Single- and multiple-dose mibefradil pharmacokinetics in normal and hypertensive subjects

OBJECTIVE: To determine the safest method of hepatic vascular clamping associated with the least ischemia-reperfusion injury of the liver during liver surgery. SETTING: University laboratories. SUBJECTS: Sixty-five adult male Wistar rats. METHODS: The hilar area of the left lateral and median lobes of rat liver was clamped for 10 minutes (group 1), 15 minutes (group 2), or 20 minutes (group 3) followed by 5 minutes of reperfusion. The procedure was repeated for a total period of ischemia of 60 minutes in each group. Control rats underwent laparotomy without vascular clamping. In addition to histological examination, we determined calpain mu activity, a marker of liver injury, by Western blotting using specific antibodies against the intermediate (activated) and proactivated forms of calpain mu. Measurements were performed at the end of ischemia and after 2 hours of reperfusion. We also determined the degradation of talin, an intracellular substrate of calpain mu, by Western blotting. RESULTS: The level of adenosine triphosphate and energy charge at 2 hours after reperfusion did not change after ischemia-reperfusion irrespective of the duration of ischemic cycle. After 60 minutes of intermittent ischemia followed by 2 hours of reperfusion, cell membrane bleb formation, calpain mu activation, and talin degradation were detected in groups 2 and 3 but not in group 1. CONCLUSION: The safest method of hepatic vascular clamping that produces a minimum or no ischemia-reperfusion injury is 60 minutes of 6 cycles of 10-minute vascular clamping interrupted by 5 minutes of reperfusion.     

Changes in plasma and urine magnesium following subcutaneous insulin

In 7 of 13 patients given subcutaneous insulin as part of the assessment of their endocrinological status, serum magnesium levels fell below the lower limit of the normal range for the laboratory 1 to 2 hours after insulin administration. This relative hypomagnesaemia was not accompanied by any change in the red cell magnesium concentration, and did not bear a close relationship to the degree of hypoglycaemia developed. During the 2 1/2 hour period following insulin therapy there was renal conservation of magnesium ion.     

Serum and plasma concentrations of clindamycin following a single intramuscular injection of clindamycin phosphate in maintenance haemodialysis patients and normal subjects

Serum levels of clindamycin bioactivity and total clindamycin were studied after single intramuscular injections of 300 mg of clindamycin phosphate in a group of 6 normal subjects and a group of 6 maintenance haemodialysis patients. The patients were studied during a non-dialysis period and then again during haemodialysis. Peak levels tended to be higher and elimination half-lives shorter in the patients than in the normal subjects. Possible reasons for these differences are discussed. There was no evidence that haemodialysis per se influenced the pharmacokinetics of clindamycin phosphate. The proportion of unhydrolysed clindamycin phosphate tended to be higher in the renal failure patients and the reason for this is not apparent. Little, if any, dosage modification is necessary in severe renal fialure although there is probably little point in exceeding a dose of 300 mg intramuscularly every 5 h even in severe infections in patients with severe renal failure. The higher peak levels in patients with advanced renal failure indicate the need for further studies with repeated doses.     

Reaction time in normal and defective subjects following varied warning conditions.

As a test of a stimulus-trace theory of behavioral inadequacy, normal and mentally defective Ss performed on a simple reaction-time task with warning intervals of 2, 4, 8, 12 sec. The warning stimulus was a light which for ? of the Ss in each group was on for 1.5 sec. at the beginning of the warning interval. For the other Ss the warning signal was on throughout the warning interval. The signal to respond was a buzzer. The normal Ss performance did not differ for the 2 warning conditions but there were marked differences between the defective groups. A 2nd experiment using only defective Ss provided a control for a possible task artifact. The results were interpreted as suggesting a deficiency in short-term memory in defective Ss. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Seasonal variations in the composition of urine from normal subjects: a longitudinal study

The volume, pH and composition of 24-h urine samples, collected by 13 healthy male adults, were followed over a period of one year. Significant and systematic variations in urine pH, calcium, phosphate, oxalate, uric acid, potassium and magnesium were observed. A significant but non-sinusoidal variation in sodium excretion was found but there were no significant changes in urinary volume, creatinine or hydroxyproline. Many of the observed changes could be attributed to variations in the pattern of food consumption throughout the year but calcium, phosphate and oxalate were exceptions in that seasonal variations in these parameters appeared to be due to the effects of sunlight (or vitamin D) rather than to the diet.     

