Biomedical subjects

M I Wilde

Publications and source records attributed to M I Wilde.

At least 19 recordsLinked to original sources

PubMed1998

Midodrine. A review of its therapeutic use in the management of orthostatic hypotension.

Midodrine is a prodrug which undergoes enzymatic hydrolysis to the selective alpha 1-adrenoceptor agonist desglymidodrine after oral administration. Oral midodrine significantly increases 1-minute standing systolic blood pressure compared with placebo. The drug also improves standing time and energy level and clinical symptoms of orthostatic hypotension including dizziness, light-headedness and syncope. Comparative studies have shown midodrine to have similar efficacy to dihydroergotamine mesylate, norfenefrine, fludrocortisone and etilefrine, and to be more effective than dimetofrine and ephedrine in patients with orthostatic hypotension. Midodrine is well tolerated, with the most commonly reported adverse events being piloerection, pruritus, paraesthesias, urinary retention and chills. The risk of supine hypertension, which is associated with midodrine therapy in up to 25% of patients, can be reduced by taking the final daily dose at least 4 hours before bedtime. Thus, oral midodrine is an effective therapeutic option for the management of various forms of orthostatic hypotension. This well-tolerated agent is likely to be useful in conjunction with standard nonpharmacological care.

Adrenergic alpha-Agonists↗

PubMed1998

Milnacipran. A review of its use in depression.

UNLABELLED: Milnacipran is a cyclopropane derivative which acts by inhibiting noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake at presynaptic sites; no postsynaptic receptor activity has been demonstrated. It is most commonly administered at a dosage of 50 mg twice daily for the treatment of major depressive disorder. Improvement usually occurs within 2 weeks of treatment initiation, but some patients do respond sooner. Most studies which evaluated milnacipran were of short (4 to 8 weeks) duration and results were not published in full with rigorous peer review. Nonetheless, the drug is significantly more effective than placebo for the treatment of in- or outpatients with moderate to severe major depressive disorder. Limited data suggest that it may prevent relapse and be effective for long term use, although this requires confirmation. Milnacipran 200 mg/day is generally not significantly different from amitriptyline 150 mg/day in terms of onset and efficacy. However, when doses are titrated (not a requirement for milnacipran), milnacipran 50 or 100 mg/day has a slower onset than the tricyclic antidepressant. At a dosage of 100 mg/day for 4 to 12 weeks, milnacipran generally has similar efficacy to imipramine and clomipramine 150 mg/day, although milnacipran 50 to 150 mg/day had a faster onset of activity than imipramine 50 to 150 mg/day in Japanese patients. In a 6-month trial, milnacipran was less effective than clomipramine. Milnacipran 50 or 100 mg twice daily was as effective as fluoxetine 20 mg once daily or fluvoxamine 100 mg twice daily in 4- to 12-week studies. At a dosage of 50 then 100 mg daily it was also as effective as mianserin 30 then 60 mg daily in a 4-week study. However, when administered once daily (in the evening), milnacipran 100 mg/day was not as effective as fluoxetine 20 mg/day after 6 weeks. The drug is generally well tolerated, producing no more adverse events (including anticholinergic events) than placebo, selective serotonin reuptake inhibitors or mianserin and fewer adverse events than tricyclic antidepressants in clinical trials. However, dysuria has been reported in 7% of male patients receiving milnacipran. CONCLUSIONS: Data from predominantly short term trials suggest that milnacipran generally has similar efficacy to tricyclic antidepressants and SSRIs. Although further published data are required to confirm its efficacy, good tolerability profile and pharmacokinetic profile which suggests a low potential for drug interactions, milnacipran should be considered a promising agent for the treatment of patients with major depressive disorder.

Animals↗

PubMed1998

Omeprazole. A review of its use in Helicobacter pylori infection, gastro-oesophageal reflux disease and peptic ulcers induced by nonsteroidal anti-inflammatory drugs.

