[Carrier systems for drugs--a new principle in drug therapy?].
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Blood Platelets↗
Biomedical subjects
A Korn
Publications and source records attributed to A Korn.
Release of vitamin B12 from carrier erythrocytes in vitro.
Resealed erythrocyte ghosts (carrier erythrocytes) are potential in vivo carriers for exogenous enzymes or drugs, but data on carrier erythrocyte survival and clearance rate in humans are not available. We have measured the in vitro efflux of vitamin B12 encapsulated in human red cell by hypo-osmotic dialysis, as a preliminary for its use as a marker for in vivo human studies. Vitamin B12 was encapsulated into erythrocytes at a relative incorporation efficiency of 60%. In vitro hemolysis of carrier erythrocytes was minimal over 40 h, but vitamin B12 was rapidly lost from the cells, efflux t/2 was 5 h, presumably by diffusion through the intact cell membrane. Vitamin B12 (Vit B12) may, nevertheless, be a suitable marker for short-term human studies on carrier erythrocyte splanchnic clearance.
Blood Specimen Collection↗
Acute effects of nimodipine on the cerebral blood flow and intracranial pressure.
The effects of nimodipine, a calcium antagonist with preferential cerebrovascular activity, on the global and regional cerebral blood flow (CBF and rCBF), the intracranial pressure (ICP), and the cerebral perfusion pressure (CPP), were investigated in an acute study. The rCBF of 54 patients was measured by the Xe133 inhalation method under identical conditions before and 60 min after oral administration of nimodipine. 12 patients with focal cerebral circulation disturbances of arteriosclerotic origin, who had suffered a cerebral accident (TIA, PRIND, minor stroke) no more than 3 weeks previously, were given a placebo (test-retest controls) and 25 patients of the same diagnosis and age group were given 40-80 mg nimodipine orally. 11 patients with acute subarachnoid hemorrhage (SAH) from ruptured anterior communicating artery aneurysms and clinical and angiographic signs of vasospasm (Hunt- and Hess grade 3) were likewise treated with nimodipine by the oral route. 6 patients with cerebral vasospasm received nimodipine in i.v. doses of 0.5-2 mg/h. The cerebral blood flow, assessed on the basis of the initial slope index (ISI), before and after the medication, was compared by statistical methods. 12 patients with head injury were given nimodipine intravenously in a dose of 0.5-2 mg with continuous monitoring of the ICP and the blood pressure. The pressure values were evaluated continuously by computer, with calculation of the perfusion pressure, and tested for statistical significance. Oral nimodipine therapy resulted in a significant (14%) increased of the CBF (taking account of the arterial pCO2), the improvement of blood flow being even more pronounced in the hypoperfused regions.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Intracranial effects of nicardipine.
Preliminary investigations indicated that the calcium antagonist nicardipine improved cerebral vascular circulation and cerebral metabolism. Therefore we examined the effect of nicardipine on the cerebral vessels, cerebral oxygen tension, and intracranial pressure (ICP) in patients with cerebrovascular disturbances. In patients with previous minor stroke undergoing surgery for extra-intracranial anastomosis, we applied nicardipine topically to the operation site by means of a perfusor and measured the diameter of the cerebral vessels. After several minutes, the topically applied nicardipine produced marked dilatation in the small arterial cortical vessels and relaxation of vasospasm. In the two patients studied so far, we observed a rapid increase in the cerebral PO2, which remained elevated after the initial peak as long as the infusion continued. With a lower dose the increase in the intracranial pulse amplitude (PAICP) was antagonized by the considerable drop in blood pressure which occurred after 10 mg h-1 nicardipine. The results indicate that nicardipine dilates the cerebral vessels and increases the cerebral oxygen tension.
Blood Pressure↗
Biochemical, physical and psychological findings in patients suffering from cardiac neurosis.
In 10 patients suffering from cardiac neurosis changes in plasma norepinephrine (NE) and epinephrine (E) were studied by an upright bicycle exercise and during psychological stress. Psychometric tests were also performed. 6 healthy subjects served as a control group. At exercise, no relevant differences in blood pressure and heart rate regulation between patients and controls were present. The NE and E increase was normal and similar in both groups. During psychological stress an equal plasma NE increase was seen in both groups. During recovery, however, a sustained release of NE was present in patients. It is concluded that patients with cardiac neurosis respond to psychological stress by an inappropriate sustained activation of the sympathetic nervous system.
