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Biomedical subjects
Publications and source records attributed to M Aylward.
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The medical community must recognize that support of claims for Incapacity Benefit and related commercial schemes places the patient in a small and special sub-population of clinical practice which may require specialist investigation, treatment, and documentation. Determination of functional capacity and of disability requires knowledge either not available or unfamiliar to most physicians with caring and therapeutic roles, especially of legal or contractual provisions and occupational data. However, it is not necessary for them to determine disability and they should not be asked to do so. The new, medical assessment procedures for Incapacity Benefit in the UK do not require this, and the largest provider of related commercial schemes (Long Term Disability; Permanent Health Insurance) has already eliminated this requirement from its application process. When such application is anticipated or requested, the medical record should be prepared and appropriate consultation obtained. Subjective issues should be identified and addressed. Comprehensive psychiatric evaluation, especially in subjective impairment, is critical in chronic incapacity. The estimation of functional capacities in the absence of objective data is particularly troublesome, but, clinicians can provide the Disability Medical Analyst with appropriate medical documentation.
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The authors have tested a new preparation of dihydroergotamine (microgranules in a capsule) by comparing the clinical results obtained in 30 patients suffering from morning migraine with the plasma levels of the active substance measured in 8 healthy subjects. The microgranules were administered in doses of 30 mg/24 hours and compared with a similar dose of a dihydroergotamine solution. The close correlation observed between sustained plasma levels and prolonged therapeutic effects indicates a truly programmed delivery of dihydroergotamine by the microgranule preparation.
Plasma kinetics of dextromethorphan (as dextrorphan ) and codeine were investigated after acute oral doses in 8 patients with pathological cough; after which the patients participated in an acute dose-response study of the antitussive effects of each drug administered as syrups. Maximum plasma codeine concentrations averaged 384 ng.ml-1 (s.d. +/- 78.3) occurring between 0.75 and 2h after ingestion of 60 mg codeine phosphate; in comparison mean peak plasma dextrorphan levels were 386 ng.ml-1 (s.d. +/- 107.2) and 388 ng.ml-1 (s.d. +/- 101.3) respectively, after administration of 60 mg dextromethorphan syrup and tablet formulations. Bioavailability of dextromethorphan tablets was comparable to syrup. No correlation emerged between instantaneous plasma concentrations of either dextrorphan or codeine and antitussive responses; however, peak antitussive effect was significantly related to log dose with both drugs. Antitussive effects of 30 mg codeine phosphate and 60 mg dextromethorphan hydrobromide did not differ significantly; both were superior to 30 mg dextromethorphan hydrobromide and placebo.
With the combined pharmacokinetic-pharmacodynamic approach, the bioavailability and venoconstrictor effects of two DHE formulations (programmed release capsules and oral solution) have been compared after acute oral dose administrations in the healthy volunteer subjects. The bioavailability of DHE from programmed release capsules has been significantly greater than that shown by the oral solution. DHE capsules formulation has seemed to provide appropriate plasma concentrations for at least 10 h after administration. That may well account for its efficacy in the treatment of morning migraine.
The absorption, metabolism and excretion of cytidine diphosphate choline (CDP-choline, citicoline, Somazina) were investigated in six adult healthy subjects after a single oral dose of 300 mg of the 14C-labelled compound. The compound was well tolerated by the subjects. Absorption was virtually complete with less than 1% of the dose being found in the faeces during the 5-day collection period. Two peaks were found in the plasma radioactivity time profile: the first at 1 h, and a second larger peak at 24 h post-dose. Elimination of the ingested dose occurred via respiratory CO2 and through urinary excretion; the former predominating, and both routes exhibited biphasic patterns characterized by an early phase followed by slower decline. It is postulated that in the healthy human subject CDP-choline is metabolized in the gut wall and in the liver; the products arising from the compound's extensive hepatic metabolism being subsequently available for diverse biosynthetic pathways, tissue metabolism, and excretion.
Cytidine diphosphate choline (CDP-choline, citicoline, Somazina) was administered to 12 adult healthy volunteer subjects in two short-term chronic oral dose regimens (600 mg X day-1 and 1g X day-1), each of 5 consecutive days, and compared with a corresponding regimen of matched placebo. Transient headaches were the only untoward events recorded, occurring in 4 and 5 subjects, respectively, on the lower and higher dose regimens but in only one subject during placebo administration.
Seventeen patients with Raynaud's disease were followed whilst receiving treatment with 40 mg thymoxamine hydrochloride 4-times daily for period ranging between 11 and 19 months. Digital artery patency and blood flow changes, assessed by Doppler ultrasound techniques after different thermal stresses, were monitored regularly as were platelet aggregation to ADP and collagen, platelet adhesion to glass beads, measures of blood coagulation and fibrinolysis, and plasma viscosity. Significant clinical improvement noted at 1 month appeared to improve further at 3 months and was maintained thereafter. Vessel patency rates at 10 degrees C and 21 degrees C improved significantly during treatment and both collagen- induced aggregation and platelet retention were significantly inhibited. These unexpected effects on platelet function are not readily explained by the drug's documented activity as a selective alpha-adrenergic antagonist and they may represent other hitherto unrecognized pharmacological effects which merit further exploration. The study also confirmed the usefulness of Doppler techniques for continuous atraumatic evaluation of digital vessel patency and investigation of therapeutic regimens on intermittent digital artery obstruction in Raynaud's disease.
