Biomedical subjects

A J Wagstaff

Publications and source records attributed to A J Wagstaff.

At least 19 recordsLinked to original sources

PubMed2001

Estradiol and norgestimate: a review of their combined use as hormone replacement therapy in postmenopausal women.

The focus of this review is hormone replacement therapy (HRT) with continuous administration of micronised, oral 17beta-estradiol 1 mg/day (herein referred to as continuous estradiol) plus micronised, oral norgestimate 90 microg/day administered for 3 days then withdrawn for 3 days in a 6-day repeating sequence (herein referred to as intermittent norgestimate). According to data from randomised, comparative trials of 1 year's duration, continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day relieves climacteric symptoms (vasomotor symptoms and vulvovaginal atrophy) in postmenopausal women. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day appeared as effective as estradiol 1 mg/day alone or continuous estradiol 2 mg/day plus continuous norethisterone acetate 1 mg/day in the treatment of postmenopausal women with vasomotor symptoms. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day was as effective as continuous estradiol 1 mg/day in causing the maturation of vaginal epithelial cells. In a randomised, double-blind study, bone mineral density (BMD) increased to a significantly greater extent and the rate of bone turnover was slower in postmenopausal women treated with continuous oral estradiol 1 mg/day plus intermittent norgestimate 90 microg/day than in placebo-treated patients. Two randomised, double-blind studies indicated that the addition of norgestimate 90 microg/day to continuous estradiol 1 mg/day did not attenuate the beneficial effects of estradiol on lipid parameters. Continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day was associated with increases in mean serum high density lipoprotein (HDL)-cholesterol levels and decreases in total cholesterol, low density lipoprotein (LDL)-cholesterol and lipoprotein (a) levels, compared with baseline. There was no statistically significant increase in triglyceride levels. In comparative trials, continuous oral estradiol 1 mg/day plus intermittent oral norgestimate 90 microg/day was well tolerated. Headache, breast pain or discomfort, abdominal pain or discomfort, uterine bleeding, dysmenorrhoea, oedema, nausea and depression were the most commonly reported adverse events. Continuous estradiol 1 mg/day plus intermittent oral norgestimate 90 microg/day was associated with a favourable uterine bleeding profile that improved over time. In a randomised trial, 80% of women were free from bleeding (irrespective of spotting) during month 12 of treatment. Norgestimate 90 microg/day was effective in protecting postmenopausal women against induction of endometrial hyperplasia by continuous estradiol 1 mg/day. In conclusion, data from a limited number of randomised studies indicate that HRT with continuous estradiol 1 mg/day plus intermittent norgestimate 90 microg/day is effective in relieving climacteric symptoms, increasing BMD and slowing the rate of bone turnover in postmenopausal women. This HRT regimen is well tolerated and is associated with a similar incidence of adverse events to that reported in recipients of continuous estradiol 1 mg/day. The norgestimate component of the regimen provides good endometrial protection and is associated with a favourable bleeding profile. Long-term studies investigating the associated risk of breast cancer and thromboembolic events in recipients of continuous estradiol plus intermittent norgestimate are needed. In the meantime, continuous oral estradiol plus intermittent oral norgestimate can be regarded as an effective new option for HRT in postmenopausal women.

Contraceptives, Oral, Synthetic↗

PubMed2001

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

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

Cyclosporine↗

PubMed2001

Once-weekly fluoxetine.

The relatively long half-life of the selective serotonin reuptake inhibitor fluoxetine has allowed the development of a delayed-release (enteric-coated) formulation containing 90 mg fluoxetine per capsule for once-weekly oral administration. The cumulative relapse rate in patients switched to once-weekly fluoxetine 90 mg for 25 weeks (after responding to 13 weeks of fluoxetine 20 mg/day) was similar to that in patients continuing to receive fluoxetine 20 mg/day and significantly lower than seen in patients switched to placebo. The efficacy of the once-weekly formulation was also similar to that of the daily formulation in other assessment parameters (modified 17-item Hamilton Rating Scale for Depression, Clinical Global Impressions - Severity of Illness Scale). Patient compliance (measured using an electronically monitored tablet bottle) was maintained at 87.5% in evaluable patients receiving once-weekly fluoxetine 90 mg for 12 weeks from a baseline of 85.4% after responding to 4 weeks of fluoxetine 20 mg/day; in contrast, compliance declined significantly (from 87.3% at baseline to 79.4%; p < 0.001) in patients continuing to receive 20 mg/day for 12 weeks. Once-weekly fluoxetine is well tolerated, with a tolerability profile similar to that of the immediate-release formulation.

