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Previously, we reported that ethanol produces a fall in total serum calcium in rats. In this study we show that the rapid (30 min) fall in total plasma calcium from 5 to 4.59 mEq⁄1 after a single oral dose of ethanol (6 g⁄kg) was ssociated with a significant (p < 0.001) fall in plasma ionic calcium from 2.78 to 2.55 mEq⁄1. The percent changes from controls in both total calcium and ionic calcium were similar, being approximately 8% each. A significant (p < 0.001-0.005) rise in serum magnesium also was observed at 3.5 and at 4 hr after alcohol administration. The hypermagnesemia associated with the hypocalcemia was demonstrated both with a single oral dose of alcohol (6 g⁄kg) and with repeated administration of a smaller dose (0.2 g⁄kg) every 0.5 hr for 2 hr (total dose = 0.8 g⁄kg). In acutely thyroparathyroidectomized rats, the effects of parathyroid hormone and alcohol on serum calcium were antagonistic. The data suggested that in intact rats the calcium-raising effect of the parathyroid hormone, secrete...

The urinary excretion of secbutobarbitone (I) and its metabolites has been studied quantitatively using combined gas chromatographymass spectrometry. After a single oral dose was given to healthy male volunteers, unchanged drug (5–9%), 2′-hydroxysecbutobarbitone (II, 1·7–3·2%), 2′-oxosecbutobarbitone (III, less than 1%), and the carboxylic acid (IV, 24–34%) were found. The kinetics of the excretion process were studied.

A 5-day treatment period using varying doses of carbaryl (8.5, 17 or 34 mg/kg daily, po) failed to alter significantly the ability of the prostate gland to assimilate [1,2- 3 H]testosterone. Neither testicular nor sex accessory gland weights were affected by these regimens of carbaryl. A single oral dose of [ 14 C]carbaryl (24 μCi/kg equivalent to 0.9 mg/kg) led to detectable amounts of radioactivity in several organs of reproduction including the prostate gland, seminal vesicles and testes. Very low concentrations of labeled carbaryl and/or its radiometabolites were detected in the epididymal fat pads and in the seminal plasma.

1. Chlormethiazole and five of its metabolites excreted in urine in man have been investigated by g.l.c.-mass spectrometry. 2. Four metabolites have been identified by comparison with authentic compounds as 5-acetyl-4-methylthiazole, 5-(1-hydroxyethyl)-4-methylthiazole, 5-(2-hydroxyethyl)-4-methylthiazole and 4-methyl-5-thiazoleacetic acid; 4-methyl-5-thiazoleacetaldehyde is proposed for the other metabolite. 3. The amounts of chlormethiazole and its identified metabolites excreted in urine have been quantitatively determined after a single oral dose in three healthy adults. Approximately 16% of the dose was excreted as chlormethiazole, 5-acetyl-4-methylthiazole, 5-(1-hydroxyethyx)-4-methylthiazole and 4-methyl-5-thiazoleacetic acid.

Sixty male patients aged between sixteen and thirty years suffering from acute gonococcal urethritis in whom a urethral exudate had been present from one to thirty-nine days participated in this study here described. Each patient was given one single oral dose of ampicillin-probenicid and follow-up examinations were carried out before the end of the fifth day, between the eighth and twelfth days, and in many cases also between the fifteenth and twentieth days post-dose. In fifty-eight of the sixty cases urethral exudate disappeared and cultures were negative within ten to forty-eight hours after dosing; thus demonstrating a 96·7% cure rate. This form of single oral dose treatment for gonorrhoea, apart from proving extremely effective, was highly acceptable to all of the patients admitted to this study and produced no side-effects.

In a double-blind study, indoprofen was superior to placebo in decreasing pain in patients with primary and metastatic cancer and with neuralgia. A single oral dose of 200 mg was more active than a 100-mg dose. The preferences of patients proved to be a more sensitive parameter in this study than scores of pain intensity, pain relief, and other related measurements (SPID, TOTPAR, and Peak PID).

