnolence, insomnia, constipation, asthenia and hallucinations. The most commonly reported adverse events in pramipexole recipients with advanced disease were orthostatic hypotension, dyskinesias, extrapyramidal syndrome (defined as a worsening of the Parkinson's disease), dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia and urinary frequency. The incidence of some adverse events did not greatly differ between pramipexole and placebo recipients. CONCLUSIONS: Pramipexole is effective as adjunctive therapy to levodopa in patients with advanced Parkinson's disease. However, the potential beneficial effects of pramipexole on disease progression need to be confirmed in clinical studies. The efficacy of pramipexole monotherapy in patients with early disease has also been demonstrated, although the use of dopamine agonists in early Parkinson's disease remains controversial.

Antiparkinson Agents↗

PubMed1998

Fexofenadine.

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

Animals↗

PubMed1998

Sumatriptan. An updated review of its use in migraine.

UNLABELLED: Sumatriptan is a selective agonist at serotonin 5-HT1-like receptors, including 5-HT1B/1D subtypes. It is an effective treatment for acute migraine attacks and the injectable form has also shown efficacy in the treatment of cluster headaches. In placebo-controlled clinical trials, sumatriptan, administered subcutaneously, orally, intranasally or rectally was significantly more effective than placebo in relieving migraine headache and in producing resolution or reduction of other symptoms associated with migraine, including nausea, photophobia and phonophobia. Improvements in clinical disability were also significantly greater after sumatriptan than after placebo. Headache recurred in 21 to 57% of patients who received oral or subcutaneous sumatriptan, but most patients responded to a second dose of the drug. Results of comparative trials showed that subcutaneous sumatriptan 6 mg was significantly more effective than either patients' usual antimigraine treatments or intranasal dihydroergotamine mesylate 1 mg in relieving migraine headache. Subcutaneous sumatriptan 6 mg and subcutaneous dihydroergotamine mesylate 1 mg provided similarly effective migraine relief, but the headache recurrence rate was significantly higher after sumatriptan than after this formulation of dihydroergotamine mesylate. Response rates achieved after oral sumatriptan were similar to those reported after treatment with oral naratriptan, rizatriptan or lysine acetylsalicylate plus metoclopramide. Treatment of acute migraine attacks with oral or subcutaneous sumatriptan leads to less loss of workplace productivity than other antimigraine therapies. Several pharmacoeconomic analyses showed that gains in workplace productivity in sumatriptan recipients ranged from 12.1 to 89.8 hours per patient per year. Significant improvements from baseline in overall health-related quality-of-life scores were also experienced by sumatriptan recipients. Sumatriptan is generally well tolerated. Nausea, vomiting, malaise and fatigue are the most common adverse events with oral sumatriptan. Injection site reactions occur in 10 to 40% of patients receiving the drug subcutaneously. A bitter taste at the back of the mouth occurs frequently after intranasal administration. Serious adverse events occur in about 0.14% of patients with migraine treated with sumatriptan. As the drug is associated with the rare development of cardiovascular effects, it is contraindicated in patients with a history of cardiovascular disease. CONCLUSIONS: Despite its relatively high acquisition cost, reductions in lost workplace productivity experienced by patients treated with sumatriptan may result in savings in the overall cost of migraine to society. Thus, sumatriptan is a useful first- or second-line treatment option for patients with moderate or severe migraine.

Administration, Intranasal↗

PubMed1998

Montelukast.

Montelukast is a selective antagonist of the leukotriene D4 (LTD4) receptor. In patients with asthma, montelukast 5 to 250 mg/day attenuated LTD4-induced bronchoconstriction and, at a dosage of 10 mg, significantly reduced early and late airway response to allergen (dust mite extract) relative to placebo. In studies evaluating the effects of various dosages of montelukast on exercise-induced bronchoconstriction the optimal dose of the drug was found to be 10 mg. Montelukast 10 mg/day controlled asthma significantly more effectively than placebo in a 3-month randomised double-blind study. In a 9-month open extension of this trial, during which patients were randomised to treatment with montelukast 10 mg/day or beclomethasone (approximately 400 micrograms/day), daytime symptom score and beta-agonist use decreased to a similar extent in each group. In a further study, treatment with montelukast 10 mg/day permitted clinically significant tapering of corticosteroid dosage in patients with stable asthma. Montelukast (5 mg/day) has also demonstrated efficacy in childhood asthma. The tolerability profile of montelukast was similar to that of placebo in placebo-controlled clinical trials in adults and children; the most common adverse event was headache.

Acetates↗

PubMed1998

Telmisartan.

Telmisartan is a nonpeptide angiotensin II receptor antagonist which selectively and insurmountably inhibits the angiotensin II AT1 receptor subtype without affecting other receptor systems involved in cardiovascular regulation. Oral telmisartan dose-dependently reduced blood pressure (BP) in various animal models of hypertension. In transgenic rats, telmisartan reduced cardiac hypertrophy and glomerulosclerosis. When administered at dosages of 40 to 160 mg once daily to patients with mild to moderate hypertension, telmisartan significantly reduced systolic and diastolic BP compared with placebo and was at least as effective as atenolol 50 or 100 mg and lisinopril 10 to 40 mg. One study showed telmisartan 80 mg/day to be more effective than enalapril 20 mg/day. In 2 studies that used ambulatory BP monitoring, once daily telmisartan provided better control of diastolic BP for the full dosing interval than losartan potassium 50 mg or amlodipine 5 or 10 mg. In a single study in patients with severe hypertension, a telmisartan-based regimen had antihypertensive efficacy similar to that of an enalapril-based regimen. Telmisartan had a tolerability profile similar to that of placebo in clinical studies.

Angiotensin Receptor Antagonists↗

PubMed1998

Theophylline. A review of its potential steroid sparing effects in asthma.

UNLABELLED: Theophylline is generally considered to be a bronchodilatory drug. However, recent pharmacodynamic studies indicate that it has anti-inflammatory effects. It reduced eosinophil survival rates in vitro, and reduced eosinophil accumulation in bronchial tissue in patients with atopic asthma. Theophylline has also been shown to reduce T cell proliferation and accumulation. These changes were mirrored by improved pulmonary function in patients with asthma in studies that evaluated this parameter. Three randomised double-blind studies have evaluated the potential role of theophylline as an anti-inflammatory treatment in patients with asthma not controlled by low doses of inhaled corticosteroids. Patients were randomised to receive low dose theophylline (400 to 750 mg daily) plus low dose inhaled corticosteroids, or an increased dose of inhaled corticosteroids. Clinical pulmonary function improved to the same or a greater extent in patients who received low dose inhaled corticosteroids plus theophylline than in those treated with high dose inhaled corticosteroids plus placebo. Where reported, the dosages of theophylline used in these studies resulted in serum theophylline concentrations of approximately 9 to 10 mg/L. Approximate monthly costs were provided in one study: these were $60 (year and currency not specified) for theophylline plus budesonide 800 micrograms/day, compared with $100 for budesonide 1600 micrograms/day, and $155 for a regimen of budesonide 800 micrograms/day and salmeterol 100 micrograms/day. CONCLUSIONS: Low dose theophylline has been shown to reduce requirements for inhaled corticosteroid therapy in patients with asthma and may reduce overall treatment costs.

Adrenal Cortex Hormones↗