Administration, Oral↗

PubMed2001

Transdermal fentanyl: an updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control.

UNLABELLED: Fentanyl is a synthetic opioid agonist which interacts primarily with the mu-opioid receptor. The low molecular weight, high potency and lipid solubility of fentanyl make it suitable for delivery by the transdermal therapeutic system. These patches are designed to deliver fentanyl at a constant rate (25, 50, 75 and 100 microg/h), and require replacement every 3 days. Data from randomised, nonblind trials suggest that transdermal fentanyl is as effective as sustained-release oral morphine in the treatment of chronic cancer pain, as reported by patients using visual and numerical analogue scales as well as verbal description scales. No obvious differences in health-related quality of life were found in patients with chronic cancer pain when comparing transdermal fentanyl with sustained-release oral morphine. Nevertheless, significantly more patients expressed a preference for transdermal fentanyl than for sustained-release oral morphine after a randomised, nonblind, crossover trial. Because of the formation of a fentanyl depot in the skin tissue, serum fentanyl concentrations increase gradually following initial application, generally levelling off between 12 and 24 hours. Thereafter, they remain relatively constant, with some fluctuation, for the remainder of the 72-hour application period. Once achieved, steady-state plasma fentanyl concentrations can be maintained for as long as the patches are renewed. The most frequently observed adverse events during transdermal fentanyl administration (as with other opioid agonists) included vomiting, nausea and constipation. Data from a nonblind, randomised trials suggest that constipation occurs less frequently in patients receiving transdermal fentanyl than in those given sustained-release oral morphine. The most serious adverse event reported in US premarketing trials was hypoventilation, which occurred with an incidence of approximately 2%. Adverse reactions related to skin and appendages (i.e. rash and application site reactions - erythema, papules, itching and oedema) were reported in 153 patients with cancer at a frequency between 1 and 3%. CONCLUSION: Transdermal fentanyl is a useful opioid-agonist for the treatment of moderate to severe chronic cancer pain. The advantages of transdermal fentanyl include ease of administration and the 3-day application interval. These factors coupled with a lower incidence of constipation are likely to contribute to the reported patient preference of transdermal fentanyl over sustained-release oral morphine.

Absorption↗

PubMed2001

Tianeptine: a review of its use in depressive disorders.

UNLABELLED: Tianeptine is an antidepressant agent with a novel neurochemical profile. It increases serotonin (5-hydroxytryptamine; 5-HT) uptake in the brain (in contrast with most antidepressant agents) and reduces stress-induced atrophy of neuronal dendrites. Like the selective serotonin reuptake inhibitors (SSRIs) and in contrast with most tricyclic antidepressant agents, tianeptine does not appear to be associated with adverse cognitive, psychomotor, sleep, cardiovascular or bodyweight effects and has a low propensity for abuse. Tianeptine has a comparatively favourable pharmacokinetic profile. It is not subject to first-pass hepatic metabolism, has high bioavailability and limited distribution, and is rapidly eliminated. While this offers advantages for tianeptine over the tricyclic antidepressant agents in terms of dose titration, treatment changes and potential drug interactions, its rapid elimination makes adherence to dosage schedules more important. Tianeptine differs from most antidepressants in that it is not primarily metabolised by the hepatic cytochrome P450 system, indicating less likelihood of drug-drug interactions; this is of particular interest for elderly patients. Tianeptine, in dosages of 25 to 50 mg/day, has been investigated in patients with major depression, depressed bipolar disorder, dysthymia or adjustment disorder. It has equivalent antidepressant efficacy to several classical antidepressant agents (amitriptyline, clomipramine, imipramine, mianserin) and the SSRIs fluoxetine (in most patients), paroxetine and sertraline. Comparison with maprotiline indicated superior efficacy for tianeptine but dothiepin appeared superior in another study. Extended treatment with tianeptine decreases the incidence of relapse/recurrence of depression. Tianeptine appears to be as effective as fluoxetine, sertraline, amitriptyline, clomipramine and mianserin and more effective than maprotiline in improving associated anxiety in patients with depressive disorders. Depression and anxiety symptoms in alcohol dependant patients also respond well to tianeptine. The adverse effects associated with tianeptine are similar in many respects to those of the SSRIs and minimal in comparison with the tricyclic antidepressants. The most common adverse effects are nausea, constipation, abdominal pain, headache, dizziness and changes in dreaming. Anticholinergic effects occur less often with tianeptine than with tricyclic agents. Hepatoxicity is rare. The dosage should be decreased in elderly patients and those with severe renal failure, but adjustment is not necessary in patients with alcoholism or hepatic impairment, or those undergoing haemodialysis. CONCLUSIONS: The antidepressant efficacy and favourable tolerability and pharmacokinetic profiles of tianeptine in patients with depression, including those with associated anxiety, have been proven; the data indicate that it may have additional potential in specific subgroups of depressed patients such as the elderly and those with chronic alcoholism.