The false-positive rate of thoracic outlet syndrome shoulder maneuvers in healthy subjects

Cytokines are considered as mediators of immune and inflammatory responses. Cisternal CSF levels of interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1 (MCP-1) and of the soluble adhesion molecule E-selectin were evaluated in patients operated on for intracranial aneurysms. Cisternal CSF samples were obtained at surgery in 41 selected patients (31 with diagnosis of subarachnoid hemorrhage (SAH) and 10 control patients operated on for incidental unruptured aneurysms); 14 patients were operated within 72 h after SAH (early surgery) and 17 were operated after day 10 after the hemorrhage (delayed surgery). The CSF levels of cytokines were evaluated using radioimmunoassay and their concentrations were related to the timing of surgery, the amount of cisternal subarachnoid blood clots and the onset of clinical and angiographical evidence of arterial vasospasm. Mean cisternal CSF levels of IL-6, IL-8 and AMCP-1 are significantly higher in samples obtained from patients early operated after SAH, while levels of E-selectin were below the threshold value of the method in all 41 cases. In the early operated group 7 patients presented symptomatic vasospasm: levels of IL-8 and MCP-1 were not significantly different were compared to those of uncomplicated cases; on the other hand, significantly higher levels of IL-6 were shown in the subgroup of patients operated within 72 h after SAH and developing vasospasm. Among the patients undergoing delayed surgery 5 presented symptomatic vasospasm, but no significant difference was shown in cisternal CSF levels of cytokines measured. The results of the present study show that in patients with unruptured aneurysms cytokines are present in cisternal CSF in scarce quantities and that in subarachnoid spaces after SAH there is an impressive increase of IL-6, IL-8 and MCP-1. Moreover, the higher cisternal CSF levels of IL-6 found in the early stage after SAH might have a predictive value regarding the occurrence of symptomatic vasospasm.     

Reflex and mechanical circulatory effects of graded Valsalva maneuvers in normal man

In 17 normal subjects we studied the changes evoked by five levels of expiratory pressure (EP) ranging from 2.5 to 30 mmHg in a number of circulatory variables during the last 10 s of a 30-s Valsalva maneuver. Variables studied included mean arterial (MAP) and pulse (PP) pressures; right atrial (RAP) and peripheral vein (PVP) pressures; cardiac output (CO); total peripheral resistance (TPR) and heart rate (HR). EP-circulatory response curves were obtained in each subject a) before autonomic block; b) after cardiac effector block (atropine + propranolol); c) after "total" autonomic block (atropine + propranolol; guanethidine + phentolamine). Mechanical effects were determined from results during "total" autonomic block. They included EP-related rises in RAP and PVP each to about 0.7 mmHg/mmHg applied EP, and falls in CO, MAP, and PP to levels of approximately 50%, 70%, and 80% of resting respectively at EP 30 mmHg, but no changes in TPR and HR. Reflex effects included EP-related rises in HR and in TPR and in MAP, to levels of 160%, 160%, and 115% of resting respectively at EP 30 mmHg. The afferent input profile is probably complex, and the role of the different receptor groups may vary at the different levels of EP.     

Circulating basophils in normal subjects and in subjects with hay fever

The relationship of hay fever symptoms and changes in the number of circulating basophils was studied in 12 subjects clinically sensitive only to ragweed and in 10 nonatopic subjects before, during, and after the ragweed season. Total white blood counts, absolute basophil counts, and symptom scores were recorded twice weekly from mid-June through October, 1974, and compared with the ragweed pollen count. The results indicated that the absolute and relative number of basophils were significantly elevated (p less than 0.001) in the hay fever group when symptoms occurred. As the symptom score of the allergic group increased during the ragweed season, the number of basophils also increased, only to decrease to control values when symptoms subsided. The basophil counts of the atopic group were significantly higher than those of the nonatopic group during the control periods. The nonatopic group also showed a significant elevation of basophils during the ragweed season, but to a much lesser extent than the atopic group. It is concluded that: (1) subjects with symptomatic hay fever have a significantly elevated absolute and relative basophil count which correlates with the exacerbation and remission of symptoms; (2) nonatopic subjects also have a small but significant elevation of basophils during the ragweed season; and (3) the elevation of basophils in the atopic group during symptoms is significantly greater than in the nonatopic group during the ragweed season.     

