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The effects of isoprenaline and salbutamol administered orally, by inhalation, or by intravenous infusion were compared in 13 asthmatic patients. Bronchodilator activity was assessed by serial measurement of specific airways conductance (SGaw). Log-dose response curves were obtained for both drugs and showed them to be equipotent as bronchodilators. Cardiovascular effects were variable, but in general, isopenaline caused greater rise in pulse rate and a greater change in blood pressure than the same dose of salbutamol.Cardiorespiratory measurements during continuous intravenous infusion of increasing doses of both drugs suggested a greater effect of isoprenaline than the same dose of salbutamol on metabolic rate, pulmonary ventilation, pulmonary gas exchange, cardiac output, and heart rate. The effect of salbutamol on the heart rate was about 10 times less than that of isoprenaline but lasted longer.

The title of this article may raise a smile from colleagues in the field of basic pharmacology. To them, pharmacology has always been about molecular interactions, and this title may simply confirm a suspicion that clinical pharmacology is mainly about semi-quantitative observations that have only a limited foundation in hard science. They are partly right, at least regarding a communication problem. In a discussion about systems biology, an exasperated engineer once remarked that biologists and physicians do not even use the same routine software packages that engineers do. Similarly, a basic pharmacologist might note that, whereas he measures drug concentrations in micromoles, the clinical pharmacologist uses micrograms per milliliters. Nevertheless, as clinical pharmacologists seek to make more quantitative observations at the molecular level in living humans, our colleagues in basic pharmacology are delving into cellular signal transduction systems governed by complex protein-protein interactions and regulated by positive and negative feedback loops. In seeking to understand these systems, they face problems that are similar to the challenge of measurement in intact humans.

Lapatinib is a clinically important component of the treatment for HER2-positive metastatic breast cancer and has an acceptable safety profile. Lapatinib-associated Hy's Law cases have been characterized using human leukocyte antigen (HLA) DQA1*02:01/DRB1*07:01 and Gilbert's syndrome UGT1A1*28/*28 genotypes. The HLA-positive cases had higher alanine aminotransferase (ALT) elevation, whereas the HLA-negative cases had a higher incidence of Gilbert's syndrome. The findings of our study, which extend this HLA association to lapatinib-associated serious liver injury, emphasize the importance of Gilbert's syndrome in the interpretation of Hy's Law and may lead to methods for enhancing patient safety.

The objectives of this study were to compare the effects of two centrally-acting antihypertensive drugs on measures of quality of life in a three-month double-blind trial of hypertensive patients randomized to methyldopa (n = 79) or rilmenidine (n = 78). We studied men and women aged over 21 y attending eight hospital out-patient clinics in the United Kingdom. They had average diastolic blood pressures between 95 and 110 mm Hg and systolic pressures below 210 mm Hg after a 4-week placebo run-in period. The doses ranged from 1 to 2 mg daily of rilmenidine and 500 mg to 1 g of methyldopa. Hydrochlorothiazide (25 mg daily) was added after 8 weeks when the diastolic blood pressure remained at 90 mm Hg or more in 29% of patients on rilmenidine and 35% of those on methyldopa. Quality of life was assessed from self-completed questionnaires using standardized instruments. Both drugs reduced blood pressure, but at the end of the trial the fall in the methyldopa group (19.3/13.0 mm Hg) was significantly greater than in the rilmenidine group (13.2/10.0 mm Hg). Ten patients in the methyldopa group withdrew from the trial compared with three in the rilmenidine group, primarily because of adverse effects. In both groups there was a significant increase in the overall reporting of adverse effects. Reports of dry mouth increased on both drugs, and sleepiness on rilmenidine but not methyldopa. There was no significant difference between the drugs in the overall reporting of adverse effects or of individual adverse effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelets produce a range of bronchoconstrictor mediators. Measurements of plasma factors have implicated platelet activation in allergic asthma, and sensitised guinea pigs challenged with ovalbumin show pulmonary platelet aggregation accompanying bronchoconstriction. To investigate this further we injected autologous platelets labelled with indium 111 and red cells labelled with technetium 99m into three young volunteers with atopic asthma and three non-asthmatic volunteers and, after equilibration of platelets between blood and splenic pool, monitored lung 99mTc and 111In activities continuously. Comparison with the corresponding activities in blood samples allowed calculation of pulmonary platelet to red cell transit time ratio (tp/tr). This ratio was 0.9, 1.02, and 0.98 in the non-asthmatic subjects compared with 1.04, 0.97, and 1.17 in the asthmatic subjects. This argues against the existence of an intrapulmonary platelet pool in normal subjects; transpulmonary transit time was slightly prolonged in one asthmatic subject. Bronchial challenge with Dermatophagoides pteronyssinus was performed in the asthmatic subjects and monitoring continued for a further 30 minutes. Antigen induced falls in FEV1 of 20-50% were accompanied by small decreases in the 111In but not in the 99mTc lung signal. In line with this tp/tr fell to 0.89, 0.89, and 1.05. Antigen induced bronchoconstriction was therefore not accompanied by intrapulmonary platelet accumulation. Platelet survival was normal at 10.2 days in both groups of subjects.

