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Biomedical subjects

R F Johnson

Publications and source records attributed to R F Johnson.

At least 91 records · Page 5Linked to original sources
PubMed1985

Circadian rhythms in food intake and activity in domestic cats.

Daily patterns of food intake and activity were determined for normal cats and cats with pontile lesions. Food intake in the dark and in the light of LD (light/dark) cycles were determined separately by weighing the food, and a "percentage nocturnal" score was calculated. The measure of activity was infrared photobeam interruptions, with the photobeam placed in front of the cages, over the food bowl. No differences between normal cats and cats with pontile lesions were detected for any of the measures. Food intake of cats was influenced by simulated starlight and moonlight conditions and by the presence of humans. Cats in isolation from humans and human noises exhibited random patterns of activity in constant light and free-running circadian rhythms in constant dark. Idiosyncratic differences in entrainment to LD cycles were found among cats, and the relevance of this variability is noted for studies of photoperiodic phenomena in this species.

Animals↗
PubMed1985

Effects of influenza virus vaccine on hepatic drug metabolism.

Experimental and more limited clinical studies have suggested that influenza vaccination may depress the oxidative hepatic metabolism of various drugs and lead to drug toxicity. The alleged mechanism is the formation of interferon and the resulting decrease in cytochrome P-450 available for drug oxidation. Because of the clinical and basic science implications of these reports, we undertook to study the effects of influenza vaccine on the metabolism of three commonly used drugs: chlordiazepoxide, theophylline, and lorazepam. Our healthy male subjects were studied just before and 1 and 7 days after vaccination. As expected, lorazepam metabolism, which proceeds by glucuronidation and not oxidation, was not altered by vaccination. Surprisingly, however, the oxidation of chlordiazepoxide was also not depressed by the vaccine. Theophylline oxidation, which proceeds primarily by microsomal oxidation (demethylation), was significantly decreased 1 day, but not 7 days, after vaccination. Serum alpha-interferon levels rose after vaccination for only about 8 hours, and levels of gamma-interferon rose to about 500 IU/ml at 24 hours, peaked at 72 hours, and returned to normal by 100 hours after dosing. It appeared that the higher the theophylline clearance before vaccination, the greater the degree of clearance depression after vaccination. Thus the inhibition of drug oxidation after influenza vaccination is selective and each drug should be studied individually. The degree of depression of theophylline clearance is small and transient and appears to be greater in subjects with higher prevaccination clearance.

Adult↗
PubMed1985

Lack of effect of nizatidine on hepatic drug metabolism in man.

The effect of nizatidine, a new H2-receptor antagonist, on the hepatic metabolism of three probe drugs was studied in normal volunteers. The drugs studied were chlordiazepoxide and theophylline which are metabolized in part by N-demethylation by the hepatic microsomal cytochrome P-450 system and lorazepam which is conjugated to lorazepam glucuronide. A 7 day course of nizatidine did not interfere with the disposition of any of these therapeutic agents in man.

Adult↗
PubMed1985

Use of 99mTc-sulfur colloid to assess lymphatic dysfunction in filarial infection.

Investigations of lymphatic dysfunction in animals infected with filarial parasites has been hampered by a paucity of techniques to measure efficiency of lymphatic drainage. In this study a 99mTc-sulfur colloid technique was used to assess the efficiency of lymphatic drainage in Patas monkeys infected with filarial nematodes. In all 15 uninfected hind limbs there was rapid and consistent appearance of labeled colloid in the primary lymph node (popliteal) and subsequently in the secondary nodes (abdomino-pelvic) in 11 of 15 limbs. In contrast, in all eight limbs tested 1-9 months after infection there was reduced rate of migration of the colloid and initial appearance in the abdomino-pelvic region: subsequent accumulation was seen in the popliteal region in only four of the limbs. This data indicated that lymphatic vessels were blocked and that collateral vessels channeled the colloid to the secondary lymph nodes. The lymph flow patterns demonstrated by the isotope technique were supported at autopsy.