Two groups of investigators have used the classical model for the distribution of thiopental following iv injection to predict the distribution of dieldrin following accidental ingestion. They concluded that the concentration of dieldrin in the brain is reduced first by redistribution to muscle and only later by redistribution to fat. The model as originally designed for thiopental had been evaluated by analysis of samples from persons undergoing surgery under thiopental anesthesia. Since it is not appropriate to give large doses of dieldrin to humans or to collect samples of muscle and various vital organs from them, the distribution of dieldrin was studied in rats. Dieldrin dissolved in corn oil was administered to these animals by stomach tube. The highest concentration of dieldrin in the brain was reached in 4 hr, and the concentration decreased gradually thereafter. The concentration in muscle remained essentially steady during the interval from 4 to 48 hr. There was no peak for muscle that could be interpreted as replacing a peak for brain. The concentration of dieldrin in fat was already slightly higher than that in the brain at 1 hr, very much higher at 4 hr when the concentration in the brain was maximal, and the concentration in the fat continued to increase during the first 24 hr. Either on the basis of concentration or on the basis of the total amount in each organ, no reason was found to assign any special importance to muscle as a sink into which dieldrin is redistributed from the brain. The fat appears to be far more important in this regard. The results indicate the danger of applying a mathematical model to a new situation without checking the results experimentally.

Endoscopic and Histological study of the locally administered prostaglandin 15 (R) 15 methyl-E 2 -methyl ester on the gastric mucosa in patients with peptic ulceration was carried out. The results show that the Prostaglandin analogue in a single oral dose of 150 μg possesses a powerful stimulant effect on the mucus-secreting cells of the gastric mucosa. The implications of these finding in the healing of gastric ulceration is discussed.

Intrauterine contraction of the ductus arteriosus in fetuses followed a single oral dose of 15 mg/kg indomethacin to pregnant rats 12 or 18 h prior to delivery. This ductal contraction studied by the whole-body freezing technique was markedly pronounced up to 30 min after delivery. Blood gas measurements showed a low pH at 30 min which returned to normal at 120 min. Cyanosis was persistant in the indomethacin groups. Intrauterine ductal closure may be a danger to the fetus and subsequent postnatal adjustment. The present results need confirmation in other species to predict a similar risk in the human fetus.

The disposition of propoxyphene and its major biotransformation product norpropoxyphene was studied in normal subjects following a single 130 mg oral dose. The concentration of propoxyphene and norpropoxyphene in samples of plasma and urine was determined by use of gas-liquid chromatography. The peak plasma level of propoxyphene occurs at 2 hours followed by a rapid elimination with an average apparent half-life of 3.0 hours (range 1.6 to 4.1 hours). The plasma level of norpropoxyphene renches a peak at 4 hours and slowly decays with an apporent half-life of 16.8 hours (range 11.5 to 28.8 hours). For a given subject, the ratio of the concentration of propoxyphene over the norpropoxyphene in plasma at 4 hours after a 130 mg dose is well correlated with the apparent plasma half-life of propoxyphene. This suggests that this single plasma sample may provide an indication of the rewtive rate of N-demethylation in a population. The data indicate that individual ditJerences in absorption and biotransformation may be responsible for the substantial variation of the pklsma propoxyphene levels seen in subjects receiving the same dose.

Spiramycin concentrations were determined in plasma and parotid and sublingual fluids of unanesthetized dogs 1 to 6 and 24 hours after a single oral dose of the antibiotic. Plasma levels were highest 1 to 4 hours after dosage. Sustained sublingual secretion and peak parotid levels of spiramycin occurred at later collection times.

Rats were given a single oral dose of MMT diluted in Wesson Oil. Eight groups of animals were used and the dosages varied from 15 to 150 mg/kg body weight. Necropsies were performed and tissues were taken for histopathological and Mn determinations from animals dying during the study and from a selected number of animals euthanatized at the end of the study. The LD 50 14 was 58 mg MMT/kg body weight. Histopathological changes were found in the lungs, liver and kidney. The severity of the changes was related to the dose. Concentrations of Mn in selected tissues were elevated in animals dying from exposure. At 14 days post ingestion, the Mn concentrations had fallen to approximately normal values.

The plasma half-life and metabolic clearance rate of antipyrine, a drug metabolized by hepatic microsomal enzymes, were determined in 33 normal volunteers during a basal state and during fever induced with a single intramuscular injection of etiocholanolone. Of the 14 normal volunteers who achieved significant fever (fever index greater than 50), in 11 plasma antipyrine half-life was prolonged after a single oral dose of 10 mg/kg and antipyrine metabolic clearance rate was decreased. There was no significant change of these mean values in 19 normal volunteers who failed to develop significant fever (fever index smaller than 50). Therefore, under the conditions of this study plasma antipyrine half-life was prolonged, probably due to impaired hepatic metabolism, during etiocholanolone-induced fever, although no correlation was observed between the magnitude of fever and the extent to which plasma antipyrine half-life was prolonged. Failure to obtain such a correlation may be attributable to the very small range of temperature elevation, extending from 37.9 degrees C to 39.2 degrees C, in the group of 14 subjects achieving significant etiocholanolone-induced fever (fever index greater than 50). A higher dose of antipyrine (18 mg/kg) suppressed induction of fever by etiocholanolone; antipyrine is the only orally administered drug thus far shown to be effective in repressing etiocholanolone-induced fever.