The development of fluorescein angiography has stimulated a great deal of interest in the vascular physiology of the retina and choroid by providing a method for examining different aspects of the ocular circulation in vivo. Of particular interest is the role of the blood supply to the optic disc in the production of field defects in glaucoma, and its relationship to pathological disc cupping (Hayreh, I969, 1970; Blumenthal, Best, Galin, and Toyofuku, 1971; Goldmann and Blok, 197I). A number of experiments in animals and man have been carried out to demonstrate the influence of acute and chronic rises in the intraocular pressure on the choroidal supply to the disc and peripapillary region (Blumenthal, Gitter, Best, and Galin, I970; Swietliczko and David, 1970; Blumenthal, Best, and Galin, 197I). In these conditions of high intraocular pressure, whether pathological or experimental, several observations have been made on the accompanying reduction of blood velocity in the retinal arteries but, apart from the studies by Dollery, Henkind, Kohner, and Paterson (I968), little quantitative data exists on this relationship between altered perfusion pressure and retinal blood flow. The present series of experiments was designed as an extension of the work of Dollery and his co-workers to investigate the changes in retinal blood flow velocity and retinal blood flow at different intraocular pressures, and to study the effects of measures used to treat retinal artery obstructions in man.

Human alpha-atrial natriuretic peptide (h-alpha ANP) makes the urine of dehydrated volunteers hypotonic to plasma despite high circulating concentrations of antidiuretic hormone. Urinary dilution with h-alpha ANP also occurs in subjects receiving indomethacin. Therefore, h-alpha ANP antagonises effects of antidiuretic hormone on distal tubular V2-receptors in man, probably without involving prostaglandins.

In man, circulating adrenaline has little or no direct effect on the control of blood pressure. A small proportion of adrenaline secreted by the adrenal medulla is accumulated in sympathetic nerve endings and may be re-released by sympathetic nerve stimulation. Recent pharmacological studies have suggested that adrenaline acts on a presynaptic beta-receptor on sympathetic nerve endings to facilitate noradrenaline release, and it has been proposed that adrenaline re-released from these nerve endings is therefore a functionally important "co-transmitter". Intermittently elevated secretion of adrenaline from the adrenal medulla could therefore lead indirectly to a sustained increase in neuronal release of noradrenaline and hence to hypertension.

The decision to request intravenous urography in a hypertensive patient has been examined, together with the abnormalities discovered and the resulting changes in clinical management. The records of 405 hypertensive patients newly referred to a single clinic, were examined for the years 1955, 1965 and 1971. Intravenous urography was requested more frequently in younger than in older patients, and the number of requests increased with the level of diastolic blood pressure. The more recent the date of presentation, the more often was the investigation requested. Thirty-five patients had IVU abnormalities against 185 with a normal urogram. The urograms reported in 1971 were reviewed without the knowledge of the previous report and the non-agreement between the standard report and the review is discussed. Nine per cent of the patients who had an IVU in 1971 had a change in medical management as a result of the investigation. When an abnormality was detected on urography the plasma urea and presenting blood pressure were significantly higher and the patients age (adjusted for blood pressure and plasma urea) significantly lower than when the urogram was normal. Based on these results a multiple regression equation is discussed relating the presence of an abnormality ( Y ) to plasma urea, age and systolic blood pressure as independent variables. A value of Y can be found which would detect most of the significant abnormalities and avoid the request in several of the patients without an abnormality. These decision rules require testing in a prospective study.

