Biomedical subjects

D McTavish

Publications and source records attributed to D McTavish.

At least 37 records · Page 2Linked to original sources

PubMed1995

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

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

AIDS-Related Opportunistic Infections↗

PubMed1995

Fluconazole. An update of its antimicrobial activity, pharmacokinetic properties, and therapeutic use in vaginal candidiasis.

Fluconazole is a bis-triazole antifungal drug which has a pharmacokinetic profile characterised by its high water solubility, low affinity for plasma proteins, and metabolic stability. After a single 150 mg oral dose, therapeutic concentrations in vaginal secretions are rapidly achieved and are sustained for a duration sufficient to produce high clinical and mycological responses in nonimmunocompromised patients with vaginal candidiasis (candidosis). At this dosage, clinical and mycological responses have compared favourably with responses achieved after multiple dose regimens of other oral and intravaginal antifungal agents. Clinical efficacy rates have ranged between 92 and 99% at short term evaluation (5 days post-treatment). At 80 to 100 days post-treatment clinical efficacy rates of 91% have been reported. In addition, limited data indicate that fluconazole is more effective than placebo as prophylactic treatment of frequently recurring vaginal candidiasis. Single oral doses of fluconazole 150 mg are well tolerated. Most frequently observed adverse events are gastrointestinal symptoms, which are generally mild and transient in nature. Thus, fluconazole is a valuable alternative to established systemic and intravaginal azole antifungal drugs which are used to treat vaginal candidiasis. Moreover, in view of its favourable patient acceptability and compliance profile compared with alternative treatments, single-dose oral fluconazole should be considered as a first-line therapeutic choice for the treatment of women with vaginal candidiasis.

Administration, Oral↗

PubMed1995

Simvastatin. A reappraisal of its pharmacology and therapeutic efficacy in hypercholesterolaemia.

Simvastatin is an HMG-CoA reductase inhibitor used in the treatment of patients with hypercholesterolaemia. Since the time simvastatin was previously reviewed in Drugs, a number of large clinical trials have confirmed its clinical efficacy. Thus, reductions from baseline were approximately 20 to 40% for serum levels of total cholesterol, 35 to 45% for low density lipoprotein (LDL)-cholesterol and 10 to 20% for triglycerides in patients with primary hypercholesterolaemia receiving simvastatin 10 to 40 mg/day. High density lipoprotein (HDL)-cholesterol levels were increased modestly by about 5 to 15%. Recent data from long term studies indicate that little or no attenuation of these changes in serum lipid and lipoprotein levels occurred with administration of simvastatin for 3 to 5.4 years. Comparative studies with other HMG-CoA reductase inhibitors (lovastatin, pravastatin and fluvastatin), which were lacking at the time of the previous review of simvastatin, demonstrated greater reductions in serum levels of total cholesterol and LDL-cholesterol with simvastatin than equal dosages of lovastatin or pravastatin. Reductions in serum levels of total cholesterol and LDL-cholesterol were similar between agents only when lovastatin or pravastatin were administered at a total daily dosage twice that of simvastatin and when fluvastatin was administered at a total daily dosage approximately 8 times that of simvastatin. In general, simvastatin 10 to 40 mg/day was also more effective than standard dosages of bile acid sequestrants, fibrates or probucol in lowering serum levels of total cholesterol and LDL-cholesterol; however, fibrates usually produced greater reductions in serum triglycerides and greater elevations in HDL-cholesterol levels. The Scandinavian Simvastatin Survival Study (4S), a large secondary prevention study in patients with coronary heart disease and concomitant hypercholesterolaemia, demonstrated that simvastatin 20 to 40 mg/day for a median of 5.4 years significantly reduced overall mortality (the primary end-point of the study) by 30% compared with placebo, which was attributed to a 42% relative reduction in coronary mortality. Coronary morbidity was also significantly reduced by simvastatin in the 4S trial. The tolerability profile of simvastatin appears to be comparable to that of other HMG-CoA reductase inhibitors. The most frequently reported adverse events are gastrointestinal disturbances, which are generally mild and tend to occur less frequently than with cholestyramine. In conclusion, simvastatin is among the most effective agents available for treating patients with hypercholesterolaemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗

PubMed1995

Nifedipine gastrointestinal therapeutic system (GITS). A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in hypertension and angina pectoris.

