Comparative dilator effect of verapamil and sodium nitroprusside in forearm arterial bed and dorsal hand veins in man: functional differences between vascular smooth muscle in arterioles and veins.

Verapamil and sodium nitroprusside induce a dose dependent dilatation in the forearm arterial bed and preconstricted dorsal hand vein in man. Verapamil is about twenty times more effective in dilating arterioles than veins; sodium nitroprusside is about ten times more effective in veins than arterioles. These differences can be related to functional differences between the two types of vessel.

Long-term efficacy of calcium antagonists in resistant hypertension.

Verapamil and nifedipine are calcium-blocking agents that have a selective dilator effect on resistance vessels. Both drugs have been shown to lower arterial pressure when given in long-term therapy under conditions of a double-blind controlled trial. Both agents may be effective as sole therapy or when given in combination with a diuretic; nifedipine has been used successfully in conjunction with beta-adrenoceptor antagonist/diuretic combinations. Calcium-blocking agents do not evoke tolerance in long-term treatment; in contrast to other directly acting dilator drugs, they do not consistently lead to a rise in plasma renin activity and they induce little or no sodium retention. Calcium-blocking agents do not all share the same mechanism of action, and they vary considerably in their effect on the heart. These differences may be important in determining which compound is best suited for use in particular clinical situations.

Parkinsonism: differential age-trend in Helicobacter pylori antibody.

BACKGROUND: Parkinsonism is associated with prodromal peptic ulceration. Dopamine antagonists provoke experimental ulcer, dopaminergic agents protect, and might inhibit growth of Helicobacter pylori. OBJECTIVE: To describe the relationship between H. pylori serology and parkinsonism. METHODS: Serum H. pylori anti-urease-IgG antibody was measured in 105 people with (idiopathic) parkinsonism, 210 without, from same locality. None had received specific eradication therapy. RESULTS: Controls showed a birth-cohort effect: antibody titre rose from 30 to 90 years (P < 0. 001). Parkinsonism obliterated this (disease status. age interaction, P < 0.05), the differential age trend not being attributable to social class. Those with diagnosed parkinsonism were more likely to be seropositive (odds ratio 2.04 (95% CI: 1.04, 4.22) P < 0.04) before 72.5 years. Overall, titre fell (P=0.01) by 5 (1, 9)% per unit increase in a global, 30-point rating (median 14 (interquartile range 10.5, 17)) of disease severity. No individual category of anti-parkinsonian medication (92% taking) had a differential lowering effect. CONCLUSIONS: Higher prevalence of seropositivity in parkinsonism, before 8th decade, may be due to host susceptibility/reaction, or, conversely, infection with particular H. pylori strain(s) lowering dopaminergic status. Absence of a birth cohort effect in parkinsonism, despite similar social class representation, may be consequent on eradication, spontaneous (gastric atrophy) or by anti-parkinsonian medication.

Downward shift in serum IgM with Helicobacter pylori seropositivity.

OBJECTIVE: To determine whether Helicobacter pylori infection is associated with premature immune ageing, with respect to circulating immunoglobulins. METHODS: Serum immunoglobulin classes and H. pylori anti-urease antibody were measured in 205 subjects (aged 30-89 years), obeying inclusion/exclusion criteria. RESULTS: IgM decreased (P<0.001) by 0.9 (95% C.I. 0.3, 1.4)% per year, H. pylori seropositivity having an effect equivalent to 25 years of ageing (P<0.02). IgA increased by 0.5 (0.1, 0.8)% per year (P<0.007), IgG being unaffected by age. Seropositivity had no effect on IgA or IgG. CONCLUSIONS: Increasing age and H. pylori seropositivity are each associated with a downward shift in circulating IgM. If clinical extrapolation is justified, H. pylori eradication may be important in combating susceptibility to infection in old age.

Link between Helicobacter pylori infection and idiopathic parkinsonism.

The conventional concept for an environmental cause of idiopathic parkinsonism is an insult (e.g. neurotoxin or encephalitis), superimposed on age-related attrition of nigral dopaminergic neurons, and temporally remote from neurological diagnosis. To the contrary, we describe the fit of Helicobacter pylori. This commonest of known bacterial infections, usually acquired in childhood, persists, and has been linked with peptic ulcer/non-ulcer dyspepsia, immunosuppression and autoimmunity. Acquired immunosuppression, predisposing to auto-immunity, is assessed as a model for the pathogenesis of parkinsonism and parkinsonian-like attributes of ageing. Eradication of a trigger has potential to change the approach to parkinsonism, just as it did to peptic ulcer. The tenet of inevitable age-related attrition of dopaminergic neurons may also require revision.

Significantly higher frequency of Helicobacter suis in patients with idiopathic parkinsonism than in control patients.

