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The effect of dazoxiben, a thromboxane synthetase inhibitor, on cold- induced forearm vasoconstriction was determined in two groups of human volunteers, those in whom dazoxiben abolished the platelet aggregation and release reaction induced by sodium arachidonate (group I) and those in whom it did not (group II). Dazoxiben abolished cold-induced forearm vasoconstriction in group I volunteers but not in those of group II. These results imply a correlation between platelet behaviour and cold- induced changes in vascular tone. In the group I volunteers the effect of dazoxiben on cold-induced vasoconstriction was abolished by 1800 mg of aspirin, but not by 40 mg. Since the lower dose of aspirin inhibits platelet cyclo-oxygenase but has no effect on cyclo-oxygenase in blood vessel walls, it is possible that platelets play no part in the modulation of vascular tone by dazoxiben. It is more likely that the effects of dazoxiben are confined to the vessel wall. [ABSTRACT FROM AUTHOR]

1 In healthy male volunteers dazoxiben (UK 37248), an inhibitor of thromboxane synthetase, abolished the arterial and venous vasoconstriction produced in the forearm by cold stimulation. 2 Aspirin alone had no effect on this vasoconstriction but negated the effect of dazoxiben. 3 In vitro dazoxiben increased the production of prostacyclin by human arteries and veins. 4 By reducing the synthesis of thromboxane A2, a potent vasoconstrictor, and by increasing the synthesis of prostacyclin, a potent vasodilator, dazoxiben may have a therapeutic role in conditions associated with abnormal vasoconstriction. [ABSTRACT FROM AUTHOR]

1 We have studied the effects on platelet behaviour of ingestion of the thromboxane synthetase inhibitor dazoxiben (UK 37248), by healthy subjects, and compared the results with the effects of a low dose of aspirin (a cyclo-oxygenase inhibitor), and of a combination of dazoxiben and a low dose of aspirin. 2 Dazoxiben ingestion prevented the release reaction induced by sodium arachidonate (NaAA) in platelet- rich plasma (PRP) from some individuals ('responders') but not in PRP from others ('non-responders'). In vitro testing of PRP from the same subjects, incubated with 10(-4)M dazoxiben, correlated with the effect of dazoxiben ingestion on NaAA-induced release. Platelets from 'non- responders' tended to undergo a more extensive release reaction than platelets from 'responders' even in the absence of any drug although there was some overlap between the results in the two groups. Platelets from 'non-responders' required significantly lower concentrations of NaAA to induce release reaction than platelets from 'responders'. Platelets from 'responders' and 'non-responders' did not differ in the amount of malondialdehyde (MDA) produced or in the effectiveness with which dazoxiben ingestion inhibited MDA production. 3 Low dose aspirin had comparable effects on NaAA-induced release to dazoxiben, but in contrast to dazoxiben, the effectiveness of low-dose aspirin in inhibiting NaAA induced release reaction was related to its effectiveness in inhibiting MDA generation. 4 Neither dazoxiben nor low- dose aspirin significantly affected the release reaction induced by adenosine diphosphate (ADP), although both drugs significantly inhibited adrenaline-induced release. 5 A combination of dazoxiben and low dose aspirin had a greater effect on platelet behaviour in response to NaAA, ADP, and adrenaline than either drug alone. [ABSTRACT FROM AUTHOR]

Background: There is little information on the costs of maintaining a district nebuliser compressor service. This retrospective study examines the issue, reliability, and maintenance costs of electrical compressors to assist the prediction of future costs, taking into account recent safety legislation., Methods: Records of issue, repair, and replacement for the period 1982-91 were reviewed. The current policy of repairing and replacing as necessary, and three other theoretical costings, were considered., Results: The number of compressors being issued is increasing. Repaired compressors are less reliable and frequency of repair is a function of compressor age. The current policy is the most cost effective., Conclusions: To repair and replace nebuliser compressors as necessary is the most economical policy under the present terms offered by the manufacturers, but changes in safety legislation will affect the provision of such services.

