Screening international travellers in China for SARS.

Faced with the spread of SARS through international travel, the World Health Organisation (WHO) advised against inessential travel to certain areas with local SARS transmission, and also the screening of travellers from such areas. This report looks at the steps taken in China for the screening of travellers. Travellers were asked about contact with SARS and possible symptoms, were screened for high fever, provided with health information and observed for any clinical signs. Arrangements were in place for dealing with ill travellers and for contact tracing of fellow travellers. There were also extra measures that could only be justified by the reassurance they provided. The overall impact of these measures in preventing international spread of SARS is unknown, but the experience could contribute to the control of future epidemics.

Research and development in the new NHS: another challenge for the profession.

The continued implementation of the NHS research and development (R&D) strategy is the latest pressure point in the interaction between the medical profession and the new NHS. As the established funding routes for the support of clinical research are scrutinised and desegregated, there will be disaffected losers as well as winners. Further discussion and debate are needed.

Dual molecular mechanisms mediate ligand-induced membrane Ig desensitization.

We have previously shown that ligation of murine B cell membrane IgM or IgD can lead to inactivation of the signal transducing ability of unligated Ag receptors. We describe further studies of the molecular basis of this desensitization. Consistent with the possibility that ligand induced desensitization is mediated by protein kinase C (PKC) are findings that demonstrate that both Ig binding ligands and PKC activators (DIC8 or PMA) induce desensitization in virtually all resting B cells. However, ligand-induced desensitization is longer lived than PMA- or DIC8-induced desensitization and insensitive to the PKC inhibitor staurosporine. Further, biochemical studies indicate that insufficient PKC activation is induced by ligation of membrane Ig to mediate the observed desensitization. Thus data indicate that PKC must play only a minor role in ligand-induced membrane Ig desensitization. Further studies explored the molecular source and target of effectors that mediate ligand-induced desensitization. Data indicate that phosphoinositide hydrolysis is neither necessary nor sufficient for ligand induction of desensitization. Finally, ligand-induced desensitization appears to be mediated by uncoupling of membrane Ig from G proteins that regulate phospholipase C because ligand desensitized cells are hyperresponsive to agents including ALF4- and mastoparan which activate G proteins leading to mobilization of Ca2+. Thus, the function of G proteins and further downstream elements that mediate Ca2+ mobilization is intact. Taken together, these data are most consistent with ligand-induced membrane Ig desensitization being mediated by a non-PKC, non phosphatidylinositol 4,5-bisphosphate hydrolysis involving mechanism that has as its target a structure that is very proximal to the receptor, such as the receptor itself or a transducer complex analogous to CD3.

Suspected adverse drug reactions in elderly patients reported to the Committee on Safety of Medicines.

1. Spontaneous reports of suspected adverse drug reactions (ADRs) reported to the Committee on Safety of Medicines (CSM) have been studied in relation to patient age. 2. The proportion of reports received for the elderly increased between 1965 and 1983. 3. There was a correlation between the use of drugs and the number of ADR reports. Thus age-related prescription figures for two non-steroidal anti-inflammatory drugs (NSAI) and co-trimoxazole matched ADR reports for each drug in each age group. 4. The reported ADR was more likely to be serious or fatal in the elderly. 5. The commonest ADRs reported for the elderly affected the gastrointestinal (GIT) and haemopoietic systems, where more reports were received than would be expected from prescription figures. 6. The drug suspected of causing a GIT reaction was a NSAI in 75% of the reports. 7. Ninety-one per cent of fatal reports of GIT bleeds and perforations associated with NSAI drugs were in patients over 60 years of age.

Ligand-induced desensitization of B-cell membrane immunoglobulin-mediated Ca2+ mobilization and protein kinase C translocation.