Adult↗
Dose linearity and other pharmacokinetics of ofloxacin: a new, broad-spectrum antimicrobial agent.
After oral administration of a single dose of ofloxacin (100, 300 or 600 mg) to 13 healthy male volunteers in an open, randomized crossover study, concentrations of the unchanged drug were estimated at various times in serum and urine, over 28 hours and 48 hours, respectively. Each dose was followed by a wash-out period of 1 week. Ofloxacin concentrations were determined using both high pressure liquid chromatography (HPLC) and a microbiological assay. The measurements obtained were compared by linear distribution independent regression, and were found to be equivalent, indicating no major metabolism of ofloxacin. Maximum serum concentrations (Cmax) of ofloxacin after administration of 100, 300 or 600 mg were, respectively, 1.0, 3.4 and 6.9 mg/ml (HPLC, median values). A linear relationship between Cmax and dose was demonstrated within the range tested (coefficient of correlation r = 0.88). The same applied to AUC0-28 (r = 0.98) and to urinary recovery of the drug (r = 0.98). Time to reach Cmax varied between 0.5 and 1.1 hours (median values), indicating rapid absorption of the drug. Biological half-life (t1/2 beta) was determined by fitting a two-compartment open model to the date: t1/2 beta was in the range 5.6 to 6.4 hours (HPLC, median values) and was not relevantly dose-dependent. Urinary concentrations of ofloxacin remained above 1 microgram/ml, i.e. above the minimum inhibitory concentrations (MIC90) for most bacterial strains at all dosages tested, for at least 36 hours after drug administration. General tolerability was good; no side-effects were reported.
Administration, Oral↗
The effect of a new specific alpha-amylase inhibitor on post-prandial glucose and insulin excursions in normal subjects and Type 2 (non-insulin-dependent) diabetic patients.
Trestatin (Ro 9-0154), a new specific alpha-amylase inhibitor of microbial origin, was tested in six normal subjects and seven Type 2 (non-insulin-dependent) diabetic patients. In normal subjects the maximal increases in blood glucose following a 115-g starch meal were 2.19 +/- 0.57 mmol/l (mean +/- SEM) with placebo, but 1.32 +/- 0.39 mmol/l with 10 mg, 1.06 +/- 0.26 mmol/l with 20 mg, 0.43 +/- 0.07 mmol/l with 50 mg (p less than 0.05) and 0.26 +/- 0.14 mmol/l with 100 mg (p less than 0.05) Trestatin . The corresponding increases in plasma insulin were 116.5 +/- 19.6 mU/l; 74.8 +/- 17.5 mU/l; 50.7 +/- 8.3 mU/l; 28.7 +/- 6.9 mU/l (p less than 0.05) and 16.5 +/- 3.2 mU/l (p less than 0.05). In the diabetic patients the maximal increases in blood glucose following a 50-g starch meal were 6.09 +/- 0.02 mmol/l with placebo, but 3.17 +/- 0.59 mmol/l (p less than 0.05) with 10 mg and 1.69 +/- 0.41 mmol/l (p less than 0.05) with 30 mg Trestatin . The corresponding insulin increases were: 58.8 +/- 12.7 mU/l, 31.5 +/- 9.7 mU/l (p less than 0.05) and 23.4 +/- 4.8 mU/l (p less than 0.05). Trestatin fully retained this pharmacological activity during treatment for 4 weeks in the diabetic patients. Trestatin did not influence glucose and insulin profiles after oral glucose and sucrose. These results are consistent with a specific inhibition of alpha-amylase in man.
Adult↗
Effect of cianopramine, a tricyclic antidepressant, on platelet serotonin uptake and peripheral adrenergic function.
