What knowledge and skills are essential for specialists in Clinical Pharmacology and Therapeutics? Results of a Delphi study.

AIMS: To identify the knowledge and skills that should be considered essential for specialists in Clinical Pharmacology and Therapeutics (CPT) with a commitment to the National Health Service (NHS). METHODS: A Delphi study using a sample of current specialists. RESULTS: Members of the expert panel (20 in all, representative of the Clinical Section membership) identified 78 statements for consideration, in four domains (core of knowledge, therapeutic skills, educative skills, and investigative skills), of which 58 (74.4%) were accepted by more than two-thirds of respondents. Of these, 35 were knowledge items, whereas 23 were skills (11 therapeutic, 4 educative and 8 investigative). The large majority (79.3%) of these statements were endorsed by at least four out of five panel members. CONCLUSIONS: Despite the varied work patterns and responsibilities of specialists in CPT, it is possible to identify a core of knowledge and skill that most consider essential for the delivery of their commitment to the NHS. The findings will provide NHS Trusts with a clear idea of what they can expect from these specialists, and will act as a checklist for specialists themselves to direct their Continuing Professional Development within the consultant appraisal process. The results also describe a curriculum for continuing education in CPT, which the BPS Clinical Section can use to develop information resources and training opportunities.

Continuing Medical Education in Clinical Pharmacology and Therapeutics: report of a questionnaire survey.

AIMS: To seek the views of medically qualified members of the Clinical Section of the British Pharmacological Society (BPS) on their perceived needs for Continuing Medical Education (CME); on how and by whom these needs should be addressed; and on how the outcome of any educational intervention might best be assessed. METHODS: A structured questionnaire. RESULTS: Of 233 recipients, 140 (60%) responded, but only 123 of these fulfilled the criteria for analysis. A large majority of respondents were clinicians, most of whom devoted at least 25% of their working week to their NHS commitment. There was widespread reliance on textbooks and journals as sources of CME, supplemented by discussions with specialist peers at national and international meetings. Many felt that fulfilling even this agenda was stretching their commitment to the limit, and their greatest need was for protected time in which to learn. There was a desire among 49% of all respondents for the BPS Clinical Section to take some responsibilty for addressing the future needs of its members, and 75% took the view that academic departments should contribute to the development and updating of materials. There was no clear agreement about what these should comprise, but around half of all respondents favoured web-based, journal-based or computer-assisted educational material offering self-assessment opportunities; and CME symposia or workshops at BPS meetings. Almost half (46%) felt that assessment of CME should be integrated with a well-organized appraisal system and the use of portfolios. Six out of 10 respondents were already, or were about to be, regularly appraised at their place of work. CONCLUSIONS: The questionnaire survey revealed a broad canvas of views and little evidence of consensus except for a general plea for more time in which to learn. The aim of the Clinical Section should be to facilitate and help its members to organize their learning, in a way that is consistent with national trends in Continuing Professional Development. The Clinical Section should co-ordinate the setting up of an electronic library of appropriate published material, compiled by academic and industrial sources, that would guide members seeking up-to-date knowledge of Clinical Pharmacology and Therapeutics. The British Journal of Clinical Pharmacology (BJCP) should commission review articles on recent developments where no suitable published material exists. Academic departments should also be invited to identify or develop self-assessment material that members could use to reinforce their learning, and demonstrate their knowledge to relevant professional bodies. The Clinical Section should organize Symposia and Workshops at which contentious issues in Clinical Pharmacology and Therapeutics can be discussed and resolved.

How can we afford costly medicines?

Affording the ever-increasing cost of medicines is a struggle throughout the NHS. A College Working Party has addressed the issues in an extensive recent report that analyses the cost of medicines, their licensing and evaluation, priority setting and its ethical and legal implications. It considers options for increasing the available resource, but explains why everyone concerned with the evaluation, funding and use of medicines must recognise the need to set priorities. Though the report does not pretend to have solved the problem facing the NHS, it describes many examples of good practice and suggests a way forward.

Studies of the oral bioavailability of alendronate.

