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[Fluid carbenicillin levels after intravenous administration].

Intravenous infusion of carbenicillin was followed by a determination of the concentration of this antibiotic in both the liquor and serum. The examinations, of which the results are reported in this paper, were made on six patients who had undergone surgical operations to the posterior cranial fossa and on whom lumbar punctures were postoperatively performed every day, as well as on seven hydrocephalic patients where a temporary relief of pressure was obtained by draining excess liquor. The level of carbenicillin in the liquor were found to enable even gram-negative problem germs (e.g., Proteus germs) to be controlled.

Adolescent

Plasma concentration of alpha-methyldopa and sulphate conjugate after oral administration of methyldopa and intravenous administration of methyldopa and methyldopa hydrochloride ethyl ester.

The plasma concentrations of free alpha-methyldopa and methyldopa sulphate conjugate were measured in 7 hypertensive patients with normal renal function following alpha-methyldopa (1 g) orally. Five of these patients subsequently received alpha-methyldopa ethyl ester (250 mg) (methyldopate) intravenously and two further patients received 250 mg of alpha-methyldopa intravenously. After oral administration a large amount of total plasma alpha-methyldopa was present as sulphate conjugate. There were wide interindividual differences in the ratio of free: conjugated alpha-methyldopa in plasma (ratio at 4 hours ranged from 3.73-0.83) suggesting that individual differences in the extent of sulphate conjugation may occur. There was no close correlation between the degree of conjugation and the fall in arterial pressure. At all time intervals examined, plasma concentrations were higher following intravenous alpha-methyldopa than alpha-methyldopate. The plasma concentration of alpha-methyldopa (free and esterified) 60 minutes after i.v. alpha-methyldopate was 1.7+/-0.3 mug/ml while at the same time after the same dose of methyldopa by the same route the mean concentration was 5.9 mug/ml. Although small amounts of sulphate conjugate were detected after i.v. alpha-methyldopate, insignificant quantities of conjugate were found after i.v. alpha-methyldopa. The average fall in mean arterial pressure was 27 mm/Hg following i.v. alpha-methyldopa but only 2.7 mm Hg following alpha-methyldopate. These results suggest that sulphate conjugation of alpha-methyldopa occurs in the gastrointestinal tract during absorption. Hydrolysis of alpha-methyldopa ethyl ester does not appear to be instantaneous and pharmacokinetic differences between the ester and free alpha-methyldopa have been demonstrated.

Administration, Oral

Zinc metabolism in humans after oral and intravenous administration of Zn-69m.

Seventeen patients were studied after separate oral and intravenous administration of 50 muCi Zn-69m to determine if Zn-69m is suitable for studying zinc metabolism in humans and to determine if the route of administration affects kinetics. Patients stayed on a metabolic ward for each study. Activity was measured in the total body, urine, feces, blood, plasma, red blood cells, and by detectors over liver and thigh. Five day urine to fecal ratios were 0.44 (intravenous), 0.018 (oral). Most activity went rapidly to liver, then followed two component exponential loss patterns in both cases. Thigh area doubling time was 5.7 days whether the zinc was given orally or intravenously. Plasma activity decreased to less than 2% of that injected by 24 hr after intravenous administration and decreased from a maximum of 1.2% of that ingested, 3 hr after oral administration to 0.7% by 24 hr. Red blood cell activity increased through the 5-day study period to maximum values of 6.4% of that injected after intravenous administration and 2.4% of that ingested after oral administration. Similar metabolic patterns were observed regardless of whether Zn-69m was administered intravenously or orally, suggesting that these patterns were not affected by the mode of administration for the cases studied.

Administration, Oral

[Importance of the fibrinogen-heparin complex in the fibrinolytic activity of the blood euglobulin fraction after the intravenous administration of thrombin or plasmin].