Heterogeneity of plasma glucagon. Circulating components in normal subjects and patients with chronic renal failure

Plasma immunoreactive glucagon (IRG) concentrations were measured in 36 patients with chronic renal failure (CRF) and 32 normal subjects. In addition, the components of circulating IRG were analyzed by gel filtration in the fasting state and after physiological stimuli. Fasting IRG was elevated (P less than 0.001) in CRF patients (534 +/- 32 pg/ml) compared with the levels found in healthy subjects (113 +/- 9 pg/ml). Oral glucose suppressed plasma IRG in CRF patients from a basal level of 568 +/- 52 to a nadir of 354 +/- 57 pg/ml (120 min). This degree of suppression (38%) was comparable to that found in normal subjects (basal = 154 +/- 20 to 100 +/- 23 pg/ml) at 120 min (35%). Intravenous infusion of arginine (250 mg/kg) resulted in a 71% rise in IRG in CRF patients and a 166% increase in normal subjects. Gel filtration of fasting plasma from CRF patients showed three major peaks. The earliest (A) was found in the void volume (mol wt greater than 40,000) and constituted 16.5 +/- 4.7% of the elution profile. The middle peak (B) eluted just beyond the proinsulin marker (approximately 9,000 mol wt) and constituted the largest proportion of the elution profile (56.5 +/- 3.4%). The third peak (C) coincided with the standard glucagon and [125I]glucagon markers (3,485 mol wt) and comprised 27.0 +/- 4% of the IRG profile. In contrast, only peaks A and C were found in fasting plasma of normal subjects (53.6 +/- 10.4% in A and 46.4 +/- 10.4 in C). After oral glucose, glucagon immunoreactivity in the 3,500 mol wt peak (C) was markedly suppressed, while the B peak in patients with CRF declined to a lesser extent. The A peak in both groups was unchanged. After an arginine infusion only the C peak increased in both groups of subjects. Gel filtration of plasma in 3 M acetic acid gave similar profiles to those obtained in glycine albumin buffer. Exposure of serum to trypsin indicated that the B and C peaks were digestible, while the A peak was resistant to the action of the enzyme. In one sample, peak C increased after a 2-h exposure of serum to trypsin. We conclude that circulating IRG in normal subjects and patients with CRF is heterogenous. The hyperglucagonemia of renal failure is largely due to an increase in IRG material of approximately 9,000 mol wt, consistent with proglucagon, although the 3,500 mol wt component is also considerably elevated (threefold). The significance of circulating IRG levels should be interpreted with caution until the relative biological activity of the three components is established.     

Immunoassayable beta-endorphin level in the plasma and CSF of heroin addicted and normal subjects before and after electroacupuncture

The present study was undertaken to evaluate if plasma or CSF beta-endorphin level can be induced to rise during the treatment of heroin addiction by electroacupuncture. Based on the examination of 30 addicts, we obtained no evidence indicating an increase of beta-endorphin level in either the plasma or the CSF after 30 min of acupuncture. In spite of this, the majority of the addicts experienced a reduction of withdrawal symptoms during treatment. Since electroacupuncture may only induce a highly localized secretion of beta-endorphin in the brain, our results cannot unequivocally exclude the possibility that this peptide is involved in mediating the action of acupuncture.     

