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Human immunodeficiency virus (HIV)-infected individuals are at a higher risk of developing metabolic disturbances. The pathogenesis of these complications is complex and not fully explored.The aim of the study was to investigate the effect of HIV infection and antiretroviral (ARV) therapy on the development of metabolic changes and adipocytokine concentrations. The analysis of the differences in the investigated parameters among lipodystrophic and nonlipodystrophic patients was also performed.A total of 42 HIV‑infected patients on ARV therapy (HIV[+]ARV[+]), 13 HIV‑infected ARV naive patients (HIV[+]ARV[-]), and 20 healthy controls were included in the study. A lipid profile, fasting free fatty acids (FFAs), glucose, insulin, and insulin resistance (homeostasis model assessment of insulin resistance--HOMA‑IR) were tested. Serum concentrations of tumor necrosis factor α (TNF‑α), interleukin 6 (IL‑6), adiponectin, leptin, and fatty acid-binding protein 4 (FABP4) were determined.Increased FFA levels were observed in HIV(+)ARV(-) patients. HIV(+)ARV(+) patients had significantly higher triglycerides and insulin level compared with controls. HOMA‑IR showed a tendency to be higher in HIV(+)ARV(+) patients compared with the other study groups. The ARV therapy longer than 2 years resulted in more pronounced metabolic abnormalities. HIV infection itself had a significant effect on inflammation expressed by elevated TNF‑α and IL‑6 levels. We did not observe differences in adiponectin and FABP4 concentrations among the study groups, while the leptin concentration was significantly lower in HIV‑infected lipodystrophic than in nonlipodystrophic patients.HIV infection induces lipid disorders, especially associated with fatty acid turnover augmented by ARV therapy. Compared with FABP4, leptin is a better biological marker of metabolic complications in HIV‑infected patients.

Hypertrophic cardiomyopathy (HCM) is a genetic disease. The role of phospholamban (PLN) gene mutations is the development of HCM has not been established.To screen for PLN gene mutations in a group of HCM patients from the southern Poland.We included 50 consecutive patients (31 males, mean age 42 ± 14 years) diagnosed with HCM on the basis of typical clinical, echocardiographic, and haemodynamic features. The control group consisted of 50 (sex-, age-matched) healthy subjects with normal echocardiograms.The genetic analysis was focused on R9C mutation with the ability to block PLN phosphorylation leading to chronic inhibition of SERCA2a activity. Another analysed mutation causing the alteration of PLN level in cells was related to the substitution of a leucine residue at position 39 with a premature stop codon (L39X). The sequence analysis of selected coding regions of the PLN gene did not show the presence of mutations in either the patients or the control subpopulations.Systematic mutation screening did not reveal any mutation in the selected regions of the PLN gene. Additionally, no polymorphisms were detected in any patients. Therefore, PLN gene mutations were not found to be associated with HCM in the study group.

Reduced nitric oxide (NO) production is associated with pathological changes in the cardiovascular system. In our study we analyzed the relationship between two polymorphisms (Glu298Asp and VNRT in the intron 4) of the endothelial nitric oxide synthase (eNOS) and ambulatory blood pressure (ABP), left ventricular mass index (LVMI) and vascular phenotypes.The study population consisted of 127 parents and 167 offspring. All subjects underwent 24 hr ABP monitoring using a SpaceLabs 90207 device. 2D and M-mode echocardiograms were obtained. Pulse wave velocity (PWV) between the common carotid and femoral artery was measured with the Complior device and the carotid intima-media thickness (IMT) was assessed by ultrasound. For statistical analysis co-variables and correlations between relatives were taken into account.There was no relationship between the eNOS gene polymorphisms and ABP or LVMI neither in parents nor their offspring. Among parents, who were carriers of the 298Asp allele higher IMT values were noted as compared with Glu/Glu homozygotes (0.94 vs. 0.70 mm; p = 0.007). Among offspring there was a similar tendency towards higher IMT (0.60 vs. 0.53 mm; p = 0.10), but also higher PWV in carriers of the 298Asp allele as compared with Glu/Glu homozygotes (8.47 vs. 8.17 m/sec; p = 0.14). Polymorphism VNRT in intron 4 was not associated with vascular phenotypes.The Glu298Asp polymorphism of eNOS gene identifies patients with larger carotid IMT.