Nifedipine 'gastrointestinal therapeutic system' (GITS) is a recently developed formulation that slowly releases the drug into the intestinal tract over a 24-hour period. When administered once daily, it is of similar efficacy to sustained release formulations of felodipine, verapamil, and diltiazem and at least as effective as standard formulations of lisinopril and enalapril, and long-acting propranolol and atenolol in the treatment of patients with mild to moderate essential hypertension. Substitution of nifedipine GITS for conventional formulations of nifedipine, diltiazem or verapamil, maintained adequate control of anginal symptoms in patients with stable angina pectoris. Nifedipine GITS appears to maintain quality of life and is apparently better tolerated than those formulations of nifedipine which require 2 or 3 times daily administration in both elderly and younger patients. In addition, it has minimal effect on lipid and glucose metabolism and reverses left ventricular hypertrophy, and is thus suitable for treatment of the majority of patients with mild to moderate hypertension or angina pectoris.

Administration, Oral↗

PubMed1995

Budesonide. A review of its pharmacological properties and therapeutic efficacy in inflammatory bowel disease.

Budesonide is a glucocorticoid with high topical activity, but low systemic bio-availability which results in reduced systemic effects in comparison with other glucocorticoids. To date, it has been evaluated for use in patients with inflammatory bowel disease when administered either orally as a controlled ileal release formulation or rectally as an enema. In comparative trials, daily treatment with budesonide enema 2 mg/100ml for 4 weeks produced endoscopic remission or improvement in 46 to 84% of patients with active distal ulcerative colitis and/or proctitis and histological remission or improvement in 45 to 68%. In general, this regimen was effective as regimens of hydrocortisone, methylprednisolone, prednisolone or mesalazine (5-amino-salicylic acid, mesalamine) enemas, but caused less suppression of plasma cortisol levels than the other glucocorticoids. Oral treatment with controlled release budesonide 9 mg/day for 8 weeks produces clinical remission in 42 to 67% of patients with active Crohn's disease of the ileum, ileocaecal region and/or ascending colon and significantly reduces Crohn's disease activity index scores compared with baseline and placebo. Results of a quality-of-life questionnaire reflected these clinical improvements. Budesonide has similar efficacy to prednisolone. Response to budesonide is maintained after dosage tapering at 8 weeks. Compared with placebo, maintenance treatment with oral budesonide 3 or 6 mg/day increases the duration of remission in patients with Crohn's disease, but does not appear to affect the 1-year relapse rate. Thus, budesonide, administered rectally to patients with distal ulcerative colitis or proctitis or orally to patients with Crohn's disease of the ileum, ileocaecal region and/or ascending colon, is a favourable option for the treatment of acute exacerbations of inflammatory bowel disease. Because of the low incidence of adverse glucocorticoid-related effects associated with oral budesonide, it may also be a useful agent for longer term maintenance therapy if further clinical trials confirm its efficacy in this indication.

Animals↗

PubMed1995

Levocabastine. An update of its pharmacology, clinical efficacy and tolerability in the topical treatment of allergic rhinitis and conjunctivitis.