UNLABELLED: Omeprazole is a well studied proton pump inhibitor that reduces gastric acid secretion. This review examines its use in Helicobacter pylori infection, gastro-oesophageal reflux disease (GORD) with or without oesophagitis and gastrointestinal damage caused by nonsteroidal anti-inflammatory drugs (NSAIDs). Optimal omeprazole regimens for anti-H. pylori therapy are those that administer the drug at a dosage of 40 mg/day (in 1 or 2 divided doses) for 7, 10 or 14 days in combination with 2 antibacterial agents. As a component of 3-drug regimens in direct comparative studies, omeprazole was at least as effective as lansoprazole, pantoprazole, bismuth compounds and ranitidine. However, a meta-analysis suggests that triple therapies with omeprazole are more effective than comparable regimens containing ranitidine, lansoprazole or bismuth. Omeprazole also appears to be successful in triple therapy regimens used in children with H. pylori infection. In patients with acute GORD with oesophagitis, omeprazole is at least as effective as lansoprazole or pantoprazole in promoting healing, and superior to ranitidine, cimetidine or cisapride in oesophagitis healing and symptom relief. Omeprazole was similar to lansoprazole and superior to ranitidine in preventing oesophagitis relapse in patients with all grades of oesophagitis, but may be superior to lansoprazole or pantoprazole in patients with more severe disease. More patients with symptomatic GORD without oesophagitis experienced symptom relief after short term treatment with omeprazole than with ranitidine, cisapride or placebo, and symptoms were more readily prevented by omeprazole than by cimetidine or placebo. Omeprazole was effective in healing and relieving symptoms of reflux oesophagitis in children with oesophagitis refractory to histamine H2 receptor antagonists. Omeprazole is superior to placebo in preventing NSAID-induced gastrointestinal damage in patients who must continue to take NSAIDs. It is also similar to misoprostol and superior to ranitidine in its ability to heal NSAID-induced peptic ulcers and erosions, and superior to misoprostol, ranitidine or placebo in its ability to prevent relapse. In long and short term studies, omeprazole was well tolerated, with diarrhoea, headache, dizziness, flatulence, abdominal pain and constipation being the most commonly reported adverse events. Usual omeprazole dosages, alone or combined with other agents, are 10 to 40 mg/day for adults and 10 to 20 mg/day for children. CONCLUSIONS: Omeprazole is a well studied and well tolerated agent effective in adults or children as a component in regimens aimed at eradicating H. pylori infections or as monotherapy in the treatment and prophylaxis of GORD with or without oesophagitis or NSAID-induced gastrointestinal damage.

Animals↗

PubMed1997

Dorzolamide. A review of its pharmacology and therapeutic potential in the management of glaucoma and ocular hypertension.

Dorzolamide (dorzolamide hydrochloride), the first topical carbonic anhydrase (CA) inhibitor to become available for clinical use, lowers intraocular pressure (IOP) by reducing aqueous humour formation. It is formulated as a 2% eyedrop for use in the management of glaucoma and ocular hypertension. When administered 3 times daily, dorzolamide is effective in lowering IOP in patients with open-angle glaucoma or ocular hypertension. Mean IOP was reduced by approximately 4 to 6 mm Hg at peak (2 hours postdose) and 3 to 4.5 mm Hg at trough (8 hours postdose) in clinical trails. A 1-year comparative study showed that the ocular hypotensive efficacy of dorzolamine 2% 3 times daily was similar to that of betaxolol 0.5% twice daily, but slightly inferior to that of timolol 0.5% twice daily. Dorzolamide has additive ocular hypotensive effects when used in conjunction with topical beta-adrenergic antagonists and was as effective as pilocarpine 2% 4 times daily as adjunctive therapy in patients receiving timolol. Dorzolamide does not appear to produce the acid-base or electrolyte disturbances and severe systemic adverse events associated with oral CA inhibitors, and unlike beta-adrenergic antagonists, it is not contraindicated in patients with asthma, reactive airways disease or heart disease. Furthermore, as CA inhibitors do not cause miosis, they may cause less interference with vision than pilocarpine or epinephrine (adrenaline). The most common adverse effects associated with dorzolamide are bitter taste and transient local burning or stinging. Conjunctivitis was the most common reason for discontinuation of dorzolamide in one large study. Thus, available data suggest that dorzolamide has potential as an alternative therapy option in patients with glaucoma or ocular hypertension who are intolerant of, or unable to receive, ophthalmic beta-adrenergic antagonists and as adjunctive therapy in patients already receiving these agents. Further efficacy and tolerability data are needed to determine the place of dorzolamide in therapy.

Absorption↗

PubMed1997

Diacerein.

Rhein, the active metabolite of diacerein, inhibits interleukin-1 activity. Consequently, collagenase production in articular cartilage is reduced. Rhein dose-dependently inhibits superoxide anion production, chemotaxis and phagocytic activity of neutrophils, and macrophage migration and phagocytosis. Articular cartilage damage is reduced by diacerein in animal models of osteoarthritis. Diacerein does not alter renal or platelet cyclooxygenase activity and may therefore be tolerated by patients with prostaglandin-dependent renal function. In clinical trials of < or = 6 months' duration, oral diacerein 50mg twice daily was associated with improvement in 57 to 85% of patients with osteoarthritis. Pain scores and measures of joint function were generally reduced compared with baseline and placebo. Diacerein had similar efficacy to NSAIDs, but a slower onset of action, in comparative trials of < or = 2 months' duration conducted in patients with osteoarthritis. The predominant adverse effects of diacerein are diarrhoea and related disorders.