Intravenous administration of plasmin as distinct from thrombin inhibited or did not provide a secretion of endogenous heparin into circulation. In these conditions non-enzymatic fibrinolysis was not observed both in fraction of euglobulins and in fibrinogen-heparin complex, isolated from euglobulins, due to insufficiency of heparin. Exogenous heparin, injected into circulation or added to corresponding fractions, enabled to produce the active heparin complexes. About 70% of total fibrinolytic activity was due to fibrinogen-heparin complex in euglobulin fraction of blood plasma, isolated from blood of animals intravenously administered with thrombin.

Animals

Dissociation of beta-hydroxy-beta-methylglutaryl-CoA reductase activity from the overall rate of cholesterol synthesis in the liver following the intravenous administration of lipid.

After the intravenous administration to the intact rat of triglyceride carried in either intestinal lipoproteins or in an artificial fat emulsion, the enzymatic activities of microsomal beta-hydroxy-beta-methylglutaryl-CoA reductase activity in the liver assayed in vitro became markedly elevated. This elevation of enzyme activity was not associated with a corresponding change in the overall rate of cholesterol synthesis in the rat liver slice as measured by the incorporation of either [3H]water or [1-14C]octanoate into nonsaponifiable lipids or into digitonin-precipitable sterols. The degree of dissociation of hydroxymethylglutaryl-CoA reductase activity from the overall rate of cholesterol synthesis correlated closely with the amount of lipid administered to the animal, the level of circulating lipids, and the level of ketone synthesis manifest in the liver cell suggesting that this phenomenon might be the consequence of a detergent effect of elevated cellular levels of fatty acids. In any event, under these experimental circumstances hydroxymethylglutaryl-CoA redutase activity no longer reflects the rate at which the liver cell is synthesizing cholesterol.

Acetates

Pulmonary edema and emphysema in cattle after intraruminal and intravenous administration of 3-methylindole.

Intraruminal and intravenous administration of 3-methylindole (3MI; skatole) caused interstitial pulmonary edema and emphysema in cattle. In 3 adult heifers given the intraruminal dose of 0.2 g of 3 MI per kilogram of body weight, clinical signs of respiratory disease appeared between 6 and 12 hours after dosing, and death due to pulmonary edema and emphysema occurred at 33, 69, and 72 hours. The mean plasma concentration of 3MI became maximal (18.5 mug/ml) at 3 hours and then decreased to low concentrations by 48 hours. In 2 heifers given an intraruminal dose of 0.1 g of 3MI/kg, clinical signs developed, but they did not die during the 96-hour experiment. The mean plasma concentration of 3 MI became maximal (16.8 mug/ml) at 3 hours and decreased to 1.6 and 0.4 mug/ml at 12 and 36 hours, respectively. At necropsy of the heifers, the lung were large, firm, dark red, and heavier than normal. Diffuse pulmonary edema was the predominant change in cattle which died early, and interstitial emphysema was more severe at later stages of the disease. During the early stages, alveoli were overdistended, and a few more ruptured. Most alveolar spaces were filled with proteinaceous residue, but the alveolar septums were smooth and of normal thickness. At later stages, proliferation of alveolar cells was observed, and alveolar septums were thickened. In 3 cows given 0.06 g of 3MI/kg by jugular infusion, clinical signs appeared in all cows, and 1 cow died of pulmonary edema and emphysema 56 hours after the infusion was started. Severe pulmonary lesions seen in all of the cows given a 3MI infusion were similar to those in the cows given an intraruminal dose of 3MI. The mean plasma concentration of 3MI increased to 10.7 mug/ml at 9 hours after starting the infusion and decreased to 0.5 mug/ml at 18 hours. The results indicate that 3MI, a product of ruminal tryptophan fermentation, can cause pulmonary edema and interstitial emphysema in cattle and support the hypothesis that 3MI is the causative agent in tryptophan-induced pulmonary disease.

Administration, Oral

[Optimal regime of intravenous administration of lincomycin in osteomyelitis].

