The influence of dose and ethnic origins on the pharmacokinetics of nifedipine.

The pharmacokinetics of nifedipine capsules was investigated in healthy young Caucasian and South Asian subjects. Both the area under the plasma concentration-time curve (AUC) and terminal half-life of nifedipine were significantly higher in South Asians compared with Caucasian subjects after single oral doses of 10 and 20 mg. The AUC and half-life values of the nitropyridine metabolite were also higher in South Asians than in Caucasian subjects. The serum protein binding of nifedipine was similar in the two groups. The pharmacokinetics were essentially linear in both Caucasian subjects (0 to 30 mg; n = 27) and South Asians (0 to 20 mg; n = 16). There was no indication of a separate subgroup of Caucasian subjects with high AUC values equivalent to the poor metabolizers reported previously. Pharmacodynamic modeling for South Asians gave estimates comparable to those previously reported in Caucasian subjects. Patients of South Asian origin may require lower doses of nifedipine.

Measurement of glomerular filtration rate with technetium-99m DTPA: comparison of plasma clearance techniques.

We have compared several techniques for measuring [99mTc]DTPA plasma clearance following single injection to estimate glomerular filtration rate (GFR). Half hourly measurements of disappearance of plasma activity were used to calculate a reference GFR corrected for one-pool assumption and body surface area. Alternative methods involving (i) single blood sample, (ii) two blood samples, (iii) external detector clearance rate, and (iv) a combination of (i) and (iii) were then compared. Closest correlations were obtained with (i) two blood samples at 2 hr and 4 hr (s.e.e. 2.8 ml/min) and (i.v.) external rate constant from 2-5 hr with a blood sample at 3 hr (s.e.e. 3.0 ml/min). Correlations with single blood sample were closest at 3 hr and 4 hr postinjection (s.e.e. 5.4 and 4.5 ml/min, respectively). External detector disappearance rate constant alone was least accurate (s.e.e. greater than 10 ml. min).

Right ventricular function at rest and during exercise in chronic obstructive pulmonary disease. Comparison of two radionuclide techniques.

Right ventricular function was assessed in 24 patients with COPD, at rest and during submaximal exercise, using both technetium-99m (99mTc) blood-pool and krypton-81m (81mKr) equilibrium ventriculography. Technetium-99m right ventricular ejection fraction (RVEF) at rest was lower than 81mKr RVEF (0.39 +/- 0.12 and 0.54 +/- 0.08, respectively; p < 0.001). During submaximal exercise, there was no increase in RVEF using either imaging technique. This observation contrasted with an increase in RVEF in a group of age-comparable normal subjects during modest submaximal exercise. An inability to obtain spatial separation of right heart structures using 99mTc imaging leads to a value for RVEF that is consistently lower than that measured using 81mKr ventriculography. Resting RVEF is well preserved at rest in most patients with COPD. In contrast to normal subjects, many show an inability to augment right ventricular function during exercise that may contribute to the reduced exercise capacity observed in these patients.

Effect of drug treatment on quality of life in mild to moderate heart failure.

The most frequently reported symptoms in heart failure are fatigue and dyspnoea, which limit exercise tolerance. However, several surveys reveal other changes in physical and psychological well-being which affect the patient's perception of 'quality of life'. The introduction of new treatments for heart failure has stimulated interest in their impact on quality of life. Until recently, attempts to quantify well-being were restricted to assessment of symptoms which affect exercise capacity or classification of the functional capacity of the patient from his ability to perform everyday tasks. Although drug treatment can improve these measures, they are insensitive to change and also provide little information on the more subtle disturbances which patients may perceive as important determinants of their overall well-being. More comprehensive assessments of quality of life have been devised and validated in heart failure. Early results indicate that inotropic drugs such as digoxin and xamoterol can improve these measures. However, at present there is too little information from studies using these questionnaires to compare the wider benefits of individual drug treatments.

Thyroid function and urine-concentrating ability during lithium treatment.

It has been suggested that adenylate cyclase inhibition may be important in the development of both nephrogenic diabetes insipidus and hypothyroidism during lithium treatment. We measured serum thyroxine and urine-concentrating ability (Umax) in response to desmopressin (DDAVP) in 85 patients receiving lithium. Hypothyroidism developed in eight patients while they were taking lithium. Impaired Umax was found in both euthyroid and hypothyroid patients while some hypothyroid patients concentrated their urine well. It is concluded that the dominant mechanisms by which lithium exerts these two effects are different.

Doxazosin in renal impairment.

