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.

Optimal nitrate therapy with a once-daily sustained-release formulation of isosorbide mononitrate.

During long-term prophylaxis of angina with oral nitrates, sustained high plasma nitrate concentrations produce partial or complete tolerance to both the haemodynamic and the clinical effects of the drug. There is substantial evidence that this can be prevented by an adequate nitrate-free or nitrate-low period during each 24 h dosing interval. However, a nitrate-free interval carries the risk of a rebound increase in myocardial ischaemia. Once-daily formulations of isosorbide mononitrate deliver high plasma nitrate concentrations that improve exercise tolerance in patients with angina for at least 12 h after dosing. During the remainder of the dosage interval, plasma nitrate concentrations fall but are sufficient to protect against coronary artery spasm overnight. Myocardial ischaemia has a marked circadian rhythm. All ischaemic events (total ischaemic burden, myocardial infarction and sudden cardiac death) are most frequent in the hours immediately after waking. Oral anti-ischaemic prophylaxis should ideally provide protection during this critical period, in order to minimize symptoms, maximize exercise capacity and perhaps also to reduce the risk of clinical events. The ideal long-acting nitrate formulation should therefore provide a rapid rise in plasma nitrate concentration as well as maintaining prolonged efficacy throughout the dosing interval. Elantan LA is a sustained-release capsule formulation of isosorbide mononitrate for once-daily dosing. This capsule contains pellets which release 30% of the dose immediately, while 70% is released slowly to maintain the therapeutic response. The pharmacokinetic profile of this formulation prevents the development of tolerance, while also conferring long-term anti-anginal efficacy. Patients reported an improvement in both severity of angina and quality of life indices when their therapy was changed from multiple daily dosing with isosorbide dinitrate to once-daily dosing with Elantan LA (50 mg). The anti-anginal effect of Elantan LA is attained rapidly after dosing. Within 30 min of ingestion, there are clinically significant improvements in exercise tolerance, comparable with the speed of onset after an immediate-release formulation of isosorbide mononitrate. Elantan LA is an effective once-daily prophylaxis for angina which also produces a rapid onset of therapeutic effect. The release profile of this formulation maximizes protection against the morning surge in myocardial ischaemia.

The influence of two types of meal on the pharmacokinetics of a modified-release formulation of nifedipine (Adalat Retard).

OBJECTIVE: The effect of two different types of meal on the absorption of a modified-release formulation of nifedipine (Adalat Retard) was studied. RESULTS: A light breakfast produced a delay in gastric emptying (indicated by the rate of paracetamol absorption) compared with the fasting state but did not alter the tmax or Cmax for nifedipine significantly. After a cooked breakfast, there was less delay in gastric emptying and again no delay in tmax for nifedipine. However, the Cmax for nifedipine was significantly higher than in the fasting state. Neither meal influenced the bioavailability of nifedipine. CONCLUSION: The results suggest that the nature of the meal has an important influence on the absorption profile of this formulation of nifedipine, probably by an effect on its dissolution. This study illustrates the importance of considering the effects of different types of meal before concluding that food does not affect the pattern of drug absorption.

Double-blind comparative study of the antidepressant, unwanted and cardiac effects of minaprine and amitriptyline.

1. A double-blind, multicentre study comparing the efficacy and safety of minaprine and amitriptyline in patients with major depression was carried out. Five hundred and thirty-one patients were randomly assigned to treatment with either minaprine 100 mg, 200 mg or 300 mg day-1 or with amitriptyline 150 mg day-1 (75 mg during the first week). The medication was administered for 6 weeks. 2. Efficacy was assessed using the Hamilton rating scale for depression (HDRS), the Montgomery-Asberg depression rating scale (MADRS) and visual analogue assessments of depression carried out by both the investigators and patients. Unwanted effects were assessed by a questionnaire and spontaneous reporting. In a subgroup of patients cardiovascular effects were investigated by high speed ECG and systolic time intervals. 3. Patients in each treatment group showed a significant clinical improvement (P < 0.01) from baseline. The mean HDRS and MADRS scores adjusted for baseline differences, showed significantly less improvement in the minaprine 100 mg once daily (P < 0.01) and the minaprine 300 mg daily (P < 0.01) groups than in the amitriptyline group at both week 4 and week 6. The MADRS score at week 4 suggested that 200 mg day-1 minaprine was less effective than amitriptyline (P < 0.05), but there was no difference between the two groups at week 6 on either the HDRS or the MADRS. 4. Both drugs were well tolerated and there were no significant differences between treatment groups in any of the safety and tolerance assessments. In the ECG, amitriptyline produced a significant increase in the heart rate and PR interval while minaprine had no effect on electrocardiographic measurements. Neither drug produced changes in the systolic time intervals.

The effects of co-administration of benzhexol on the peripheral pharmacokinetics of oral levodopa in young volunteers.