BACKGROUND: There is increased proportional mortality from Parkinson's disease amongst livestock farmers. The hypokinesia of Parkinson's disease has been linked to Helicobacter pylori. H. suis is the most common zoonotic helicobacter in man. AIM: To compare the frequency of H. suis, relative to H. pylori, in gastric biopsies of patients with idiopathic parkinsonism (IP) and controls from gastroenterology services. METHODS: DNA extracts, archived at a Helicobacter Reference Laboratory, from IP patient and gastroenterology service biopsies were examined anonymously for H. suis, using species-specific RT-PCR. RESULTS: Relative risk of having H. suis in 60 IP patients compared with 256 controls was 10 times greater than that of having H. pylori. In patients with IP and controls, respectively, frequencies of H. suis were 27 (exact binomial 95% C.I. 15, 38) and 2 (0, 3)%, and of H. pylori, 28 (17, 40) and 16 (12, 21)%. Excess of H. suis in IP held when only the antral or corporal biopsy was considered. Of 16 IP patients with H. suis, 11 were from 19 with proven H. pylori eradication, 3 from 17 pre-H. pylori eradication, 2 from 24 H. pylori culture/PCR-negative. Frequency was different between groups (P = 0.001), greatest where H. pylori had been eradicated. Even without known exposure to anti-H. pylori therapy, H. suis was more frequent in IP patients (5/41) than in controls (1/155) (P = 0.002). Partial multilocus sequence typing confirmed that strains from IP patients (6) and control (1) differed from RT-PCR standard strain. CONCLUSIONS: Greater frequency of H. suis in idiopathic parkinsonism appears exaggerated following H. pylori eradication. Multilocus sequence testing comparison with porcine strains may clarify whether transmission is from pigs/porcine products or of human-adapted, H. suis-like, bacteria.

Maintenance digoxin after an episode of heart failure: placebo-controlled trial in outpatients.

The need for maintenance digoxin treatment was assessed in a double-blind, variable-dose, crossover comparison with placebo. Forty-six outpatients who had been prescribed the drug for heart failure were studied; 33 were in sinus rhythm and the remainder in atrial fibrillation. Mean serum digoxin concentrations in those with sinus rhythm averaged 1-33 nmol/l, but a lower concentration, averaging 0-97 nmol/l, was accepted in those with atrial fibrillation as six of them developed bradycardia. Sixteen of the 46 patients deteriorated on placebo, and eight completely recovered when digoxin was reintroduced; in the remainder additional diuretics were required temporarily. Spirometric values deteriorated on changing to placebo whether or not the patient showed clinical evidence of recurrence of heart failure. In a separate study of nine patients who showed no clinical evidence of deterioration on placebo, reintroduction of digoxin caused a shortening of left ventricular ejection time, which persisted for at least a month. This suggests that the inotropic response to digoxin is sustained during maintenance treatment.

Effects of nifedipine on resistance vessels, arteries and veins in man.

1 The effect of nifedipine on peripheral blood vessels has been studied in man. 2 Nifedipine induced dilatation of the forearm resistance vessels when given either by local intra-arterial infusion or sublingually (10 mg). 3 Local infusion of the drug did not relax hand veins preconstricted by infusion of noradrenaline and neither local infusion nor sublingual administration prevented constriction mediated by the sympathetic nervous system. Nifedipine was, however, a potent inhibitor of hand vein contractions induced by high concentrations of potassium provided that the noradrenergic component of the response was suppressed by simultaneous infusion of phentolamine. 4 Sublingual nifedipine (10 mg) did not dilate the elbow collateral arteries. 5 The effects of nifedipine on peripheral blood vessels are similar, but not identical, to those of verapamil. The pattern of action, with dilatation of resistance vessels but not capacitance, resembles that of hydralazine rather than glyceryl trinitrate and this suggest that nifedipine may prove useful in the treatment of hypertension.

Acquired tolerance to dilator action of hydrallazine during oral administration.

1 The effect on forearm blood flow of local intra-arterial infusion of hydrallazine has been studied in twelve patients with essential hypertension and six normal subjects. 2 When the patients with hypertension were not taking hydrallazine by mouth, they responded to intra-arterial infusions with a dose-dependent increase in forearm blood flow that was not significantly different from that in normal subjects. 3 When the patients were taking hydrallazine by mouth, the increase in forearm flow in response to intra-arterial infusions was reduced and forearm vascular resistance did not fall as low as it did in the control study (P less than 0.01). 4 In four patients, the response to intra-arterial hydrallazine was attenuated to a major extent, and in three of these, there was little or no response to oral treatment. In eight patients, the response to intra-arterial hydrallazine did not fall below one half of that in the control study and this minor reduction in sensitivity might be expected to impair, but not abolish, the response to oral treatment. 5 It is concluded that the resistance vessels commonly develop tolerance to the dilator action of hydrallazine during long-term oral therapy. In some patients a high degree of tolerance develops and this is an important cause of failure to respond to oral treatment.