Two hundred and nine patients with moderate to severe chronic heart failure, all of whom remained symptomatic despite at least 80 mg of frusemide daily, were randomized to 12 months treatment with flosequinan or captopril. The patients were stratified into two groups, a treadmill group and a corridor walk test group, depending upon their exercise capability. Sixty-five out of 102 patients randomized to flosequinan and 43 out of 107 randomized to captopril (p < 0.001) did not complete the study. There was no difference between the groups in mortality: 19 patients died while taking flosequinan and 15 while taking captopril. Both drugs had similar effects on treadmill exercise tolerance; the mean increase at week 52 was 117 seconds in the flosequinan group and 156 seconds (p = 0.57) for the captopril group. For those patients stratified to the corridor walk test only, there was also very little difference in the improvement at 52 weeks; the mean increase for patients randomized to flosequinan was 61 meters and captopril was 75 meters (p = 0.65). However, when the walk tests from all patients are examined, captopril produced a significant improvement compared with flosequinan at week 52 (p = 0.015). Flosequinan has similar long-term efficacy to captopril but is associated with a higher incidence of adverse events.

Objective: To study bronchial responsiveness to inhaled histamine among HIV-infected patients., Design: A prospective study in a regional infectious diseases unit., Methods: Three groups of patients were studied. Group A consisted of AIDS patients (n = 7) who had had Pneumocystis carinii pneumonia (PCP), group B of AIDS patients (n = 7) not known to have had PCP, and group C of asymptomatic HIV-positive patients (n = 7). Inhalational histamine challenge in cumulative doses (0.03-3.91 mumol) was administered by a nebulizer. It was stopped when the forced expiratory volume in 1 sec (FEV1) had fallen by more than 20% of the baseline value or when the cumulative dose administered exceeded 3.91 mumol. Response was measured as percentage change in FEV1 from the baseline value, and plotted on a linear scale against log dose histamine to enable the dose of histamine causing a 20% fall in FEV1 (PD20-FEV1) to be determined. Statistical analysis was performed by analysis of variance., Results: AIDS patients previously infected with PCP (group A) had a significantly lower PD20-FEV1 [(mean, 0.31 mumol; range, 0.07-0.95; s.d., 0.31; s.e., 0.12; 95% confidence interval (CI), 0.03-0.60)] than AIDS patients without PCP (group B; mean, 1.01 mumol; range, 0.20-2.00; s.d., 0.67; s.e., 0.25; 95% CI, 0.39-1.64) or asymptomatic HIV-positive patients (group C; mean, 1.28 mumol; range, 0.49-1.80; s.d., 0.51; s.e., 0.19; 95% CI, 0.81-1.76) (P < 0.05). There was no significant difference between groups B and C. All patients recorded PD20-FEV1 within the asthmatic range of bronchial hyper-responsiveness., Conclusions: These results suggest that development of PCP in a small group of HIV-infected patients induces a significantly greater degree of bronchial hyper-responsiveness.

Clinical and neurophysiological studies were conducted in 47 patients with chronic obstructive airways disease and compared with 46 age-matched control subjects. Symptomatic neuropathy was reported in 13% and ankle jerks were absent in 45% of hypoxic patients. Peroneal and median nerve conduction velocities and median and sural sensory nerve amplitudes were significantly reduced in hypoxic patients (p less than 0.01). Six hypoxic patients underwent biopsy of the sural nerve, soleus muscle and overlying skin. Nerve glucose, sorbitol, fructose and myo-inositol concentrations were normal. Detailed light and electronmicroscopy revealed both nerve fibre and microvascular pathology. Segmental demyelination (32%) and unmyelinated fibre degeneration were found to be prominent lesions. The sural nerve perineurium was thickened due to an increase in the number of perineurial lamellae and an increase in intraperineurial space. Basement membrane thickening was observed in capillaries of nerve, muscle and skin. Endothelial cell hyperplasia and hypertrophy were observed in nerve and muscle capillaries but not in skin capillaries. In conclusion, this study has provided neurological, neurophysiological and neuropathological evidence of a neuropathy in hypoxic patients with chronic obstructive airways disease. These findings may be of relevance to some aspects of the aetiology of human diabetic neuropathy.