The variable effect of excessive vitamin A intake on alimentary cholesterolemia was investigated in cockerels of strains of White Leghorns and New Hampshires. With the New Hampshire cockerels, the feeding of 0.5% of dietary cholesterol resulted in greater cholesterolemia when the diet contained 1 700 I.U. of vitamin A per kilogram than when it contained 22 000 I.U. of vitamin A per kilogram. With the White Leghorn cockerels, on the other hand, cholesterolemia was enhanced with the higher level of dietary vitamin A. Absorption of a single oral dose of cholesterol was increased in birds of both breeds when vitamin A had been given previously by injection. In the White Leghorn cockerels the percentage of newly absorbed cholesterol in the hepatic pool was reduced by vitamin A administration, whereas in the New Hampshire cockerels the percentage was increased. It was concluded that excess vitamin A may have divergent effects on alimentary cholesterolemia in chickens of different genetic backgrounds as a result of opposite effects on the liver–blood ratio of a large load of cholesterol.

Antihypertensive effect of KK-25-S, a new potent ganglionic blocking agent, was evaluated in patients with moderate to severe essential hypertension. In 7 subjects, hypotensive responses after single oral dose were tested. Significant blood pressure reduction occurred within one or 2 hours after the administration of the drug and persisted for 4 hours or more. Thirty-two patients were treated with KK-25-S for periods of 2 to 29 weeks. Seven of 9 patients treated with KK-25-S alone failed to maintain significant hypotensive effect, whereas in 20 of 26 patients who received KK-25-S combined with other hypotensive drugs, significant blood pressure reduction was maintained throughout the treatment. Side-effects of the drug due to parasympathetic blockade were seen but readily controlled. Postural hypotension was relatively infrequent and slight in degree. Comparative studies on hypotensive potencies were made among different ganglionic blocking agents. It is concluded that KK-25-S is a potent hypotensive drug and is useful for the treatment of hypertension.

Plasma prolactin has been found to be elevated acutely following a single intramuscular injection of chlorpromazine in all of twelve endocrinologically normal subjects and in one patient with isolated growth hormone deficiency. The peak response occurs 1 to 2 hours following chlorpromazine injection. Two patients with panhypopituitarism showed no response. Pretreatment with L-dopa in normal subjects markedly inhibited the prolactin rise after chlorpromazine. In four patients with chronically elevated plasma prolactin, a single oral dose of L-dopa produced rapid lowering of the prolactin levels. These methods are suggested as useful, tests of pituitary function.

The larger extravascular spaces play an important role in the distribution of Ethambutol and resulting blood levels in children. For this reason serum levels in children of different age groups 2 – < 6 years, 6 – < 10 years and 10–14 years were determined after administration of 15 mg/kg and 25 mg/kg body weight in a single oral dose. Blood samples were drawn before, 1, 2, 4 and 7 hours after the ingestion of Ethambutol. Serum levels were determined by a modified tube vertical diffusion test using our own mycobacterial strain with the same sensitivity as strain ATCC 607. After 15 mg/kg the 2 mcg/ml serum concentration which is necessary for therapeutic efficacy (according to Pyle and Schmidt) was not achieved. The administration of 25 mg/kg produced serum concentrations of 2 mcg/ml and more only in the 10–14 years age group. According to v. Harnack and C. Simon, chemotherapeutic agents must be administered according to square meters of body surface to give equal serum concentrations in all age groups. Taking this into account and according to our results the dosage of 25 mg/kg body weight is too low for children in the age group 2 to < 10 years.