Clinical studies were performed to examine the oral bioavailability of alendronate (4-amino-1-hydroxy-butylidene-1,1-bisphosphonate monosodium). All studies, with the exception of one performed in men, involved postmenopausal women. Short-term (24 to 36 hours) urinary recovery of alendronate after an intravenous dose of 125 to 250 micrograms averaged about 40% in both men and women. In women, oral bioavailability of alendronate was independent of dose (5 to 80 mg) and averaged (90% confidence interval) 0.76% (0.58, 0.98) when taken with water in the fasting state, followed by a meal 2 hours later. Bioavailability was similar in men [0.59%, (0.43, 0.81)]. Taking alendronate either 60 or 30 minutes before a standardized breakfast reduced bioavailability by 40% relative to the 2-hour wait. Taking alendronate either concurrently with or 2 hours after breakfast drastically (> 85%) impaired availability. Black coffee or orange juice alone, when taken with the drug, also reduced bioavailability (approximately 60%). Increasing gastric pH, by infusion of ranitidine, was associated with a doubling of alendronate bioavailability. A practical dosing recommendation, derived from these findings and reflective of the long-term nature of therapy for a disease such as osteoporosis, is that patients take the drug with water after an overnight fast and at least 30 minutes before any other food or beverage.

Transepithelial water movement in response to carbamazepine, chlorpropamide and demeclocycline in toad urinary bladder.

1. Osmotic water movement across toad isolated hemibladders was measured by a gravimetric method. 2. The influence of carbamazepine, chlorpropamide and demeclocycline on the antidiuretic hormone (ADH)-induced water flow rate was examined. 3. No antidiuretic activity due to carbamazepine alone was observed but a slight inhibition due to ADH-induced water flow was observed in the presence of carbamazepine over a selected dose-range. This was unexpected and is inconsistent with data from in vivo studies in man. 4. Chlorpropamide potentiated ADH-induced water flow, in keeping with the hypothesis that chlorpropamide sensitizes the renal tubules to ADH-induced water flow. 5. Demeclocycline inhibited ADH-induced water flow. The mechanism of action remains unclear.

A single oral dose method for predicting steady state theophylline concentrations in clinical practice.

A single dose, single point method of predicting patients' oral maintenance theophylline dosage has been compared with a noninvasive method. Twenty patients with obstructive lung disease received an oral dose (6 mg kg-1) of micro-crystalline theophylline. The plasma theophylline concentration after 8-10 h was then used to calculate the optimum maintenance dose of sustained release aminophylline required to achieve steady state concentrations between 55 and 110 mumols l-1. The mean steady state plasma theophylline concentration for this dosage schedule was also predicted by a method using population average pharmacokinetic parameters (assumed clearance method). These predictions were then compared with observed concentration-time profiles at steady state. The mean difference between the observed values and those predicted from a morning test dose was -0.11 mumol l-1 (95% CI -7.0 to +7.2). A larger difference (-7.4 mumol l-1 95% CI -18.2 to +3.4) was found for the assumed clearance method. Since the confidence intervals contain zero, these differences are not significantly different from zero at the 5% level, although the morning test dose method allowed prediction of the whole concentration-time profile and was more precise. An evening test dose was also used in the study, but the mean difference between the observed values and those predicted from this method was larger at -24.8 mumol l-1 (95% CI -32.89 to -17.21) and was significantly different from zero. This study indicates that a morning test dose followed by a single blood sample can be used to establish maintenance theophylline therapy quickly and safely in selected patients.

Perceptions of pain relief after surgery.

OBJECTIVE: To assess patients' satisfaction with postoperative pain relief. DESIGN: A descriptive and questionnaire study of patients' experience. SETTING: Two surgical and two gynaecological wards. PATIENTS: 50 Patients admitted to hospital for cholecystectomy and 51 admitted for hysterectomy. MAIN OUTCOME MEASURES: Visual analogue scales with no divisions were completed by the patients immediately after each dose of postoperative analgesia was administered throughout their stay in hospital. A questionnaire completed on the fifth postoperative day recorded patients' recollections of their experience. Opinions were also sought from medical and nursing staff. RESULTS: During the first 24 hours after surgery recorded pain levels were 60% of the maximum and were not influenced by age, sex, or the type of operation performed. The median interval between the return of pain and a further injection of analgesic was 2 hours (interquartile range 1 to 3.5 hours). Expectations of pain relief were low, and for 70% of the patients the pain was at least as bad as they had expected. Only half of the medical and nursing staff questioned thought that postoperative analgesia should relieve pain completely; drugs were prescribed and administered with too little attention to the patient's response and too much concern about adverse effects and opioid dependence. CONCLUSIONS: The results suggest that the standard of postoperative pain relief is poor because of inadequate education of patients in what to expect (and demand), and of medical and nursing staff in how to prescribe and administer analgesia with reference to individual drug response.

The fate of drugs in pregnancy.