Aminopyrine disposition: studies on breath, saliva, and urine of normal subjects and patients with liver disease

To investigate aminopyrine disposition, breath, saliva, and urine were collected from 25 control patients, 15 patients with hepatocellular disease, and 26 patients with hepatic neoplasm after oral administration of 2 muCi [14C]aminopyrine. The percentage 14C excreted in breath 14CO2 in 2 hr (aminopyrine breath test, ABT) correlated with the breath 14CO2 elimination rate (r = 0.92, p less than 0.01), with the aminopyrine metabolic clearance rate (MCR) (r = 0.85, p less than 0.01), and with the plasma half-life of 4-aminoantipyrine (r = -0.54, p less than 0.05). The ABT permits study of aminopyrine disposition with simplicity, accuracy, and safety.     

Prognosis of occlusive cerbrovascular diseases in normotensive and hypertensive subjects

Comparison of the clinical features, especially prognosis, in cerebral infarction was made between nine normotensive subjects and 16 hypertensive patients with an 80% stenosis or occlusion of the intracranial or extracranial arteries. Our own criteria for evaluating hypertension were employed on the basis of the following items: a past history of hypertension, blood pressure levels on admission and during hospitalization, degree of retinopathy, and ECG changes. In 17 of 25 cases, brain circulation was measured by the intravenous RISA technique. Abnormalities of the EEG and reduction of cranial blood flow were greater, and an early prognosis for neurological deficits in the first two months after the onset of stroke was poorer in the hypertensive group than inthe normotensive group. These results are contradictory to the observations of others.     

Postprandial plasma glucose, insulin, glucagon and triglyceride responses to a standard diet in normal subjects

A uterine pouch was prepared surgically in ewes before mating to study the production and chemical composition of uterine secretions during pregnancy. Pregnancy was established in 6 sheep and in the first 55 days uterine fluid was present in small amounts (less than 5 ml), whereas between 109 days post coitum and 3 days post partum the volume ranged from 90 to 775 ml. The chemical composition of uterine fluid in pregnancy differed from that of plasma especially in respect of its high concentration of total calcium (up to 83.5 mM) and prostaglandin (PG) F-2a (up to 1500 ng/ml). Progesterone was implicated as an important endocrine factor since uterine fluid (188 ml) with a high concentration of total calcium (53-5 mM) and PGF-2a(235ng/ml) was recovered from a non-pregnant sheep treated with progesterone for 115 days.     

Prevalence of obesity and ischaemic heart disease in hypertensive subjects

In the present study the prevalence of obesity and its association with ischemic heart disease, recognized according to clinical criteria (chest pain or previous infarction) and/or instrumental data, were described in 8,847 normotensive subjects and in 867 hypertensive subjects, hospitalized during a ten years period (1983-1992), through a cross-sectional study. In view of this all the subjects were considered as lean or obese according to their body mass index (BMI) and to sex specific cut-off values reported in the Italian Consensus Conference on Obesity. In particular, according to BMI values, the subjects were grouped as lean, overweight, moderate and severe obese subjects. Our results indicated that 3,982 normotensive subjects (45%) could be considered lean, whereas 2,654 of them (30%) were overweight, 1,769 of them (20%) were moderate obese and 442 of them (5%) were severe obese. On the contrary only 206 hypertensives (23.7%) might be considered lean, whereas 313 (36.1%) were overweight, 302 (34.8%) were moderate obese and 46 (5.3%) were severe obese. According to age subgrouping (lower than or equal to 65 years or higher than 65 years) the distribution of hypertensives within the lean, overweight, moderate and severe obese groups did not change significantly, but, according to sex subgrouping, the distribution of hypertensives within the BMI groups was significantly different (chi 2, p < 0.001). When we considered the degree of hypertension, distribution of hypertensives was significantly different according to c2 test (p < 0.004), suggesting that the percentage of the subjects with severe hypertension increased only in subjects with severe obesity. Concomitant ischaemic heart disease (IHD) was also documented in 350 normotensives (4%) and in 119 hypertensives (13.8%). The prevalence of IHD was not significantly different in lean, overweight, moderate and severe obese hypertensives, also when sex and smoking habits were considered. Our data indicated a strong association between obesity and hypertension. In addition they may be consistent with the suggestion that obese hypertensives were not characterized by a lower risk of ischaemic heart disease (IHD), than lean hypertensives.