Polymorphisms of the angiotensin-converting enzyme gene and endothelial nitric oxide synthase gene have been suggested to be associated with left ventricular hypertrophy. The aim of our study was to asses the association between above polymorphisms and left ventricular hypertrophy in patients with cardiac syndrome X. The presence of allele 4 of eNOS VNTR polymorphism could predispose to cardiac hypertrophy. The pathological course of postprandial lipemia in patients with CSX may add to the understanding of the CSX pathology.

The aim of the study was to evaluate selected markers of thrombin generation and subsequent fibrinolysis in patients with aneurysmal subarachnoid haemorrhage (SAH) and to assess the relationship between thrombin generation/fibrinolysis and clinical course and outcome.This prospective study included 72 patients after aneurysmal SAH who underwent surgery within 72 hours after onset of symptoms. The results were compared with 84 control patients without SAH. Selected markers of thrombin generation (thrombin-antithrombin complexes, TAT), fibrinolysis (D-dimer) and fibrinogen level were examined in blood just after admission and on day 7 after surgery. The relationship between levels of those markers and selected clinical and radiological data, and outcome at 3-6 months after surgery, were assessed.On admission, patients with SAH had higher levels of TAT (p0.001), D-dimer (p=0.048), and fibrinogen than the control group (p0.001). Also, patients with severe bleeding demonstrated higher TAT (p0.001) and D-dimer (p=0.04) levels. The admission level of TAT (higher than 24 g/l; odds ratio = 10.8) and the elevated blood fibrinogen level (odds ratio = 1.2) showed a strong correlation with mortality. Furthermore, a level of TAT higher than 24 g/l (odds ratio = 9.98) and the level of fibrinogen (odds ratio = 1.3) strongly correlated with poor outcome. There was no significant correlation between markers of coagulation on the 7th day after surgery for SAH and the outcome.Activation of blood coagulation as well as the fibrinolytic system occurred early in the course of SAH. Such activation was associated with poor clinical status of patients on admission, greater amount of subarachnoid blood, and poor clinical outcome. Thus, blood levels of TAT and fibrinogen are independent factors associated with mortality and morbidity after aneurysmal SAH.

Familial LCAT deficiency (FLD) is a rare genetic disorder associated with corneal opacities, anaemia and proteinuria with renal failure. Here we report detailed analyses on plasma lipids, lipoproteins, and the molecular defect in two siblings from a Polish family presenting classical symptoms of FLD and their family members with newly discovered Val309Met mutation in exon 6 of LCAT gene. Both patients displayed low total (2.19 and 2.94 mmol/l) and HDL-cholesterol concentrations (0.52 and 0.48 mmol/l), low percentage of cholesteryl esters (CE) (11.1 and 12%), and decreased apo AI and apo AII serum levels. Low LDL-cholesterol, apo B and Lp(a) levels, and increased oleate/linoleate ratios in CE could be of importance in the development of atherosclerosis in these patients with low HDL-cholesterol. LCAT activity was 10% of normal, alpha-LCAT activity was 0, and LCAT concentration was undetectable by immunoassay. Plasma CETP activity was at lower limits of normal. PCR and sequence analysis of DNA from the proband and affected brother revealed a novel G-->A mutation in exon 6 of LCAT gene, which resulted in an amino acid substitution of valine for methionine (Val309Met). The proband and affected brother were both homozygous carriers, while the mother, siblings and children of patients were heterozygous carriers of a newly discovered mutation. This is the first LCAT mutation described in the Slavic population.

Cardiological syndrome X (CSX) is defined as effort anginal pain, positive exercise tolerance test and absence of angiographically documented stenosis in coronary arteries. Some genetic predispositions and metabolic disturbances can participate in development of this syndrome. The aim of our study was to investigate the associations between some biochemical parameters and polymorphism of ACE and eNOS (VNTR and Glu298Asp) genes in patients with CSX. 36 patients with CSX and a control group of 30 healthy volunteers were included in the study. The genotypes were determined by the polymerase chain reaction. Our study revealed that patients with CSX exerted lower fasting NOx levels, tended to have higher insulin values measured at 1 h of oral glucose tolerance test and higher levels of triglycerides and free fatty acids during oral lipid tolerance test. Patients with genotype T/T Glu298Asp of eNOS and 4/4 VNTR of eNOS revealed lower levels of NOx compared to patients with genotypes G/G and 5/5, respectively (30.5 +/- 7.2 vs 13.2 +/- 4.5; 28.6 +/- 8.4 vs 14.2 +/- 7.4; p0.05). Thus, we conclude that disturbances in free fatty acid utilization, estimated by postprandial lipaemic test play important roles in the development of endothelial injury in CSX.