The response of mother and fetus/neonate to drugs administered to the pregnant woman is determined largely by drug disposition and elimination within and between mother and fetus. Physiological changes occurring in pregnancy may result in reduced plasma protein binding, an increase in the apparent volume of distribution, and more rapid metabolic and renal clearance of certain drugs than are usually found in non-pregnant women. The consequences are relevant for the peak concentration of drug achieved after a single dose, the half-life of the drug, and the drug concentration to which the fetus is exposed via the placenta. Drugs whose dosage may need to be altered in pregnancy include most anticonvulsants, lithium, digoxin, certain beta-blockers, ampicillin and cefuroxime; for drugs which have not been specifically investigated, no generalizations are possible. Very few drugs given in pregnancy fail to cross the placenta and, as a rule, drug molecules not bound to plasma protein diffuse along a concentration gradient to establish and maintain an equilibrium. Because movement of drug molecules is bidirectional, the placenta is the main portal of exit from, as well as entry to, the fetus. The pharmacological response of the fetus to drugs which it receives depends mainly on the unbound concentration of drug in fetal blood--unwanted effects seldom occur if the maternal dose is correct; exceptions include tetracycline, antithyroid drugs, coumarin anticoagulants, aspirin, indomethacin and cerebral depressant drugs (opiates, barbiturates and phenothiazines). The total (bound plus unbound) drug concentration on the fetal side of the placenta is usually lower than on the maternal side except where differences in blood pH and/or protein binding lead to 'trapping' of drug in the fetus; the latter phenomenon may prove hazardous after birth because of the neonate's limited capacity to eliminate drugs by metabolism and excretion.

The effects of diabetes mellitus, exercise, and single doses of biguanides upon lactate metabolism in man.

The polymorphism of phenformin oxidation has been investigated in 103 non-insulin-dependent (Type II) diabetics. The frequency distribution was clearly bimodal and 14 poor metabolisers were identified. The frequency of the recessive allele (0.369) was not significantly different from that found previously in non-diabetics. Six of the extensive metabolisers of phenformin were matched for age, sex and oxidizer phenotype with non-diabetic controls. All subjects underwent a standard 3-min exercise test, using a bicycle ergometer, after which plasma lactate concentration was monitored for 90 min. There was no significant difference between groups in lactate accumulation or elimination. Ten extensive metabolisers, ten poor metabolisers and seven non-diabetics (matched for age, sex and phenotype with seven of the diabetic extensive metabolisers) were challenged with a fasting oral dose of phenformin (50 mg), after which plasma lactate, and blood pyruvate and glucose concentrations were monitored for 4 h. A further ten diabetics (five extensive and five poor metabolisers of phenformin) received a single dose of metformin (1 g) following an identical protocol. No significant changes were observed in any group.

The rise and fall of serum theophylline concentration: a comparison of sustained-release formulations in volunteers with rapid theophylline clearance.

The pharmacokinetics of four sustained-release formulations of theophylline have been examined after single doses (Nuelin SA, Phyllocontin, Slo-phyllin and Theo-Dur) and at steady-state (Phyllocontin, Theo-Dur) in six healthy adult volunteers, selected because they all eliminated theophylline rapidly after an intravenous dose of aminophylline. After a single dose of Theo-Dur, the peak concentration of theophylline was smaller and occurred later than after single doses of Nuelin SA, Phyllocontin and Slo-phyllin, suggesting that absorption occurs over a longer period. The systemic availability of theophylline was virtually complete after all four formulations. After repeated 12-hourly dosing to steady-state, and adjustment of dose to achieve trough concentrations of between 5 and 10 mg l-1 (28-55 mumol l-1), theophylline concentration fluctuated to a significantly greater extent within a dose interval when the subjects were taking Phyllocontin than when they were taking Theo-Dur.

Determinants of plasma alpha 1-acid glycoprotein (AAG) concentrations in health.

The concentration of alpha 1-acid glycoprotein (AAG) was measured in plasma from 200 healthy subjects belonging to 78 family units. The AAG concentration varied markedly between individuals (mean 0.77, range 0.36-1.46 g 1(-1]. When the genetic contribution to the variability was assessed, the only significant correlation observed was that between husband and wife and this was weak. We conclude that in addition to the known effects of age and gender, environmental (rather than genetic) factors largely determine the variance of AAG concentrations.

A comparative study of the bioavailability of five different phenytoin preparations.

The concentration of phenytoin in saliva has been measured in 8 healthy volunteers at intervals after an intravenous dose and after single oral doses of five formulations commercially available in the United Kingdom. The six doses (all 300 mg) were given in random order and at least one week apart. There were no significant differences in the mean values of the peak saliva concentration, the time-to-peak and the area under the saliva concentration-time curve between the five oral formulations. The absolute bioavailability of phenytoin varied between 68 and 74%.