Animals↗

PubMed1997

Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification.

Acamprosate (calcium acetylhomotaurinate), a synthetic compound with a similar chemical structure to that of gamma-aminobutyric acid, is thought to act via several mechanisms affecting multiple neurotransmitter systems; inhibition of neuronal hyperexcitability by antagonism of excitatory amino acid activity and reduction of calcium ion fluxes has been suggested as its predominant mechanism of action. The drug is the first agent specifically designed to maintain abstinence in alcohol (ethanol)-dependent patients after detoxification. Voluntary oral ethanol consumption in ethanol-preferring or ethanol-dependent rats is dose-dependently reduced by acamprosate: total fluid intake and food consumption are not affected. The drug does not potentiate the acute or chronic toxic effects of ethanol and has no hypnotic, antidepressant, anxiolytic or muscle-relaxant effects in animals. There is no evidence of abuse potential with acamprosate. Oral acamprosate 1.3 or 2 g/day in 3 divided doses administered for 3 to 12 months to alcohol-dependent patients after detoxification was more effective than placebo in preventing alcohol relapse according to abstinence rates, duration of abstinence, gamma-glutamyl transferase levels and/or a variety of other clinical or biological end-points. Concomitant psychosocial/behavioural therapies were used in some trials. Compared with those with placebo, the superior abstinence rates and durations of abstinence with acamprosate were maintained during 6- to 12-month post-treatment follow-up periods, and greater abstinence rates with acamprosate were confirmed in a pooled analysis of data from 11 randomised placebo-controlled trials involving a total of 3338 patients with alcohol dependence. The efficacy of acamprosate appears to be dose dependent and enhanced by the addition of disulfiram. Acamprosate was generally well tolerated in placebo-controlled trials. The most common adverse events were gastrointestinal (especially diarrhoea) or dermatological and were mostly mild and transient. The percentage of patient withdrawals because of adverse events was similar in acamprosate and placebo groups. No trials have compared the efficacy or tolerability of acamprosate with those of other treatment approaches (including opiate antagonists or selective serotonin reuptake inhibitors) aimed at maintaining abstinence in detoxified alcohol-dependent patients. Thus, acamprosate, as an adjunct to psychosocial/behavioural therapies, represents a novel advance for the management of alcohol-dependent patients in the postdetoxification period. Longer term and comparative trials with other active therapies are required to confirm these promising results.

Acamprosate↗

PubMed1997

Lisinopril. A review of its pharmacology and use in the management of the complications of diabetes mellitus.

Lisinopril, like other ACE inhibitors, lowers blood pressure and preserves renal function in hypertensive patients with non-insulin-dependent or insulin-dependent diabetes mellitus (NIDDM or IDDM) and early or overt nephropathy, without adversely affecting glycaemic control or lipid profiles. On available evidence, renoprotective effects appear to be greater with lisinopril than with comparator calcium channel blockers, diuretics and beta-blockers, despite similar antihypertensive efficacy. As shown by the EUCLID (EUrodiab Controlled trial of Lisinopril in Insulin-Dependent Diabetes) trial, lisinopril is also renoprotective in normotensive patients with IDDM and microalbuminuria. The effect in normotensive patients with normoalbuminuria was smaller than in those with microalbuminuria, and no conclusions can yet be made about its use in patients with normoalbuminuria. In complications other than nephropathy, lisinopril has shown some benefit. Progression to retinopathy was slowed during 2 years' lisinopril therapy in the EUCLID study. Although not yet fully published, these results provide the most convincing evidence to date for an effect of an ACE inhibitor in retinopathy. The drug may also improve neurological function, but this finding is preliminary. Lastly, post hoc analysis of the GISSI-3 trial indicates that lisinopril reduces 6-week mortality rates in diabetic patients when begun as early treatment after an acute myocardial infarction. The tolerability profile of lisinopril is typical of ACE inhibitors and appears to be similar in diabetic and nondiabetic individuals. Hypoglycaemia has occurred at a similar frequency with lisinopril and placebo, as shown in the EUCLID trial. In addition, the GISSI-3 study indicates that the incidence of persistent hypotension and renal dysfunction is increased with lisinopril in general, but the presence of diabetes does not appear to confer additional risk of these events in diabetic patients with acute myocardial infarction receiving lisinopril. In summary, lisinopril lowers blood pressure and produces a renoprotective effect in patients with IDDM and NIDDM without detriment to glycaemic control or lipid profiles. Like other ACE inhibitors, lisinopril should thus be viewed as a first-line agent for reducing blood pressure and preventing or attenuating nephropathy in hypertensive diabetic patients with IDDM or NIDDM and microalbuminuria or overt renal disease. The EUCLID study, using lisinopril, provides new data supporting an additional place in managing normotensive patients with microalbuminuria and IDDM. These findings, together with some evidence for an effect of lisinopril in delaying progression of retinopathy and in reducing mortality, suggest a broader role for the drug in managing diabetic vascular complications.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Ibutilide. A review of its pharmacological properties and clinical potential in the acute management of atrial flutter and fibrillation.