The key enzyme of the renin-angiotensin-aldosterone system angiotensin-converting enzyme (ACE), shows the genetic polymorphism responsible for the varying activity of this enzyme. In a study of randomly chosen families we analyzed the relationship between insertion/deletion (I/D) polymorphism of the ACE and ambulatory blood pressure (ABP), left ventricular mass index (LVMI) and carotid intima-media thickness (IMT).The study population consisted of 127 parents and 167 offspring. All subjects underwent 24 hr ABP monitoring using a SpaceLabs 90207 device. 2D and M-mode echocardiograms were also obtained. The carotid intima-media thickness (IMT) was assessed by ultrasound. The I/D polymorphism of the ACE gene was measured with the use of PCR method. For statistical analysis, co-variables and correlations between relatives were taken into account.The frequency of genotypes was: 27.2% for DD homozygotes, 49.7% for DI heterozygotes and 23.1% for II homozygotes, being in Hardy-Weinberg equilibrium (P=0.97). There was no relationship between the ACE gene polymorphism and ABP, LVMI or carotid IMT in parents nor their offspring. The transmission disequilibrium tests for quantitative traits showed only a slight tendency towards the influence of the polymorphism on LVMI (P=0.06).In the study group of nuclear families, I/D polymorphism of the ACE gene did not influence blood pressure, left ventricular mass or carotid intima-media thickness.

Accelerated vascular calcification is an important cause of excess mortality in patients on dialysis therapy. The aim of the study was to evaluate the trends in coronary artery calcification (CAC) score (CaSc) during a 1-year period in a group of stable peritoneal dialysis (PD) patients and identify factors that may be associated with CaSc changes.Sixty-one stable patients (28 women, 33 men) on PD therapy with a mean age of 50.4 +/- 13.6 years were included. Forty-seven patients survived the entire study period on PD therapy and were suitable for the final analysis. CaSc was assessed at baseline and after 12 months by using multislice spiral computed tomography. Proinflammatory cytokines (interleukin-6, tumor necrosis factor-alpha [TNF-alpha]), acute-phase proteins (C-reactive protein [CRP], fibrinogen), calcium-phosphate balance, and lipid profile were assessed at baseline and after 6 and 12 months.Median CaSc was 22.6 Agatston units (range, 0 to 5,502.8 Agatston units) at baseline and increased to 84 Agatston units (range, 0 to 5,001.3 Agatston units) at a 1-year follow-up (P0.05). In the entire group of patients, 3 subgroups were identified: patients with progression (n = 21; P = 0.02 for the difference between initial versus follow-up CaSc), patients with regression (n = 12; P = 0.05), and subjects without change in CaSc after 1 year (n = 14). Patients without progression showed no calcifications at baseline and follow-up and were younger, less overweight, and characterized by significantly lower mean TNF-alpha, leptin, and CRP levels during 1 year compared with both progressors and regressors. Mean serum phosphate and calcium x phosphate product (Ca x P) values were gradually increasing from regressors through the no-calcification group to progressors (P0.01 for phosphate levels, P0.02 for Ca x P product). Significant correlations were found between changes in CaScs and mean values for phosphate (R = 0.44; P0.0005) and Ca x P product (R = 0.38; P0.005).Chronic nonspecific inflammation does not directly attribute to progression in CaScs. Calcium-phosphate balance abnormalities appear to be the only important factors promoting CAC, although a permissive or promoting role of inflammation cannot be ruled out.

