Doses Of HCl Research Articles

Influence of nutritional status on plasma levels and relative bioavailability of tetracycline.

Relative bioavailability after oral administration of a single dose and Cmin levels of tetracycline in plasma after multiple doses were determined in groups of well-nourished and under-nourished subjects. The relative bioavailability of tetracycline, assessed by the area under serum concentration time-curves, did not differ in under-nourished and well-nourished patients. The plasma levels were not different in the two groups after the conventional dose of tetracycline HCL 250 mg at 6 hour intervals. However, in these studies under-nourished subjects received a higher dose per kg body weight, which could have compensated for any effect of a shortened half life of the drug. When the dose per kg body weight was reduced, the Cmin levels were lower. On the other hand, with the same dose per kg body weight at more frequent intervals, the plasma concentrations were similar to those in well-nourished subjects. These studies indicate that the dosage regimen should be based both on body weight and on the nutritional status of the individual.

Plasma and cerebrospinal fluid concentrations of chlordiazepoxide and its metabolites in surgical patients.

Thirty otherwise healthy patients received a 100-mg oral dose of chlordiazepoxide HCl just prior to surgical procedures using spinal anesthesia. Fourteen of these patients had also received 100 mg on the night before surgery. Simultaneous samples of venous blood and cerebrospinal fluid (CSF) were taken immediately prior to injection of spinal anesthesia and were assayed for concentrations of chlordiazepoxide (CDX) and its major metabolite, desmethylchlordiazepoxide. Plasma concentrations of CDX ranged from 2.32 to 13.34 mug/ml. Simultaneous CSF concentrations were considerably lower, ranging from 0.04 to 0.34 mug/ml. Equilibration of CDX between plasma and the lumbar sampling site appeared to be complete within 2 hr of the most recent dose. After attainment of distribution equilibrium, simultaneous plasma and CSF concentrations of CDX were hightly correlated (r = 0.76), with a mean CSF-plasma concentrations ratio of only 0.043 (range; 0.02 to 0.06). The limited passage of CDX into human CSF is probably due to extensive binding to plasma protein. Assuming that transfer of CDX from plasma to CSF is governed by passive diffusion, the extent of plasma protein binding of CDX in healthy individuals averages about 96%.

Effect of chronic administration of pentobarbital on methadone analgesia and toxicity

In mice implanted with pentobarbital pellets (75 mg) for three days, the AD50 of methadone at 60, 90 or 120 min after the administration of the drug was about twice that of the control animals. Also with the four doses of methadone HCl tested, pentobarbital-treated animals exhibited a mean positive analgetic response less than that of the control group. The studies revealed that the decrease in methadone analgetic response was dependent on duration of pentobarbital pellet implantation. The LD50 of methadone-HCl increased 1.7 times that of the placebo control group. The pentobarbital pellet implantation resulted in reduction of methadone toxicity and attenuation of methadone analgesia which correlated with an induction of hepatic microsomal N-demethylase activity.

Dose-dependent facilitation or supression of rat fighting by methamphetamine, phenobarbital, or imipramine.

To clarify the effects of different doses of methamphetamine HCl, Na phenobarbital, and imipramine HCl on aggressive behavior, the drugs were administered to pairs of rats trained to regularly fight on an electric shock grid. Fighting time and motor activity were measured during the shock sessions. Each drug was given to a different group of rats, in the following doses (mg/kg i.p.): methamphetamine HCl 0, 0.25, 0.50, 1, 2, and 4; Na phenobarbital 0, 5, 10, 20, 40, and 80; imipramine HCl 0, 2.5, 5, 10, and 20. At lower doses methamphetamine and phenobarbital both stimulated fighting behavior, and at higher doses both reduced it. Motor activity rose above control with lower doses of both of these drugs; it fell markedly with higher doses of phenobarbital, while remaining elevated at higher doses of methamphetamine. Imipramine reduced fighting time at higher doses. The results show that, depending upon the dose, the “stimulant”, methamphetamine, and the “sedative”, phenobarbital, can both increase or decrease aggressive behaviors. Together with previous animal studies, these findings fit with clinical observations that amphetamines and barbiturates can increase aggressive behavior, and suggest that dose may be important in that increase.

Acute toxicity of propoxyphene salts

The acute toxicity of oral and parenteral doses of propoxyphene HCl was studied in laboratory animals. Large iv, im, or ip doses of propoxyphene HCl produced clonic and tonic convulsions in mice, rats, and dogs. Death from oral doses of propoxyphene HCl was preceded by convulsions in dogs but not in rodents or rabbits. Other effects included hypoactivity and body rigidity in rodents, and salivation, ataxia, and weakness in dogs. Animals given lethal doses of propoxyphene showed profound respiratory depression, which was judged to be the primary cause of death. Respective LD50 values for propoxyphene HCl in the mouse, rat, and dog were 28, 15, and 29 mg/kg iv and 282, 230, and 100 mg/kg po. Comparative acute oral toxicity tests were conducted on the 2-naphthalene sulfonate (napsylate) salt of propoxyphene. In equimolar doses, propoxyphene napsylate, a relatively insoluble salt, was about one-half as toxic as propoxyphene HCl in rodents and clearly less toxic in dogs. Plasma concentrations of propoxyphene indicated that the differences in the acute oral toxicity of propoxyphene HCl and propoxyphene napsylate were due to the more gradual absorption of the latter salt.