Response of forearm resistance vessels to verapamil and sodium nitroprusside in normotensive and hypertensive men: evidence for a functional abnormality of vascular smooth muscle in primary hypertension.

1. The response of the forearm resistance vessels to local intra-arterial infusion of verapamil and sodium nitroprusside has been assessed by a plethysmographic method in 23 men with normal arterial pressure and 35 men with primary hypertension. 2. In the 20 patients with hypertension for whom full dose-response curves were determined, the dilator response to verapamil was significantly greater than that in the normal controls, whereas the response to sodium nitroprusside was reduced. 3. Comparison of responses to the two dilators in individual subjects enabled the scattering effect of variables common to both drugs to be reduced. Analysis of the results in this way showed a highly significant difference between the hypertensive men as a whole and the normotensive controls (P less than 0.00001); 24 out of the 35 hypertensive men showed responses that were outside the normal range. 4. The abnormal pattern of response observed in the hypertensive group cannot be accounted for by structural changes in the vessels and strongly suggests a functional abnormality of the vascular smooth muscle.

Nifedipine in the treatment of hypertension: report of a double-blind controlled trial.

1 The effect of oral nifedipine has been examined in patients with hypertension in whom arterial pressure was not adequately controlled by the combination of a beta-adrenoceptor antagonist (or alpha-methyldopa) and a diuretic. 2 In 42 patients, nifedipine (10 mg capsules) was added to the existing therapy in a final dose of 20-60 mg daily. Six patients had to stop the drug on account of side-effects. In the 36 patients who continued treatment, arterial pressure fell by an average of 24/9 mmHg supine and 26/10 mmHg standing. 3 In 11 of these patients who subsequently completed a double-blind, cross-over, placebo controlled trial, nifedipine (30-60 mg daily) was found to reduce arterial pressure by an average of 19/11 mmHg supine and 21/12 mmHg standing. 4 In all 11 patients who were changed to a sustained release preparation of nifedipine, control of arterial pressure was at least as good as it had been when taking the capsules.

Effect of treatment with chlorthalidone and atenolol on response to dilator agents in the forearm resistance vessels of men with primary hypertension.

The forearm resistance vessels of men with primary hypertension respond to verapamil with a greater than normal dilatation relative to that induced by sodium nitroprusside. We have examined the effect on this functional abnormality of treatment with chlorthalidone (50 mg daily in 16 patients) and atenolol (100 mg daily in eight patients and 200 mg daily in two). The responsiveness of the forearm resistance vessels to local intra-arterial infusion of verapamil and sodium nitroprusside was assessed before treatment and again after a minimum of 1 month of drug therapy. Forearm blood flow was measured by venous occlusion plethysmography. Chlorthalidone induced significant reductions in calculated mean arterial pressure, which fell from 135 +/- 4 to 117 +/- 4 mm Hg, and the dilator response to verapamil at 5 micrograms/min, which was reduced from 2.4 +/- 0.2 to 1.5 +/- 0.2 ml min-1 100 ml-1 forearm; the response to sodium nitroprusside at 3.2 micrograms/min was not significantly changed. Atenolol induced significant reductions in mean arterial pressure, which fell from 134 +/- 6 to 123 +/- 6 mm Hg, heart rate which fell from 72 +/- 3 to 55 +/- 2 beats/min, and response to verapamil at 5 micrograms/min which fell from 2.7 +/- 0.2 to 2.1 +/- 0.2 ml min-1 100 ml-1 forearm; the response to sodium nitroprusside was not significantly changed. Both drugs caused reversion towards normal of the relative enhancement of responsiveness to verapamil that was present before treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Breadth of base whilst walking: effect of ageing and parkinsonism.

BACKGROUND: The effect of healthy ageing and of parkinsonism on breadth of base whilst walking had not been adequately documented. DESIGN: Height-specific reference ranges for mean foot separation at mid-swing were derived for males and females, age not proving to be a significant influence. METHOD: Normative data were obtained from 164 healthy volunteers, and foot separation in idiopathic parkinsonism (99 patients) was characterized by comparison. RESULTS: Parkinsonism was associated with significantly greater within- and between-subject variability in foot separation. There was a linear trend from increased separation in those with bilateral signs but little functional impairment, to decreased separation in the severely impaired but not yet chair or bed bound. Foot separation was best explained by two clinical signs, rigidity and anatomical postural abnormality. A flexed posture was associated with increased separation, rigidity with decreased, the separation manifested being determined by the net effect. CONCLUSION: In early idiopathic parkinsonism, falling may depend on abnormal posture, and increased breadth of base be compensatory. Later, the decrement in foot separation may become a primary determinant of falls.