Endothelial dysfunction has been implicated in the pathophysiology of cardiovascular diseases, including arterial hypertension. The present study was undertaken to assess endothelial function in postmenopausal women with arterial hypertension receiving hormone replacement therapy and antihypertensive treatment.A group of 76 women with natural menopause and essential mild to moderate arterial hypertension entered the study. Forty women received a transdermal, combined hormone replacement therapy (HRT) of 17 -estradiol and norethisterone acetate, whereas 36 served as controls. At baseline and at 3 and 12 months, all patients underwent 24-hr blood pressure monitoring and an exercise test, before which, at peak exercise, and after a 15-min recovery period venous blood was drawn to measure the level of nitrite/nitrate (NOx) according to the GriessAt 3 and 12 months after beginning HRT, the level of NOx at rest was slightly increased, with marked individual differences in response to HRT. In women not receiving HRT, NOx did not change. In the HRT group, 52.5% at 3 months and 47.5% at 12 months had significantly increased levels compared with the baseline values (17.8+/-6.7 vs. 32.8+/-4.5 vs. 28.7+/-1.1 Kmol/l; p=0.002). The increased NOx level in responders was associated with decreased LDL cholesterol (3.62+/-1.2 vs. 3.53+/-1.3 vs. 2.6+/-0.6 mmol/l; p=0.01). At 12 months, blood pressure values did not differ from those at baseline in either group.The significant increase of NOx in half of the women receiving HRT suggests that only responders experience the cardioprotective effects of HRT.

Previous studies have suggested that genetic variation in the beta2 (b2-AR) and beta3 (b3-AR) adrenergic receptor genes are associated with obesity and insulin resistance. The aim of this study was to evaluate the influence of beta2 (Gln27Glu) and beta3 (Trp64Arg) adrenoreceptor gene polymorphisms on BMI and carbohydrate-lipid metabolism in Polish obese families.122 persons (84 women, 38 men) from 40 obese families (BMI 33.5I7.7) were included. PCR-RFLP analysis of genotype was plotted against anthropometric parameters and the results of glucose and lipid oral tolerance tests. Venous blood samples were analysed for concentrations of glucose, insulin, free fatty acids, triglycerides, total cholesterol, HDL-chol, LDL-chol, leptin, and vWF.We found 39% Glu27 with 8% Arg64 allele frequencies. The blood glucose and insulin concentration during OGTT and blood FFA and TG level during OLTT was lower in patients with the Glu/Glu b2-AR polymorphism than Glu/Gln and Gln/Gln. In the obese patients the same effect was observed; however, the percent of fat body mass, leptin concentration, and BMI was higher in this group. Patients with the Trp/Trp polymorphism in the b3-AR gene were characterized by higher glucose and insulin concentration during OGTT and higher blood concentration of FFA and TG during OLTT. These results were independent of BMI value.The b2-AR 27Glu and b3-AR 64Arg alleles have a protective effect against metabolic disorders in obese families from southern Poland.

The significance of lipid abnormalities as the risk factor for stroke remains uncertain. The aim of this study was to compare the concentrations of lipoprotein (a) [lp(a)] in stroke patients with large and small vessel disease. We studied 71 patients being 3 to 12 months after ischemic stroke (including 30 subjects with large vessel disease and 41 subjects with small vessel disease) and 30 controls. We excluded patients with stroke of cardioembolic, rare or uncertain etiology, subjects with diabetes, with history of myocardial infarction, arrhythmia, valvular heart disease, hypo- or hyperthyreoidism, hepatic or renal insufficiency, and treated with statins or fibrates. We assessed basal lipid fractions and nephelometrically measured the concentration of lp(a). The concentrations of total and LDL-cholesterol were similar in studied groups. Patients with large vessel disease had lower levels of HDL-cholesterol and higher levels of triglycerides than patients with small vessel disease and than controls. Median concentrations of lp(a) were similar in all studied groups (8.4 mg/dl in all stroke patients; 10.85 mg/dl in large vessel disease; 7.7 mg/dl in small vessel disease and 6.3 mg/dl in controls; p = n.s.). The percentage of subjects with increased lp(a) concentrations (i.e.30 mg/dl) was greater in large vessel disease (36.7%) than in small vessel disease (12.2%; p0.05) and in controls (10%; p0.05). The concentrations of basal lipid fractions were similar in subjects with normal and with increased concentration of lp(a), both in stroke patients and in controls.