A slightly modified Middlesex Hospital Questionnaire was given to 946 patients with hypertension who were receiving treatment at two hospital clinics. The response rate was 90%. Compared with previously published results for the general population the hypertensive patients scored significantly higher for free-floating anxiety, phobic anxiety and depression. Male hypertensive patients, but not female patients, also scored higher for obsession and hysteria. The high scores for hypertensive patients could not be closely correlated with any particular drug therapy with the possible exception of phobic anxiety and propranolol in women but not in men. There was a weak but statistically significant correlation between systolic blood pressure and both somatic complaint rate and phobic anxiety.

The response to a standard dose of heparin was studied in 20 patients with venous thromboembolism. The heparin regimen consisted of intravenous injection of 70 units per kg, followed after 90 minutes by a maintenance dose of 400 units per kg per 24 hours given by continuous infusion. Plasma heparin activity and the activated partial thromboplastin time (APTT) were measured at intervals to determine clearance of the initial injection and the response to maintenance dose. Large inter-individual variations were found in the anticoagulant effect and these were due in part to differences in heparin clearance and in part to differences in the APTT response to given amounts of heparin (heparin effect index). The heparin half-life was 63 +/- 15 minutes when plasma heparin activities were used for this calculation and 84 +/- 71.5 minutes when the APTT was used. These results are similar to values previously reported in normal volunteers. Four of the 20 patients had pulmonary embolism and in these heparin half-life was significantly shortened (P less than 0.005).

Branch and hemisphere vein occlusion were produced in rhesus monkeys by argon laser photocoagulation. The following observations were made: (1) Immediately after occlusion there was venous dilatation, delayed filling of the artery, delayed drainage by the occluded vein, and capillary leakage. (2) Two patterns of evolution were identified within the first week. In some animals the fundus changes resolved and the retina returned to normal, while in others there was progressive retinal capillary closure. (3) Those animals destined to have capillary closure had diffuse or cluster retinal haemorrhages at 24 hours. (4) Capillary closure took place over 1 week and was usually complete over large areas of retina. (5) Retinal atrophy and major vessel changes occurred over several weeks. (6) Retinal revascularisation occurred in those areas of closure, though this was often limited. It was concluded that the early changes mimicked those seen in human retinal vein occlusion, though persistent retinal oedema and preretinal neovascularisation were not identified.

The complex mechanisms that maintain the blood pressure can be interfered with at many points by drugs. A drug acting at one point may be potentiated by another which blocks a compensatory reflex minimizing the effect of the first. Many therapeutically useful drug combinations have a nonspecific mechanism of this kind although drugs that act upon different points in the sympathetic efferent vasomotor pathway have not been proved to have a useful additive effect. It is not easy to prove a synergistic action of two drugs unless it is large. The best supported examples are combinations of either a diuretic or a vasodilator with a sympathetic blocking drug. These combinations are the ones most widely used in treatment of hypertension. They allow the dose of each active substance to be reduced so that unwanted side-effects are decreased without losing the desired action on the blood pressure. Drug combinations have special risks besides their obvious advantages. Patients are more likely to become confused and take the wrong doses if their treatment regime is complicated. Two drugs which are individually nontoxic may have dangers when used together. Oliguria and a mounting blood urea may follow combined use of powerful modern diuretics. Toxic effects may be entirely unrelated to the main therapeutic action of the drug, as with the enhanced diabetogenic effect of diazoxide used with hydrochlorothiazide. Several potent cardiovascular drugs modify the response to drugs which might be given to raise the blood pressure in an emergency. No drug in common therapeutic use seriously reduces the response to injected noradrenaline but some, such as sympathetic blockers and monoamine oxidase inhibitors, greatly increase sensitivity. Pressor amines that act indirectly by noradrenaline release may be ineffective in the presence of drugs which deplete or insulate the stores of the transmitter in adrenergic nerve endings. The advantages and disadvantages of drug interactions deserve more thought and study than they usually receive.

