The effect of isosorbide dinitrate following experimental coronary occlusion

A new case, the third in Israel, of subcutaneous sporotrichosis is presented. A pigmentary strain of Sporothrix schenckii was cultured from the unopened and necrotic nodules of the left hand and forearm of an 80-year-old male. Experimental inoculation of the isolated fungus into mice led to the dissemination of the organism in the liver, kidneys and lungs inoculated intraperitoneally, and the development of orchitis with abscess formation in those inoculated intratesticularly. In both groups of mice the causative agent was successfully recovered. Three months of treatment with oral potassium iodide led to the disappearance of the lesions. The source of contamination was found to be the soil adhering to fragments of wood. Two strains of a fungus, morphologically identical to the human S. schenckii, were isolated through the mouse procedure and agar-plating method from soil samples collected in the vicinity of the patient's residence. The soil isolates also proved to be pathogenic in animal inoculation. This is the first isolation of S. schenckii from soils in Israel. The possible relationships between the soil isolates and Ceratocystis stenoceras are discussed.     

Vascular hyporeactivity persists despite increased contractility after long-term administration of isosorbide dinitrate in portal hypertensive rats

BACKGROUND/AIMS: Portal hypertension is associated with decreased vascular responsiveness to vasoconstrictors, which may contribute to the hyperdynamics. Isosorbide dinitrate is an effective portal hypotensive drug. The present study aimed to investigate whether chronic administration of isosorbide dinitrate could affect vascular responsiveness in portal hypertensive rats. METHODS: Portal hypertension was induced by partial portal vein ligation. Sham-operated (Sham) rats served as controls. There were four animal groups for this study: portal vein ligation-isosorbide dinitrate group, portal vein ligation-vehicle (Veh) group, Sham-isosorbide dinitrate group and Sham-Veh group. Isosorbide dinitrate (5 mg x kg(-1) x 12 h(-1) was given by gavage for 8 days starting 1 day before ligation and continuing thereafter. Mesenteric arteries were removed for contractile study after hemodynamic measurement. RESULTS: Contractile responses to KCI (15-90 mM) and phenylephrine (10(-9)-10(-4) M) were recorded. Both vascular reactivity and sensitivity were significantly reduced in portal vein ligation rats as compared to Sham rats. Chronic isosorbide dinitrate treatment reduced portal venous pressure in portal vein ligation rats. Moreover, the maximal contractile responses to KCl and phenylephrine were significantly enhanced in both portal vein ligation and Sham rats after isosorbide dinitrate treatment, but relative hyporeactivity persisted in portal vein ligation rats. In contrast, a single dose of isosorbide dinitrate did not alter the contractile sensitivity or reactivity to KCl or phenylephrine in either portal vein ligation or Sham rats. CONCLUSION: Our results show that long-term administration of isosorbide dinitrate enhanced vascular contractility in both portal vein ligation and Sham rats, but relative hyporeactivity persisted in portal vein ligation rats.     

Successful management of right coronary air embolus after intracoronary administration of verapamil

The incidence of classic Kaposi's sarcoma (CKS) has been reported to be high in Jewish populations living in Israel and in immigrants originating from the Mediterranean basin. No population-based reports are available on the incidence of CKS in Israeli Arabs. We analyzed the incidence of CKS cases occurring between 1970 and 1993 among Arabs living in Israel. Reporting systems were the Israel Cancer Registry, the medical documentation of all-Kaposi's sarcoma cases and the registry of human immunodeficiency virus-seropositive patients. Population figures were derived for census surveys (1972 and 1983) and inter-census data based on annual updating of demographic characteristics. Age-standardized incidence rates (ASR) were 6.87 per million in men and 2.18 per million in women. The ASR did not increase between 1970 and 1993 in either men or women. The age-adjusted male to female ratio was 2.0 below 50 years of age and 3.5 above it. The observation of a stable and relatively high incidence of CKS in Israel-born Arabs, comparable to other populations living in the Mediterranean basin, suggests that risk is related to geographical origin. CKS incidence, however, is lower than that in Israel-born Jews.     