Through the combined use of deuterium labeling and GC-MS analysis, eight urinary metabolites of d-propoxyphene have been identified in man following a single oral dose of 130 mg of d-propoxyphene. The metabolites present were: norpropoxyphene, dinorpropoxyphene, cyclic dinorpropoxyphene, propoxyphene carbinol, norpropoxyphene carbinol, dinorpropoxyphene carbinol, p-hydroxypropoxyphene and p-hydroxynorpropoxyphene. The latter two metabolites occur as conjugates. The persistent metabolite, previously identified as norpropoxyphene, was found to be a mixture of norpropoxyphene and dinorpropoxyphene.

Within 24 hr. after receiving a single oral dose (10 mg./kg.) of 14C-labeled prazepam, two dogs excreted small quantities (4.6 and 1.8%) of the radioactivity into the urine. Thin-layer chromatograms showed the presence of at least eight radioactive compounds in these urine collections. Six of the labeled compounds were identified, and accounted for 86% of the 14C in the urine from Dog 1 and 95% of the 14C in the urine from Dog 2. These compounds and their contributions to the urinary radioactivity were: prazepam (1%, Dog 1; 0.2%, Dog 2); desalkylprazepam (2%, Dog 1; 0.4%, Dog 2); 3-hydroxyprazepam glucuronide (9%, Dog 1; 11%, Dog 2); oxazepam (14%, Dog 1; 3%, Dog 2); oxazepam glucuronide (52%, Dog 1; 72%, Dog 2), and 4′-hydroxyoxazepam glucuronide (8%, Dogs 1 and 2).

A single oral dose of mestranol (l7ct-ethynylestradiol 3-methyl ether) was administered to two groups of eight adult female beagle dogs each on Day 6 or 21 after first acceptance of the male. Based on corpora lutea counts, embryonic loss was 95.5 and 67.3%, respectively, for the two treatment groups, and only 34.5% for the control. In a second study a group of 12 beagles were used to determine the effect of mestranol on ova transport. Nine bitches were dosed on Day 6 and the reproductive tracts were removed between 1 and 5 days later and three controls were examined on Day 11. Thirty-nine of a possible 56 ova were flushed from the tracts of the treated females and all but one were from the oviducts. Eighteen (46%) of the ova were degenerating. The controls produced 17 normal zygotes out of a possible 24, and all were flushed from the uteri. Mestranol apparently did not accelerate ova transport, and the possibility of both a direct effect on the ova and an indirect effect via a delay in ova transport is discussed.

The effect of a single oral dose of sodium nitrite on mouse-liver microsomal-enzyme activity was studied. Sodium nitrite (100 mg/kg) produced a rapid and marked inhibition of both aminopyrine-demethylase and aniline-hydroxylase activity. Inhibitory effects of approximately 50% were observed as early as 15 min after treatment and were still persisting at 90 min. The responses at 45 min after treatment were dose-dependent, no response being observed at 25 mg/kg. Daily oral administration of 25 or 50 mg sodium nitrite/kg for 8 days produced no subacute inhibition of microsomal-enzyme activity. The mechanism of this response involves non-competitive inhibition of enzyme activity. While 300 mg sodium nitrite/kg had little effect on the K m of aminopyrine demethylase. V was decreased from 2·35 to 1·54 μmols formaldehyde/g liver/hr.

A relatively large dose of ABBOTT-16612 was tolerated by most species when the compound was given as a single oral dose to mice, rats, guinea pigs, hamsters, rabbits, cats, dogs, swine, rhesus monkeys, African green monkeys, chimpanzees, and quail. Marked species susceptibility was seen following repeated medication of at least 2 weeks' duration. The order of increasing sensitivity is: monkey, swine, rat, cat, and dog. All major organs were essentially free of microscopic anatomical changes, except for adverse hepatic changes seen only in dogs and in rats after repeated adminstration of relatively large doses. Hematology and clinical chemistries were essentially negative.

Nialamide at a single oral dose of about 3 mg./Kg. body weight produced decreased prothrombin activation by rendering the platelets less effective. It also decreased the adhesiveness of the platelets as measured by two different technics. A new technic for measuring the adhesiveness of the platelets has been described. It utilized a principle by which venous blood directly circulated through a column of fine glass beads, after which the platelets were reduced in number.

Diallylmelamine is an effective hypotensive agent in hypertensive dogs and rats, having a duration of action exceeding twenty-four hours from a single oral dose. It has limited efficacy in normotensive rats. Hypotensive activity of gradual onset is preceded by a latent period of up to two hours and becomes maximal six hours or more after dosing. This agent does not depress cardiac output or sympathetic vasoconstrictor activity. It is suggested that its hypotensive activity results from a direct effect upon vascular smooth muscle.