Animals↗
PubMed1984

Diphenhydramine disposition in chronic liver disease.

Diphenhydramine (DPHM) disposition was examined in nine patients with chronic alcohol-related liver disease and in eight normal subjects. Sleep of 1 to 2 hr duration was induced in all subjects by a 0.8 mg/kg iv dose without an apparent increase in cerebral sensitivity in the patients with cirrhosis. Protein binding as determined by equilibrium dialysis (3H-DPHM) revealed a 15% decrease in the cirrhotic patients, while recovery of unchanged DPHM in urine (2%) was of the same order in the two groups. Computerized biexponential curve analysis was used to compare the plasma profiles for five of the patients and six of the normal subjects. Monoexponential curve analysis of the terminal beta-phase, including all subjects, was also used to compare the two groups. The means of plasma clearance and apparent volume of distribution in cirrhotic patients were respectively less and greater than in normal subjects, but these differences were not significant. The t1/2 for the beta-phase (t1/2 beta), which reflects this reciprocal trend, was increased in the patients (15.2 +/- 1.5 and 9.3 +/- 0.9 hr). This correlated in part with severity of disease, with r = 0.723 between t1/2 beta and the serum bilirubin levels. In conclusion, a single intravenous dose of DPHM provided safe and effective sedation in patients with cirrhosis.

Adult↗
PubMed1983

Mediation of the photoperiodic effect on grooming reflexes by glucocorticoid hormones and serotonin.

The role of serotonin and glucocorticoid hormones in the mediation of the effect of photoperiod on the size of the receptive field for grooming reflexes was determined in cats with pontile lesions. Nineteen adult male cats with pontile lesions were used to form four groups. One group of cats with pontile lesions was adrenalectomized, another group received 5,7-dihydroxytryptamine injections in the superior colliculi, and the other two groups of cats with pontile lesions were used to provide the baseline response to photoperiod. Then, for all four groups, the receptive fields for the grooming bite, lick, and scratch reflexes were determined under different photoperiods. Both adrenalectomy and 5,7-DHT treatment blocked the effect of photoperiod. After the photoperiodic manipulations, the efficacy of intramuscular injections of hydrocortisone and 5-hydroxytryptophan in abolishing the receptive fields was demonstrated. The data indicate a modulatory effect of serotonergic neurons on the photoperiodic regulation of glucocorticoid hormones. Comparisons of this study with previous photoperiodic studies established that a complex seasonal rhythm exists which is controlled by the annual rhythm in photoperiod.

Adrenalectomy↗
PubMed1983

Inhibition of caffeine elimination by short-term ethanol administration.

Short-term ethanol ingestion has been shown to inhibit the metabolism of a number of drugs metabolized by cytochrome P-450 in both man and laboratory animals. However, the effects of short-term ethanol administration on the metabolism of cytochrome P-448-dependent drugs in man is unknown. Caffeine is a commonly used drug that is metabolized predominantly by a component of the hepatic microsomal mixed-function oxidase complex, known as cytochrome P-448. Therefore the elimination of caffeine given orally was studied in normal volunteers after receiving either orange juice or 0.8 gm/kg ethanol as a 25% solution in orange juice. Short-term administration of ethanol resulted in a significant decrease in the plasma clearance of caffeine from 96.6 +/- 13.4 ml/min to 60.7 +/- 10.5 (mean +/- S.E., p less than 0.05). There was also a corresponding significant increase in the elimination half-life of caffeine from 4.03 +/- 0.52 hr to 6.04 + 0.73 (mean + S.E., p less than 0.01). To determine whether the decrease in caffeine elimination was due to an inhibition of caffeine metabolism by ethanol or to an effect on caffeine absorption, caffeine disposition was studied in four healthy, mongrel dogs after intravenous administration. Each animal served as its own control. Caffeine clearance decreased significantly from a baseline value of 19.6 +/- 1.5 ml/min to 8.0 +/- 1.5 (mean +/- S.E., p less than 0.05) after administration of 3.0 gm/kg ethanol given orally 1 hr before intravenous caffeine injection. These results imply that short-term administration of ethanol inhibits the metabolism of caffeine, a predominantly cytochrome P-448-dependent substrate, in both man and dogs.