The pharmacokinetics of lincomycin in the blood of 8 patients with osteomyelitis was studied on the drug single and uninterrupted intravenous administration in therapeutic doses. It was found that when the antibiotic was administered continuously according to the routine scheme, its therapeutic blood levels were attained only 1.5 hours after the drug infusion. The optimal regimen of lincomycin uninterrupted infusion providing its constant rate in combination with the single intravenous administration was estimated with the help of the constants of the two-compartment model of lincomycin pharmacokinetics. According to the calculations the rate of the antibiotic administration necessary for providing therapeutic levels should be 2.2 mg/kg in complex with the loading dose equal to 5.4 mg/kg. Practical trials showed that intravenous administration of lincomycin with the above regimen remained within therapeutic range already 10 to 20 minutes after the beginning of the drug infusion. Therefore, from the pharmacokinetic point of view the recommended regimen for lincomycin infusion should be considered preferable to that used presently.

Adolescent

Lignocaine: a new technique for intravenous administration.

Current practices of intravenous lignocaine administration may result in a significant drop in blood level between the peak serum level from the initial bolus and the subsequent steady state from the constant infusion. This can cause a significant interval when plasma lignocaine levels are less than therapeutic, and ventricular ectopy may occur. To eliminate this subtherapeutic interval, a new therapeutic approach was devised. Seven patients were studied who had no evidence of congestive heart failure or liver disease. Lignocaine was infused at a rate of 25 mg/min; infusion dosages were selected by patient weight. The above therapeutic regimen eliminated the subtherapeutic hiatus and did not result in clinical toxicity. Therefore, this new infusion technique has significant clinical advantages in patients who require therapy with intravenous lignocaine.

Adult

Comparison of intraduodenal and intravenous administration of amino acids on gastric secretion in healthy subjects and patients with duodenal ulcer.

The ability of an amino acid mixture given intraduodenally or intravenously to stimulate gastric secretion is compared in healthy subjects and in duodenal ulcer patients. Graded amounts of amino acids by both routes produced a similar increase in acid output in healthy subjects, reaching about 30% of the maximal response to pentagastrin. Serum gastrin concentrations remained virtually unchanged but serum alpha amino acid nitrogen levels were about twice as high with intravenous as with intraduodenal administration. Intravenously administered amino acids produced a significantly higher acid output in patients with duodenal ulcer than in healthy subjects, but did not produce a significant increase in gastric acid or pepsin secretion when combined with a pentagastrin infusion as compared with pentagastrin alone. Cimetidine (2 mg/kg/h) added to intravenous amino acid infusions caused almost complete suppression of acid secretion. This study indicates that amino acids are capable of stimulating gastric secretion after intraduodenal and after intravenous administration. The response to the latter is significantly higher in patients with duodenal ulcer than in healthy subjects, does not appear to involve gastrin release, is not affected by pentagastrin, and is strongly suppressed by histamine H2-blocker.

Adult

Relationships between the concentrations of doxycycline in serum and in thoracic duct lymph after oral and intravenous administration in man.

The concentrations of doxycycline in serum and in thoracic duct lymph at various times after oral and intravenous administration of 200 mg of the drug were determined in 10 patients subjected to thoracic duct cannulation for diagnostic purposes. After oral administration, a mean peak serum concentration of 2.4 mug/ml (n=7) was obtained within 3 h; then the levels successively declined. The concentrations in thoracic lymph were lower, a mean peak concentration of 1.6 mug/ml being found 3 and 6 h after the intake. After intravenous administration (n=3), the concentrations of doxycycline in thoracic duct lymph were lower than but closely followed those in serum. The difference in concentrations between serum and lymph 1-6 h after the start of the infusion never exceeded 30%. The results suggest that doxycycline is rapidly distributed to the extracellular tissue fluids.

Administration, Oral

The hypotensive response to rapid intravenous administration of hypertonic solutions in man and in the rabbit.