Pharmacokinetics of isosorbide dinitrate in healthy volunteers after 24-hour intravenous infusion

No studies have examined the pharmacokinetics of isosorbide dinitrate (ISDN) after infusion of long duration, even though such infusions are used in patients. We therefore measured ISDN and its active metabolites, isosorbide-5-mononitrate (IS5MN) and isosorbide-2-mononitrate (IS2MN), in plasma of 9 healthy volunteers who received a continuous intravenous infusion of ISDN for 24 hours at a dose rate that lowered diastolic blood pressure by 10% during the first 30 minutes of infusion. All subjects tolerated the infusion except one who experienced intolerable headache. Five subjects received 1 microgram.min-1.kg-1, one 2 micrograms.min-1.kg-1, and two 4 micrograms.min-1.kg-1 ISDN, whereas the full rate of 6 micrograms.min-1.kg-1 was used continuously in one subject. At all infusion rates the plasma concentrations of ISDN were higher at 24 hours than at earlier times, suggesting that a steady-state condition had not been reached at that time. The same was true for the mononitrate metabolites, which reached higher plasma concentrations and were cleared more slowly than the parent compound after the end of the infusion. Apparent elimination half-lives of ISDN, IS2MN, and IS5MN were 67 +/- 10 minutes, 115 +/- 13 minutes, and 272 +/- 38 minutes, respectively. Comparison of low-rate infusions (1 and 2 micrograms.min-1.kg-1) with high-rate infusions (4 and 6 micrograms.min-1.kg-1) showed that the plasma concentration ratios at 24 hours of mononitrate metabolites to parent drug and apparent plasma clearance of ISDN were almost halved at the higher infusion rates.     

Effect of isosorbide dinitrate on pulmonary venous compliance

Irreversible poor pulmonary venous compliance (PV comp) could worsened natural course of patients (pts) with high pulmonary capillary wedge pressure especially pts with mitral stenosis. Nitrates (isosorbide dinitrate-ISDN) possessing venous dilating action could increase PV comp in most of pts. The main aim of that study was to assess hemodynamic effects of ISDN, in pts with MS, with special emphasis on PV com changes. PV comp was estimated according to Hirakawa equation (dV/dp = 0.4*k2*SV/(v-d) in 35 pts with MS, during preoperative right heart catheterisation with VYGON 5155-180 thermodilution catheters during rest and effort in supine position (25W). The same protocol was performed after Iso-Mack sprawy 3.75 mg. According to the PV comp response to ISDN, pts were divided in two groups: good responders (I)-15% and higher increase in PV comp and poor responders (II). ISDN increased PV comp in the whole group according to the response to ISDN, there were significant differences in stroke volume index (SVI) and heart rate (HR). In the group of good responders mean right atrial pressure (RA), mean pulmonary artery pressure (PAP), mean pulmonary wedge pressure (PWP) decreased significantly with simultaneous slight not significant decrease in SVI and not significant increase of HR. In the group of poor responders SVI decreased significantly by about 20% with significant increase of HR. In conclusion significant decrease in pulmonary pressures (PAP, PWP) in pts with good response to ISDN are secondary to the increase of PV comp, while among poor responders the same effects are due to diminished flow secondary to the decrease of the systemic venous return.     

Plasma concentrations of ethynyl oestradiol and norethindrone after oral administration to women

Rapid vasicular resistance adjustments in the brain and in the circle of Willis have been continuously measured and enhanced by signal averaging methods. Naftidrofuryl, a drug chemically similar to local anesthetics and to beta adrenergic blocking agents, increases local CBF by reducing resistance in brain and in extracerebral supply arteries. It has also been reported to affect brain metabolism. Other similar drugs merit study for potential effects on CBF and brain metabolism which may be useful in treatment.     

Plasma diazepam concentrations following prolonged administration

Plasma diazepam and N-desmethyl diazepam concentrations were measured in patients receiving diazepam 5 mg or 10 mg i.v. at 4-h intervals for periods of 6-22 days. At both doses there was an accumulation of both diazepam and its metabolite, the latter reaching concentrations of up to two to three times that of the parent drug. Plasma diazepam concentrations reached a plateau after 8 days while the concentration of N-desmethyl metabolite continued to increase throughtout the period of drug administration. On discontinuation of diazepam therapy both diazepam and N-desmethyl diazepam concentrations decreased slowly, the former with a half-life of 2-4 days and the latter with a half-life of 4-8 days.     