Adult↗
PubMed1981

Lack of tolerance and rapid recovery of cimetidine-inhibited chlordiazepoxide (Librium) elimination.

Cimetidine has been shown to inhibit oxidative metabolism of several drugs while sparing the glucuronidation pathways of drug metabolism. We studied the time-course of inhibition and recovery of cimetidine-inhibited chlordiazepoxide elimination in 7 healthy subjects. Chlordiazepoxide elimination was studied after cimetidine treatment for 1 and 30 days, and after withdrawing cimetidine for 48 h. The plasma clearance of chlordiazepoxide was reduced by 54% (p less than 0.001) after 24 h of cimetidine, by 57% (p less than 0.001) after 30 days of cimetidine and returned to normal after cimetidine was stopped for 48 h. In the absence of changes in volume of distribution, these changes resulted in proportional increases in the elimination half-life (t 1/2 beta) after 24 h and 30 days cimetidine treatment, and returned to pretreatment values after stopping cimetidine. In addition, the impaired chlordiazepoxide elimination was accompanied by inhibition of generation and subsequent elimination of N-desmethylchlordiazepoxide, the first metabolite of chlordiazepoxide metabolism. This study demonstrates a rapid inhibitory effect on chlordiazepoxide elimination, an absence of tolerance to this effect and a rapid reversal of this effect upon stopping cimetidine. These findings may have important therapeutic implications for patients receiving both drugs simultaneously.

Adult↗
PubMed1981

Normal metabolism of morphine in cirrhosis.

Morphine disposition and elimination was studied in 6 healthy male subject s and 6 male patients with cirrhosis, to assess the role of differences, if any, on the reported intolerance of morphine in cirrhosis. In addition the elimination of indocyanine green was studied in the same subjects on a separate occasion. The elimination half-life of indocyanine green was increased and its plasma clearance was markedly reduced in patients with cirrhosis as compared with controls (p less than 0.05). In contrast the disposition and elimination of morphine were unaffected by moderate to severe cirrhosis. Furthermore, while marked sedation was observed in normal subjects, the cirrhotics demonstrated mild sedation with no clinical evidence of hepatic coma. The normal elimination of morphine in cirrhosis is in contrast to the decreased elimination of high clearance drugs metabolized by oxidation, such as lidocaine and meperidine. Morphine is also normally a high clearance drug that is detoxified by conjugation with glucuronic acid. Since intra- or extrahepatic shunting, or both, in cirrhosis do not significantly impair morphine clearance, we postulate that significant extrahepatic morphine conjugation may occur in both normal subjects and in patients with cirrhosis. Furthermore, the reported morphine intolerance to the central effects of morphine cannot be explained by impaired drug elimination and increased availability of morphine to cerebral receptors.

Adult↗
PubMed1980

Impaired elimination of caffeine in cirrhosis.

The effect of cirrhosis on the disposition and elimination of caffeine was examined. Caffeine (250 mg) was administered orally to 15 healthy controls and eight patients with cirrhosis. The elimination half-life was prolonged from 5.2 +/- 2.4 hr (mean +/- SD) in controls to 6.1 +/- 1.9 hr in cirrhotics, although this did not reach statistical significance. The plasma clearance, however, was significantly higher (1.4 +/- 0.5 ml/min/kg) in controls as compared to cirrhotics (0.9 +/- 0.3 ml/min/kg) (P less than 0.05). The plasma binding of caffeine was also lower in cirrhotics (31.3 +/- 1.8% vs 25.5 +/- 4.0%, P less than 0.01). The plasma clearance of unbound caffeine therefore was reduced from 2.0 +/- 0.7 ml/min/kg in controls to 1.2 +/- 0.4 ml/min/kg (P less than 0.01) in cirrhotics, demonstrating impaired elimination of caffeine in cirrhosis.