Ibutilide is the first 'pure' class III antiarrhythmic drug to become available. Its predominant action is prolongation of the myocardial action potential duration. This appears to be achieved by a unique ionic mechanism of action that involves activation of a late inward sodium current and possibly blockade of the rapidly activating component of the cardiac delayed rectifier potassium current. Intravenous ibutilide 0.01 to 0.025 mg/kg or 1 to 2 mg successfully converted atrial flutter or fibrillation to sinus rhythm in 33 to 49% of patients in 2 placebo-controlled trials involving 439 patients with sustained arrhythmia. In a third trial in 300 patients who developed atrial flutter or fibrillation after cardiac surgery, ibutilide 2 mg successfully converted the arrhythmia in 57% of patients. The mean times to conversion were < or = 30 minutes in these trials. In 3 comparative trials, ibutilide was significantly more effective than racemic sotalol or procainamide in terminating atrial flutter or fibrillation. The pretreatment duration of the arrhythmia is an important predictor of the success of ibutilide treatment; the greatest conversion rates are achieved when the arrhythmia is of recent onset (i.e. < or = 30 days' duration). Ibutilide is more effective in terminating atrial flutter than atrial fibrillation. Adverse events associated with ibutilide are predominantly cardiovascular. Sustained polymorphic ventricular tachycardia developed in 1.7%, and non-sustained polymorphic ventricular tachycardia in 2.7%, of 586 patients treated with ibutilide in clinical trials. However, no proarrhythmia-related deaths have been reported with the use of ibutilide. The drug has minimal haemodynamic effects and is associated with few noncardiovascular adverse events. Thus, ibutilide is a useful agent for the pharmacological cardioversion of recent-onset atrial fibrillation or flutter, provided that adequate steps are taken to monitor for proarrhythmic events. The drug causes few noncardiovascular adverse events and has minimal haemodynamic effects. Furthermore, it appears to be more effective than procainamide (especially in patients with atrial flutter) and racemic sotalol.

Anti-Arrhythmia Agents↗

PubMed1997

Lansoprazole. An update of its pharmacological properties and clinical efficacy in the management of acid-related disorders.

Lansoprazole is a proton pump inhibitor that reduces gastric acid secretion. It has proved effective in combination regimens for the eradication of Helicobacter pylori and as monotherapy to heal and relieve symptoms of gastric or duodenal ulcers and gastro-oesophageal reflux. After initial healing, it may be used to prevent recurrence of oesophageal erosions or peptic ulcers in patients in whom H. pylori is not the major cause of ulceration and to reduce basal acid output in patients with Zollinger-Ellison syndrome. Usual dosages are 15 to 60 mg/day, although dosages of < or = 180 mg/day have been used in patients with hypersecretory states. In patients with duodenal or gastric ulcer, short term lansoprazole monotherapy was similar to omeprazole and superior to histamine H2 receptor antagonists in achieving healing rates > 90%. Lansoprazole was as effective a component of H. pylori eradication regimens as omeprazole, tripotassium dicitrato bismuthate (colloidal bismuth subcitrate) or ranitidine. Lansoprazole was superior to ranitidine in symptom relief and healing of gastro-oesophageal reflux disease and tended to relieve symptoms more rapidly than omeprazole, although initial healing was similar. As maintenance treatment, lansoprazole was similar to omeprazole and superior to ranitidine in relieving symptoms and preventing relapse. Lansoprazole was also superior to ranitidine in healing and relieving symptoms of oesophageal erosions associated with Barrett's oesophagus; healing was maintained for a mean of 2.9 years in > or = 70% of patients. Lansoprazole was also superior to ranitidine in prophylaxis of redilatation of oesophageal strictures. After > or = 4 years of use in patients with Zollinger-Ellison syndrome, lansoprazole 60 to 180 mg/day effectively controlled basal acid output. Dosages may be reduced in some patients once healing and symptom relief has been achieved. Preliminary studies of lansoprazole in patients at risk of aspiration pneumonia or stress ulcers show promise. Although studies show lansoprazole is potentially effective in treating gastrointestinal bleeding, future studies should assess patients' H. pylori status. Lansoprazole has been well tolerated in clinical trials, with headache, diarrhoea, dizziness and nausea appearing to be the most common adverse effects. Tolerability of lansoprazole does not deteriorate with age and the drug is well tolerated in long term use (< or = 4 years) in patients with Zollinger-Ellison syndrome or reflux disease. Thus, lansoprazole is an important alternative to omeprazole and H2 receptor antagonists in acid-related disorders. In addition to its efficacy in healing or maintenance treatment, it may provide more effective symptom relief than other comparator agents.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1997

Insulin lispro: a review of its pharmacological properties and therapeutic use in the management of diabetes mellitus.