Aged↗

PubMed2001

Daclizumab: a review of its use in the management of organ transplantation.

UNLABELLED: The humanised monoclonal antibody daclizumab is an immunosuppressive agent that reduces acute rejection in solid organ transplantation. It is specific for the alpha subunit (Tac/CD25) of the interleukin (IL)-2 receptor on activated T cells and achieves immunosuppression by competitive antagonism of IL-2-induced T cell proliferation. When added to standard triple immunosuppression regimens, daclizumab significantly reduces the rate of acute rejection at 1 year in renal transplantation by 36% and there are indications that it may be effective in other solid organ transplantations. Three-year outcomes of two phase III clinical trials in renal transplantation indicate similar values for graft and patient survival between daclizumab and placebo when given in addition to triple immunosuppression; however, these pivotal trials were not designed with sufficient power to demonstrate any statistical significance. The addition of daclizumab induction shows potential in allowing calcineurin inhibitor- and corticosteroid-sparing regimens without increasing the rate of acute graft rejection or adverse effects in renal and liver transplantation. Preliminary reports indicate that daclizumab may also be a useful agent in delayed graft function and graft versus host disease (GVHD). Further investigation of its efficacy in these groups and in children is needed. Data from clinical trials show daclizumab to be well tolerated in solid organ transplantation. It does not increase the incidence of infection, including cytomegalovirus infection, when compared with placebo or no induction groups. Preliminary comparative data with muromonab CD3 indicate that daclizumab may be associated with a lower rate of infectious complications and similar or better efficacy. CONCLUSIONS: In conclusion, daclizumab has been proven to reduce acute rejection in renal transplant recipients when given in addition to traditional baseline immunosuppression. It has shown potential to reduce acute rejection in other solid organ transplants; however, well designed, randomised studies are required to confirm this. Clinical experience from trials to date indicate that daclizumab has a tolerability profile similar to placebo with no significant effect on the incidence of infection. The relative efficacy and tolerability of daclizumab compared with other induction agents has yet to be defined. Available data suggest that daclizumab may allow the use of calcineurin inhibitor-sparing and corticosteroid-sparing regimens and may have potential in the treatment of GVHD.

Animals↗

PubMed1998

Detrimental effects on villus form during conventional oral rehydration therapy for diarrhoea in calves; alleviation by a nutrient oral rehydration solution containing glutamine.

This paper examines the possibility that treatment of diarrhoea with conventional oral rehydration solutions (ORSs) may be detrimental to villus structure by imposing nutrient deprivation and that such detrimental effects may be reduced or avoided by using a nutrient ORS. A conventional WHO-type ORS (W) was compared with two nutrient solutions (N and G) both containing high glucose concentrations and the latter containing glutamine; their effects on enteric structure were assessed by morphometric analysis of samples obtained from diarrhoeic calves after 96 h treatment. Comparisons were also made with samples from controls and diarrhoeic calves at the stage where oral rehydration would have begun in the treated groups. As in our previous ORS studies, diarrhoea was induced with enterotoxigenic Escherichia coli (09:K30:K99). We measured villus length and width, crypt depth and width and calculated villus surface area in proximal, mid and distal small intestine (PSI, MSI, DSI), using standard morphometric techniques. Proximal and distal spiral colon samples (PC, DC) were examined for crypt depth and width; mitoses per crypt were counted in samples from all regions. Non-diarrhoeic calves showed the expected gradient of villus length through PSI, MSI and DSI, hence data for each region are normalized as a percentage of the control value for that region. PSI showed the greatest loss of villus length and surface area (50%) with diarrhoea. In MSI and DSI the villus loss was greater with solution W and N or G, as were increased mitoses and crypt depth. Crypt depth and mitoses also increased in the colon with solution W. Colonic crypt width increased with diarrhoea and conventional oral rehydration but less so with G; there is reason to believe that such changes have functional significance. Crypt changes in colon, MSI and DSI were least with solution G. The changes developing in diarrhoeic calves prior to treatment were thus less apparent in those treated with a nutritional ORS, particularly if it contained glutamine.