Pharmacokinetics of isosorbide dinitrate examined by physiologically-based pharmacokinetic model

To make a physiologically-based pharmacokinetic model of isosorbide dinitrate (ISDN), the author infused ISDN at 1, 10, 30 micrograms.kg-1.min-1 into anesthetized rabbits and measured concentrations of ISDN and its metabolites (2-ISMN and 5-ISMN) in plasma and in the brain, liver as well as fat tissue. There was the accumulation of ISDN in the brain and fat tissue. There was no significant difference in concentrations of ISDN between the plasma and liver, or in concentrations of its metabolites among plasma, and the tissues of the brain, liver and fat. Using these informations, the author constructed a physiologically-based pharmacokinetic model to human and estimated values were compared with observed values to determine the validity of the model. There was no remarkable differences between the estimated values and observed values. This suggests the validity of the model. The plasma concentrations of ISDN estimated by this model, showed a linear increase (Y = 25 X) with the infusion rate less than 6.0 micrograms.kg-1.min-1. The accumulation of ISDN, especially in the brain was suggested by this model.     

Influence of combination therapy (isosorbide dinitrate and molsidomine) on the incidence of angina pectoris in patients with coronary heart disease

Angina pectoris in patients with severe 3-vessel-disease refractory to treatment is a challenge for the treating physician. We have therefore tested the treatment efficacy of isosorbide dinitrate combined with molidomine on the frequency of angina pectoris in patients with symptoms refractory to treatment. PATIENTS AND METHODS: 15 patients with severe coronary heart disease were included in the study. The protocol included a 2-weeks stabilisation phase, followed by a 4-weeks treatment phase with 100 mg isosorbide dinitrate in the morning as well as 8 mg slow-release molsidomine at 6 p.m. RESULTS: Initially all of the 15 patients reported about daily angina pectoris attacks. After 4 weeks of treatment 4 out of 15 patients became free of symptoms. From the other 11 patients 6 reported an improvement, 5 an unchanged frequency of attacks. DISCUSSION: Combination treatment with isosorbide dinitrate with molsidomine in a slow-release form (in the nitrate free interval) showed a distinct improvement in patients with angina pectoris refractory to treatment with reduction of complaints. The effect of the combination is possibly based on a prolonged vasodilatation of the stenosed vessels and a prolonged reduction of filling pressure (reduction of preload).     

Plasma follistatin concentrations increase following lipopolysaccharide administration in sheep

1. The effect of inflammation induced by lipopolysaccharide (LPS) injection on plasma follistatin (FS) concentrations was investigated. 2. Plasma FS and tumour necrosis factor-alpha concentrations increase following LPS administration in ewes. 3. The rise in FS is similar, but more sustained, to that previously observed after surgery. 4. These results indicate a possible functional link between FS, inflammation and the acute-phase response.     

Plasma concentrations of phenobarbital in mother and child after combined prenatal and postnatal administration for prophylaxis of hyperbilirubinemia

Phenobarbital is known to reduce serum bilirubin concentration in the newborn infant, but optimal dosage is unknown. Ten pregnant women and their infants were given a standard regimen including prenatal maternal administration and postnatal administration to the infant during the first week of life. The plasma levels of phenobarbital in the infants were found to increase during the period of administration, and to remain high for many days beyond the period of hyperbilirubinemia. Optimal dose schedules for phenobarbital should be based both upon pharmacologic effects (including those other than bilirubin disposition) and upon the pharmacokinetic profile of the drug in the newborn infant.     

Treatment of chronic anal fissure with isosorbide dinitrate: long-term results and dose determination

Individuals with a genetic predisposition to pemphigus will develop the disease only when one or more additional factors are present. The nature of these factors is as yet unknown, but our starting point was that certain drugs (penicillamine, captopril, and rifampicin) are recognized as such factors. Since some nutrients have chemical compositions similar to these known causative drugs, these nutrients may act similarly and, therefore, nutritional factors should also be suspected. As when drugs are involved, elimination of the inciting ingredients may be crucial for management of the disease. This article discusses the possible role of nutritional ingredients in the disease process of pemphigus, including fruit, leaves, roots, seeds, and even water. Possible causative candidates are thiol, thiocyanate, phenols, and tannins.     