Postmenopausal lack of estrogens may accelerate cardiovascular atheromatic changes. Standard exercise test (SET) challenges hidden signs of the vascular involvement. Although the test is known not to carry a risk of thromboembolic complications, it may influence plasma concentrations of endothelial and platelet factors. The question is if and to what extend the menopause aggravates the SET induced changes.Plasma concentrations of nitric oxide, endothelin-1, beta-thromboglobulin and von Willebrand factor activity before, at the maximum exercise and 15 minutes after the SET referred to, as a recovery time were estimated.SET was performed according to Bruce protocol in group of 31 premenopausal and 57 postmenopausal women. Standard RIA kits for plasma beta-thromboglobulin (beta-TG) (Boehringer Mannheim) and endothelin-1 (Et-1) (Blotrack) concentration were used. The von Willebrand factor (vWF) activity was assayed by ELISA system (Boehringer Manheim). Plasma nitric oxide (NO) concentration was calculated from nitrides/nitrates levels, by Griess reaction, modified by use of NADPH reductase.Mean plasma levels of beta-TG, Et-1, NO and vWF activity do not differ between pre and postmenopausal women. The standard exercise test significantly increases both beta-TG plasma concentration and vWF activity (p0.00001). During the 15 minutes rest period the changed values do not return to preexercise levels. Neither plasma NO nor Et-1 plasma concentrations change during the exercise test. There was a similar increase in beta-TG plasma levels and vWF activity during the SET in pre- and postmenopausal women and a slighter increase of plasma Et-1 levels in postmenopausal women (p0.04). The close relationships between NO plasma concentration and both vWF activity (p0.002) and vascular endothelial growth factor (VEGF) level (p0.04) were observed in postmenopausal women. The vWF activity in postmenopausal; women inversely correlates with insulin-like growth factor-I (IGF-I) concentration (p0.001). In premenopausal women the important modulators of vWF activity were: body mass (p0.04), serum total cholesterol (p0.02) and sex hormone binding globulin (SHBG) levels (p0.04). The postmenopausal beta-TG increase during SET depends on body mass (p0.02), whereas the preexercise levels seem to be related to VEGF level (p0.03) and inversely to Et-1 (p0.007) and dehydroepiandrosterone sulfate (DHEAS) concentration (p0.03) Both the basal and stimulated by exercise vWF activity are higher in obese women (p0.003), but the net increase is larger in lean group (BMI30 kg/m2). In premenopausal women plasma NO concentration depends on 17 beta-estradiol serum level (p0.02). The higher VEGF (p0.01) levels as well as vWF activity was observed (p0.03) in hypercholesterolemic women.The standard exercise test increases the procoagulatory von Willebrand factor activity so as the platelets activity (beta-thromboglobulin concentration) in both pre and postmenopausal women. The slight endothelin-1 rise has been found at the maximum exercise in postmenopausal women. The close relation between plasma nitric oxide and endothelin-1 levels was found in postmenopausal women. Obesity and hypercholesterolemia may contribute to the observed changes.

The study was performed in cooperation of the Department of Neurotraumatology and the Department of Clinical Biochemistry Jagiellonian University in Cracow. In patients with central nervous system injury, diagnosed upon computerized tomography scan, melatonin levels were measured. The most frequent reason of damage was severe craniocerebral trauma. Consciousness, assessed according to Glasgow Coma Scale, was between 3 to 13 points. Melatonin levels were measured at 8 a.m. The investigation could not demonstrate any correlations between consciousness disturbances after head injury and serum melatonin levels in the morning. To draw a final conclusion further experiments are necessary. They will help to explain the role of endogenous melatonin in patients after craniocerebral injury.

There is a growing evidence on the relations between apoprotein E (apo E), in particular apoE4, cardiovascular disease and Alzheimer's disease. However, little is known on the prevalence of apoE in Polish population. The goal of this paper was to assess the frequency of apoE phenotypes and isoforms in the sample of elderly people. Studied group were 90 men and 92 women, residents of Polish rural province (Tarnobrzeg Voivodship) at age 65-78 years. Identification of apoE isoforms was done using the immunoblotting method. The most frequent phenotype was apoE3/3, which was found in 70% of men and 73% of women. Phenotype apoE3/2 was identified in 20% men and 15% women. Both in men and in women phenotypes apoE4/2 and apoE4/3 were more rare-in total 10% and 12% participants, respectively. There was nobody with phenotype apoE4/4. In women there was also nobody with phenotype apoE4/2, but in men phenotype apoE4/2 was found in 4% of participants. No person was found with phenotype apoE2/2. Frequency of homozygotes apoE4/4 was low in studied population and could little contribute to the epidemy of cardiovascular disease and dementia in the elderly. However, the 10% frequency of heterozygotes with isoform apoE4 could have more impact.