Animals↗

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

Domperidone. A review of its use in diabetic gastropathy.

UNLABELLED: Domperidone is a selective antagonist at peripheral dopamine D2 receptors, with gastroprokinetic and antiemetic properties. It increases the frequency and duration of antral and duodenal contractions, thus decreasing/improving transit time of food through the gastrointestinal tract. Gastric emptying of liquids and solids is significantly improved with oral domperidone 40 to 120 mg/day in patients with diabetic gastropathy. Oral domperidone 40 to 80 mg/day significantly decreased the severity of symptoms of gastropathy from baseline values in 66 to 88% of patients with type 1 (insulin-dependent) or insulin-requiring diabetes mellitus. Double-blind withdrawal of domperidone from patients who had responded previously led to greater deterioration of symptoms in patients with delayed gastric emptying than in those who continued receiving the drug. Quality of life was significantly improved in patients who showed a symptomatic response to domperidone. The administration of domperidone 40 to 120 mg/day significantly reduced hospitalisation rates in patients with gastropathy. The symptomatic improvement with domperidone 80 mg/day was similar to that seen with cisapride 40 mg/day or metoclopramide 40 mg/day, and therapeutic benefits seen in symptoms of gastropathy were maintained with domperidone for up to 12 years. Domperidone 40 to 80 mg/day may be effective in patients who are refractory to metoclopramide, and a combination of domperidone 80 mg/day with cisapride 80 mg/day may improve some symptoms in patients who do not respond to either agent alone. Domperidone 40 to 120 mg/day was well tolerated for periods up to 12 years in trials in patients with diabetic gastropathy. Adverse events with domperidone 80 mg/day were similar to those seen in placebo recipients and significantly fewer than in patients receiving metoclopramide 40 mg/day. Although significant elevation of plasma prolactin levels (unrelated to dosage and duration of treatment) occurred in all domperidone recipients, prolactin-related adverse events were observed in only 10 to 20% of patients. CONCLUSIONS: The available data suggest that domperidone 40 to 80 mg/day is an effective agent for the management of symptoms of gastropathy in patients with type 1 diabetes mellitus. In addition, it may provide symptom improvement in patients with gastropathy refractory to other gastroprokinetic agents. Domperidone maintains efficacy in the long term (up to 12 years) and appears to have a better tolerability profile than metoclopramide 40 mg/day.

Animals↗

PubMed1997

Fallibility of plasma urea and creatinine as indices of renal function in diarrhoeic calves treated with conventional or nutritional oral rehydration solutions.

Changes in plasma urea, creatinine and glomerular filtration rate (GFR) were measured in calves before and after development of diarrhoea and during treatment with a conventional (WHO-type) or a nutritional oral rehydration solution (ORS). Changes in urea and creatinine failed to represent the extent of pre-renal failure. The two ORSs differed in their impact on GFR with the nutritional ORS improving GFR whereas with the WHO-type solution it deteriorated further.

Animals↗

PubMed1997

Evaluation of a glutamine-containing oral rehydration solution for the treatment of calf diarrhoea using an Escherichia coli model.

A high-calorie oral rehydration solution (ORS) with glutamine (n=11) was more effective in correcting plasma, extracellular fluid and blood volume than solutions without (one WHO-type solution, n=6, and two high-glucose but glutamine-free solutions, n=7, n=12). It was the only solution to improve plasma volume significantly within 48 h and sustain the improvement throughout treatment; similarly, it was the only solution to correct packed-cell volume within 48 h and sustain the benefit to the end of treatment. At the end of treatment, the glutamine-treated calves were the only ones to avoid a significant weight loss compared with their pre-diarrhoeic values. The crucial difference between this solution and those used with glutamine previously is that it gave significant nutritional support whereas WHO type solutions did not. It also had more favourable effects on hyponatraemia and metabolic acidosis than a standard ORS. Use of a high-calorie ORS for 4 days (rather than 2 days of 50:50 admixture with milk replacer) brought additional beneficial effects on blood glucose and body weight.

Animals↗

PubMed1997

Tizanidine. A review of its pharmacology, clinical efficacy and tolerability in the management of spasticity associated with cerebral and spinal disorders.