The pharmacokinetics of doxazosin given once daily are similar in patients both with normal and with impaired renal function and consequently doxazosin can be used effectively in both at similar doses. Renal blood flow is well preserved during long-term treatment but effects on glomerular filtration rates are less consistent and small reductions may occur. It is uncertain whether these reflect a reduction in perfusion pressure, progression of the underlying renal disease or a combination of the two. Postural hypotension may occur in some patients after an initial dose of 1 mg.

A qualitative and quantitative study of the incidence, features and aetiology of near death experiences in cardiac arrest survivors.

AIM: To carry out a prospective study of cardiac arrest survivors to understand the qualitative features as well as incidence, and possible aetiology of near death experiences (NDEs) in this group of patients. METHOD: All survivors of cardiac arrests during a 1 year period were interviewed within a week of their arrest, regarding memories of their unconscious period. Reported memories were assessed by the Greyson NDE Scale. The postulated role of physiological, psychological and transcendental factors were studied. Physiological parameters such as oxygen status were extracted from the medical notes. Patients' religious convictions were documented in the interviews and hidden targets were used to test the transcendental theories on potential out of body claims. Those with memories were compared to those without memories. RESULTS: 11.1% of 63 survivors reported memories. The majority had NDE features. There appeared to be no differences on all physiological measured parameters apart from partial pressure of oxygen during the arrest which was higher in the NDE group. CONCLUSIONS: Memories are rare after resuscitation from cardiac arrest. The majority of those that are reported have features of NDE and are pleasant. The occurrence of NDE during cardiac arrest raises questions about the possible relationship between the mind and the brain. Further large-scale studies are needed to understand the aetiology and true significance of NDE.

The effect of acute hypoxia on right ventricular function in healthy adults.

Right ventricular ejection fraction and right ventricular volumes were derived in 12 healthy male subjects using krypton-81m equilibrium radionuclide ventriculography whilst subjects breathed 30% (high inspired oxygen) and then 8-12% oxygen in nitrogen mixture (hypoxia). 'Physiological' tricuspid valve regurgitation was identified in 7 of the subjects by Doppler echocardiography, and right ventricular peak systolic pressure was estimated during high inspired oxygen and during hypoxia. Mean right ventricular peak systolic pressure was 24.1 +/- 3.3 mmHg during high inspired oxygen and increased to 41.3 +/- 8.4 mmHg during hypoxia (P less than 0.01). Mean right ventricular ejection fraction was 0.612 +/- 0.075 during high inspired oxygen and was unchanged at 0.590 +/- 0.073 during hypoxia. There was no significant change in right ventricular end-diastolic volume or stroke volume in response to hypoxia. The systolic performance of the normal right ventricle is well-maintained during an acute rise in afterload induced by hypoxia.

Effect of food and activity on the reproducibility of isotopic GFR estimation.

The reproducibility of the plasma clearance of 99Tcm DTPA was studied in 26 patients under standardized conditions with the subject fasting and at rest. The coefficient of variation of duplicate measurements in patients with glomerular filtration rates (GRF's) ranging from 11-103 ml min-1 was 8%. Mean GFR following a breakfast containing 670 kcal and 31 g protein was increased significantly from 40.7 +/- 28.1 ml min-1 to 43.6 +/- 30.8 ml min-1. When fasted but permitted free exercise there was no consistent trend in GFR but the coefficient of variation of duplicate estimates increased significantly to 12.1%. It is recommended that routine GFR measurement should be carried out fasting or following a light diet with restricted activity.

Measurement of glomerular filtration rate with a portable cadmium telluride detector.

The plasma clearance rate constant of 99Tcm-DTPA was measured with a portable cadmium telluride detector over anterior chest wall and lateral leg sites to obtain an empirical estimate of glomerular filtration rate (GFR). Thirteen patients with a range of renal dysfunction were studied to compare the accuracy of the estimates over various time periods compared to GFR estimated from plasma sampling. The chest site was more accurate for GFR assessment over all time periods assessed up to 4 h following injection. The clearance rate constants obtained up to 1 h after injection from the chest site were not significantly less accurate then those from later time periods.

Dosimetry assessment of 81Krm peripheral venous infusion studies.

Calculation of S factors for 81Krm for a full range of target organs from each source organ relevant in 81Krm peripheral venous infusion imaging has been performed. Typical equilibrium activities in the source organs have been measured using quantitative planar gamma camera imaging for a generator with a mean activity at imaging time of 468 MBq eluted at 10 ml min-1. Based on the above measurements and assuming a 10 min infusion period, the mean effective dose equivalent for 81Krm infusion imaging in the assessment of right heart function in adults was found to be 0.365 mSv.