Insulin lispro, a recombinant insulin analogue, is identical to human insulin except for the transposition of proline and lysine at positions 28 and 29 in the C-terminus of the B chain. The resultant reduced capacity for self-association in solution translates into more rapid absorption of insulin lispro than human regular insulin from subcutaneous sites. Maximum insulin concentrations are higher and are reached earlier with insulin lispro than with human regular insulin, and insulin concentrations return to baseline values more quickly with insulin lispro; consequently, insulin lispro has a more rapid onset and a shorter duration of glucose-lowering activity. These pharmacological properties provided the rationale for comparative clinical trials of subcutaneous insulin lispro (administered within 15 minutes before meals, preferably immediately before meals) and subcutaneous human regular insulin (administered 20 to 45 minutes before meals) in patients with type 1 diabetes (insulin-dependent diabetes mellitus) or type 2 diabetes (non-insulin-dependent diabetes mellitus) requiring premeal insulin therapy plus basal insulin therapy. Available clinical trials are well designed and results suggest that 1- and 2-hour postprandial blood glucose levels with insulin lispro are similar to or lower than those with human regular insulin; 1- and 2-hourpostprandial glucose excursions are similar to or less pronounced than those with human regular insulin. Glycated haemoglobin A values were generally similar with both agents. Continuous subcutaneous insulin infusion was associated with greater improvements in postprandial blood glucose levels and glycated haemoglobin A1 values with insulin lispro than with human regular insulin. Confirmatory data are required. The incidence of hypoglycaemia with insulin lispro was similar to or lower than that with human regular insulin. In particular insulin lispro appears to be associated with a lower incidence of night-time and severe hypoglycaemic episodes. Evidence also suggests that patients perceive their quality of life to be improved with insulin lispro compared with human regular insulin, and that satisfaction with treatment is greater with the insulin analogue. Thus, in patients with type 1 or 2 diabetes requiring premeal insulin therapy, insulin lispro appears to provide greater postprandial glycaemic control than human regular insulin without increasing the risk of hypoglycaemia. Furthermore, the reduced injection-meal interval with this agent offers greater convenience for the patient than regular human insulin. If longer term clinical experience supports these promising results it is likely that insulin lispro will offer important advantages over human regular insulin.

Amino Acid Sequence↗

PubMed1997

Danaparoid. A review of its pharmacology and clinical use in the management of heparin-induced thrombocytopenia.

Danaparoid, a low molecular weight heparinoid consisting of a mixture of heparan, dermatan and chondroitin sulfates, has well established antithrombotic activity. The drug has a high antifactor Xa to antifactor IIa (thrombin) activity ratio, a low tendency to cause bleeding and minimal effects on the fibrinolytic system. Danaparoid has a low cross-reactivity rate with heparin-associated antiplatelet antibodies (0 to 20%; mean approximately 10%). This represents a significant advantage over low molecular weight heparins (LMWHs) as a potential replacement agent for unfractionated heparin (UFH) in patients with immune-mediated (type II) heparin-induced thrombocytopenia (HIT). In a worldwide compassionate-use programme involving a total of 667 patients with HIT to date, 93% of danaparoid treatment courses were considered to be successful. Thrombocytopenia resolved in 91% of episodes. In a multicentre randomised comparative trial of danaparoid and dextran in patients with HIT plus thrombosis (HITT), significantly more danaparoid than dextran recipients had resolution of thromboses, and an effective clinical response was achieved in significantly more danaparoid recipients. Results of a retrospective case-controlled study of danaparoid and ancrod in patients with HITT showed significantly fewer new or progressive thromboses with danaparoid. In the compassionate-use programme, danaparoid was associated with a mortality rate of 10.4% during treatment (up to 3.5 years) and 7.8% during the follow-up period (3 months). 14 of 114 deaths during the follow-up period were considered to be related to danaparoid therapy. A mortality rate of 23.5% was reported in patients accepted for but not treated with, danaparoid. Mortality rates with danaparoid, ancrod and dextran in the comparative studies were similar (7, 11 and 12%, respectively). Severe bleeding was reported in 3.1% of patients in the compassionate-use programme, persistent or recurrent thrombocytopenia in 2.6% and new thromboembolic events/extension of existing thrombosis in 1.7%. The incidence of bleeding was similar with danaparoid and dextran in a comparative trial. Although in vitro cross-reactivity does not always translate into clinical cross-reactivity, testing is currently recommended, when possible, before initiation of danaparoid therapy. Thus, danaparoid appears to be an effective and well tolerated replacement agent for UFH in many patients with HIT who require further anticoagulation. The drug has low cross-reactivity with HIT-associated antibodies. Further comparative trials are needed to confirm these promising findings.