1. The effects of benzhexol on the absorption and pharmacokinetics of an oral dose of levodopa have been studied in 10 young healthy volunteers. Subjects were given a suspension of levodopa (250 mg) 90 min after either benzhexol (5 mg) or placebo in a randomized cross over design with doses separated by at least 1 week; on each occasion carbidopa was given 1 h before and 5 h after the dose of levodopa. Soluble paracetamol and radiolabelled DTPA were given with the levodopa as markers of gastric emptying. 2. Most subjects showed two peaks in the levodopa plasma concentration-time curve on the placebo day, with the second minor peak occurring 1-2 h after the dose. After benzhexol administration all subjects showed two or more peak levodopa concentrations in plasma. Benzhexol administration caused a significant decrease in the maximum concentration (43%; P < 0.05) of the initial peak and an increase (22%; P < 0.1) in the maximum concentration of the second peak. This change in absorption profile caused by benzhexol significantly altered the ratios of the second peak compared with the initial peak for both the maximum concentrations (P < 0.02) and for the AUC values (P < 0.05). Benzhexol administration did not affect the total AUC of levodopa (7.30 +/- 1.09 vs 7.19 +/- 1.26 micrograms ml-1 h; means +/- s.d.). 3. The plasma concentration-time curves for paracetamol showed similar profiles to those for levodopa and the ratios of the peak concentrations and AUC values for the second peak compared with the initial peak were increased significantly by benzhexol administration (P < 0.05). The total AUC of paracetamol was not affected by benzhexol administration (39.4 +/- 8.2 vs 40.0 +/- 8.9 micrograms ml-1 h; mean +/- s.d.) 4. Benzhexol altered the gastric emptying profile, shown by gamma-scintigraphy, with a reduced extent of initial emptying prior to the establishment of the plateau which is characteristic of levodopa administration in the fasting state. In consequence the ratio of the second to the initial phase of emptying was significantly higher (P < 0.01) following benzhexol treatment. 5. Benzhexol reduces the initial phase of gastric emptying after a dose of levodopa so that there is a decrease in the initial peak and a greater proportion of the dose is absorbed subsequently following the second phase of gastric emptying which occurs approximately 1 h later. Theoretically, this altered concentration-time profile could be an advantage for some patients with Parkinson's disease.

Xamoterol improves right ventricular systolic and diastolic function in pulmonary heart disease.

OBJECTIVE: Abnormal right ventricular function in patients with pulmonary heart disease (PHD) may contribute to their reduced exercise capacity. We have evaluated the effect of subacute dosing with xamoterol, a beta-1 adrenoreceptor partial agonist with inotropic properties, on right ventricular function in patients with PHD. PATIENTS: Twelve patients with advanced chronic obstructive pulmonary disease and clinical evidence of PHD received xamoterol 200 mg twice daily or placebo for 7 days in a randomised double-blind crossover study. Right heart krypton-81m radionuclide ventriculography was used to derive right ventricular ejection fraction (RVEF) both at rest and during submaximal exercise, and indices of right ventricular systolic and diastolic function at rest. RESULTS: During treatment with placebo, mean RVEF was 0.53 at rest and was unchanged during exercise. After xamoterol, mean RVEF was 0.55 at rest and increased to 0.59 during exercise. Xamoterol increased right ventricular peak ejection rate from 3.04 to 3.45 EDV.s-1 and mean early diastolic filling rate from 1.00 to 1.20 EDV.s-1. CONCLUSION: Subacute treatment with xamoterol in patients with PHD improves right ventricular systolic and diastolic function at rest and results in a favourable augmentation in right ventricular function during submaximal exercise.

The effect of selegiline on the peripheral pharmacokinetics of levodopa in young volunteers.

The plasma pharmacokinetics of levodopa were studied in eight healthy young subjects following an i.v. infusion of 50 mg over 5 min. Subjects were studied on two occasions in random order following treatment with carbidopa; on one occasion they were pretreated with selegiline (four doses of 10 mg over the preceding 3 days) and on the other with a placebo. The mean plasma concentration-time curves on each occasion were essentially superimposable and there were no significant differences in any calculated pharmacokinetic parameter. Selegiline does not significantly alter the distribution or elimination of levodopa from plasma.

Factors affecting the absolute bioavailability of nifedipine.

1. Nifedipine was administered to eight volunteers (seven Caucasian, one East Asian of Chinese origin) as a single 10 mg capsule orally and as 2.5 mg intravenously. The pharmacokinetics were determined under fasting conditions and following 200 ml double strength grapefruit juice taken orally both 2 h before and at the time of dosing. 2. In a separate study, the pharmacokinetics of nifedipine were defined in eight South Asian volunteers (with both parents originating from the Indian subcontinent) following 10 mg nifedipine orally and 2.5 mg intravenously. 3. The administration of grapefruit juice did not alter the pharmacokinetics of intravenous nifedipine, but resulted in a significantly increased area under the plasma concentration-time curve (AUC) (191 +/- 59 c.f. 301 +/- 95 ng ml-1 h, P < 0.05) and bioavailability (0.63 +/- 0.18 c.f. 0.86 +/- 0.15, P < 0.05) following oral nifedipine. The elimination half-life was unchanged by administration of grapefruit juice and there was no evidence of decreased formation of the nitropyridine first-pass metabolite. 4. The AUC of nifedipine after intravenous administration was significantly higher in South Asian subjects than in Caucasians (146 +/- 39 c.f. 74 +/- 18 ng ml-1 h, P < 0.002). This was due to a lower systemic clearance in the South Asians which was 50% of that in the Caucasians. The half-life was markedly prolonged in South Asians (4.1 +/- 1.9 c.f. 1.7 +/- 0.5 h, P < 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Normal right ventricular systolic and diastolic function assessed by krypton-81m equilibrium ventriculography.