Levocabastine is a potent and selective histamine H1-receptor antagonist which has been evaluated as a topical treatment (nasal spray and/or eyedrops) for allergic rhinitis and/or conjunctivitis. Data available at the time of the previous review in Drugs, together with more recent results, have clearly demonstrated that levocabastine nasal spray and eyedrops are clinically effective, have a rapid onset of action and are well tolerated in patients with nasal and/or ocular allergic conditions. Previous evidence indicating that topical levocabastine has efficacy similar to or better than that of topical sodium cromoglycate (cromolyn sodium) has been confirmed in more recent studies. Furthermore, results from a number of controlled clinical trials have also shown that topical levocabastine is at least as effective as oral terfenadine for the treatment of allergic rhinoconjunctivitis. Notably, topical levocabastine appears to be more effective than oral terfenadine in improving the severity of selected symptoms. Limited data indicating efficacy equivalent to that of oral loratadine, oral cetirizine or azelastine nasal spray will need to be confirmed. Data from several studies have shown that topical levocabastine has a tolerability profile similar to that of placebo, topical sodium cromoglycate or oral terfenadine. The main adverse events seen in patients treated with topical levocabastine are ocular irritation after application of eyedrops, and headache, nasal irritation, somnolence and fatigue after administration of the nasal spray. Administered doses of topical levocabastine, and subsequent plasma concentrations, are low, and the risk of systemic adverse events is therefore expected to be minimal. Thus, topical administration of levocabastine rapid and effective symptom relief with no apparent serious adverse events in patients with allergic rhinitis and/or conjunctivitis. Topical levocabastine is a useful alternative to topical sodium cromoglycate or oral terfenadine. Additional data supporting current evidence that topical levocabastine can provide more effective symptom relief than oral terfenadine, together with clarification of the relative efficacies of these agents in relation to varying pollen exposure, would help to further confirm its clinical potential. However, the results available to date suggest that the topical formulations of levocabastine are a valuable treatment option in patients with allergic rhinitis and/or conjunctivitis.

Aerosols↗

PubMed1995

Budesonide. An appraisal of the basis of its pharmacoeconomic and quality-of-life benefits in asthma.

Budesonide is an inhaled corticosteroid that is used prophylactically to reduce the underlying inflammation and consequent airways narrowing associated with asthma. Widespread clinical experience has shown that inhaled budesonide is effective and well tolerated, and its use is well established in the management of adult and childhood asthma. In developed countries, asthma is a major health problem and consumes a large proportion of healthcare resources. Both the prevalence and severity of asthma appear to be increasing. Additionally, asthma-related mortality has been reported to have gradually increased since the mid- to late-1970s in many countries, possibly due to undertreatment and/or suboptimal management of the disease. Current guidelines recommend a shift away from initial treatment with oral bronchodilators, such as theophylline, or regular use of beta 2-agonist inhalers, toward the earlier use of more expensive inhalers containing corticosteroids. Inhaled bronchodilators are still used as indicated for treatment of acute attacks. Data suggest that the acquisition cost of budesonide is more than offset by decreased morbidity and reductions in costs associated with acute asthma exacerbations. Both once-daily administration and its administration in dry powder form via Turbuhaler appear to be well accepted by patients; these factors may potentially improve patient compliance with therapy. Budesonide appears to have positive effects on some quality-of-life indices, although studies using validated quality-of-life instruments are needed to confirm these conclusions. Modelling studies would be helpful in order to assess the possible economic benefits to society through reduction of the considerable direct and indirect costs of asthma and cost-effectiveness comparisons with other inhaled corticosteroids are needed to clarify its relative positioning in this regard. Until then, the available data provide an encouraging pharmacoeconomic rationale for budesonide as first-line asthma therapy, and a good basis for future pharmacoeconomic analysis of asthma management.

Asthma↗

PubMed1994

Transdermal estradiol/norethisterone. A review of its pharmacological properties and clinical use in postmenopausal women.

The combined transdermal estradiol/norethisterone therapeutic system is designed to deliver both estradiol and norethisterone into the systemic circulation at a constant rate for up to 4 days when affixed to the skin. Transdermal administration avoids hepatic first-pass metabolism, allowing therapeutic concentrations of the progestogen and estrogen to be maintained in postmenopausal women following low dose administration. Transdermal norethisterone does not appear to alter the potentially beneficial effects of transdermal estradiol on total cholesterol, low-density lipoprotein (LDL) or triglyceride levels, or metabolic parameters of bone resorption or vaginal cytology. Protection of the endometrium from the effects of unopposed estradiol is achieved by sequential treatment with transdermal estradiol/norethisterone for 2 weeks of each 28-day cycle, and the majority of patients experience a regular vaginal bleeding pattern with this treatment regimen. Menopausal symptoms are improved to a similar extent during the transdermal estradiol-only and combined estradiol/norethisterone treatment phases. The transdermal therapeutic system has been well accepted by patients in clinical trials. It is generally well tolerated, the most common adverse effect being local irritation at the site of application. Estrogen- and progestogen-related systemic adverse events are reported in a small proportion of patients. Thus, the combined estradiol/norethisterone transdermal delivery system offers a more convenient and consistent method of progestogen administration. Together with its therapeutic efficacy when administered at lower dosages than oral therapy, it is likely to further improve patient compliance during hormone replacement therapy.