Binding of ligand to B-cell membrane immunoglobulin (mIg) can lead to activation of a number of distinct biologic responses, including altered expression of genes encoding c-fos, c-myc, and Ia, as well as proliferation and immunologic tolerance. Tolerance could reflect a functional uncoupling of receptors from systems that generate intracellular second messengers (i.e., receptor desensitization). To better understand the molecular basis of immune regulation, we examined the ability of mIg to function as a signal transducer after the cell's initial contact with mIg-binding ligand. The results show that ligand binding to as little as 2-10% of mIgM or mIgD renders the cell unresponsive to ligand binding to the reciprocal isotype as judged by Ca2+ mobilization and protein kinase C translocation responses. This heterologous receptor desensitization lasts longer than 24 hr and does not reflect loss of receptor from the cell surface. Studies with the calcium ionophore ionomycin, 1,2-dioctanoyl-sn-glycerol, and the protein kinase inhibitor staurosporine indicate that both protein kinase C-dependent and protein kinase C-independent (staurosporine-insensitive) mechanisms mediate heterologous desensitization after mIg crosslinking.

Effects of single oral dose administration of a hydantoin prostaglandin analogue BW 245C in man.

Following an open pilot study, BW 245C , a hydantoin prostaglandin analogue, was given by mouth in an aqueous solution to six healthy volunteers. The subjects received BW 245C 50 and 150 micrograms and placebo on separate occasions according to a double blind randomised design. Heart rate, blood pressure and, using visual analogue scales, facial flushing, abdominal discomfort and headache, were measured before dosing, at 15 minute intervals after dosing for 2 hours and at 30 minute intervals for a further 2 hours. Platelet aggregation responses to ADP and to collagen were measured before dosing and at 15 minutes, 45 minutes, 2 hours and 4 hours after dosing. Cutaneous bleeding time was measured before and 45 minutes after dosing. 150 micrograms BW 245C produced significant (p less than 0.05) facial flushing over the period from 15 to 120 minutes after dosing. Heart rate increased slightly but significantly (p less than 0.05) in response to both doses of 245C only at 75 minutes after dosing. Systolic and diastolic blood pressures were unchanged by either dose of BW 245C . Platelet aggregation responses to ADP were significantly (p less than 0.05) inhibited only at 120 minutes after 150 micrograms BW 245C . Aggregation responses to collagen were significantly (p less than 0.05) inhibited 45 and 120 minutes after 150 micrograms BW 245C and also at 120 minutes after 50 micrograms BW 245C . Bleeding time was unchanged in response to either dose of BW 245C . There was no change in headache or abdominal discomfort scores following either dose of BW 245C . Nausea was reported after 7 out of 12 administrations of BW245C but not after placebo. Nasal congestion was experienced by two subjects receiving 150 micrograms BW 245C and muscle tension and stiffness, especially of the jaw muscles, was also reported following administration of BW 245C but not of placebo. BW 245C is active when given by mouth and has similar pharmacodynamic effects to prostacyclin in man.

Effect of indomethacin on cerebral blood flow, carbon dioxide reactivity and the response to epoprostenol (prostacyclin) infusion in man.

Cerebral blood flow (CBF) has been measured using a non-invasive Xenon133 clearance technique in six normal subjects after 2 days pretreatment with oral indomethacin at a dose of 100 mg/day. The results were compared with placebo given in a double blind balanced cross-over design. Indomethacin was found to result in a reduction in resting CBF of about 25% but the reactivity of the cerebrovascular circulation to carbon dioxide was preserved at normal levels. Infusions of epoprostenol (prostacyclin, PGI2) at a dose of 5 ng/kg/min resulted in a reduction of CBF of about 10% after placebo but no significant change in CBF after indomethacin. The results suggest that prostaglandins are involved in the maintenance of cerebrovascular tone but not in the mechanism of cerebral vasodilation accompanying hypercapnia. The combination of indomethacin and PGI2 has been proposed as a treatment of cerebral artery spasm and the findings suggest that the combination therapy would not be accompanied by undesirable intracerebral steal.

Dipyridamole increases red cell deformability.

The effects of dipyridamole on red cell filterability both in vitro and ex vivo were measured. In a balanced, randomised and double-blind trial, six healthy male and female volunteers (22-37 years) were given dipyridamole 400 mg/day or matching placebo in four divided doses for 3 days, and heparinised venous blood samples were taken 1 h after the ingestion of the last dose. Filterability of red cells was increased significantly (P less than 0.05 paired t-test) when the subjects were on dipyridamole compared with placebo. In separate experiments, 15 min incubation with 2 or 20 micrograms/ml dipyridamole in vitro was found to have no effect on the filterability of freshly prepared red cell suspensions. After 24 h storage at 4 degrees C, the filterability of red cells was significantly decreased (P less than 0.01) and this could be partially prevented by adding dipyridamole to the stored cells (P less than 0.05). These results suggest that dipyridamole has an effect on the behaviour of the red cell membrane to increase the deformability of the cells. This may contribute to its therapeutic effect.