Transient hypotension has been observed in patients after rapid intravenous administration of mannitol, 25 per cent, in clinical doses. These studies were conducted to determine the mechanism for the hypotension, to determine dose and rate of injection response curves in rabbits, and to determine which vascular beds were most reactive. Studies in six patients showed mean decreases in blood pressure of 23 +/- 6.0 per cent (+/-SE) and in total peripheral resistance of 38 +/- 7 per cent after infusion of mannitol. Studies in 18 patients during cardiopulmonary bypass with mechanically fixed cardiac output demonstrated decreases in mean blood pressure of 30 +/- 5 to 40 +/- 3 per cent, depending on dose and rate of administration of mannitol. Patients not on bypass compensated for large decreases in total peripheral resistance by increases in cardiac output (3.6 +/- .4 at baseline to 4.4 +/- .4 l/min) during mannitol-induced hypotension with no change in heart rate. Serum osmolality increased as blood pressure decreased. Significant but clinically unimportant decreases in sodium and potassium ions, hemoglobin, pH, and base excess values were observed. Studies in 18 rabbits showed that the greater the dose or rate of injection of mannitol the greater the decrease in blood pressure. Injection of radiolabeled microspheres in rabbits demonstrated a near doubling of blood flow to skeletal muscle tissue during the hypotension. This occurred with both equiosmotic hypertonic glucose (17 +/- 3 to 32 +/- 7 per cent) and mannitol (17 +/- 1 to 31 +/- 5 per cent), but not after isotonic saline solution. Changes in blood flow to other organ beds were variable and unimportant. The results suggest that hypotension following the intravenous administration of hyperosmotic solutions is due primarily to vasodilation in skeletal muscle.

Acid-Base Equilibrium

Paradoxical excitement following the intravenous administration of azaperone in the horse.

The rapid intravenous administration of the butyrophenone tranquilliser, azaperone, at a dose rate of 0.29-0.57 mg/kg body weight resulted in the immediate onset of excitement and ataxia of varying degree in over half the animals. The severity of the reaction appeared to be related to the size of the animal. Other side effects such as salivation, sweating, muscle tremor and vocalisation were also observed. The possible causes of this paradoxical reaction to the tranquilliser are discussed.

Animals

Oral versus intravenous administration of butylbiguanide: effect on oral glucose tolerance in normal humans.

1. The effect of oral and intravenous administration of butylbiguanide on the oral glucose tolerance test was investigated in 12 normal human volunteers. Orally administered butylbiguanide lowered the oral glucose tolerance curve and the corresponding serum insulin values, whereas intravenously injected butylbiguanide had no effect. 2. The lactate/pyruvate ratio determined 180 min. after glucose ingestion increased after oral butylbiguanide administration. No effect was observed after intravenous administration. 3. The decrease in serum phosphate levels observed after oral glucose loading was not influenced by butylbiguanide administered by either route. In addition, no effect of this drug was observed on fasting levels of glucose, insulin, phosphate, bicarbonate, lactate and pyruvate. 4. These results are compatible with recent observations that biguanides inhibit active transport mechanisms in the intestine. In addition, the effect of biguanides on blood levels of glucose metabolites is discussed with respect to their known action on oxidative phosphorylation.

Administration, Oral

Metabolic effects of salbutamol: comparison of aerosol and intravenous administration.

The effects of intravenous salbutamol (4 mug/kg) were compared with those of aerosol salbutamol (200 mug) in 10 asthmatic patients in a double-blind placebo-controlled study. Both methods of administration produced equal bronchodilatation. Intravenous salbutamol caused significant increases in plasma insulin and glucose levels and a fall in serum potassium concentration in addition to tachycardia and tremor, whereas aerosol salbutamol produced only a small transient increase in the plasma glucose level. The initially raised non-esterified fatty acid levels decreased significantly after aerosol and placebo but not after intravenous salbutamol.

Adult