The capacity of venous tissue for prostacyclin synthesis was determined in 68 patients undergoing surgery for removal of varicose veins. A single dose of aspirin (81 mg or 300 mg) taken 14 h preoperatively strongly inhibited its synthesis, and the effect of 300 mg was still evident 48 h after ingestion. A single dose of 40 mg aspirin taken 14 h preoperatively had no effect on prostacyclin synthesis. The capacity of blood platelets to synthesise thromboxane (measured as malondialdehyde) was determined in volunteers before and at various times after ingestion of 300 mg or 40 mg aspirin. Both doses had an inhibitory effect that lasted for at least 96 h. The length of time for which the amount of thromboxane synthesised was insufficient to support platelet aggregation and the platelet release reaction depended on both the donor and the dose of aspirin. If prostacyclin and thromboxane are important in the pathogenesis of thrombosis, then doses of aspirin much lower than those used previously should be tested. The long-lasting effect of 300 mg aspirin on both venous tissue and platelets indicates that this dose is unlikely to produce a favourable prostacyclin/thromboxane balance.

Prostacyclin (PGI2) synthesis by human mesenteric arteries and veins was measured ex vivo in 62 patients who received either no medication or a single oral dose of aspirin 40 mg, 75 mg or 300 mg approximately 24 hrs pre-operatively. Each dose of aspirin caused a significant reduction in both arterial and venous PGI2 synthesis compared with the untreated group. Arterial PGI2 synthesis did not differ significantly from venous PGI2 synthesis whether assessed by sample weight or sample area.

The effects of different regimens of 40 mg aspirin on platelet thromboxane A2 synthesis and vascular prostacyclin synthesis were determined in patients who were undergoing elective surgery for removal of varicose veins. Aspirin 40 mg taken at intervals of 48 hours consistently reduced platelet thromboxane A2 synthesis to a level at which it failed to support platelet aggregation and the associated release reaction. This effect lasted for at least 36 hours. In contrast, aspirin 40 mg every 72 hours did not have the same consistent effect. Both dose regimens led to a reduction in vascular prostacyclin synthesis 12 hours after the last dose, but 36 or 72 hours after the last dose prostacyclin synthesis was not reduced; thus the inhibition of prostacyclin synthesis was short lived. If the balance between platelet thromboxane A2 and vascular prostacyclin synthesis is important in thrombosis 40 mg aspirin every 48 hours may have the maximum antithrombotic effect.

One hundred and two female asthmatic patients responded to a questionnaire concerning the relationship between their asthma symptoms and the menstrual cycle. Thirty-six subjects stated that their asthma worsened just prior to or at the time of their menses. Daily monitoring of peak expiratory flow rate (PEFR) showed a significant reduction at the time of menstruation in those who worsened compared with those subjects who were unaffected. Cycle length was significantly shorter in the group who worsened but the duration of the menses was not significantly different.

Ten patients with severe congestive heart-failure were treated with a vasodilator, prazosin, in addition to diuretics; their exercise capacity was assessed by testing on a treadmill. After the withdrawal of prazosin the condition of three patients deteriorated markedly.

Ex vivo venous prostacyclin synthesis was measured in 24 patients who received no medication, or a single oral dose of aspirin 300 mg, sodium salicylate, 500 mg, or a combination of sodium salicylate 500 mg followed by aspirin 300 mg 1 1/2 or 3 hr later. Aspirin alone substantially reduced PGI2 synthesis but sodium salicylate alone had no effect. Sodium salicylate administration prior to aspirin did not reverse the inhibitory effect of aspirin on PGI2 synthesis.

Twenty-four patients received either propranolol, lidoflazine (Clinium), or propranolol/lidoflazine combinations in a study designed to evaluate the effect of these drugs in angina pectoris. Five patients developed ventricular tachycardia when receiving either lidoflazine or lidoflazine and propranolol in combination; one of these patients died. In addition, one patient died suddenly while being treated with propranolol alone. Lidoflazine therapy was associated with a significant prolongation of the QT interval of the electrocardiogram. Lidoflazine either alone or in combination with propranolol, appears to induce ventricular tachycardia.