Blood Coagulation↗

PubMed1996

Amitriptyline. A review of its pharmacological properties and therapeutic use in chronic pain states.

Amitriptyline is a tricyclic antidepressant agent which also has analgesic properties. Whether its analgesic effects are linked to its mood-altering activity or attributable to a discrete pharmacological action (or a combination of both) is unknown. Clinical trials demonstrate that oral amitriptyline achieves at least a good or moderate response in up to two-thirds of patients with post-herpetic neuralgia and three-quarters of patients with painful diabetic neuropathy, neurogenic pain syndromes that are often unresponsive to narcotic analgesics. Amitriptyline has also demonstrated efficacy in heterogeneous groups of patients with chronic non-malignant pain. Other possible areas of use for amitriptyline are in patients with fibromyalgia or as an adjuvant for uncontrolled cancer pain, although evidence for the latter application is limited. Adverse events resulting from the antimuscarinic activity of amitriptyline (primarily dry mouth and sedation) are commonly reported, even at the low dosages used for the control of pain. Low starting doses and careful dosage titration may help to minimise these effects. Orthostatic hypotension and tachycardia, sometimes associated with tricyclic antidepressant agents, may also pose a problem in the elderly. In summary, amitriptyline has a valuable place in the treatment of chronic pain conditions that affect the elderly provided that the drug is used judiciously to minimise adverse effects. Importantly, amitriptyline remains the best studied of the antidepressant agents in post-herpetic neuralgia and diabetic neuropathy and is an important and effective treatment option in these syndromes.

Aged↗

PubMed1996

Muromonab CD3: a reappraisal of its pharmacology and use as prophylaxis of solid organ transplant rejection.

The murine monoclonal antibody muromonab CD3 (OKT3) is directed against the CD3 antigen on peripheral human T cells and effectively blocks all T cell function. Prophylaxis with muromonab CD3 (5mg intravenously once daily for 10 to 14 days) as induction therapy together with corticosteroids, azathioprine and delayed cyclosporin (sequential therapy) optimises early graft function by delaying the potentially nephrotoxic and hepatotoxic effects of cyclosporin until graft function is established. Although clinical data are limited (by inconsistencies in trial design and trial size), prophylactic muromonab CD3-based sequential therapy is significantly more effective than standard triple therapy in the prophylaxis of allograft rejection in renal and hepatic, but not cardiac, transplant recipients. Benefits are particularly notable in patients with delayed graft function. No significant between-treatment differences in patient survival have been observed. The overall efficacy of muromonab CD3- and polyclonal-based prophylactic regimens appears to be similar, although results vary between investigators and confirmation is needed. An anti-interleukin-2 monoclonal antibody-based prophylactic regimen improved graft and patient survival compared with muromonab CD3-based prophylaxis in hepatic transplant recipients. Antimuromonab CD3 antibodies may develop; however, muromonab CD3 may be successfully reused in patients with low titres. Preliminary pharmacoeconomic data suggest that mean drug costs are greater with quadruple immunosuppressive regimens containing muromonab CD3, antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) than with triple therapy. Drug costs with prophylactic muromonab CD3-based regimens were similar or greater than those with polyclonal-based protocols. The first doses of muromonab CD3 are associated with the 'cytokine-release syndrome'. More severe first-dose events include aseptic meningitis, intragraft thromboses, seizures and potentially fatal pulmonary oedema. The incidence and/or severity of cytomegalovirus infection with prophylactic muromonab CD3 based immunosuppression is similar to or greater than that with triple therapy and ATG- or ALG-based regimens. However, the risk of infection and also the observed increase in lymphoproliferative disorders appears to be related to the degree of immunosuppression rather than to the drug itself Thus, sequential muromonab CD3-based therapy is more effective than standard triple therapy (in renal and hepatic transplant recipients) and appears to be similar to that of polyclonal-based regimens in the prophylaxis of transplant rejection. Although the routine use of prophylactic muromonab CD3 in low-risk patients with primary graft function does not appear to be justified, prophylactic muromonab CD3-based therapy has a role in patients at high risk of rejection.

Animals↗

PubMed1996

Ebrotidine.