The central alpha 2 adrenoceptor agonist tizanidine is a myotonolytic agent used in the treatment of spasticity in patients with cerebral or spinal injury. Wide interpatient variability in the effective plasma concentrations of tizanidine means that the optimal dosage must be titrated over 2 to 4 weeks for each patient (dosages of 2 to 36 mg/day have been used in clinical trials). Maximum effects occur within 2 hours of administration. Antispastic efficacy has been demonstrated for tizanidine in placebo-controlled trials, with reduction in mean muscle tone scores of 21 to 37% versus 4 to 9% for patients receiving placebo. Improvement in muscle tone occurred in 60 to 82% of tizanidine recipients, compared with 60 to 65% of baclofen and 60 to 83% of diazepam recipients. Spasm frequency and clonus are also reduced by tizanidine. The most common adverse effects associated with tizanidine are dry mouth and somnolence/drowsiness. Muscle strength, as assessed by objective means, appears not to be adversely affected by tizanidine and subjective muscle weakness is reported less often by tizanidine recipients than by those receiving baclofen or diazepam. Global tolerability was assessed as good to excellent in 44 to 100% of patients receiving tizanidine, compared with 38 to 90% of baclofen and 20 to 54% of diazepam recipients. In conclusion, tizanidine is an antispastic agent with similar efficacy to that of baclofen and a more favourable tolerability profile. While drowsiness is a frequently reported adverse effect with both agents, subjective muscle weakness appears to be less of a problem with tizanidine than with baclofen. Tizanidine, therefore, appears to be an attractive therapeutic alternative for patients with spasticity associated with cerebral or spinal damage.

Adrenergic alpha-Agonists↗

PubMed1997

Grepafloxacin.

Grepafloxacin (OPC-17116) is a new once-daily fluoroquinolone antimicrobial agent which appears to have high tissue penetration and the wide spectrum of antimicrobial activity typical of this class of agents, but with improved activity against Gram-positive organisms, notably Streptococcus pneumoniae. The in vitro activity of grepafloxacin was similar to or slightly lower than that of ciprofloxacin against Enterobacteriaceae but better than that of ciprofloxacin against most Gram-positive organisms. In particular, grepafloxacin showed good activity against pathogens implicated in community-acquired pneumonia, with 4-fold higher potency than ciprofloxacin against S. pneumoniae, including penicillin-resistant strains. In animal studies, grepafloxacin did not induce convulsions when administered at high doses in conjunction with nonsteroidal anti-inflammatory agents. Grepafloxacin has a weak propensity for causing phototoxicity, similar to that of ciprofloxacin. In comparative clinical trials, grepafloxacin demonstrated similar efficacy to amoxicillin in community-acquired pneumonia, ofloxacin in pneumonia and chronic respiratory tract infection, and cefixime in uncomplicated gonococcal urethritis and gonococcal cervicitis. Grepafloxacin has also shown clinical efficacy in preliminary studies in patients with chlamydial endocervical infection or bacillary dysentery.

Anti-Infective Agents↗

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

Carvedilol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders.

Carvedilol competitively blocks beta 1, beta 2 and alpha 1 receptors. The drug lacks sympathomimetic activity and has vasodilating properties that are exerted primarily through alpha 1-blockade. Animal models indicate that carvedilol confers protection against myocardial necrosis, arrhythmia and cell damage caused by oxidising free radicals, and the drug has no adverse effects on plasma lipid profiles. Recent data have confirmed the antihypertensive efficacy of carvedilol in patients with mild to moderate essential hypertension. Carvedilol has similar efficacy to other beta-blocking agents, calcium antagonists, ACE inhibitors and hydrochlorothiazide. Carvedilol also improves exercise tolerance and ischaemic symptoms in patients with stable angina pectoris. Significant reductions in serious cardiac events after acute myocardial infarction and in frequency and severity of ischaemic events in patients with unstable angina have also been demonstrated. Interest in the use of carvedilol in patients with congestive heart failure (CHF) has culminated in the publication of a cumulative analysis of data from 1094 patients with mild to severe CHF who participated in the US Carvedilol Heart Failure Study Program (4 trials). After a median follow-up of 6.5 months, a significant overall reduction in mortality relative to placebo (3.2 vs 7.8%) was revealed in patients who had received carvedilol 6.25 to 50 mg twice daily (plus diuretics and ACE inhibitors). All-cause mortality, risk of hospitalisation for cardiovascular reasons and hospitalisation costs were also reduced significantly (by 65, 28% and 62%, respectively) in these trials. In addition, the Australia and New Zealand Heart Failure Research Collaborative Group showed a 26% reduction in the combined risk of death or hospitalisation with carvedilol 12.5 to 50 mg/day relative to placebo after a mean 19-month follow-up period in 415 patients with CHF (relative risk 0.74). Adverse events with carvedilol appear to be less frequent than with other beta-blocking agents, are dosage-related and are usually seen early in therapy. Events most commonly reported are related to the vasodilating (postural hypotension, dizziness and headaches) and the beta-blocking (dyspnoea, bronchospasm, bradycardia, malaise and asthenia) properties of the drug. Carvedilol appears to date to have little effect on the incidence of worsening heart failure. Concomitant administration of carvedilol with some medications requires monitoring. Carvedilol is therefore likely to have a beneficial role in the management of controlled CHF, but further clinical studies are required to show the place of beta-adrenoceptor blocking therapy in general in this indication, and the position of carvedilol relative to other similar agents. Carvedilol is also confirmed as effective in the management of mild to moderate hypertension and ischaemic heart disease.