Administration, Cutaneous↗

PubMed1994

Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders.

Trazodone is a triazolopyridine derivative, chemically and pharmacologically unrelated to other currently available antidepressants. It possesses antidepressant, and also some anxiolytic and hypnotic activity. Results from a small number of short term (4 to 6 weeks) comparative studies in a total of 320 evaluable elderly patients with major depression, suggest that trazodone at therapeutic doses is superior to placebo and as effective as amitriptyline, imipramine, fluoxetine and mianserin in relieving depressive symptoms. Trazodone has also been successfully used in a small number of patients with depression and pre-existing cardiovascular disease. More recently, trazodone has been used as a hypnotic for psychotropic-induced or other insomnias with some success. However, further clinical experience is needed to confirm these preliminary results. In the elderly, maximum tolerated doses of trazodone are 300 to 400 mg/day, although higher doses of up to 600 mg/day are tolerated by younger patients. Drowsiness is commonly reported, but the incidences of both anticholinergic and cardiovascular effects were notably lower in elderly patients treated with trazodone compared with older tricyclic antidepressants. However, undesirable effects such as orthostatic hypotension, arrhythmias and priapism need to be closely monitored. In comparison with other currently available agents, particularly the tricyclic antidepressants, trazodone is relatively safe in overdose. In terms of therapeutic efficacy, trazodone appears to confer little advantage over other available antidepressants. While limited data suggest that trazodone may be better tolerated than older tricyclic antidepressants, especially in the elderly, there is a paucity of data at present comparing trazodone with the secondary amine tricyclic agents, serotonin reuptake inhibitors or moclobemide. Bearing this in mind, trazodone may be of use in elderly patients in whom anxiety and insomnia are problematic, and in those patients who are unresponsive to or cannot tolerate therapy with other agents. Studies are also required to define the place of trazodone in long term prophylactic therapy for recurrent depression. Future trials comparing both its efficacy and tolerability with those of newer agents will ascertain whether trazodone becomes a first line agent within these subsets of elderly patients.

Aged↗

PubMed1994

Tacrine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in Alzheimer's disease.

Tacrine is a centrally acting cholinesterase inhibitor with additional pharmacological activity on monoamine levels and ion channels. It has been postulated that some or all of these additional properties may also be relevant to the mode of action of the drug. There are wide interindividual variations in pharmacological and clinical response to tacrine, possibly related to interindividual variation in bioavailability. Tacrine appears to improve cognitive function and behavioural deficits in a proportion of patients with Alzheimer's disease, at dosages of 80 to 160 mg/day. In the best designed trials, 30 to 51% of evaluable patients showed an improvement of at least 4 points on the cognitive subscale of the Alzheimer's Disease Assessment Scale, versus 16 to 25% of placebo recipients. A similar proportion of tacrine recipients were judged to have improved when global assessment scales were used. There was a significant dose-response relationship up to 160 mg/day. However, large numbers of patients were withdrawn during the trials, many because of tacrine-associated increases in transaminase levels. Elevated liver enzyme levels occurred in about 50% of tacrine recipients (reaching clinical significance in about 25%). Cholinergic symptoms also occurred more often in tacrine recipients than in those receiving placebo. A gradual increase in tacrine dosage, at 6-week intervals, is recommended when initiating therapy, and weekly serum transaminase monitoring is required for 6 weeks after each dosage increase. Despite the limitations implied by the low proportion of responders and high incidence of hepatic adverse effects associated with therapy, tacrine appears to make a measurable difference in both cognitive and behavioural function in a proportion of patients with Alzheimer's disease--a welcome advance in an area previously devoid of acceptable treatment options.