INTRODUCTION IT COULD BE of great economic importance to the husbandryman to be able to remove domestic fowl from lay for a predicted period of time, by some relatively simple method. While working with 17-alpha-ethyl-l7-hydroxynorandrostenone (Nilevar) (Winget and Griffin, 1962), it soon became apparent that this compound, at least theoretically, could provide this method. Therefore, the present study was conducted to evaluate the effect of various levels of Nilevar on rate of lay, and also to determine the most efficient method of administering this drug. METHOD Laying SCWL hens, approximately one year old, were treated with Nilevar to cause cessation of lay. One series of birds received a daily oral dose (Groups A, B, C, D), a second series was given the drug in a single oral dose (Group E), and a third series received a single intramuscular injection of the Nilevar preparation (Group F). Table 1 shows the number …

The highest single oral doses of buquinolate tested were not lethal to mice, rats, dogs, turkeys, or chickens. No toxicosis resulted from subacute and acute toxicity tests with 1–10 times the level of buquinolate recommended for anticoccidiosis medication. No changes due to the drug were detectable in macroscopic or microscopic examination of tissues and organs from treated animals or birds. The highest tolerated single oral dose of buquinolate in mice and rats is greater than 7500 mg/kg. Rats given 0.3% buquinolate in the ration for 31 days had no signs of toxicosis. Growth and food consumption were unaffected. No changes due to the drug were observed in microscopic examination of tissues and organs. Buquinolate at 0.8% of the ration caused no signs of toxicosis in a 90-day rat toxicity study. Blood values were normal. No pathologic changes in tissues were seen grossly or microscopically. Buquinolate as tested is nontoxic to dogs. At levels of 100 mg/kg/day for 34 days and 450 mg/kg/day for 90 days there were no signs of toxicosis; blood, urine, tissues, and organs were normal. In toxicity tests of buquinolate in chickens, single oral doses of 20 g/kg were nontoxic to 7-day-old chicks. No signs of toxicosis appeared in chickens given 0.088% buquinolate in the ration for 31 days. No pathologic changes in tissues and organs were seen grossly or microscopically. Food consumption and growth of buquinolate-medicated chickens were similar to nonmedicated controls. Buquinolate at levels of 0.0055 – 0.044% of the ration for 10 weeks caused no evidence of toxicity in White Rock chickens. Food consumption and food efficiency were similar to controls. Blood chemical values were similar in treated and control birds. No drug-related pathologic changes were seen in microscopic examination of tissues and organs. Buquinolate at 0.011% of the ration throughout the growing period, or continuously through both growing and laying period, caused no microscopically detectable changes in tissues of growing pullets or laying hens. Turkeys 2 weeks of age given single oral doses of buquinolate at 10 g/kg were lethargic for several hours. They appeared normal after 24 hours, and none died during a 10-day observation period. Buquinolate in turkey feed at concentrations of 0.022 – 0.088% for 33 days caused no signs of toxicosis. Hematologic and blood chemical values were normal. Turkeys given 0.088% buquinolate had no changes in tissues or organs due to the drug.

Rats were given a single oral dose of cholestane-3beta,5alpha,6beta-triol-4-(14)C, and their feces were collected. The two major neutral metabolites were separated and isolated by use of solvent fractionation and chromatographic methods. The metabolites were identified as cholestane-3beta,5alpha-diol-6-one and a mixture of long-chain fatty acid esters of cholestane-3beta,5alpha,-6beta-triol. Cholestane-3beta,5alpha-diol-6-one was identified using thin-layer and gas-liquid chromatography, infrared spectroscopy, and the spectrum produced by reaction with 65% sulfuric acid. The mixed esters of cholestane-3beta,5alpha,6beta-triol were subjected to basic hydrolysis, and the steroid moiety was identified using the same techniques employed for cholestane-3beta,5alpha-diol-6-one. The fatty acids were analyzed by gas-liquid chromatography of their methyl esters.

The whole body retention, excretion, distribution, thyroid uptake, and metabolism of 2( 131 I),3,5-triiodobenzoic acid (TI*BA) were studied in goats and a cow. A single oral dose of TIBA exhibited a two-component whole body radioactivity retention curve and was excreted primarily in the urine. TIBA plus nine metabolites, four of which were identified, were found in the urine. The major metabolite was 2,5-diiodobenzoic acid (2,5-DIBA). Trace amounts of 2,3-diiodobenzoic acid (2,3-DIBA), orthoiodobenzoic acid (OIBA), and iodide ion were found. TIBA was metabolized by deiodination. Iodide ion was concentrated in the thyroid and excreted by way of milk and urine.