The aim of the study was to assess the relation between urinary excretion of epinephrine and norepinephrine, and stroke severity, prognosis and standard biochemical investigations in acute phase of ischaemic stroke. The study was done on the material of 36 patients (17 women and 19 men, aged 41-89 years, mean: 69 +/- 13 years) admitted to the stroke unit of the Neurology Department within 24 hours (mean: 7.7 hours), after the first ever ischaemic stroke affecting the territory of the internal carotid artery circulation, confirmed by CT. Patients with the history of diabetes mellitus, cardiac insufficiency and infection on admission were excluded from the study. The 24-hour urine collection for catecholamines (epinephrine and norepinephrine) was done on the first and third day of hospitalization. An even single increased daily excretion of epinephrine (10 micrograms/24 hr) was found in 21 and norepinephrine (50 micrograms/24 hr) in 10 of 36 patients. No correlation between daily excretion of epinephrine and norepinephrine was found. Statistical analysis revealed a significant relation between norepinephrine, but not epinephrine, and neurological deficit, prognosis and some biochemical parameters of investigated patients. Patients with increased daily excretion of norepinephrine showed worse neurological deficit (p0.01), greater mortality assessed on the 30-th and 90-th day of stroke (p0.05) and increased plasma glucose, sedimentation rate, white blood cells count, creatinine kinase activity as well as microalbuminuria and decreased plasma kalium concentration.

The patients were divided by chance into 2 groups: the first one (15 persons) was given a natrium salt of prostacyclin (Epoprostenol Wellcome or Chinoin) in a dose of 5 mg/kg/min. intravenously by an infusion pump in 5 infusions; the control group (15 persons) received instead of prostacyclin a placebo (0.1 M glycine buffer of pH 10.5). Besides all the patients were given Doxium or Calcium dobesilate, Rutinoscorbin, Vitamin C, and Polopyrin S (Soluble Aspirin). Immediately after the completion of the treatment the authors did not find any essential differences between the examined groups. In prolonged observations however one demonstrated a significantly smaller frequency of the development of neovascularization in the eyes of persons treated by prostacyclin in comparison with the control group.

Prostacyclin (PGI2) connects all the pharmacologic properties of drugs being used till now in sudden deafness. 30 patients with sensori-neural sudden deafness were treated by prostacyclin and placebo in the double-blind test situation. In therapeutic group of 15 patients were 87% of complete recovery, but in placebo only 6%.

Summary Nasal polyp pieces and homogenates from 14 aspirinsensitive patients and 22 subjects without this sensitivity were incubated in the presence of arachidonic acid (33 μM) and aspirin (167 μM). The prostaglandin-like material generated was bioassayed in PGE2 — equivalents. In polyp pieces of aspirin sensitive patients aspirin completely inhibited the arachidonate-stimulated release of prostaglandins (p 0.1). Aspirin also more effectively inhibited prostaglandin biosynthesis in polyp homogenates from aspirin-sensitive patients than in the control group. Thus, the enzymic system generating prostaglandins in polyp pieces of aspirin-sensitive patients has an increased susceptibility to the inhibitory action of aspirin.

Summary 1′(Isopropyl-2-indolyl)-3-pyridyl-3-ketone (L 8027) inhibited biosynthesis of thromboxane A 2 from arachidonic acid in human platelet rich plasma and inhibited platelet aggregation. The anti-enzymic and anti-aggregating potencies of L 8027 were closely linked to each other and both of them were inversely proportional to concentrations of arachidonic acid which platelets were exposed to. Very low concentrations of L 8027 (0.1 fM – 40 nM) were needed to inhibit generation of thromboxane A 2 and aggregation of platelets by the threshold pro-aggregatory concentrations of arachidonic acid. A concentration of 4 uM of L 8027 was sufficient to inhibit platelet aggregation induced by any concentration of arachidonic acid. L 8027 inhibits the activity of the arachidonate cyclo-oxygenase in many biological systems including platelets. However, unlike indomethacin L 8027 is a more potent thromboxane A 2 synthetase inhibitor than a prostaglandin synthetase inhibitor.