Cianopramine, a new tricyclic antidepressant, is a potent inhibitor of neuronal serotonin (5-HT) uptake in animals. We studied the effect of cianopramine on 5-HT uptake (ex vivo) in platelets and on peripheral neuronal adrenergic function in catecholamine pressure response tests in normal subjects. The inhibition of 14C-labeled 5-HT uptake into platelets was 57% +/- 12% 2 hr after 0.5 mg (after 24 hr: 27% +/- 13%), 59% +/- 10% 2 hr after 1 mg (24 hr: 41% +/- 13%), and 80% +/- 2% 2 hr after 2 mg cianopramine (24 hr: 52% +/- 10%). Systolic blood pressure response to intravenous tyramine and norepinephrine was unchanged after 2 mg cianopramine. The phenylephrine dose required for an increase of 40 mm Hg in systolic blood pressure was 67 +/- 25 micrograms/min before cianopramine and 86 +/- 32 micrograms/min 2 hr after 2 mg cianopramine, which suggests weak alpha-receptor antagonism of cianopramine. Our results in man are consistent with potent, specific 5-HT uptake inhibition by cianopramine without a clinically relevant effect on peripheral neuronal norepinephrine reuptake.
Administration, Oral↗
Impaired plasma amino-acid clearance in patients with cirrhosis of the liver and portocaval shunt--its relation to insulin resistance.
To study the interdependence of utilization of branched chain amino acids and glucose and of hyperinsulinaemia in patients with liver cirrhosis the plasma disappearance of glucose and amino acids was estimated in seven patients with cirrhosis and portocaval shunt and in seven healthy controls following infusion of glucose and essential amino acids during suppression of endogenous hormone release by somatostatin. Exogenous insulin was infused by means of an automated glucose controlled insulin infusion system. The data demonstrate that (i) insulin requirement almost doubled in patients as compared to controls to obtain similar blood glucose responses to i.v. glucose, and (ii) the plasma disappearance rates of the infused amino acids were reduced in the patients as compared to controls despite hyperinsulinaemia sufficient to achieve normal glucose assimilation. Thus, in cirrhotic patients insulin resistance may be overcome by excess insulin as far as glucose homoestasis is concerned, whereas amino-acid metabolism still remains impaired.
3-Hydroxybutyric Acid↗
Cardiocirculatory effects of moclobemide (Ro 11-1163), a new reversible, a short-acting MAO-inhibitor with preferential type A inhibition, in healthy volunteers and depressive patients.
The benzamide-derivative moclobemide (Ro 11-1163) is a new short-acting, reversible MAO-inhibitor, preferentially affecting Type A MAO, which is, being developed as an antidepressant agent. The effect of moclobemide on heart rate, blood pressure, electrocardiographic and systolic time intervals was assessed in eight healthy volunteers and seven depressive patients. The volunteers received single doses of 100 mg, 150 mg and placebo in radomized single-blind order. Seven patients received placebo and 100 mg as single doses and five patients were also given chronic treatment with individually assessed optimal therapeutic dose (100-400 mg). No change in blood pressure, heart rate, ECG or systolic time intervals was found. The compound was well tolerated. The findings suggest that moclobemide may be a safe MAO-inhibitor as far as sympathetic responsiveness and cardiovascular effects are concerned.
Adult↗
[Controlled randomized double-blind study for the comparison of the treatment of patients with essential hypertension with homeopathic and with pharmacologically effective drugs].
In a randomized double-blind cross-over study the effects of antihypertensive pharmacotherapy were compared with those of homeopathic treatment in 10 patients with essential hypertension. The conclusions are: 1. The blood pressure lowering effect under pharmacotherapy is clearly superior to that under homeotherapy, where it was negligible and statistically not significant. 2. As far as improvement of subjective complaints of the patients is concerned there was no superiority of pharmacotherapy over homeopathic treatment. 3. The cross-over design appears less suitable than, perhaps, a design with parallel treatment groups because of the long duration of such a study and the observed carry-over effect.
Amiloride↗
Adrenergic mechanisms and blood pressure regulation in diabetes mellitus.