Epoprostenol (prostacyclin,PGI2) increases apparent liver blood flow in man.

When epoprostenol (prostacyclin, PGI2) is given by infusion to man, cardiac output is increased, and it appears that the gastrointestinal tract may receive a disproportionate share of this. We have used the clearance of indocyanine green dye to estimate liver blood flow in 8 healthy subjects. During an infusion of PGI2 at a dose of 5 ng/kg/min, apparent liver blood flow increased from 925 +/- 220 ml/min (Mean +/- s.d) to 1320 +/- 453 ml/min, an average increase of 41.1%. Significant changes in heart rate, headache, facial flushing, systolic blood pressure, and pulse pressure were noticed. We suggest that endogenous epoprostenol (PGI2) may be of importance in the physiological regulation of liver blood flow in man. As this dose of epoprostenol could be tolerated readily, epoprostenol therapy could prove a therapeutic advance in some liver disorders, particularly liver transplantation, and possibly in the therapy of certain drug overdoses.

Effects of intravenous epoprostenol on platelets and the cardiovascular system are not potentiated by dipyridamole.

Normal subjects received infusions of epoprostenol (prostacyclin, PGI2) at doses of 2, 4, 6, and 8 ng/kg/min on each of two occasions after pretreatment with dipyridamole (400 mg/day for 3 days) or placebo. Baseline headache and bleeding time were increased and preejection period (PEP) shortened after dipyridamole. The baseline heart rate was increased on dipyridamole by an amount that correlated to the blood dipyridamole level. PGI2 infusion increased heart rate, systolic blood pressure (BP), pulse pressure, left ventricular ejection time index, and degree of flushing and severity of headache, and reduced diastolic BP, PEP, and T wave height. There was no apparent interaction between PGI2 and dipyridamole on these variables. PGI2 inhibited adenosine diphosphate-induced platelet aggregation and increased bleeding time. We conclude that, despite the synergism between dipyridamole and PGI2 that might be predicted and has been demonstrated in some animal experiments, no such interaction is apparent in normal humans after standard doses.

Indomethacin does not attenuate the effects of hydralazine in normal subjects.

Indomethacin 100 mg/day or matching placebo was given for 2.5 days to 9 healthy volunteers in a double-blind cross-over study, followed by an intravenous injection of 0.2 mg/kg of hydralazine. Compared to placebo, indomethacin produced no statistically significant change in pulse rate or blood pressure in both standing and supine positions. Hydralazine injection was followed by a statistically significant fall in lying and standing diastolic pressure and a rise in lying and standing pulse after both indomethacin and placebo pretreatments. There were no significant differences in these effects following indomethacin compared to placebo pretreatment. These results do not support the hypothesis that endogenous prostaglandins are involved in the mechanism of action of hydralazine.

Effect of epoprostenol (prostacyclin, PGI2) on cerebral blood flow in man.

Cerebral blood flow has been measured using the non-invasive Xenon133 clearance technique in eight normal subjects during an infusion of epoprostenol (prostacyclin, PGI2) at a dose of 5 ng/kg/min. The results were compared with a control infusion of saline given in a balanced order. PGI2 was found to result in a reduction in cerebral blood flow of about 8%. PGI2 also caused a small drop in diastolic blood pressure and it is proposed that the fall in cerebral blood flow may have been the result of disturbed autoregulation. The findings suggest that the therapeutic use of PGI2 in patients with cerebral artery spasm would not be accompanied by undesirable intracerebral steal.

The cardiovascular and platelet effects of epoprostenol (prostacyclin, PGI2) are unaffected by beta-adrenoceptor blockade in man.