Ebrotidine is the first of a new generation of H2 receptor antagonists with gastroprotective activity It stimulates epithelial cell proliferative activity and produces beneficial physicochemical changes in the gastric mucus that contribute to its gastro-protective action against ethanol-, aspirin- or stress-induced gastric mucosal damage The antisecretory properties of ebrotidine are similar to those of ranitidine and approximately 10-fold greater than those of cimetidine This drug exhibits anti-Helicobacter pylori activity that is synergistic with a number of antibacterial agents; it inhibits the urease enzyme and the proteolytic and mucolytic activities of H. pylori, and counteracts the inhibitory effects of H. pylori lipo-polysaccharide Ebrotidine is as effective as ranitidine for the treatment of patients with gastric or duodenal ulcers or erosive reflux oesophagitis Ebrotidine therapy results in significantly better ulcer healing rates than ranitidine treatment in patients who smoke.

Animals↗

PubMed1996

Ondansetron. A review of its pharmacology and preliminary clinical findings in novel applications.

The use of ondansetron, a selective serotonin 5-HT3 receptor antagonist, is well established in patients with nausea and vomiting associated with cancer chemotherapy, radiotherapy or anaesthesia and surgery. The wide distribution of 5-HT3 receptors in the body and the role of these receptors in disease have provided the rationale for investigation of ondansetron in novel applications. Preliminary data have shown ondansetron to have clinical benefit in patients with nausea and vomiting associated with drug overdosage or poisoning, anti-infective or antidepressant therapies, uraemia or neurological trauma, and in patients with pruritus. Patients with gastrointestinal motility disorders (e.g. carcinoid syndrome, irritable bowel syndrome, diarrhoea associated with cryptosporidiosis or diabetes, and chronic refractory diarrhoea) have also shown some improvement when treated with ondansetron, as have patients with certain pain or CNS-related disorders [e.g. alcohol (ethanol) dependence, opiate withdrawal, vertigo, cerebellar tremor and Parkinson's disease treatment-related psychosis]. In contrast to conventional antiemetics, ondansetron is generally well tolerated with a lower incidence of sedation and only isolated case reports of extrapyramidal reactions. Furthermore, unlike dopamine receptor-blocking neuroleptics, ondansetron does not appear to worsen the symptoms of Parkinson's disease. Thus, in addition to its established indications, preliminary results suggest that ondansetron may be beneficial in a number of novel applications. This drug may represent a treatment alternative in patients with refractory disease, or an effective treatment of conditions for which current therapies are either poorly tolerated or not available. Further investigation of ondansetron in a range of potential new applications appears to be warranted.

Animals↗

PubMed1996

Tamsulosin. A review of its pharmacological properties and therapeutic potential in the management of symptomatic benign prostatic hyperplasia.

Tamsulosin is the first subtype-selective (alpha IA) alpha 1 adrenoceptor antagonist with specificity for prostatic alpha 1 adrenoceptors (alpha 1A adrenoceptors are thought to be involved in prostatic smooth muscle contraction) to become available for the treatment of patients with symptomatic benign prostatic hyperplasia (BPH). With tamsulosin, the incidence of adverse events commonly associated with alpha 1 adrenoceptor antagonism is similar to that with placebo (except for ejaculation disorders) and alfuzosin. The incidence of other adverse events is similar with tamsulosin and placebo. Furthermore, blood pressure and heart rate are not significantly affected by tamsulosin in patients with symptomatic BPH. In contrast, blood pressure is significantly reduced by alfuzosin compared with tamsulosin. Tamsulosin is available as a controlled release formulation suitable for once daily administration; dose titration is not required. The overall efficacy of this agent administered at a dosage of 0.1 to 0.4 mg/day in Japan, 0.4 mg/day in Europe and 0.4 to 0.8 mg/day in the US to patients with symptomatic BPH is greater than that of placebo was similar to that of alfuzosin or prazosin in the 2 available studies. Efficacy was primarily assessed by changes in maximum and average urinary flow rates, residual urinary volume and total symptom scores. Improvements in these parameters in short term trials (< or = 13 weeks) appear to be maintained in the longer term (< or = 60 weeks). Quality-of-life effects also appear to be similar with tamsulosin and alfuzosin. In conclusion, the pharmacodynamic properties of this agent appear to translate into tolerability and administration advantages over other alpha 1 adrenoceptor antagonists. If future investigations confirm its promising efficacy and tolerability, tamsulosin will be ideally placed as a valuable therapeutic option for patients with symptomatic BPH and in patients awaiting surgery or in those unable to undergo surgery.

Adrenergic alpha-Agonists↗

PubMed1995

Tianeptine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depression and coexisting anxiety and depression.