Effects of changes in pulmonary arterial (Pa), venous (Pv), and alveolar (Pa) pressures on the over-all pressure-blood flow relations of an isolated dog lung have been re-examined. In the preparation used, the distribution of blood flow was predictable from previous measurements with radioactive gases. The results showed that the pressure-flow relations of the whole lung were greatly affected by the distribution of blood flow within it. For example, the pulmonary vascular resistance (PVR) of the lung depended on whether all the lung was perfused with blood or not, and thus whether there was an unperfused zone at the top of the lung where Pa was less than Pa ( zone 1). Again the pressure-flow relations of the lung were shown to depend on how much of the lung had a Pv less than Pa ( zone 2), and how much had a Pv which exceeded Pa ( zone 3). The effects on PVR of changing Pv or Pa could be explained on this basis. No evidence of a critical closing pressure in the vessels of the expanded lung was found. It was concluded that although the over-all pressure-flow relations of the whole lung were complicated, the flow through individual vessels could be accounted for by the simple mechanical effects of pressures inside and outside the vessels. hydrostatic effect; pulmonary vascular resistance; Starling resistor; vascular waterfall; critical closing pressure Submitted on May 4, 1964

A self-administered symptom questionnaire was completed by 477 patients in a hypertension clinic. The complaints of the patients were analysed according to the type of therapy being given and the dose of drug taken. Methyldopa therapy was associated with sleepiness, weakness of the limbs, sleeping longer at night, and rising more frequently at night to pass urine. Diarrhoea, impotence, failure of ejaculation, blurred vision, depression, and the symptoms of postural hypotension were not related to methyldopa therapy. Bethanidine administration was related to postural hypotension, impotence, and failure of ejaculation but not to weakness of the limbs, blurred vision, depression, or diarrhoea. Patients receiving guanethidine complained of postural hypotension, failure of ejaculation, and had their bowels open more frequently. Similarly, patients receiving propranolol had an increased frequency of defaecation but also tended to complain of weakness of the limbs. Considering each drug individually, 5% of patients failed to take the prescribed dose of diuretic whereas

The results of a titrated-dose cross-over comparison of clonidine with methyldopa are reported. Only one third of those entering the trial completed it. The blood pressure lowering effect of the two drugs is seen to be very similar. Patients experienced significantly more dry mouth whilst on clonidine but sedation was equally distributed over the two treatments. A hypertensive rebound occurred in some patients after sudden withdrawal of clonidine. The place of this new compound in routine management of hypertension is discussed.

A quantitative approach to measuring events in the retinal circulation is now possible. Caliber changes of retinal vessels ranging in size from 25μ to 110μ can be documented with considerable precision by measurements made from color photographs. The velocity of flow in the retinal arterioles can be measured with moderate accuracy by determining the velocity of the leading edge of the axial stream of fluorescent dye by frame analysis of cinephotographs obtained by using an image intensifier with a light gain of approximately half a million times. The velocity of flow in the human superior temporal arteriole is between 20 and 40 mm/sec with volume flow rate of approximately 7μl/min.

A method is described for the quantitative study of the life cycle of microaneurysms in diabetic retinopathy. This method was applied to a series of 21 patients, 9 with mild and 12 with severe retinopathy, 6 of whom had pituitary ablation. — The study showed a variable survival of microaneurysms; overall disappearance rates were 3.3%/month in mild and 3.2 %/month in severe retinopathy. The disappearance rate was almost always higher in the early months of the study (11.6% and 9.3 % per month) than later (0.8 % and 1 %/month) indicating more than one population of microaneurysms. — There was no significant difference in the formation and disappearance of microaneurysms between patients with mild and severe retinopathy. — Some microaneurysms showed intermittent perfusion. — Following pituitary ablation the disappearance rate of microaneurysms increased, while the formation rate of new ones decreased significantly.