Summary When challenged with antigen fragments of mesentery of immunized guinea pigs released histamine and a prostaglandin-like substance (PGs). The release of both mediators was inhibited by hydrocortisone hemisuccinate (1.0–30.0 μg/ml) and dexamethasone (10.0 μg/ml). Indomethacin (10.0 μg/ml) and hydrocortisone hemisuccinate at low concentrations (0.05–0.6 μg/ml) suppressed the release of PGs, while the release of histamine was stimulated. It is suggested that glucocorticosteroids exert these effects due to their interaction with biomembranes.

Rat brain slices released spontaneously and after challenge with A23187 LTC4-like radioimmunoactivity. Total cat brain ischemia followed by short postischemic reperfusion period resulted in the increased release of lipid peroxides and PGE2 but not in LTC4-like substance by brain slices. In lumbar cerebrospinal fluid of patients with completed stroke presence of LTC4-like material was observed.

The release of PGI2-like activity into the circulation in response to cholinergic agonists and modification of this response by beta-adrenergic antagonists was investigated in anaesthetized cats and healthy humans. Antiaggregatory activity in the arterial blood was continuously assayed by measuring platelet aggregation on blood superfused collagen strip. In some of the human experiments, after the administration of the drugs, the conversion of [14C]-arachidonate to [14C]-prostaglandins in the pulmonary vascular bed was studied. Cholinergic agonists stimulated the release of PGI2-like activity into the circulation, which effect was potentiated in cats by beta-adrenergic antagonists. In humans the latter agents did not stimulate the conversion of [14C]-arachidonate to prostaglandins in the pulmonary circulation and, moreover, inhibited the stimulatory cholinergic effect. The results suggest that an interplay between cholinergic and beta-adrenergic mediators may be involved, although in a different way in cats and in humans, in the release of PGI2-like activity into the systemic circulation.

Thirty patients with acute ischaemic stroke were allocated randomly into a group treated with prostacyclin and a group receiving placebo. The treatment was started 24 to 72 hours after the onset of stroke. Prostacyclin sodium (Wellcome, U.K. or Chinoin, HPR) or its solvent (glycine buffer) were administered intravenously once daily during 2 weeks in 6-hour infusions. Prostacyclin was infused at rates of 2.5-5.0 ng/kg/min. Statistically significant improvement appeared from the second day on in the prostacyclin group, and only from the eighth day on in the placebo group. However, the final improvement was not statistically different between these groups.

Chopped samples of myometrium, decidua and extrinsic blood vessels from the pregnant rat uterus when incubated at room temperature generated a prostacyclin-like substance. Activity in the incubation mixtures was compared against authentic prostacyclin in two assay systems: relaxation of strips of bovine coronary artery and inhibition of ADP-induced aggregation of rabbit platelet-rich plasma. Results estimated from inhibition of platelet aggregation showed that activity generated by all samples was low on day 12 of pregnancy (less than 0.25 ng/mg). However at the time of delivery (day 22) myometrial synthesis had increased 18.5 fold to over 3 ng/mg of prostacyclin whereas decidual production had only increased 5 times. As there was no increase in synthesis by the extrinsic uterine blood vessels over this period it is proposed that the myometrial muscle cells are the probable source of the prostacyclin-like material.

Infusion of PGI2 at a dose of 5 or 10 ng/kg/min during 72 hours into patients with peripheral vascular disease was followed by increased susceptibility of platelets to proaggregatory action of ADP and collagen but not that of arachidonate. The above effects were observed 24 hours after termination of infusion of PGI2. A tendency to an increased formation of TXA2 in PRP aggregated by arachidonate was also noticed. Infusion of PGI2 at a dose of 2 mg/kg/min during 72 hours into the patients caused the decreased platelt aggregability to ADP and arachidonate but not to collagen, and a decreased tendency of production of TXA2 in PRP aggregated by arachidonate. The existence of a “rebound effect” in platelets after a long term PGI2 therapy is suggested.