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A double-blind, between-patient, placebo controlled trial was carried out to investigate the effects of methylcysteine hydrochloride in patients with chronic obstructive bronchitis. After a 2-week washout period on placebo, 30 patients were allocated at random to treatment for 6 weeks with either methylcysteine (1200 mg daily in Week 1, 800 mg daily in Week 2, then 600 mg daily) or with identical placebo tablets on the same regimen. During the post-treatment period, all patients returned to a single-blind placebo regimen (6 tablets daily) for a further 14 days. Assessments were made at the start, at regular intervals during the trial, and at the end of the post-treatment period, of subjective and objective measures of clinical response, and measurements of pulmonary function and certain physico-chemical properties of sputum. The results showed that methylcysteine increased sputum volume, reduced the viscidity of sputum, and significantly improved the subjective assessments of ease of expectoration and severity and frequency of cough, leading to a definite improvement in the patients' clinical state. No side-effects of clinical significance were reported and no abnormalities were found in any of the haematological, hepatic and renal function tests carried out.
The metabolic fate and pharmacokinetics of Bamifylline have been investigated by high performance liquid- and gas-chromatography techniques and radio-isotopic methods in several experiments following oral and intravenous administration of single and repeated doses of 300 mg, 600 mg and 900 mg of this drug. The 300 mg single- and multiple-dose experiments were performed by comparing Bamifylline with 200 mg of Theophylline within the confines of controlled double-blind randomized cross-over studies. Bamifylline is catabolized into several closely related compounds and into sulpho- and glucurono-conjugates of an hydroxylated derivative. Its metabolites are rapidly and extensively excreted via the kidneys and the liver. Only the unchanged Bamifylline has been recorded in the blood following administration of the radio-labelled parent compound. Bamifylline achieves peak plasma levels more rapidly than Theophylline. The half-time of Bamifylline plasma concentrations ranges from 1.5 hours to 2.0 hours, which is appreciably shorter than that of Theophylline which exceeds four hours. By further contrast the distribution volumes of Bamifylline are three to ten times larger than those of Theophylline. No evidence of cumulation has been found in blood following the repeated administration off doses as high as 900 mg administered at intervals of eight hours.
Laboratory tests of blood coagulation and platelet activity were undertaken in fifty-two climacteric patients who received cyclical oestrogen regimens for six consecutive months, following which they were given cyclical sequential oestrogen/progestogen regimens for periods ranging from fifteen months to twenty-seven months. The cyclical sequential regimen employed was determined by the dosage of oestrogen prescribed during the initial six-month period: norethisterone (2.5 mg or 5.0 mg) on days sixteen to twenty-one of cyclical treatment with oestrone piperazine sulphate or conjugated equine oestrogens, and DL-norgestrel (0.5 mg daily) from day twelve to day twenty-one of cyclical oestradiol valerate treatment. The results suggest that the addition of a progestogen to the cyclical oestrogen treatment does not modify blood coagulation factors or platelet aggregation.
In a continuing prospective study, uterine curettage was undertaken on sixty-four patients attending a Menopause Clinic prior to consideration of gonadal hormone therapy. Two of these patients (3.1%) were found to have endometrial hyperplasia, and subsequently they were not given gonadal hormone therapy. Sixty-two patients with normal endometrium at pre-treatment curettage received cyclical oestrogen regimens or sequential oestrogen/progestogen treatments. Four (30.8%) of the thirteen patients in receipt of cyclical 'high-dose' oestrogens developed cystic glandular hyperplasia, whereas none of the patients taking either cyclical 'low-dose' oestrogens (thirty patients) or cyclical-sequential oestrogen/progestogen regimens (nineteen patients) developed endometrial hyperplasia. Among the patients with a normal endometrium, both before and during cyclical gonadal hormone therapy, regular withdrawal bleeding was experienced by thirty-two patients (51.6%). Breakthrough bleeding occurred in nine (14.5%), while twenty-one patients (33.9%) had no vaginal bleeding. Of the four patients with normal endometrium at pre-treatment curettage who subsequently developed endometrial hyperplasia during cyclical 'high-dose' oestrogen therapy, regular withdrawal bleeding was experienced by two patients, and in one of these breakthrough bleeding also occurred. Furthermore, in the four patients who developed endometrial hyperplasia, this condition occurred within six months in two patients and within 9 and 10 months respectively in the remaining two. In the nineteen patients receiving cyclical sequential oestrogen/progestogen regimens, all had regular withdrawal bleeding, while one patient had breakthrough bleeding during sequential therapy. It is concluded that in those climacteric patients who present with severe menopausal symptoms which necessitate the administration of high-dose oestrogen regimes it is necessary either to undertake both pretreatment uterine curettage or to add a progestogen to the oestrogen in a sequential regimen.