Tianeptine is a novel antidepressant agent, both structurally (modified tricyclic) and in terms of its pharmacodynamic profile. Unlike other antidepressant agents, tianeptine stimulates the uptake of serotonin (5-hydroxytryptamine; 5-HT) in rat brain synaptosomes and rat and human platelets, increases 5-hydroxyindoleacetic acid (5-HIAA) levels in cerebral tissue and plasma, and reduces serotonergic-induced behaviour. Tianeptine reduces the hypothalamic-pituitary-adrenal response to stress, antagonises stress-induced behavioural deficits and prevents changes in cerebral morphology. The antidepressant efficacy of tianeptine, as shown in 2 trials of patients with major depression or depressed bipolar disorder with or without melancholia, is greater than that of placebo. In patients with major depression without melancholia or psychotic features, depressed bipolar disorder or dysthymic disorder, the antidepressant efficacy of short term (4 weeks to 3 months) tianeptine therapy appears to be similar to that of amitriptyline, imipramine and fluoxetine and may be superior to that of maprotiline in patients with coexisting depression and anxiety. However, submaximal dosages of amitriptyline and maprotiline were used in these studies. Preliminary evidence suggests that tianeptine may also be effective in patients with endogenous depression. Progressive therapeutic improvements have been observed with up to 1 year of tianeptine treatment, and long term therapy may reduce the rate of relapse or recurrence. Tianeptine is effective in the treatment of depression in elderly and post-alcohol-withdrawal patient subgroups. Tianeptine was more effective in reducing psychic anxiety than placebo in patients with major depression or depressed bipolar disorder with or without melancholia. The overall anxiolytic properties of tianeptine in patients with coexisting depression and anxiety appear to be similar to those of amitriptyline, imipramine and fluoxetine and may be superior to those of maprotiline, although submaximal dosages of amitriptyline and maprotiline were used. Studies of tianeptine in patients with primary anxiety have not been conducted. Tianeptine is well tolerated in the short (3 months) and long (up to 1 year) term. The incidence of dry mouth (38 vs 20%), constipation (19 vs 15%), dizziness/syncope (23 vs 13%), drowsiness (17 vs 10%) and postural hypotension (8 vs 3%) are greater with amitriptyline than with tianeptine. Insomnia and nightmares occur in more tianeptine than amitriptyline recipients (20 vs 7%). The relative lack of sedative, anticholinergic and cardiovascular adverse effects with tianeptine makes it particularly suitable for use in the elderly and in patients following alcohol withdrawal; these patients are known to have increased sensitivity to the adverse effects associated with psychotropic drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗

PubMed1995

Gestodene. A review of its pharmacology, efficacy and tolerability in combined contraceptive preparations.

The newer progestogens gestodene, desogestrel and norgestimate were developed in an attempt to produce agents with more selective progestational activity that would improve cycle control and minimise metabolic changes and adverse events while effectively preventing pregnancy. In clinical practice, gestodene is combined with ethinylestradiol in monophasic or triphasic combined oral contraceptive preparations. The drug has pharmacokinetic advantages over the other new progestogens in that it is active per se (the others are prodrugs) and has high bioavailability (approximately 100%). The ability of gestodene-containing oral contraceptives to inhibit ovulation is similar to that of preparations containing other progestogens although the required dosage is lower. In common with oral contraceptives containing desogestrel or norgestimate, and in contrast with those containing levonorgestrel, gestodene-containing preparations are associated with neutral or positive changes in lipid and carbohydrate metabolism. The effects of gestodene preparations on coagulation parameters, like those of desogestrel and levonorgestrel, are balanced by changes in the fibrinolytic system. Although the impact of these changes on clinical cardiovascular end-points has not been determined, the altered lipid profile is not likely to have significant clinical relevance because of the predominantly thrombogenic nature of cardiovascular disease in oral contraceptive users. Pregnancy rates and Pearl Indices with gestodene-containing preparations are low and similar to those with preparations containing other progestogens. Most pregnancies are attributable to user failure. Cycle control appears to be better with gestodene preparations than with levonorgestrel preparations, and available data suggest that cycle control may also be better with monophasic gestodene/ethinylestradiol than with monophasic desogestrel- or norgestimate-containing preparations, and better with triphasic gestodene- than with triphasic levonorgestrel- or norgestimate-containing preparations. However, differences between the new progestogen-containing preparations need to be confirmed in further large-scale trials. The most common adverse events with gestodene/ethinylestradiol are headaches and breast tension; the incidence of short term adverse events, including acne, is similar to that with preparations containing other progestogens. Changes in blood pressure and bodyweight are negligible. There are no comparative data on the incidence of cardiovascular events with gestodene-containing and other combined preparations. While the risk of breast cancer appears to be increased with long term combined oral contraceptive use in certain patient subgroups, this risk needs to be balanced against the noncontraceptive benefits of these preparations.(ABSTRACT TRUNCATED AT 400 WORDS)

Absorption↗