A double-blind study on prostacyclin (5 ng/kg/min infused i.v. for 5 hrs per day during 6 consecutive days) for the treatment of peptic gastric ulcers was carried out in thirty patients (15 prostacyclin, 15 placebo). Gastroscopy and its scoring was performed 1-2 days before the treatment, as well as a day and a week after the course of treatment was completed. Basal acid output (BAO) and pentagastrin stimulated release of gastric acid (maximum acid output MAO; peak acid output PAO) were measured before the treatment, during the third infusion, and one day after all the infusions had been completed. At the same time the basal release of bicarbonate into gastric juice was determined. Prostacyclin significantly accelerated healing of the ulcers at the end point of the study. Simultaneously, in the prostacyclin-treated patients an increase in bicarbonate release into gastric juice was noted, although the acidity of gastric juice was not changed. Our study shows a cytoprotective action of prostacyclin on a damaged human gastric mucosa.

The effects of a new selective inhibitor of thromboxane biosynthesis, OKY-1581, and a potent inhibitor of cyclooxygenase, indomethacin, on gastric mucosal lesions induced by taurocholate or ethanol and mucosal generation of prostaglandins have been studied in rats. OKY-1581 prevented, dose dependently, the formation of taurocholate- but not ethanol-induced gastric necrosis, and this effect was accompanied by an increase in gastric mucosal generation of prostaglandin E2 and I2-like activity and a reduction in the thromboxane generation during platelet aggregation. OKY-1581 enhanced the cytoprotective action of "mild" irritants such as 5 mM taurocholate against gastric damage by 100 mM taurocholate, whereas indomethacin produced opposite effects. This study indicates: (1) the inhibition of thromboxane biosynthesis results in increased generation of prostaglandins which seems to contribute to the gastric mucosal integrity and, (2) thromboxanes may be involved in the pathogenesis of taurocholate-induced gastric mucosal lesions.

In a pilot study the therapeutic effect of 2 x 500 mg etofibrate (Lipo Merz retard) on lipids and lipoproteins, fibrinolytic activity and clinical parameters was studied for four weeks in hyperlipidemic patients suffering from arteriosclerosis obliterans (Fontaine stage II/III). The study parameters were evaluated prior to and after the four weeks of treatment. Administration of etofibrate resulted in a significant decrease in serum cholesterol and triglyceride levels, the decrease in LDL-/HDL-cholesterol-ratio due mainly to an elevation of the HDL-cholesterol fraction, an increase in plasma fibrinolytic activity, an increased peripheral blood flow in the ischemic leg, and an increase in the pain-free walking distance. Thus, etofibrate applied twice daily might be recommended for the treatment of hyperlipidemic patients with signs of arteriosclerosis obliterans, Fontaine stage II/III.

This study was designed to determine the role of mucosal generation of prostaglandins (PGs) in the ability of mild irritants (20% ethanol or 5% NaCl) to protect against the formation of mucosal lesions caused by necrotizing agents (100% ethanol or 25% NaCl) or acidified aspirin (ASA). Mild irritants protected against damage from necrotizing agents but not from ASA. This protection was accompanied by increased mucosal generation of PGE2 and PGI2-like substances. Exogenous PGE2 and PGI2 applied topically to the gastric mucosa in a nonantisecretory dose greatly inhibited the formation of lesions induced by either necrotizing agents or ASA. Pretreatment with indomethacin, which suppressed the generation of mucosal PGs augmented formation of lesions by necrotizing agents and partly counteracted the protective effect of mild irritants. We conclude that mild irritants, and exogenous PGs inhibit the formation of gastric lesions by necrotizing agents, at least in part, by mucosal generation of PGs.

Using our in vivo model for studying drugs which prevent deposition of thrombi or dissipate thrombi formed in extra-corporeal circulation over a collagen strip superfused with arterial blood of anaesthetized and heparinized cats, we have found that dazoxiben--a thromboxane synthetase inhibitor--possesses not only antithrombotic but also thrombolytic potency in vivo (ED50 = 3.8 mg/kg i.v.). The thrombolytic potency of dazoxiben was antagonized by aspirin at a dose of 50 mg/kg i.v. Moreover, dazoxiben stimulated the generation of prostacyclin in isolated rat aortic slices incubated in platelet rich plasma, but not in platelet poor plasma. It is suggested that the thrombolytic potency of thromboxane synthetase inhibitors after their systemic administration is associated with the release of prostacyclin and/or prostacyclin-stable metabolites by the vascular endothelium owing to feeding of prostacyclin synthetase with prostaglandin endoperoxides accumulated in platelets following the inhibition of thromboxane synthetase.