A 62 year old woman presented with an acute pulmonary vasculitis which responded to treatment with oral steroids. Investigations over one year revealed a cholangiocarcinoma of the liver. The association of vasculitis with neoplastic diseases remains a diagnostic challenge.

The relationship between change in airway calibre and change in airway reactivity after administration of bronchodilator drugs has been investigated by comparing the effect of increasing doses of inhaled salbutamol and ipratropium bromide on the forced expiratory volume in one second (FEV1), specific airways conductance (sGaw), and the dose of histamine causing a 20% fall in FEV1 (PD20) in six subjects with mild asthma. On each of 10 occasions measurements were made of baseline FEV1, sGaw, and PD20 after 15 minutes' rest, and followed one hour later, when the FEV1 had returned to baseline, by a single nebulised dose of salbutamol (placebo, 5, 30, 200 and 1000 micrograms) or ipratropium (placebo, 5, 30, 200 and 1000 micrograms) given in random order. Measurements of FEV1, sGaw, and PD20 were repeated 15 minutes after salbutamol and 40 minutes after ipratropium. Salbutamol and ipratropium caused a similar dose related increase in FEV1 and sGaw, with a mean increase after the highest doses of 0.76 and 0.69 litres for FEV1 and 1.15 and 0.96 s-1 kPa-1 for sGaw. Salbutamol also caused a dose related increase in PD20 to a maximum of 2.87 (95% confidence interval 2.18-3.55) doubling doses of histamine after the 1000 micrograms dose, but ipratropium bromide caused no significant change in PD20 (maximum increase 0.24 doubling doses, 95% confidence interval -0.73 to 1.22). Thus bronchodilatation after salbutamol was associated with a significantly greater change in airway reactivity than a similar amount of bronchodilatation after ipratropium bromide. This study shows that the relation between change in airway reactivity and bronchodilatation is different for two drugs with different mechanisms of action, suggesting that change in airway calibre is not a major determinant of change in airway reactivity with bronchodilator drugs.

A pilot study had suggested that bromocriptine (a dopamine agonist) might be of benefit in severe asthma, particularly in patients with marked diurnal variation in peak flow. Two studies are reported: (1) a longterm double-blind, controlled trial comparing bromocriptine (B) with placebo (P) in patients with severe asthma and, (2) a withdrawal study in patients who had received known bromocriptine, with apparent benefit, for at least one year. Of 27 patients (16B, 11P) admitted to the double-blind trial only eight (4B, 4P) completed 52 weeks on the trial drug as nine (6B, 3P) had been withdrawn for side-effects, eight (4B, 4P) for failure and two (2B) for both reasons. The results, based on changes in steroid dosage and other medication, daily symptom scores and PEF values, suggest that bromocriptine has little effect in asthma. In addition side-effects were frequent and troublesome. In the withdrawal study, ten patients who had been taking bromocriptine for a year or more were switched to an indistinguishable placebo if their asthma was considered to be stable. The results, of this second study, support the conclusion of the double-blind study, that bromocriptine has little beneficial effect in asthma.

Resistance to ischaemic conduction failure is a recognised but unexplained property of diabetic peripheral nerve. We have studied matched groups of control, diabetic, and non-diabetic hypoxic subjects (hypoxia: arterial oxygen tension less than or equal to 60 mm Hg (8 kPa) on at least one occasion and secondary to chronic lung disease). Similar resistance to ischaemia was seen in the hypoxic and diabetic groups compared with control subjects (p less than 0.001). The degree of resistance correlated with arterial oxygen tension at the time of testing (r = 0.72, p less than 0.01). In all individuals with acute exacerbations of hypoxia, the resistance to ischaemia was normalised with improvement of respiratory function (p less than 0.02). These results are compatible with the hypothesis that endoneurial hypoxia may be a factor in the pathogenesis of diabetic neuropathy.