Local oedema in the rat hind paw is induced by subplantar injection of a 1% suspension of carrageenin. An assay procedure for the analysis of inhibitory effects of drugs on this inflammatory process is described. The results obtained with a single oral dose of 14 antirheumatic drugs (3 steroids and 11 non-steroids) and of 49 substances without established clinical antirheumatic value are reported. Only 8 compounds were found to be completely devoid of anti-carrageenin activity. Others were active at dose levels producing striking behavioural, autonomic or toxic effects. All clinically established antirheumatic substances were active in the carrageenin test at non-toxic doses producing no obvious behavioural or autonomic effects and data on dose-response relationship of these compounds are presented. It is concluded that the assay in its present form is an acceptable preliminary screening test for antirheumatic activity.

The administration of a single oral dose of acetylsalicylic acid (100 mg./Kg.) to bishydroxycoumarin-treated male albino rats significantly decreased the one-stage prothrombin time of blood collected 20 hr. after administration of the analgesic. This antagonistic effect of acetylsalicylic acid resulted in a mean increase of 12 per cent in the prothrombin activity of rats given the anticoagulant intraperitoneally compared to an increase of 6 to 7 per cent in those taking it orally. In the latter animals the intensity of the effect seems to be related to the time that elapses between administration of the two drugs.

A method employing solvent extraction and gas-liquid chromatography has been developed for the quantitative determination of propoxyphene simultaneously with its major metabolite norpropoxyphene. Norpropoxyphene is analyzed following its conversion to a stable product, norpropoxyphene amide. Using an initial volume of 4 ml the method can detect as little as 0.010 μg of propoxyphene and 0.050 μg of norpropoxyphene per ml of plasma. Propoxyphene and norpropoxyphene plasma levels were determined in samples from a normal volunteer following a single oral dose of propoxyphene and from patients and volunteers after multiple oral doses. During the first 6 h after drug administration, propoxyphene rapidly disappeared from the plasma of the normal volunteer. In contrast, the plasma level of norpropoxyphene was more persistent. Subjects receiving multiple doses of propoxyphene were found to have a plasma level of norpropoxyphene that was, on the average, three times greater than the corresponding plasma level of propoxyphene.

The immediate effects on the mood and some mental and physical functions of a single oral dose of diazepam (10 mg) and diphenhydramine (50 mg) compared with placebo were studied in healthy human subjects. The material comprised 270 students divided into three similar groups. The mood was tested by the Nowlis adjective check list. The digit symbol test and number series were used to test the mental condition.

Single oral dose increments of levodopa (250, 500, and 1,000 mg, given on 3 consecutive days) produced significant peak levels of immunoreactive growth hormone (HGH) in 7 hospitalized healthy males. Serum glucose, cortisol, immunoreactive insulin, luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH) were not altered significantly. Levodopa has great potential as a provocative agent for stimulating growth hormone release.

Summary A controlled trial of a single oral dose of 400 mg. Micoren against placebo in a short-term study is reported. All five patients with “silent” chests showed significant increases in minute-ventilation. Three out of five patients with “wheezy” chests responded favourably. Mean increases in minute-ventilation of up to 24 per cent. were noted and were due to increases in both tidal volume and respiratory rate. The effect was at a maximum after 90 to 120 minutes. Side-effects were few. It was noted that subjective assessment of effect was unreliable. The clinical implications of the findings are discussed.

A new method is described for determining griseofulvin in the alimentary canal of rats dosed orally with the antibiotic: slightly modified, the method was used for measuring faecal griseofulvin. Attempts have been made to correlate the appearance of griseofulvin in the blood stream with its disappearance from the alimentary canal and to assess how much of a single oral dose is absorbed. Lack of griseofulvin at its main absorption sites in the alimentary tract was not responsible for the decline in blood level 4 hr. after oral dosing, because substantial amounts of unabsorbed antibiotic were then still present. Faecal elimination of griseofulvin, as determined by the new assay, is much greater than reported earlier.