Krypton-81m equilibrium ventriculography was used to study right ventricular function in 23 healthy male volunteers. Technetium-99m lung perfusion scintigraphy was employed to subtract radionuclide activity within lung during image analysis thereby enhancing image quality. The imaging technique was used to generate a time-activity curve for the right ventricle allowing the definition of indices of normal systolic and diastolic function for the right ventricle. At rest, indices of systolic ejection and diastolic filling were comparable to those previously reported for the left ventricle. Using the imaging technique, movement artifact during exercise reduces image quality and limits accurate measurement of these indices to resting studies.

Quercetin, an in vitro inhibitor of CYP3A, does not contribute to the interaction between nifedipine and grapefruit juice.

Quercetin, a flavonoid present in various fruits, is a potent in vitro inhibitor of CYP3A. Its role in the reported interaction between grapefruit juice and nifedipine has been determined in vivo in humans. Eight healthy volunteers were given in random order 10 mg nifedipine orally, either alone or with 200 ml double strength grapefruit juice, or with 400 mg quercetin. The area under the plasma concentration-time curve (AUC) for nifedipine with grapefruit juice (mean 320 ng ml(-1) h) was increased significantly (P < 0.01) compared with the AUC when nifedipine was given alone (mean 218 ng ml(-1) h). The time to peak plasma concentration for nifedipine with grapefruit juice (1.5 h) was also increased (P < 0.05) compared with control (0.5 h) suggesting delayed absorption. Although quercetin delayed the time to peak nifedipine concentration (1.3 h) it did not alter the AUC of either the parent drug (mean 209 ng ml(-1) h) or its first-pass metabolite. The results suggest that quercetin does not contribute to the effects of grapefruit juice (which contains <10 mg of quercetin 200 ml(-1)) on the metabolism of nifedipine. Oral doses of quercetin, similar to those possible from the ingestion of other fruits such as strawberries, do not produce in vivo inhibition of CYP3A mediated metabolism of nifedipine.

A comparison of the acute haemodynamic effects of nisoldipine and nifedipine during treatment with atenolol in patients with coronary artery disease.

1. The acute haemodynamic effects of intravenous nisoldipine (1, 2, 4 microg kg(-1)) and nifedipine (2.5, 5, 10 microg kg(-1)) were compared in a randomised, within-patient crossover study. Fifteen male patients with stable angina pectoris treated with atenolol were studied after undergoing routine cardiac catheterisation. 2. Nisoldipine caused a dose-related fall in systemic vascular resistance (maximum 22%) associated with an increase in heart rate and cardiac index (18%) and a fall in mean arterial pressure (7%). 3. By contrast, nifedipine was associated with a significant increase in heart rate but systemic vascular resistance, cardiac index and mean arterial pressure remained unaltered. 4. At doses with equivalent effects on heart rate (2 microg kg(-1) nisoldipine; 10 microg kg(-1) nifedipine) acute dosing with nisoldipine caused a significantly greater fall in systemic vascular resistance and increase in cardiac index, whilst nifedipine caused a greater reduction in stroke volume index and left ventricular stroke work index. 5. The results suggest that, when combined with atenolol, acute dosing with nisoldipine may have a more complementary haemodynamic profile than nifedipine. The implications of this finding for chronic oral dosing in patients with impaired left ventricular function should be evaluated.

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.

A comparison of nisoldipine and nifedipine, in combination with atenolol, in the management of myocardial ischaemia.

The effects of the addition of slow-release nifedipine 20 mg twice daily and nisoldipine 10 mg twice daily to atenolol monotherapy were compared in a double-blind placebo-controlled study of 24 patients with chronic stable angina pectoris. Neither nisoldipine nor nifedipine was associated with significant subjective benefit at these doses. Two hours post-dosing, exercise capacity improved after both nisoldipine (duration + 37 s, P < 0.01; time to angina + 67 s, P < 0.01; time to significant ST depression + 60 s, P < 0.01) and nifedipine (duration + 21 s, ns; time to angina + 56 s, P < 0.05; time to significant ST depression + 49 s P < 0.05). However, this improvement was not maintained 12 h post-dosing. Ambulatory monitoring did not demonstrate a significant reduction in the amount of silent or total ischaemia following the addition of either nifedipine or nisoldipine to atenolol monotherapy. There was no significant difference between nifedipine and nisoldipine in any parameter tested. In conclusion, like slow-release nifedipine 20 mg, the effective duration of anti-ischaemic action of nisoldipine 10 mg is less than 12 h. Since several patients experienced vasodilatory unwanted effects, more frequent administration rather than larger individual doses may be desirable to achieve a clinical response.

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.

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.

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.