Alzheimer Disease↗

PubMed1994

Idebenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in age-related cognitive disorders.

Idebenone is a benzoquinone compound which has been investigated in elderly patients with dementia. Its precise mechanism(s) of action remains unknown, but in vitro and in vivo studies suggest the drug may diminish nerve cell damage due to ischaemia, correct neurotransmitter defects and/or cerebral metabolism and facilitate memory and learning. In the small number of studies available for evaluation, idebenone was generally superior to placebo and comparable with bifemelane, oxiracetam and nebracetam on the basis of a number of objective and subjective tests and rating scales in patients with mild to moderate cognitive decline. Clinical trial results indicate that patients with mild dementia seem more likely to respond than those with greater functional decline. The degree of benefit conferred by idebenone is often difficult to determine, but in those who respond, improvement is generally mild to moderate. Therapy with idebenone appears well tolerated for up to 2 years, and no changes in vital signs or laboratory values have been seen in clinical trials. In view of the lack of a proven agent to limit or halt the progression of dementia in the elderly, idebenone may warrant consideration in patients with mild cognitive dysfunction on the basis of preliminary evidence of predominantly mild improvement of functional status in some patients and good tolerability. However, further well designed studies, including comparisons with newer and commonly used agents, such as tacrine, are required to better define the role of idebenone in this complex area of treatment.

Administration, Oral↗

PubMed1994

Sumatriptan. A reappraisal of its pharmacology and therapeutic efficacy in the acute treatment of migraine and cluster headache.

Sumatriptan is a potent and selective agonist at a vascular serotonin1 (5-hydroxytryptamine1; 5-HT1) receptor subtype (similar to 5-HT1D) and is used in acute treatment of migraine and cluster headache. Following administration of sumatriptan 100mg orally, relief of migraine headache (at 2 hours) was achieved in 50 to 67% of patients compared with 10 to 31% with placebo in controlled clinical trials. In a comparative study, oral administration of sumatriptan 100mg consistently achieved significantly greater response rates than a fixed combination of ergotamine 2mg plus caffeine 200mg during 3 consecutive migraine attacks (66 vs 48% for first attack). Oral sumatriptan 100mg was also more effective than aspirin 900mg plus metoclopramide 10mg orally in a similar study. In the majority of controlled clinical trials, headache relief (at 1 hour after administration) was achieved in 70 to 80% of patients with migraine receiving sumatriptan 6mg subcutaneously compared with 18 to 26% of placebo recipients. Approximately 40% of patients who initially responded to oral or subcutaneous sumatriptan experienced recurrence of their headache, usually within 24 hours, but the majority of these patients responded well to a further dose of sumatriptan. Patients with cluster headache were treated for acute attacks with sumatriptan 6mg subcutaneously or placebo in 2 crossover trials. Headache relief was achieved within 15 minutes in 74 and 75% of patients receiving sumatriptan in these studies compared with 26 and 35%, respectively, with placebo. Patients receiving sumatriptan 12mg had a similar response rate as those receiving 6mg, but the higher dose was associated with an increased incidence of adverse events. Based on extensive safety data pooled from controlled clinical trials, sumatriptan is generally well tolerated and most adverse events are transient. The most frequently reported adverse events following oral administration include nausea, vomiting, malaise, fatigue and dizziness. Injection site reactions (minor pain and redness of brief duration) occur in approximately 40% of patients receiving subcutaneous sumatriptan, although the incidence appears to be markedly reduced when patients self-administer the drug with an auto-injector. Chest symptoms (mainly tightness and pressure) occur in 3 to 5% of sumatriptan recipients, but have not been associated with myocardial ischaemia except in a few isolated cases. Sumatriptan is contraindicated in patients with ischaemic heart disease, angina pectoris including Prinzmetal (variant) angina, previous myocardial infarction and uncontrolled hypertension, but is not contraindicated in patients with migraine and asthma. Data from long term studies in acute treatment of migraine and cluster headache suggest that sumatriptan remains effective and well tolerated over several months.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗

PubMed1994

Trandolapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in essential hypertension.