1. (1) This was a double-blind, drug-placebo, cross-over study examining the effects on several psychological states of a single oral dose of chlordiazepoxide (25 mg) on 18 chronically anxious subjects.2. (2) Plasma levels of chlordiazepoxide ranged from 0.26 to 1.63 μg/ml. These plasma levels were not correlated with the time interval between ingestion of the drug and time of drawing the blood sample for chlordiazepoxide determination (average time interval 92 minutes, range 60 to 145 minutes), nor with body weight or sex.3. (3) Anxiety, hostility outward, and ambivalent hostility scores tended to decrease (p < 0.10) over the 50-minute observation period of this study when subjects were on chlordiazepoxide as compared to a placebo. But a statistically significant decrease in anxiety scores (p < 0.025) during this time period occurred only in those 11 subjects whose chlordiazepoxide plasma levels exceeded 0.70 μg/ml. The decrease in hostility outward, hostility inward, and ambivalent hostility scores, when these subjects were on chlordiazepoxide, did not reach a convincing level of significance.4. (4) Chlordiazepoxide plasma levels of all 18 subjects correlated with scores on anxiety (− 0.26), ambivalent hostility (− 0.42) and achievement strivings (− 0.31). Chlordiazepoxide blood levels of the 11 subjects whose levels exceeded 0.70 μg/ml also correlated with hostility outward scores (0.82) and hostility inward scores (− 0.47).5. (5) Implications of these findings are discussed as well as directions for future research.

A neutrophil granulocytosis with peak response at 5 hours develops after the administration of 40 mg. prednisolone tablets. In normal people the increment is greater than 2000 granulocytes per cu.mm. The response declines with advancing age, but is unrelated to sex, height, weight, surface area and initial neutrophil count. The largest responses are seen in young splenectomized people. Of 21 subjects with abnormal marrows only two gave normal responses. The results of this preliminary study suggest that the granulocyte increment following a single oral dose of prednisolone may prove to be a useful index of marrow function. Further studies, particularly serial observations in selected patients, are necessary to establish its validity and to define the role of age and the spleen.

Evidence is presented to show that Estriol-3-cyclopentylether when administered in a single oral dose of 125 ug, post-coitum, completely prevents pregnancy in rats. Larger doses were shown to offer protection for more than one estrus cycle. Administration of 3 mg estriol-3-cyclo-pentylether even three days before mating still prevented pregnancies. Comparison of estrogenic potencies showed no significant differences between estriol and its cyclopentylether on the immature rat uterus.

The levels of methadone in the plasma and urine of 5 subjects giaven a single oral dose of 15 mg. have been determined using solvent extraction and gas-liquid chromatography. Methadone was detected in plasma 30 minutes after drug administration. The peak plasma level occurred at 4 hours and was followed by an exponential decline during the next 20 hours. The mean apparent half-life of methadone was 15 hours. The time action of methadone-induced pupillary constriction closely coincided with the time course of methadone in plasma. An average of 52 per cent of the dose was excreted in the urine as methadone and metabolites in the 96 hours after drug administration. Nearly one half of the methadone and metabolites recovered in the urine was excreted during the first 24 hours. The renal clearance of methadone indicates that the drug is partially reabsorbed by a pH-dependent process. These results demonstrate the importance of biotransformation and renal excretion as determinants of the disposition of methadone in man.

A series of experiments was conducted to measure the effect of feeding l -O-ethylthreonine ( l -OET) on 1) the growth of young chickens, 2) the relationship of OET to isoleucine in the chicken and 3) the disposition of 14 C-labeled l -OET in chicken tissues. The maximum level of l -OET that could be fed to chickens without depressing growth was found to be 0.018% in the diet. Feeding levels of 0.05% resulted in a growth depression of approximately 40% and an apparent neurological disorder that was reversed by single oral doses of isoleucine or by supplementing the diet with 1.0% isoleucine. Supplementing a diet containing 0.05% l -OET with 0, 0.25%, 0.5%, 1% and 2% isoleucine resulted in growth depressions of 46%, 30%, 17%, 9% and 16%, respectively. The increased growth depression observed at the upper level of isoleucine supplementation was attributed to an imbalance of amino acids rather than an effect of l -OET. The studies with 14 C-labeled l -OET demonstrated that the radioactivity and probably the intact OET molecule were rapidly and firmly incorporated into the tissue proteins. Less than 0.2% of a single oral dose of 14 C-labeled l -OET was expired as CO2 and not more than 35% of the administered dose could be accounted for in the excreta over a six-day period. Tissue residue analyses demonstrated that the majority of 14 C was associated with the muscle protein.

