Experimental headache in humans

The need for valid human experimental models of headache is obvious. Several compounds have been proposed as headache-inducing agents, but only the nitroglycerin (NTG) model has been validated. In healthy subjects, intravenous infusions of the nitric oxide (NO) donor NTG induce a dose-dependent headache and dilatation of the temporal, radial and middle cerebral artery. NTG-induced headache, although less intense, resembles migraine in pain characteristics, but the accompanying symptoms are rarely present. Cephalic large arteries are dilated during migraine headache as well as during NTG headache. N-acetylcysteine enhances the formation of NO and potentiates NTG-induced headache, whereas mepyramine, a H1 -antagonist capable of blocking histamine-induced headache, has no effect. Thus, the headache is dependent on NO or other steps in the NO cascade. The model is useful for pharmacological interventions and sumatriptan reduced the NTG-induced headache. The NTG model may be a valuable tool in the development of future migraine drugs.     

Spontaneous platelet aggregation and coagulation parameters as risk factors for arterial occlusions in diabetics. Results of the PARD-study

PARD is a prospective study sponsored by the German Research Council with the aim to establish whether spontaneously enhanced platelet aggregation or changes of other hemostatic parameters are risk factors for new vascular occlusions in diabetic patients. 363 diabetic patients (aged 45-65, 232 men, 131 women) were observed for 5 years. Of the 232 men, 53 were on diet, 104 on oral antidiabetic drugs and 75 on insulin. Of 131 women 16 were on diet, 46 on oral antidiabetic drugs and 69 on insulin. At entry clinical examination and laboratory tests were performed, covering the known risk factors for cardiovascular complications. Hemostatic tests and clinical examination were performed at 3 months' intervals. The life status was followed for all patients. Endpoints were carefully defined. Until December 31, 1984, 42 patients died, 23 from cardiovascular disease and 19 from other causes. 13 patients suffered a myocardial infarction, 10 a stroke and 53 peripheral arterial occlusions. The occurrence of new vascular occlusions was significantly higher in those men with enhanced spontaneous platelet aggregation measured by PAT III angle alpha above 40 degrees at entry as compared to those with lower values. This was not the case for women. Other hemostatic parameters, which had also some relation to cardiovascular complications, in men were fibrinogen and F. VIII R:Ag. Established risk factors for which a significant relation to cardiovascular complications was observed in this study, were smoking, duration of diabetes, diastolic blood pressure, cholesterol, triglycerides and also HbA1. The results of the PARD-study have verified the hypothesis that spontaneous aggregation is a major risk factor for future vascular occlusions in diabetic men. They also lead to the hypothesis that high levels of F. VIII R:Ag and fibrinogen are further indicators of progressive vascular disease and may be useful as predictors of new vascular occlusions in combination with such established risk factors as smoking, duration of diabetes, diastolic blood pressure, cholesterol, and triglycerides.     

Plasma salicylate levels and platelet function after acute and chronic administration of slow-release acetylsalicylic acid (Monobeltin)

Summary The relationships between the antiplatelet effects and the pharmacokinetics of a slow release formulation of acetylsalicylic acid (ASA) have been investigated. After acute intake of 750 mg ASA in a slow-release formulation (Monobeltin), a slow increase in plasma ASA was paralleled by a gradual decrease in certain platelet functions. During chronic medication (750 mg twice daily), ASA was present in plasma at all times accompanied by full inhibition of platelet aggregation. For chronic antiplatelet therapy, this slow release formulation of ASA appears to be very effective, unless rapid inhibition of platelet function must be achieved.     

Cardiopulmonary effects and safety of prostaglandin E1: A review

Intraarterial and intravenous infusion of prostaglandin E₁ (PGE₁) is established treatment for severe peripheral arterial occlusive disease, particularly in Europe and Japan. In this critical appraisal, experimental and clinical studies are reviewed, with special emphasis on cardiopulmonary effects and drug safety. The pulmonary data all indicate dose-dependent dilation of the pulmonary vessels with a reduction in pulmonary resistance. The known hemodynamic effects of PGE₁ on the heart include an increase in stroke volume, cardiac index, and left ventricular ejection fraction, and a reduction in left ventricular filling pressure. Analysis of clinical trials shows a low rate of adverse effects, in particular a low incidence of cardiopulmonary side effects. If the recommendations for high-risk patients are observed, PGE₁ is both an efficacious and safe therapeutic principle.     