Right ventricular function at rest and during submaximal exercise assessed by 81Krm equilibrium ventriculography in normal subjects.

81Krm equilibrium ventriculography was used to study right ventricular function in 37 healthy male volunteers. 'Anatomical' lung subtraction using 99Tcm lung perfusion scintigraphy was compared with conventional background correction in the calculation of resting right ventricular ejection fraction (RVEF). Resting RVEF was significantly greater following 'anatomical' lung subtraction than that using background correction (0.59 +/- 0.06 versus 0.55 +/- 0.05). The exercise response of the normal right ventricle was defined in 23 subjects during exercise. Right ventricular ejection fraction showed a progressive increase during graded submaximal exercise (0.55 +/- 0.05 at rest, 0.60 +/- 0.05 at 50 W and 0.66 +/- 0.05 at 100 W). Right heart 81Krm equilibrium ventriculography is well suited to the evaluation of right ventricular function at rest and during exercise. The absolute value of RVEF will however be dependent upon the method of image analysis.

Vibrotactile sensation and response to nifedipine dose titration in primary Raynaud's phenomenon.

The clinical response to two doses of sustained-release nifedipine was assessed during a double-blind, randomized, placebo-controlled trial in 22 patients with primary Raynaud's phenomenon. Nifedipine at doses of 20 mg and 40 mg daily reduced the mean number of attacks by 40% compared with placebo with no significant differences between the two doses in the number of attacks or their severity. Unwanted effects were more common and more persistent with the higher dose of nifedipine. Fingertip vibrotactile thresholds measured at 31.5 and 125 Hz were unchanged by treatment with nifedipine. There was, however, a correlation between the pretreatment threshold at 125 Hz and the response to treatment with nifedipine, the most favorable responses occurring in patients with the lowest thresholds.

Maximising safety when prescribing non-steroidal anti-inflammatory drugs.

Current knowledge on side-effects of non-steroidal anti-inflammatory drugs (NSAIDs) is reviewed. These occur most commonly in the gastro intestinal tract and include peptic ulceration and haemorrhage as well as effects on the small and large bowel. Renal effects with many manifestations are also increasingly described. Photosensitivity is the most common adverse dermatological effect. The role of various NSAIDs in causing asthma is now well recognised. Many less common side-effects occur, the most significant of which is marrow aplasia. Phenylbutazone and indomethacin are rarely but definitely associated with this, but other NSAIDs including ibuprofen are also suspected, but unproven, causes. A strategy for minimising side-effects is outlined. Where there is not a strong indication for use of an NSAID, local physical measures or a pure analgesic can be substituted. If an NSAID is really necessary, it is best to commence with a drug of lesser potency in the first instance, unless the patient is suffering from a severe inflammatory disorder. Indomethacin and piroxicam should be reserved for when other NSAIDs have not been effective. Patients who have a past or present history of peptic ulceration but still need to continue their NSAID therapy, should combine it with an anti-ulcer drug. In the case of younger patients a H2 receptor antagonist is the drug of first choice, whereas in the older patient a mucosal protective agent such as sucralfate is preferred. In the event of ulcer relapse, combination with a prostaglandin analogue is the next step. The growing awareness of side-effects with NSAIDs suggests that monitoring of patients commencing NSAIDs and on long-term treatment, should be increasingly practiced.

The effect of captopril on autonomic reflexes in human hypertension.

The effects of acute administration of captopril on heart rate, blood pressure and physiological responses to head-up tilt, hand-grip, exercise and Valsalva manoeuvre were studied in 25 hypertensive subjects (10 untreated, 15 previously treated). After chronic administration for 8-12 weeks the effect on heart rate, blood pressure and the response to head-up tilt were studied again in 15 of these subjects. After the first dose of captopril (0.5 mg/kg), both systolic and diastolic blood pressures fell significantly, with no change in heart rate. Head-up tilting produced a significant increase in heart rate without any alteration in the blood pressure; hand-grip produced a significant increase in heart rate and blood pressure. These responses and exercise-induced tachycardia were unaltered by captopril. There was a significant reduction in the Valsalva ratio. After chronic administration the hypotensive efficacy was maintained for 10-12 h after the last dose, suggesting that twice daily dosage may be sufficient. There was a significant reduction in the basal supine heart rate by captopril. Head-up tilt produced the same physiological changes as in the acute study. These findings suggest that captopril has a vagotonic effect, possibly associated with resetting of baroceptor mechanisms. This could be one explanation for the hypotensive effect of captopril even in low-renin states.