Changes in blood pressure (BP) and plasma norepinephrine (NE) following various stimuli of the sympathetic, nervous system were studied in six healthy subjects and in 17 diabetic patients. The latter were subdivided in three groups: (1) six patients with neither peripheral neuropathy nor autonomic dysregulation, (2) six patients with severe peripheral neuropathy without autonomic dysregulation, and (3) five patients with autonomic dysregulation, three of whom suffered also from peripheral neuropathy. The following procedures were performed: (1) cold pressor test (2 min), (2) mechanical irritation of the skin by suction (0.75 kg/cm2, 10 min), (3) orthostasis (10 min), and (4) i.v. infusion of NE (50, 100, 200 ng kg-1 min-1 for 15 min each). Both the stimulated endogenous plasma NE levels and BP response to exogenous NE were the same in normal subjects, in diabetic controls and in diabetics with peripheral neuropathy without autonomic dysregulation. In contrast, diabetics with postural hypotension showed a less pronounced release of NE to standing (P less than 0.05), but not to cold pressor test and mechanical skin irritation. Furthermore, they showed increased vasoreactivity to the highest dose (P less than 0.05), but not to the lower doses of exogenous NE. Thus NE release and adrenergic BP regulation seem to be altered only in diabetics with clinical signs of autonomic dysregulation. These alterations can only be evaluated when patients are exposed to stimuli of higher intensity, such as orthostasis or infusion of a high NE dose.
Adult↗
Insulin production rate, hepatic insulin retention and splanchnic carbohydrate metabolism after oral glucose ingestion in hyperinsulinaemic Type 2 (non-insulin-dependent) diabetes mellitus.
To differentiate peripheral and hepatic insulin resistance in hyperinsulinaemic overweight Type 2 (non-insulin-dependent) diabetic patients (n = 17; 143 +/- 4% ideal body weight; mean +/- SEM) arterial concentrations and splanchnic exchange of glucose, pyruvate, lactate, non-esterified fatty acids, beta-hydroxybutyrate and acetoacetate, as well as the insulin production rate, were determined before and during oral glucose loads of 25 g or 100 g. Insulin production rate, hepatic insulin retention and splanchnic exchange of glucose and metabolites were estimated by means of the hepatic venous catheter technique. In the basal state insulin production rate was greater in overweight Type 2 diabetic patients (2.57 +/- 0.28 pmol.kg-1. min-1) than in healthy control subjects (1.68 +/- 0.17 pmol.kg-1.min-1; p less than 0.01). After ingestion of 25 g glucose, the cumulative insulin production rate exceeded normal values (p less than 0.05), but was below normal with 100 g glucose (p less than 0.01). Relative insulin trapping by the splanchnic bed in the diabetic patients was 54 +/- 3%, not different from normal. Following a 100 g glucose load, splanchnic insulin retention fell by 20% in the patients, and less consistently so in healthy controls. Splanchnic glucose output was normal in the diabetic patients both in the basal state and after glucose ingestion although the induced arterial blood glucose levels were greater in the diabetic patients than in control subjects (p less than 0.005). Splanchnic output of pyruvate (p less than 0.025), lactate (p less than 0.01), and beta-hydroxybutyrate (p less than 0.005) were greater in the basal state in the diabetic patients than in healthy subjects. However, no difference in splanchnic exchange was seen between the two groups in their metabolites' respective response to glucose ingestion. These data suggest that obese hyperinsulinaemic Type 2 diabetic patients may represent a subgroup of diabetic patients with predominantly peripheral, but compensated hepatic, insulin resistance being associated with an increased basal insulin production rate which only exhausts after ingestion of a large glucose load.
Aged↗
Cardiocirculatory effects of Ro 11-2465, a selective 5-HT (serotonin) uptake inhibitor, in healthy volunteers.
The imipramine derivative Ro 11-2465, a potent, selective 5-HT (serotonin) uptake inhibitor, is being developed as an antidepressant agent. The effects of Ro 11-2465 on heart rate, blood pressure, electrocardiogram and systolic time intervals were assessed in nine normotensive volunteers. Ro 11-2465 1 and 2 mg and a placebo were given in a single blind, cross over design study. The placebo did not induce any significant changes. With Ro 11-2465, the ECG-intervals (P, PQ, QRS, QTc) did not change, the blood pressure increased 3-6 h after administration of either dose, and the heart rate was increased 4-6 h after the 2 mg dose. There was also evidence of increased ventricular automaticity in one subject. the total electromechanical systole (QS2-index) was significantly shortened 4-8 h after administration of 2 mg, whereas neither 1 mg the dose nor the placebo had any such effect. This finding suggests the presence of a positive inotropic effect, which is probably due to a stimulatory effect of serotonin, and is not mediated by an adrenergic mechanism. The findings suggest that Ro 11-2465, as a potential new tricyclic antidepressant, might have favourable cardiocirulatory dose effects, particularly in patients with pre-existing heart disease.