About 58.5 percent of the uniformly labeled mirex-14C administered to rats as a single oral dose was excreted in feces and 0.69% in urine after 7 days. Considerable tissue storage of mirex was observed; fat, muscle, liver, kidneys and intestines contained 27.8, 3.20, 1.75, 0.76 and 0.23 percent of the total dose, respectively 7 days after treatment. While the first half-life of mirex was 38 hours, the projected second half-life was in excess of 100 days indicating a very slow rate of elimination from the body. No metabolite of mirex was detected in the feces, urine or any of the tissues. Nor was any mirex metabolite detected on incubation with rat, mouse, and rabbit liver preparations or plant root preparations. Mirex was concentrated by pea and bean roots and smaller amounts were translocated to the aerial parts when the plants were allowed to grow in water containing 1, 5 and 10 ppm mirex for 2 days. The resistance of mirex to biodegradation and its long biological half-life indicate that this insecticide may have an environmental half-life which far surpasses that of any previously studied insecticide.

ABS>Tritium-labeled myristic acid was administered orally as free acid to a lactating goat, and then the secretion of the radioactivity in the total milk lipids and milk glyceride fatty acids was followed for thirteen days. Measurable activity was found in the milk fat 4 hr after administration and the maximum specific activity occurred within 25 hr. About 10% of the radioactivity administered was recovered during the experimental period, and about 25% of the activity collected during 13 days was secreted in the first 28 hr. In the beginning the nonvolatile fatty acids had a higher specific activity than the volatile fatty acids, and there seemed to be a tendency for the specific activities in the short chain acids to increase with time; whereas the long-chain acids appeared to be less active later in the experiment. (auth)

1. Standard zinc solutions for the atomic absorption analysis of rat plasma were prepared to contain 14% (w/v) of sucrose. In this way the problems of sample nebulization were overcome with a minimum of manipulation before assay.2. Plasma Zn concentrations in rats were found to fall by approximately 40% (from 1.2 to 0.7 μg/ml) after 1 d on a Zn-deficient (< 0.25 ppm) diet. Thereafter, the fall became less marked and after 5 d the concentrations usually varied between 0.4 and 0.6 μg/ml.3. A single oral dose (20–200 μg) of Zn was reflected in high plasma Zn concentrations in the depleted rats 1.75 h after dosing, but to a much lesser extent in animals receiving 10–60 ppm Zn in their diet before dosing.4. It is suggested that the plasma Zn response to a single oral dose of zinc sulphate may provide a useful method for the detection of a subnormal Zn status in individual farm animals without the necessity of determining breed norms.

Earlier observations, in vitro, demonstrated that the ability of 4,4′-diaminodiphenylsulfone (DDS) to inhibit the glucose utilization of intraerythrocytic Plasmodium berghei is antagonized by elevation of medium glucose levels. In this study we observed that a single oral dose of DDS (100 mg per kg) was less effective in depressing malaria infections in chronically hyperglycemic mice (blood-glucose levels of about 1,000 mg %) than in normoglycemic mice. Unparasitized normoglycemic and diabetic mice possess similar whole-blood DDS levels during the 24 hr after oral dosage with 100 mg per kg of DDS. After treatment of normoglycemic, P. berghei-infected rats with a single oral dose of DDS (100 mg per kg), the parasitized blood cells removed from these animals 6 hours later consumed less glucose than identically parasitized cells from untreated rats. These observations support the possibility that DDS exerts a portion of its antimalarial activity in vivo through inhibition of utilization of intraerythrocytic parasite glucose.

Some 5-nitrothiazoles, 5-nitropyridines and 5-nitropyrimidines have been synthesised and evaluated against Trichomonas vaginalis and Trichomonas foetus in vitro and in vivo in the mouse, hamster and monkey. Although 2-amino-5-nitropyrimidine, 2-acetamido-5-nitropyrimidine and 2-trifluoroacetamido-5-nitropyrimidine were highly active in mice infected with T. vaginalis the activity was not superior to the standard 2-acetamido-5-nitrothiazole. The nitropyrimidines were highly species specific, being much more active in vivo against T. vaginalis than against T. foetus. One compound, 2-amino-5-nitropyrimidine was selected as the best of this series because of the high blood levels obtained after a single oral dose in a monkey, and its presence in a biologically active form