Trandolapril is a non-sulfhydryl prodrug which, after oral administration, is hydrolysed in the liver to its active diacid, trandolaprilat. Trandolaprilat inhibits the angiotensin converting enzyme (ACE) and displays similar pharmacodynamic properties to other ACE inhibitors, improving haemodynamic and cardiac parameters in patients with essential hypertension. Trandolapril 2 to 4mg once daily effectively controls blood pressure for at least 24 hours in patients with mild to moderate hypertension. In a small number of double-blind comparative trials, trandolapril had similar antihypertensive efficacy to that of atenolol, enalapril, hydrochlorothiazide, lisinopril and sustained release nifedipine, but was more effective than captopril. Combined therapy with trandolapril and hydrochlorothiazide or sustained release nifedipine had a significantly greater antihypertensive effect than either drug treatment alone. Further comparative trials are warranted to confirm these preliminary findings. The tolerability profile of trandolapril is similar to that of other ACE inhibitors, most adverse events being generally mild and transient in nature, and trandolapril lacks adverse effects on carbohydrate and lipid metabolism. Thus, trandolapril, with its favourable pharmacological profile and antihypertensive activity similar to that of agents currently used to treat patients with mild to moderate hypertension, is likely to provide a well tolerated option for the treatment of this disease. The results of ongoing and future clinical trials will determine its potential as a cardioprotective agent in patients following myocardial infarction.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1994

Omeprazole. An update of its pharmacology and therapeutic use in acid-related disorders.

Omeprazole, a gastric acid pump inhibitor, dose-dependently controls gastric acid secretion: the drug has greater antisecretory activity than histamine H2-receptor antagonists. Omeprazole 20 to 40 mg/day is more effective than histamine H2-receptor antagonists in the short term treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis. Available data suggest that omeprazole 10 to 40 mg/day is also more effective than ranitidine in the maintenance therapy of duodenal ulcer and reflux oesophagitis. The drug is also effective in patients with duodenal ulcer, gastric ulcer or reflux oesophagitis poorly responsive to histamine H2-receptor antagonists. The efficacy of omeprazole 20 mg/day appears to be similar to that of lansoprazole 30 mg/day in the short term treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis. However, most available studies have been reported in abstract form only, and 2 of 3 studies in patients with duodenal ulcer have shown greater healing rates at 2 (but not 4) weeks with lansoprazole. Helicobacter pylori eradication decreases duodenal ulcer relapse rates and appears to be associated with improved duodenal ulcer healing rates. Evidence also suggests that H. pylori eradication is associated with reduced gastric ulcer relapse rates. Omeprazole monotherapy may suppress but does not eradicate H. pylori infection. Eradication rates with omeprazole 20 or 40 mg twice daily plus amoxicillin usually up to 2 g/day (3 g/day in a few studies) for 2 weeks appear to be similar to those of standard triple therapy (bismuth salt plus metronidazole, plus tetracycline or amoxicillin) or omeprazole plus clarithromycin, although eradication rates vary widely. Omeprazole plus amoxicillin appears to be better tolerated than triple therapy and represents a first-line treatment alternative in patients with H. pylori-associated peptic ulcer disease. Omeprazole plus amoxicillin plus metronidazole appears to be more effective than omeprazole plus amoxicillin in patients with metronidazole-sensitive H. pylori infection. Omeprazole remains a treatment of choice in patients with Zollinger-Ellison syndrome. The dosages should be adjusted according to individual response. However, relatively low dosages of 10 to 40 mg/day may be sufficient in some patients. The drug has also shown promise in the treatment of children with severe reflux oesophagitis, in patients with reflux oesophagitis and coexisting systemic sclerosis, and in the prevention of aspiration pneumonia. Evidence suggests that omeprazole is more effective than ranitidine in patients with nonsteroidal anti-inflammatory drug (NSAID)-induced gastric damage who continue to take NSAIDs, especially in patients with large gastric ulcers; however, completion of ongoing studies is required to verify this.(ABSTRACT TRUNCATED AT 400 WORDS)

Gastric Acid↗

PubMed1994

Granisetron. An update of its therapeutic use in nausea and vomiting induced by antineoplastic therapy.