Prophylactic effect of isosorbide dinitrate on postoperative cardiac complications (author's transl)

Isosorbide dinitrate (ISD) was administered before, during and after 178 operations performed on 127 patients with arterial occlusive disease. Its influence on postoperative myocardial infarction, heart failure and mortality was tested by comparison with 188 operations performed on 140 patients with hypertension and/or old myocardial infarction receiving no ISD prophylaxis. Risk of cardiac complications was similar in both groups. Mortality in the ISD-treated group was significantly lowered as compared with the control group and was about half of the overall mortality in patients with arterial occlusive disease operated on at our hospital over the past 10 years. This difference depended partly on the influence of ISD on cardiac complications. Post-operative myocardial infarction during ISD prophylaxis occurred in 0.6% of cases as compared with 3.7% in the control group (p less than 0.05), whilst the respective values for postoperative heart failure were 5.7% and 18.2% (p less than 0.001). Both complications are related to absolute or relative hypoxia during the post-operative stress period. ISD is effective by lowering cardiac preload and afterload and thereby diminishing myocardial oxygen demand. ISD is the drug of choice for surgical patients since it provides a steady and long-lasting effect after sublingual absorption. ISD prophylaxis during the perioperative period is indicated in cases with coronary artery disease and with increased cardiac preload or afterload.     

Effects of amlodipine and isosorbide dinitrate on exercise-induced and ambulatory ischemia in patients with chronic stable angina pectoris

This study was designed to compare once-daily administration of 5-10 mg amlodipine with two daily doses of 40 mg sustained-release isosorbide dinitrate in 59 patients with stable angina using a randomized, double-blind, crossover study design. Anginal episodes, nitroglycerin consumption, and possible adverse events were recorded in a diary. A maximal symptom-limited bicycle exercise test and 48-hour ambulatory ECG monitoring were performed at baseline and at the end of each 5-week period of therapy. Exercise time, time to angina, time to ST depression, and maximal ST depression were measured during exercise. During ambulatory monitoring, the number of ischemic episodes and the duration per hour of ST depression were assessed. Amlodipine significantly reduced anginal episodes (P < 0.001) when compared with isosorbide dinitrate. Furthermore, amlodipine prolonged time to ST depression (P < 0.001) and time to angina (P < 0.05) when compared with isosorbide dinitrate. The number and duration of ischemic episodes during ambulatory monitoring were significantly reduced with amlodipine when compared with baseline values (P < 0.05), whereas no differences were found between isosorbide dinitrate and baseline. Adverse events were reported more frequently with isosorbide dinitrate than with amlodipine (P < 0.02). Amlodipine appears to be more effective and tolerable than sustained-release isosorbide dinitrate as monotherapy for chronic stable angina.     

Study of the bioequivalence of a new isosorbide dinitrate tablet formulation compared with the standard preparation

Army Chemical Corps personnel who served in Vietnam were among those service personnel with the greatest potential for exposure to herbicides. An earlier evaluation of the mortality experience of 894 Army Chemical Corps Vietnam veterans found a statistically significant excess risk of dying from digestive disease, primarily due to cirrhosis of the liver, and from motor vehicle accidents. That study was expanded to include 2,872 Vietnam veterans who served with the Army Chemical Corps and a comparison cohort of 2,737 veterans who never served in Southeast Asia but who did serve in the same occupational category. The results of the analysis comparing the Vietnam cohort to the non-Vietnam cohort support the earlier finding of a significant excess of deaths from digestive diseases (adjusted relative risk (RR) = 3.88, 95% C.I. = 1.12-13.45) primarily due to liver cirrhosis. Non-significant elevated relative risks were observed for all cancers combined, digestive and respiratory systems cancers, skin cancer, lymphopoietic cancers, and respiratory system diseases. Compared to the mortality rates in the general population, the non-Vietnam Army Chemical Corps veterans had a statistically significant deficit in mortality from all causes combined, which is consistent with a 'healthy selection bias' seen among military populations (SMR = 0.79, 95% C.I. = 0.66-0.94). For the Vietnam veterans, patterns of elevated but nonsignificant SMRs persisted for diseases of the digestive and respiratory systems and for selected cancer sites.     

Plasma progesterone concentrations in cows and steers after Repositol Progesterone treatment

Repositol progesterone was injected intramuscularly into 4 steers and 17 postpartum cows at a dose of 2.2 mg/kg body weight. In steers the plasma progesterone concentration rose to 6.8 ng/ml 1 day postinjection and declined to a mean concentration of 2.1 ng/ml on days 3 and 4 postinjection. Postpartum, presumed anestrus, cows reached a lesser progesterone concentration of 2.9 ng/ml 1 day postinjection and then declined to a lower mean of .7 ng/ml on days 3 and 4 postinjection. These data suggest different rates of metabolism and/or excretion of progesterone by cows and steers.