Adolescent↗
PubMed1980

Effects of caffeine on plasma free fatty acids, urinary catecholamines, and drug binding.

The effects of caffeine (250 mg orally) on plasma free fatty acids (FFA), urinary catecholamines, and drug binding were studied in 16 normal subjects (six men, five women on oral contraceptives, and five women not on oral contraceptives). FFA doubled 1 hr after caffeine, and remained elevated for at least 4 hr. with elevation of each FFA. Urinary excretion of epinephrine and dopamine increased (p<0.05) in the first 2 hr. returning to baseline in the next 2 hr. Plasma binding of chlordiazepoxide, diaxepam, and propranolol was estimated in each of the hourly plasma samples after caffeine; there was no change in percent unbound drug in any of the samples. In vitro addition of oleic acid to plasma samples of four subjects caused a step-wise increase in percent unbound fraction of all three drugs whereas in vitro addition of caffeine did not further alter drug binding. In our study circulating plasma FFA and urinary catecholamine levels were elevated after caffeine ingestion. In spite of a rise in FFA, there was, however, no change in plasma binding of chlordiazepoxide, diazepam, or propranolol.

Blood Proteins↗
PubMed1980

Cimetidine spares the glucuronidation of lorazepam and oxazepam.

Lorazepam (Ativan) disposition and elimination were studied in 8 normal subjects before and after 1 wk of cimetidine therapy, 300 mg taken orally four times a day. In 4 of these 8 normal subjects the disposition and elimination of oxazepam (Serax) were also studied before and after similar treatment with cimetidine. Cimetidine did not alter the elimination of either lorazepam or oxazepam. Since both drugs are eliminated exclusively after conjugation as glucuronide, this study demonstrates a relative sparing of this pathway of biotransformation of drugs in subjects receiving cimetidine.

Adult↗
PubMed1980

Impaired elimination of caffeine by oral contraceptive steroids.

The effect of OCS on the disposition and elimination of caffeine was examined. Caffeine (250 mg) was administered orally to 13 healthy males, nine healthy females taking no OCS, and nine healthy females on OCS. The t1/2 (beta) was significantly prolonged in women on OCS (10.7 +/- 3.0 hr vs. 6.2 +/- 1.6) (p less than 0.001) as compared to women taking no OCS. Women on OCS had a significantly lower total plasma clearance (0.79 +/- 0.21 ml/min/kg vs. 1.3 +/- 0.35) and free clearance (1.12 +/- 0.28 ml/min/kg vs. 1.97 +/- 0.57) that women not taking OCS. Volumes of distribution and plasma binding were similar in both groups of females. When women taking no OCS were compared with men, all pharmacokinetic parameters were similar except for volume of distribution, which was significantly larger in the women (p less than 0.05). We conclude that OCS impair the elimination of caffeine.

Absorption↗
PubMed1979

Plasma binding of benzodiazepines in humans.

Plasma binding of chlordiazepoxide, diazepam, loraxepam, and oxazepam was determined by equilibrium dialysis in 20 male, healthy volunteers, 25-86 years old. A wide range of binding was observed, with the free fraction varying twofold for lorazepam, fourfold for chlordiazepoxide and diazepam, and over 20-fold for oxazepam. Statistically significant linear relationships were not observed between the degree of binding and age, serum albumin, or total protein for any of the drugs. There was, however, a correlation between the extent of binding for the four drugs. Because of the importance of unbound benzodiazepine levels in eliciting any pharmacological response and also in disposition, consideration of the wide interindividual variability in plasma binding must be made in interpreting pharmacodynamic and pharmacokinetic data.

Adult↗