1 Atenolol 0.2 mg/kg i.v., propranolol 0.2 mg/kg i.v. or placebo were given in a double-blind crossover study to six healthy male subjects, and the effects of a subsequent infusion of epoprostenol (prostacyclin, PGI2) 0-6 ng kg-1 min-1 monitored. 2 PGI2 caused a tachycardia, a fall in diastolic blood pressure, a rise in pulse pressure, reduction in pre-ejection period (PEP) and rise in left ventricular ejection time index (LVETI), headache and facial flushing at doses of PGI2 greater than 2 ng kg-1 min-1,, (P less than 0.05). 3 Beta-adrenoceptor blockade did not prevent the tachycardia in response to PGI2, and did not interact with any of the other dynamic effects of PGI2. 4 In vitro, PGI2 at 1 and 2 ng/ml inhibited platelet aggregation to ADP (P less than 0.01), although no significant effect on platelet aggregation was seen in the in vivo study. Atenolol and propranolol at a final concentration of 1 microgram/ml did not affect this in vitro study. Atenolol and propranolol at a final concentration of 1 microgram/ml did not affect in vitro effect of PGI2 on platelet aggregation. 5 Pretreatment with atropine 0.04 mg/kg i.v. in three subjects did not attenuate the tachycardia caused by PGI2 infusion, even though the baseline heart rate was increased. 6 Adverse effects to PGI2 infusion included sudden bradycardia, pallor and sweating, suggesting that the Bezold-Jarisch reflex seen in animals in response to PGI2 may also occur in humans. 7 Neither increased sympathetic drive nor vagal withdrawal are likely causes of the tachycardia following PGI2 infusion.

Side effects occurring during administration of epoprostenol (prostacyclin, PGI2), in man.

1 Fifty infusions of epoprostenol (PGI2) were made, usually increasing the infusion rate until adverse effects were encountered. The volunteers were appraised that they might experience headache and facial flushing. 2 Facial flushing, headache, tachycardia and decrease in diastolic blood pressure were seen in almost all subjects. Erythema over the venous infusing site was also encountered in 13 infusions. Less common effects were sudden bradycardia, pallor and sweating--the vagal reflex--(seven times) and chest pain (twice). Other complaints included restlessness, abdominal discomfort, nausea and drowsiness. 3 The literature on side effects reported during PGI2 infusion is reviewed and recommendations are made concerning administration of PGI2.

Propranolol and sotalol as antagonists of isoproterenol-enhanced physiologic tremor.

Six normal subjects were studied after graded bolus injections of isoproterenol. Log dose-response curves for increases in both heart rate (mostly beta 1), and amplitude of physiologic tremor (beta 2) were constructed for each subject in the control state and 2 hr after 10 or 40 mg propranolol, 200 mg sotalol, or placebo. All heart rate curves were shifted to the right in an approximately parallel fashion by all active treatments (40 mg propranolol greater than 200 mg sotalol greater than 10 mg propranolol). The tremor curve was also shifted to the right by 10 mg propranolol in an approximately parallel fashion and to the same extent as the heart rate curve (both dose-ratios = 6.1), but the tremor curves after both 40 mg propranolol and 200 mg sotalol appeared to be flattened as well as shifted laterally. We conclude that whereas it may be possible that 10 mg propranolol acts as a competitive antagonist of isoproterenol at beta 2-sites in skeletal muscle, 40 mg propranolol and 200 mg sotalol must have additional actions in reducing isoproterenol tremor. The possibilities are discussed.

Effect of atenolol, metoprolol, and propranolol on isoproterenol-induced tremor and tachycardia in normal subjects.

The effect of single oral doses of atenolol (100 mg), metoprolol (100 mg), propranolol (40 mg), and placebo on exercise tachycardia and on heart rate and finger tremor responses to graded injections of isoproterenol was investigated in six normal subjects. Propranolol was more potent than atenolol and metoprolol in suppressing the increase in heart rate and tremor amplitude produced by isoproterenol, even though at the dose used it was the least effective of all three drugs in decreasing exercise tachycardia. Although these data are consistent with the hypothesis that the suppression of isoproterenol-induced tremor is mediated by antagonism of peripheral beta 2-adrenergic receptors, the possibility that a separate action other than beta-blockade may contribute to the tremorolytic action of propranolol cannot be excluded. The potential usefulness of examining the effect of beta-adrenoceptor blocking drugs on isoproterenol-induced tremor and tachycardia in cardioselectivity studies is discussed.