Short-term toxicity of propoxyphene salts in rats and dogs

Two salts of d-propoxyphene, the hydrochloride and the 2-naphthalene sulfonate (napsylate), were compared in short-term toxicity studies. In rats and dogs the effects produced by daily administration of equimolar doses of these salts were indistinguishable. Large daily doses of propoxyphene, representing between 40 and 110 times the maximum human clinical dose, resulted in liver enlargement, slight fatty change in the liver, and reduced growth rate in rats. Signs of developing toxicity in dogs were observed during 90 days of treatment with oral doses of 30–40 mg/kg of propoxyphene HCl or equivalent doses of propoxyphene napsylate. The following effects were dose-related in incidence or degree: loss of body weight, increased serum alkaline phosphatase values, increased liver weight, and slight fatty change in the liver. Lower doses were tolerated by dogs without significant toxicity.

The antibiotics and the peripheral nerves.

Thirty patients were divided into 3 groups. The patients of the first, second and third group received therapeutic doses of ampicillin, erythromycin and tetracycline HCl respectively. Motor nerve conduction was found to be impaired significantly on the third day of the antibiotic administration; the impairment regressed after the discontinuation of the antibiotics. The possible mechanisms involved are discussed.

Turnover rate of brain 5-hydroxytryptamine increased by D-amphetamine.

1. Administration of two doses of amphetamine HCl (5 mg/kg intraperitoneally) 45 min apart raised body temperature of rats by an average of 3.4 degrees C and increased the turnover rate of brain 5-hydroxytryptamine (5-HT) by almost one-half.2. Both effects were blocked by exposure to 4 degrees C or by pretreatment with the beta-blocker Kö 592 (1-(2-methylphenoxy)-3-isopropylamine-2-propanol), but not by the administration of the ganglionic blocker chlorisondamine combined with atropine.3. Since it has previously been shown that hyperthermia per se increases the turnover rate of brain 5-HT, and that amphetamine does not directly affect the uptake and release of 5-HT in brain slices, it is concluded that the amphetamine-induced increase in 5-HT turnover may be secondary to the rise in temperature produced by the drug.

Investigation of the amygdaloid and olfactory electrographic response in the cat after toxic dosage of lidocaine

Evidence has been presented concerning the effects of afferent inputs on the amygdaloid hypersynchronous electrographic discharge in the cat after toxic doses of lidocaine HCl. The study was divided into three parts consisting of chronically implanted animals, cerveau isolé preparations and midbrain-deafferented preparations with the reticular core intact. A brief description of each preparation is included. From the results of this study these conclusions can be drawn: 1. 1. The electrographic pattern change is not evident in high midbrain transected ( cerveau isolé) cat preparations. 2. 2. The pattern change in the midbrain-deafferented cat preparation (with reticular core intact) is essentially identical to that seen in the normal chronic cat. 3. 3. Olfactory inputs are essential to this hypersynchronous amygdaloid pattern change, with this alteration appearing initially in the olfactory apparatus, then spreading synchronously to the amygdala and hippocampus. From this study, it would appear that possible noxious afferent inputs are not implicated but that olfaction is involved in the genesis of this response to toxic doses of lidocaine HCl. It is also apparent that either an activated cerebrum or an intact reticular core is essential to the genesis of this electrographic pattern change. Based on these findings, one may conclude that the amygdaloid hypersynchronous electrographic response to toxic levels of local anesthetics results from a lowering of the threshold of the olfactory system and subsequent lowering of the amygdaloid threshold to these olfactory inputs by lidocaine HCl.

Metabolism of 14C-medazepam hydrochloride in dog, rat and man

Labeled medazepam (7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzo-diazepine-5- 14C) and metabolites were identified and measured by two-dimensional thin-layer chromatography. In the dog, 2 mg/kg of medazepam-5- 14C HCl given orally or i.v. did not yield measurable blood levels of intact drug. The close agreement of the amount of 14C excreted in the urine after oral and i.v. administration and of the rates of this excretion indicated that the labeled compound was well absorbed. Fractionation of the blood revealed that biotransformation of medazepam was a rapid process. After a higher dose, 20 mg/kg i.v., medazepam disappeared from the blood bi-exponentially with half-lives of 0.16 and 2.7 hr. Pathways of medazepam metabolism, which apparently did not include diazepam as an intermediate, were postulated on the basis of metabolites identified in experiments both in vivo and in vitro. In the rat, highest tissue concentrations of 14C were seen 2–4 hr after an oral dose of 14C-medazepam HCl. It was clear from the metabolites identified that the formation of diazepam and phenolic diazepam metabolites represented an important pathway of medazepam metabolism in this species. The labeled compound was rapidly absorbed by two human subjects who received single 30-mg oral doses. The peak blood levels of medazepam (less than 0.2 μg/ml at 1–2 hr) declined rapidly with a half-life of 1–2 hr. A marked difference between the subjects in rates of elimination of metabolites from the blood and in excretion of urinary metabolites appeared related to body weight and the activity of drug-metabolizing enzymes. Preliminary evidence for diazepam formation in man was also obtained.