Whole blood, allowed to clot at 37 degrees C in glass tubes, synthesized thromboxane A2 (TxA2) as determined by radioimmunoassay for thromboxane B2 (TxB2). The time course for TxB2 synthesis showed no further increase after 60 min and the concentration of TxB2 in serum obtained from 60 normal subjects positively correlated with the whole blood platelet count in EDTA anticoagulated blood from the same donor. Patients with chronic renal failure produced less serum TxB2 than age- and sex-matched controls; they also had lower haematocrits. After re-calculating TxB2 production as a function of platelet count and haematocrit all but one of the patients fell in the range of values obtained for controls. These results suggest that chronic renal failure may not be associated with a cyclooxygenase defect and that clotted whole blood TxB2 production should be expressed as a function of platelet count and haematocrit.

Eight normal healthy volunteers participated in a study to determine the effect of 1800 mg of aspirin on the peripheral haemodynamic changes that occur following upright exercise. Aspirin reduced the extent of calf hyperaemia (p less than 0.05) and accentuated the reduction in forearm blood flow (p less than 0.05) following exercise. It had no effect on either calf or forearm blood flow at rest. These results indicate that aspirin, possibly by inhibiting prostacyclin production, modifies the circulatory changes following upright exercise.

Rhinocerebral zygomycosis is a rare, often fatal opportunistic fungal infection involving the cranial tissues. A diabetic patient with normal humoral and cellular immunity who was successfully treated with amphotericin B and surgery is reported.

The amounts of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2) produced by the endothelial surfaces of paired samples of human pulmonary arteries and veins, obtained from patients undergoing thoracic surgery, were measured. The amounts of 6-keto-PGF1 alpha and TxB2 produced by arteries compared with veins were not different. However, both arteries and veins produced more 6-keto-PGF1 alpha than TxB2, the ratio being approximately 7.5:1 for both. 6-keto-PGF1 alpha synthesis by arteries was significantly correlated with that produced by veins but the relative amounts of TxB2 were not correlated. 6-keto-PGF1 alpha synthesis was correlated with TxB2 synthesis for veins but not for arteries. 8 of the 12 arterial samples exhibited some degree of intimal fibrosis. Incubation with the thromboxane synthase inhibitor, dazoxiben , caused a significant inhibition of vascular TxB2 synthesis and a significant increase in 6-keto-PGF1 alpha synthesis. In 3 of the 5 cases the increase in 6-keto-PGF1 alpha was too large to be explained by the fall in TxB2.

Sufficient isolated extrasystoles were recorded during a period of quiet breathing in nine patients to test the null hypothesis that there is no within-breath influence of respiration on the triggering of extrasystoles. In five patients a highly significant respiratory modulation of the firing of extrasystoles was seen. The frequency distribution of extrasystoles during the respiratory cycle appeared to be approximately sinusoidal. The phase relations varied with respiratory frequency, and the peak incidence occurred relatively later in the cycle when breaths were shorter: always at about 2 s after the start of inspiration. An autonomatic reflex mechanism, equivalent to that causing sinus arrhythmia, appears to be the most likely explanation.

We have compared the effects of the leukotriene (LT) D4 antagonist L-649,923 and placebo on the airway response to antigen challenge in eight men with mild asthma known to have both an early and late response to inhaled antigen. Subjects ingested 1000 mg of L-649,923 or placebo in a randomized, double-blind protocol and, two hours later, inhaled the dose of antigen known to induce a 20% fall in FEV1. Pulmonary function (specific conductance, FEV1, peak expiratory flow rate, and maximal flow at 25% of vital capacity) was measured at intervals before and up to 9 hours after antigen. FEV1 fell in one subject after L-649,923 ingestion. L-649,923 in the other seven subjects caused no change in baseline pulmonary function, a small reduction in the early response to antigen for FEV1, peak expiratory flow rate, and maximal flow at 25% of vital capacity but not for specific airway conductance (six subjects only) and no effect on the late response. The mean maximum fall in FEV1 in the early response was 1.35 L after L-649,923 ingestion and 1.78 after placebo ingestion. This relatively small degree of protection by L-649,923 suggests either that L-649,923 is not a sufficiently potent antagonist to diminish the effect of endogenous LTD4 in vivo or that LTD4 does not play a major role in the airway response to antigen challenge.