Adrenergic beta-Antagonists↗

PubMed1996

Fallibility of faecal consistency as a criterion of success in the evaluation of oral fluid therapy for calf diarrhoea.

It is often said that the success of oral rehydration in humans depends on the adequacy of the improvement in the composition and volume of extracellular fluid, not reduction of faecal output. Indeed, the latter may increase initially. Such increases do not prevent the treatment from being effective but they may, falsely, undermine its acceptability to patients or those caring for them. This paper provides data to show that standard oral rehydration solutions used to treat experimentally induced calf diarrhoea procure identical improvements in plasma volume during the first 48 h, whether faeces improve or not, and those calves whose faecal consistency improved actually showed greater deterioration of extracellular fluid volume. While it is important for this to be appreciated by clinicians and explained to owners, it is absolutely imperative that those responsible for the approval of new therapeutic products for registration understand and accept that faecal consistency offers no reliable insight into the effectiveness of oral rehydration therapy for calf diarrhoea. It was, however, interesting that there was some relationship with correction of acidosis--perhaps because some of the contributing factors arise from colonic dysfunction.

Animals↗

PubMed1996

Evaluation of a nutritive oral rehydration solution for the treatment of calf diarrhoea.

The essential constituents of a conventional oral rehydration solution (ORS) are sodium, glucose and a bicarbonate precursor. The glucose promotes sodium uptake but because these solutions are isotonic, it is insufficient to sustain calorie requirements. This paper examines the performance of a novel ORS with over three times the conventional glucose concentration, by comparing it with two leading commercial ORSs in calves with induced Escherichia coli diarrhoea. This solution showed greater ability than the current market-leading ORS to repair extracellular fluid and plasma volume and to correct both hyponatraemia and metabolic acidosis, especially in more severely affected calves. In acidotic calves it was more effective in correcting hyperkalaemia, probably by supplying glucose to promote cellular potassium uptake as well as by correcting the acidosis. It therefore appears possible to depart from the traditional isotonic formulations for calf ORSs and gain significant nutritional support while retaining effective rehydration and correction of acid-base and electrolyte disturbances. This seems especially important in young animals where energy deprivation imposes a particular penalty; the use of hypertonic ORSs should not, however, be extended to other species without further research.

Acid-Base Equilibrium↗

PubMed1996

Liarozole.

Liarozole prevents the catabolism of retinoic acid via inhibition of 4-hydroxylase and exhibits retinoid-sparing and retinoid-mimetic effects in vivo. Liarozole is also a potent inhibitor of estrogen (via inhibition of aromatase) and testicular androgen synthesis (inhibition of 17, 20-lyase). Although testosterone levels decrease in vivo after single dose administration of liarozole, testosterone levels normalise as a result of pituitary feedback after multiple doses. Liarozole reduced the tumour size of androgen-dependent and -independent prostatic carcinomas in animal models. Liarozole also demonstrated chemopreventive activity in vivo. In phase I and II trials in patients with relapsed prostate cancer, liarozole achieved a complete response (assessed using prostate specific antigen levels) in 4% and a partial response in 26% of patients. Cutaneous adverse events, similar to those associated with excess levels of retinoic acid, were the most frequently reported events associated with liarozole.

Animals↗