Granisetron is a selective serotonin3 (5-hydroxytryptamine3, 5-HT3) receptor antagonist which has significant antiemetic activity against chemotherapy-induced nausea and vomiting. A single prophylactic intravenous dose is sufficient to control acute nausea and vomiting in approximately 60 to 70% of patients. In comparative studies, the acute antiemetic efficacy of granisetron is equivalent or superior to that of traditional antiemetic regimens even in patients receiving highly emetogenic cisplatin-containing chemotherapy. However, limited data have suggested that granisetron therapy offers no advantages over traditional antiemetics in terms of the control of delayed emesis. Recently, a number of large randomised studies have directly compared the efficacy and tolerability of granisetron, ondansetron and tropisetron and reported no significant differences between the 3 drugs in controlling acute nausea and vomiting, although 1 study reported a modest statistical advantage for granisetron over ondansetron but not tropisetron in the complete control of vomiting. In crossover studies, significantly more patients preferred granisetron to either ondansetron or tropisetron. The efficacy of granisetron appears to be maintained with repeated doses over several cycles of chemotherapy, although the influence of various prognostic factors affecting antiemetic response has not been adequately analysed. Concomitant administration of dexamethasone significantly improves the acute antiemetic efficacy of granisetron, increasing response rates by approximately 15%. Granisetron is an effective antiemetic in children undergoing highly emetogenic chemotherapy, and effectively controls radiotherapy-induced and postoperative nausea and vomiting. Trials using an oral formulation are scarce at present, but preliminary results suggest a similar efficacy and tolerability profile to that of the intravenous formulation. Granisetron has been well tolerated in clinical trials. The most frequently reported adverse event has been headache (14%). Extrapyramidal effects, which can limit the use of traditional antiemetics such as metoclopramide, have not been reported with granisetron. Thus, recent data confirm that granisetron is an effective and well tolerated agent for the prophylactic treatment of chemotherapy-induced acute nausea and vomiting, with efficacy equivalent or superior to that of other currently available agents. It has a promising role to play in paediatric oncology, and is an effective agent in controlling radiotherapy-induced acute emesis. Granisetron offers comparable or superior efficacy in controlling acute nausea and vomiting with a much simpler dosage regimen than that of traditional antiemetic regimens.

Adult↗

PubMed1994

Ranitidine: a pharmacoeconomic evaluation of its use in acid-related disorders.

Ranitidine is a histamine H 2-receptor antagonist which, on the basis of its well established tolerability and efficacy profile, has been widely prescribed for the treatment of ulcer disease and mild to moderate reflux oesophagitis. However, the advent of more powerful gastric acid inhibitors (e.g. acid pump inhibitors) and the realisation of the role of Helicobactor pylori infection in duodenal ulcer disease could have considerable clinical and economic implications for the use of ranitidine (and other H 2-receptor antagonists). Simulation modelling studies based on current pricing policies in Europe predict that ranitidine-based treatment will be less cost effective than omeprazole in the short term healing of duodenal ulcer and reflux oesophagitis disease. During longer term treatment, omeprazole is expected to be the dominating strategy over ranitidine-based therapy in Europe and the US. However, the inherent limitations of modelling studies reinforce the need for randomised prospective trials, preferably conducted in a general practice setting and including a quality-of-life analysis. Of the currently accepted approaches for the long term management of recurrent duodenal ulcer disease, daily maintenance therapy with ranitidine has been shown to be more cost effective than intermittent treatment for up to 2 years in the US. The annual cost of providing continuous maintenance therapy with ranitidine 150 mg/day is higher than with cimetidine 400 mg/day, although the extra benefits include a reduced risk of pain and discomfort from an expected lower rate of ulcer recurrence with ranitidine. Simultaneous ulcer healing and eradication of H. pylori markedly reduces relapse rates and is likely to become the management strategy of choice in H. pylori-positive patients, particularly with the advent of more convenient, well tolerated and effective regimens. Moreover, widespread clinical acceptance of H. pylori eradication may yield substantial cost savings to society by reducing the overall need for long term antisecretory therapy. Nonetheless, maintenance therapy with histamine H 2-receptor antagonists remains indicated for patients at high risk of ulcer recurrence who are poorly responsive to or cannot tolerate H. pylori eradication regimens. In summary, the proven efficacy and tolerability of ranitidine will ensure its continued use in the treatment of many patients with duodenal ulcer and mild to moderate reflux oesophagitis. However, there is increasing clinical and economic data favouring the selection of omeprazole in patients with more severe symptoms of these diseases.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗

PubMed1994

Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy.

Valproic acid is a branched-chained fatty acid, structurally unrelated to any other antiepileptic drug. Since publication of the original review in the Journal in 1977, several clinical trials have documented its efficacy and safety in adults and children for the treatment of generalised seizures (absence, tonic-clonic, myoclonic), partial seizures (simple, complex, secondarily generalised) and compound/combination seizures (including those refractory to treatment with other antiepileptic drugs). Valproic acid monotherapy has demonstrated efficacy equivalent to that of carbamazepine, phenytoin, and phenobarbital in the treatment of both generalised and partial seizures and ethosuximide in the treatment of absence seizures. Adverse effects associated with the drug are primarily gastrointestinal (nausea, vomiting, dyspepsia) in nature, although the use of enteric-coated formulations has reduced the incidence of abdominal discomfort. Weight gain, tremor and transient hair loss are commonly reported. Importantly, valproic acid has minimal neurological adverse effects (sedation, ataxia, impairment of cognitive function) compared with other antiepileptic drugs, a finding that may be of particular relevance in many patients with epilepsy. The incidence of rare, fatal liver failure has been greatly reduced by identifying and avoiding administration of valproic acid to high risk patient populations. An estimated risk of 1 to 2% for neural tube defects, predominantly spina bifida aperta, with maternal use of valproic acid therapy has been reported. Valproic acid inhibits hepatic drug metabolism and displaces other highly bound drugs from their plasma protein binding sites. Therefore, coadministered drugs which are highly protein bound or hepatically metabolised may require dosage adjustment. Enzyme-inducing antiepileptic drugs may increase valproic acid metabolism and necessitate increasing its dosage. Thus, comparative trials and extensive clinical experience have demonstrated the efficacy and tolerability of valproic acid and support its role as a valuable and well established first-line treatment for patients with a broad range of seizure types.

Adult↗

PubMed1993

Formestane. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of breast cancer and prostatic cancer.

Formestane (4-hydroxyandrostenedione) is an effective and competitive inhibitor of aromatase, the enzyme responsible for the conversion of androgens to estrone and estradiol. Significant reductions in plasma estradiol levels are observed following intramuscular administration of formestane to postmenopausal women with advanced metastatic breast cancer. Overall response rates to intramuscular formestane in these patients are approximately 25 to 30% and a further 20 to 30% of patients experience disease stabilisation during treatment. Response rates are improved in patients with hormone responsive tumours and in those who have responded to previous endocrine therapy. Soft tissue metastases generally show the best response to formestane treatment while visceral metastases (in particular liver) show a poor response. The median duration of response is usually between 7 months and 1 year. Formestane has been generally well tolerated in the relatively small clinical trials conducted to date with adverse effects reported in approximately 13% of patients following intramuscular administration. The most frequent adverse effects are local reactions at the injection site and systemic effects mainly related to the effect of the drug on the hormonal milieu. Thus, formestane is effective as a second-line endocrine treatment for advanced metastatic breast cancer in women with natural or artificially induced menopause, with apparent tolerability advantages over older agents such as aminoglutethimide; with wider study and experience it may yet challenge tamoxifen as a first-line endocrine therapy in metastatic breast cancer.

Androstenedione↗