Carbon dioxide labeled with oxygen-15 has been used to study the regional blood flow in the lungs of patients with pulmonary stenosis. The upper and lower zone flows were normal in patients with isolated pulmonary stenosis, but both were low in patients with the tetralogy of Fallot. A comparison of the two upper zones showed a significantly higher blood flow through the left upper zone in patients with both isolated pulmonary stenosis and the tetralogy of Fallot. A significantly higher flow was also found through the left upper zone than the right of normal subjects. By contrast, patients with atrial septal defect had a higher flow through the right upper zone than the left. Neither difference was as large as in the patients with right ventricular outflow tract obstruction. Patients with ventricular septal defect and those with patent ductus arteriosus had almost identical flow through the two upper zones.

Inhaled radioactive CO2 is rapidly taken up by pulmonary blood. By external counting over the chest during breath holding, the clearance rate of radioactive CO2xs from the counting field can be recorded, and is proportional to the regional perfusion. In normal subjects, the clearance rate varied from about 20%/ sec. at the base of the lung to virtually nil at the apex, and the change was approximately linear with distance up the chest. The difference between upper and lower zones was reduced on moderate exercise and eliminated when the subject lay on his back. By relating the counting rate at the end of inspiration to the volume of lung in the counting field, the difference in ventilation between upper and lower zones was measured and found to be small. Variation in ventilation-perfusion ratio was thus determined. Alveolar-arterial O2 gradient expected from this ventilation-perfusion ratio inequality was calculated to be about 4 mm Hg. This suggests that the variation in blood flow between upper and lower parts of the lung in erect man accounts for the whole of the ventilation-perfusion ratio inequality in the normal lung. Submitted on November 23, 1959

Measurements of the distribution of blood flow in an isolated dog lung made with radioactive xenon showed a great increase in vascular resistance in the dependent zone of the lung in the presence of a raised pulmonary venous pressure in some preparations. Evidence that this increased vascular resistance was caused by perivascular edema consisted of the general correlation with interstitial edema, the regional distribution of the effect, the sensitivity to the arteriovenous pressure difference, the effect of certain infusions particularly hypertonic urea, and the demonstration of edema around the small arteries and veins in rapidly frozen sections. The mechanism of the increased resistance is postulated as an interference with the tethering effect of the lung parenchyma which normally holds the vessels open. The possible role of this mechanism in the increased pulmonary vascular resistance of patients with pulmonary venous hypertension is discussed.

1. Clonidine (1 μg/kg), given by intracisternal injection to anaesthetized rabbits, lowered mean arterial blood pressure by 33 mmHg and heart rate by 32 beats/min. 2. In animals pre-treated with 6-hydroxydopamine (6-OHD 500 μg/kg intracisternally) 7-10 days before, intracisternal clonidine (1 μg/kg) reduced mean arterial blood pressure by only 2·5 mmHg and heart rate by 4 beats/minute. 3. The hypotensive action of intravenous clonidine was reduced to 49% of control by pre-treatment with intracisternal 6-OHD. In unanaesthetized normal animals intravenous clonidine (30 μg/kg) lowered mean arterial blood pressure by 19·3 mmHg, while after 6-OHD it fell only 9·4 mmHg. 4. These studies suggest that the central hypotensive effect of clonidine is dependent on the integrity of central monoaminergic neurones.

The possibility that enalapril might damage renal function was investigated in 1098 deaths recorded in a prescription-event monitoring study. Case notes for 913 patients were examined. In seventy five there was a rise in the urea or creatinine concentration of 50% or more above pretreatment values. Enalapril appeared to have contributed to a decline in renal function and subsequent death in 10 of these patients. Several characteristics were identified among these patients, including old age, the use of high dose or potassium sparing diuretics, and pre-existing renal disease. Adding a non-steroidal anti-inflammatory drug was also associated with a deterioration in patients with previously stable renal function. No death was encountered of a patient with uncomplicated hypertension. Enalapril infrequently contributed to a substantial decline in renal function in certain vulnerable patients, especially those receiving other drugs known to be capable of adversely affecting renal function. Awareness of the characteristics of these patients and of their concomitant treatment may serve to reduce the risk.