Adult↗
Feedback inhibition by biosynthetic human insulin of insulin release in healthy human subjects.
To determine the impact of biosynthetic human insulin (BHI) on endogenous insulin release, splanchnic output and arterial concentrations of C-peptide were measured in eight healthy men after intravenous administration of 0, 0.5, 1.25, U BHI . m-2 . h-1 for 70 min each. Euglycemia was maintained by a variable glucose infusion. Arterial levels of serum insulin were 48 +/- 6 pmol/liter before and 135 +/- 12, 265 +/- 18, and 593 +/- 47 pmol/liter after BHI infusion. Splanchnic C-peptide output was reduced by BHI infusion from 88 +/- 10 pmol/min before to 50 +/- 9, 28 +/- 10, and 18 +/- 16 pmol/min (P less than 0.0025). Simultaneously, arterial concentrations of C-peptide fell from 539 +/- 54 pmol/liter by 29 and 43% when 1.25 and 2.5 U . m-2 . h-1 of BHI were administered. Hepatic insulin uptake was directly related with BHI infusion rate (r = 0.88) and rose during BHI administration from a basal value of 58 +/- 7 to an uptake of 265 +/- 31 pmol/min when 2.5 U . m-2 . h-1 were infused (P less than 0.0005). Basal hepatic insulin clearance was 4.75 +/- 0.60 ml . kg-1 . min-1 and remained unchanged after BHI infusion as did hepatic fractional extraction of insulin, which was 61 +/- 4% in the basal state. Metabolic clearance rate of immunoreactive insulin (MCRi) was dose-dependently reduced by BHI infusion, whereas the relative share of hepatic insulin clearance in total MCRi rose simultaneously (P less than 0.01). We conclude that feedback inhibition of endogenous insulin release may play an important role in vivo. Furthermore, it appears that nonhepatic insulin degradation is a saturable phenomenon as total MCRi fell in the presence of its unchanged hepatic clearance rate after the infusion of large amounts of BHI.
Adult↗
[Colorimetric determination of inflammations of the gingiva propria].
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Colorimetry↗
[Hypertension treatment in the elderly].
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Adrenergic beta-Antagonists↗
The role of "diabetogenic" hormones on carbohydrate and lipid metabolism following oral glucose loading in insulin dependent diabetics: effects of acute hormone administration.
To evaluate the relative role of "diabetogenic" hormones as insulin antagonists in severe derangements of diabetic control, glucagon, cortisol, growth hormone and adrenaline were administered by continuous intravenous infusion, separately and in combination, to ketosis-prone insulin-dependent diabetics (n = 11). The amount of insulin required for the assimilation of a 50 g glucose load during the various hormone infusions was determined by means of an automated glucose-controlled insulin infusion system and used as an index of insulin effectiveness. Raising plasma hormone concentrations acutely into the range seen in severe diabetic states (glucagon 517 +/- 70 pg/ml; cortisol 32 +/- 3 micrograms/dl; growth hormone 14 +/- 3 ng/ml) did not alter significantly blood glucose profile and insulin requirement (control 11.3 +/- 1.1 U; glucagon 11.6 +/- 2.0 U; cortisol 11.1 +/- 0.4 U; growth hormone 12.9 +/- 1.4 U), except for adrenaline (plasma level 550 +/- 192 pg/ml), which caused a marked rise in blood glucose levels and a threefold increase in insulin demand (31.1 +/- 3.7 U). Combined infusion of all hormones did not potentiate significantly the latter effect (38.3 +/- 4.7 U). The effectiveness of metabolic control by insulin was assessed by a marked decrease in plasma nonesterified free fatty acids and ketone bodies upon its administration after glucose ingestion in all groups studied. It is concluded that from the hormones investigated within this study adrenaline exerts the strongest diabetogenic action during its short term administration followed by that of growth hormone. Whereas it may well be that over-insulinization of the patients by the glucose controlled insulin infusion system has overcome and disguised the smaller diabetogenic effects of cortisol and glucagon.
Adult↗