Atropine antagonism of carbachol-induced hyperglycemia

Hyperglycemia was induced with carbachol in rats, rabbits, and dogs, and the effect in rabbits was shown to be dose related. In albino rabbits with negligible plasma esterase activity, atropine sulfate effectively prevented hyperglycemia following 25 mcg./Kg. of carbachol, and the effect appeared to be dose dependent. In rabbits with moderate esterase levels, atropine sulfate dosage as high as 0.8 mg./Kg. had little inhibitory effect on carbachol hyperglycemic or cholinomimetic responses. This plasma esterase was not effectively blocked in vivo with 20 mg./Kg. of 2-(diethylamino)ethyl-2,2-diphenylvalerate (proadifen) HCl (SKF 525-A). However, this dose of proadifen HCl did block carbachol hyperglycemia in rabbits with negligible esterase activity. Carbachol hyperglycemia was similarly prevented by atropine in rats and dogs. Hyperglycemia was induced with carbachol in rats, rabbits, and dogs, and the effect in rabbits was shown to be dose related. In albino rabbits with negligible plasma esterase activity, atropine sulfate effectively prevented hyperglycemia following 25 mcg./Kg. of carbachol, and the effect appeared to be dose dependent. In rabbits with moderate esterase levels, atropine sulfate dosage as high as 0.8 mg./Kg. had little inhibitory effect on carbachol hyperglycemic or cholinomimetic responses. This plasma esterase was not effectively blocked in vivo with 20 mg./Kg. of 2-(diethylamino)ethyl-2,2-diphenylvalerate (proadifen) HCl (SKF 525-A). However, this dose of proadifen HCl did block carbachol hyperglycemia in rabbits with negligible esterase activity. Carbachol hyperglycemia was similarly prevented by atropine in rats and dogs.

Toxicology of nortriptyline hydrochloride

The acute toxicity of nortriptyline hydrochloride was studied in four species, and the following LD 50's were determined: mouse, p.o., 327 mg/kg; mouse, i.v., 25.7 mg/kg; mouse, s.c., 145 mg/kg; rat, p.o., 502 mg/kg; rat, i.v., 22.3 mg/kg; and rat, s.c., 666 mg/kg. Rats were shown to tolerate daily subcutaneous doses of nortriptyline HCl of 20 mg/kg for 246 days with no drug-induced changes except ulceration at the site of injection. When given daily oral doses of 20 mg/kg of nortriptyline HCl, dogs survived with no deleterious drug effects for one year, but succumbed within a few days to doses of 40 mg/kg/day. No significant hematologic or histologic changes occurred in rats maintained for one year on diets containing 0.15% of nortriptyline HCl. Nortriptyline HCl did not effect reproduction or development of the offspring in rats fed at levels as high as 0.03% in the diet. Acute and long term studies of nortriptyline HCl indicate that it is safe for investigational use in man.

The Suppression of Anti-Bovine Serum Albumin Production in Rabbits by Acriflavine Hydrochloride N. F.

Summary The primary immune response of rabbits was greatly suppressed by acriflavine HCl N.F. given 2 days before and continued for 13 days after the i.v. injection of bovine serum albumin (BSA). Two such courses of acriflavine HCl N.F. and BSA induced a degree of immune paralysis to subsequent injections of BSA. Acriflavine HCl N.F. started 10 min after the injection of antigen also depressed the immune response but was not as effective as when acriflavine was given prior to the antigen. Acriflavine HCl N.F. treatment in the dosage of 4 mg/kg for 7 days had minimal effect upon the secondary immune response once a primary response was established in the absence of acriflavine. In contrast to other immunosuppressant agents, the limiting toxicity of acriflavine HCl N.F. was not caused by apparent damage to granulopoiesis and lymphopoiesis. Serum γ-globulin levels were also unaltered. Rabbits given immunosuppressant doses of acriflavine HCl N.F. appeared healthy except for a slight elevation in the blood urea nitrogen and a slight depression in the hematocrit. Toxic doses of acriflavine HCl N.F. damaged the distal convoluted tubules of the kidney to produce a renal acidosis and nephrocalcinosis. Acriflavine HCl N.F. interfered with antibody production in a manner which appeared to be different from those of other immunosuppressant agents, but the mode of action remains unknown.