Neutrophil dermatosis of the dorsal hands

Neutrophil dermatosis of the dorsal hands (NDDH) is a recently described skin manifestation regarded as a subset of acute febrile neutrophilic dermatotis (Sweet syndrome). We describe 5 cases with pustular and ulcerative plaques and/or bullae and vesicles of the dorsal hands. Three of the patients also had skin changes at sides other than the hands. Associated conditions were found in two patients, one patient treated with hemo-dialysis for chronic glomerulonephritis, and one patient had suffered from a streptococcal tonsillitis prior to the eruption. Two of the patients had fever, two had neutrophil leucocytosis in peripheral blood and two had elevated sedimentation rates. Histological findings showed signs of vasculitis in biopsies from two of the patients. NDDH is discussed on the basis of prior case reports concerning the subject, and it is concluded that Neutrophil dermatosis of the dorsal hands should be regarded as a localized variety of Sweet syndrome.     

The role of the Child Health Services in the identification of children with possible Attention Deficit Hyperactivity Disorder/Deficits in Attention, Motor Control and Perception (ADHD/DAMP)

Literature concerning the role of the Child Health Services in the identification of children with possible Attention Deficit Hyperactivity Disorder/Deficits in Attention, Motor Control and Perception (ADHD/DAMP) is summarized in order to establish a background for evaluation, discussion and conclusion.     

Platelet membrane defects in fawn hooded bleeder rats

An inbred strain of fawn hooded rats with a congenital platelet defect shows a marked bleeding tendency with prolonged bleeding time. This haemorrhagic disorder has been exclusively related to a deficiency of nucleotides in platelet dense granules. When tested in cell electrophoresis platelets from fawn hooded bleeder rats showed a significantly lower electrophoretic mobility than normal rat platelets. Subsequent studies on the platelet membrane protein pattern by high resolution two-dimensional gel electrophoresis revealed the deficiency of a membrane glycoprotein (apparent molecular mass 90.000, isoelectric point 5.6), which is detectable in normal rat platelets after surface labeling by periodate-tritiated sodium borohydride. It seems likely, that this glycoprotein defect contributes at least partially to the disorder of platelet function in fawn hooded bleeder rats.     

Reviparin sodium - a new low molecular weight heparin

Reviparin sodium (Clivarine), Knoll AG) is a low molecular weight heparin (LMWH) with a mean peak molecular weight of 3900 Da. It is characterised by a narrow molecular weight distribution profile, with an anti-factor Xa (anti-Xa):anti-factor IIa (anti-IIa) ratio of >or=3.6. In healthy human volunteers, plasma anti-Xa activity was up to five times higher and lasted three times longer with reviparin compared with unfractionated heparin (UFH). Unlike UFH, reviparin has negligible effects on global clotting tests. Reviparin has been shown to be as effective as UFH in different prophylactic indications and causes fewer injection-site haematomas. At a daily dose of 1750 IU anti-Xa it was as effective as UFH in preventing deep vein thrombosis (DVT) in moderate risk surgery (general and abdominal) and significantly reduced DVT in patients with brace immobilisation of the legs. At a daily dose of 4200 IU anti-Xa reviparin was as effective as UFH or enoxaparin in preventing DVT in high risk orthopaedic surgery and as effective as UFH in prevention of DVT and/or pulmonary embolism (PE) and/or mortality in high risk orthopaedic surgery. In patients with acute venous thromboembolism (VTE), reviparin was more effective than UFH in thrombus reduction and at least as effective as UFH in the prevention of clinical recurrence of DVT and/or PE. The use of reviparin is associated with a similar or lower incidence of bleeding complications than UFH.     

Headache induced by a nitric oxide donor (nitroglycerin) responds to sumatriptan. A human model for development of migraine drugs

Experimental "vascular" headache in humans may be used in characterizing new migraine drugs. The effects of sumatriptan on nitroglycerin-(NTG)-induced headache and arterial responses were therefore studied. Following a double-blind randomized crossover design, 10 healthy volunteers received sumatriptan 6 mg s.c. or placebo succeeded by 20 min NTG (0.12 mg/kg/min) infusion. Headache was rated on a 10 points scale. Temporal and radial artery diameters and velocity in the middle cerebral artery (MCA) were measured with ultrasound. Sumatriptan reduced the NTG-induced headache, median score 1.5 versus 4 after placebo ( p <0.01) and decreased temporal and radial artery diameters 75±3 and 86±3% of baseline respectively ( p <0.05), Blood velocity in the MCA was unaffected. The NTG model may prove to be a valuable tool in the development of future migraine drugs. The results suggest that NTG headache in non-migraineurs may share mechanisms with migraine headache.