A method for assessing responses of small arteries in man: effect of physiological and pharmacological stimuli.

1. A method has been developed for estimating resistance to blood flow in the collateral arteries around the elbow. Arterial pressure is recorded continuously from the radial artery and blood flow in the forearm and hand is measured by venous occlusion plethysmography. The brachial artery is occluded for short periods, and the pressure drop across the collaterals and the flow through them are determined. From these observations an index of resistance can be calculated. 2. During 2 min occlusions of the brachial artery, collateral arterial resistance fell progressively to reach a level that was on average 45% lower than the initial resistance (P less than 0.01). 3. There was an inverse relation between distending pressure in the collateral arteries and calculated resistance. 4. Ergotamine tartrate (0.25 mg intravenously) increased collateral resistance by an average of 135%. Glyceryl trinitrate (0.5 mg sublingually) reduced collateral resistance by an average of 45%. Hydrallazine and isoprenaline had an inconsistent dilator effect; the direct action of these drugs may have been offset by the reduction in distending pressure which they induced. 5. The elbow collateral arteries provide a useful model for studying physiological and pharmacological responses of small limb arteries in man.

Bringing gait analysis out of the laboratory and into the clinic.

The potential value of objective assessment of gait in geriatric medicine cannot be explored fully whilst gait analysis remains a laboratory research tool, imposing special conditions which often preclude its use in the elderly. We describe a method of gait analysis suitable for the geriatric clinic and illustrate its use in documenting the response to interventions in three patients presenting with falls due to parkinsonism. Irregularity between gait cycles was noted, a finding previously described in Parkinson's disease, dementia and normal old men at a fast walking speed. Such irregularity may prove to be a major risk factor for falls. Where multiple pathologies which disturb gait coexist, measurement of changes in gait in response to treatment may provide a much needed means of audit.

Measurement of axial rotation: its relevance to screening for night-time hypokinesia in old age and parkinsonism.

A novel device for continuous monitoring of axial rotation of a recumbent person is described. It is self-applicable and small enough to be mailed. A field trial showed that parkinsonian patients change their position less frequently than did their spouses: the difference became smaller where the age of the spouse was equal to or greater than that of the sufferer. The most marked difference between sufferers and their spouses was with respect to total angular displacement, which was nearly four times greater in the spouses. Further work is needed to show whether impaired rotation predates clinical idiopathic Parkinson's disease and so acts as a useful predictor. Measurement of axial rotation seems valuable in judging risk of pressure sores and gauging improvement in mobility in response to therapeutic interventions.

Association of circulating TNF-alpha and IL-6 with ageing and parkinsonism.

INTRODUCTION: We propose that the increase in TNF-alpha and IL-6 in the brain in idiopathic parkinsonism is in response to a peripheral immune/ inflammatory process, so ubiquitous as to be responsible for the resemblance between ageing and parkinsonism. METHODS: Circulating cytokine was measured in 78 subjects with idiopathic parkinsonism and 140 without, aged 30 to 90 years, all obeying inclusion/exclusion criteria. RESULTS: Serum TNF-alpha increased (P<0.0001) by 1.37 (95% CI 0.75, 2.00)% x y(-1), IL-6 by 2.63 (1.75, 3.52) (P<0.0005). TNF-alpha appeared elevated in parkinsonians whose postural and psychomotor responses were abnormal, being suppressed where they were normal: trends which contrasted with those in controls (P = 0.015 and 0.05, respectively). Parkinsonism appeared (P = 0.08) to have an effect on IL-6, equivalent to that of >10 years of ageing (28(-3, 69)%), but was not immediately related to between-subject differences in performance. CONCLUSION: Ageing and pathogenetic insult may be confounded, age being a progression, not a risk, factor.

Therapeutic drug monitoring of digoxin: help or hindrance?

A major role of therapeutic drug monitoring services is to advise on the dose of a drug which would be required to bring the concentration in the blood to within specific 'therapeutic' limits. Monitoring digoxin usage constitutes a substantial part of the work load. We have examined the potential variability in recommendations for digoxin dosages based on a series of serum digoxin measurements in each of 80 out-patients. In over a third of cases a dose, which seemed to be optimal on the basis of the first assay result, would have produced concentrations outside the conventional therapeutic range when the measurement was repeated. This was despite careful supervision of medication and the timing of the blood sample in relation to its administration. In routine practice the apparent variability in dose requirements would be far greater. Objectives of therapeutic drug monitoring services remain the same, the way forward would seem to lie in their taking on a heavy commitment to counsel and supervise patients before repeated blood sampling. However, effort and resources might be better channelled into producing simple prescribing aids relating the risk of cardiotoxicity directly to the size of the maintenance dose and the individual's renal function.