Inhibition of water intake by ouabain administration in sheep

Intracarotid infusion of ouabain (1280 ng/min) over $\text{4}\text{1}\text{2}\text{hr}$ virtually abolished water intake of sheep in response to intracarotid infusion of either angiotensin II (800 ng/min) or 4 M NaCl (1.6 ml/min for 20 min). Ouabain treatment did not affect mean arterial pressure either before or during infusion of angiotensin. Neither ouabain nor angiotensin administration affected plasma [Na] or [K] or CSF [K]. During ouabain, but not during control infusion, angiotensin administration significantly decreased CSF [Na]. Ouabain administration also decreased water intake after $\text{23}\text{1}\text{2}\text{or}\text{48}\text{hr}$ water deprivation. In the $\text{23}\text{1}\text{2}\text{hr}$ deprivation experiments, food was made available immediately prior to water presentation and the ingestion of food appeared to ameliorate the reduction in water intake. Food intake itself, was decreased in some animals, during ouabain treatment. Ouabain infused at 960 ng/min resulted in significant, but smaller, reductions in water intake induced by angiotensin, 4 M NaCl, and 48 hr water deprivation. It was concluded that ouabain treatment affected water intake by influence on Na transport either in the thirst receptors or at some other level in the neural system between receptor and effector.     

Turnover of cytidine and uridine components of acid-soluble pool and RNA of cytoplasmic ribosomes after repeated phenobarbital administration

The administration of phenobarbital in drinking water (1 g/l) to rats that had received labeled orotic acid three days before does not affect the half-life of uridine components of the liver nucleotide pool $\text{(t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 5.9}\text{days}\text{)}$. The half-life of the cytidine components in the control group is 6.2 days. In the experimental group the decrease of specific activity of cytidine components of the pool is biphasic. The decrease is faster during the first six days of phenobarbital administration $\text{(t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 4.5}\text{days}\text{)}$ whereas a slower decrease $\text{(t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 8.2}\text{days}\text{)}$ is observed during the subsequent administration of the drug. The decrease of specific activity of uridylic acid in RNA from cytoplasmic ribosomes is faster in the control group $\text{(t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 4.9}\text{days}\text{)}$ than in the experimental group $\text{(t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{= 5.9}\text{days}\text{)}$. Similarly, the decrease of the specific activity of cytidylic acid isolated from the ribosomal RNA is markedly slowed down $\text{(t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ of controls = 5.9 days, $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}\text{of experimental group}\text{= 7.5}\text{days}\text{)}$.     

Metabolic rate of phenacetin and of paracetamol in dogs before and after treatment with phenobarbital or skf 525 A

In six male mongrel dogs the apparent biological half life ($\text{t}\text{2}$) in plasma of intravenously injected phenacetin decreased from 34·6 to 27·2 min after treatment with phenobarbital (25 mg/kg/day for 8 days) (P < 0·025). In the same dogs, the apparent $\text{t}\text{2}$ of intravenously injected phenazone decreased from 78·6 to 32·4 min (P < 0·05). Treatment with SKF 525 A (25 mg/kg) increased the $\text{t}\text{2}$ of phenazone in three other dogs from 70·6 to 246·7 min, whereas the $\text{t}\text{2}$ of phenacetin remained unaffected.The concentration of phenacetin at zero time of intravenous injection increased from 29·5 ± 5·9 S.E. to 43·5 ± 12·6 μg/ml plasma (P < 0·2) after phenobarbital treatment; pretreatment with phenobarbital, however, had no influence on the mean concentration of phenazone at 0 time. SKF 525 A did not influence the zero time concentration of either phenacetin or phenazone.Beagle liver microsomal protein and cytochrome P-450 concentrations increased from 3·2 to 4·2 mg/ml and from 1·0 to 4·1 n-mole/mg protein, respectively, after phenobarbital treatment. Treatment with phenobarbital had no influence on the rates of formation of paracetamol and p-phenetidin nor was the apparent K_m of phenacetin affected.The binding of phenacetin to blood constituents increased from 50 per cent at 5 μg/ml to 59 per cent at 1 μg phenacetin/ml. In the presence of 30 μg phenobarbital/ml blood, the binding of phenacetin at 1 μg/ml blood decreased by 22 per cent.It is concluded that the decrease of the apparent $\text{t}\text{2}$ of phenacetin in dog plasma after phenobarbital treatment may be due to a change in the apparent volume of distribution and/or to some stimulation of an NADPH-dependent enzyme system of the liver less affected by treatment with SKF 525 A than in other species.     

Effect of phenobarbital on the distribution and excretion of lead in rats acutely poisoned with lead

Lead (Pb) distribution and excretion after lead injection in rats treated with phenobarbital was examined to investigate the mechanism of the mitigation of Pb toxicity by phenobarbital treatment. Male rats were given 30 $\text{mg}\text{kg}$ of phenobarbital s.c. daily for 5 days, and 24 h later a single i.p. injection of 50 $\text{mg}\text{kg}$ Pb. The amount of Pb in the liver, red blood cells and heart increased markedly after Pb injection in rats treated with phénobarbital, whereas it decreased in lungs and remained unchanged in kidneys. The excretion of Pb via urine and feces was also suppressed by phenobarbital. From these results, it may be concluded that phenobarbital increased accumulation of Pb in the liver, and suppressed the transfer of Pb to other organs.     

Effects of diphenylhydantoin and phenobarbital on protein metabolism in the rat cerebral cortex.

The effects of the anticonvulsant drugs diphenylhydantoin and phenobarbital on the incorporation in vivo of l-[4.5-³H]leucine into trichloroacetic acid-precipitable rat cerebral cortical protein were investigated. Protein specific activities were corrected for differences in precursor leucine specific activities. Plasma diphenylhydantoin levels of about 10 $\text{μg}\text{ml}$ were associated with a 41 per cent depression when radioisotope incorporation was conducted for 5 min; phenobarbital concentrations of approximately 28 $\text{μg}\text{ml}$ resulted in a 42 per cent depression after incorporation for the same period. A 3-fold increase in the diphenylhydantoin plasma levels and a 6-fold increase in the phenobarbital levels were found to invoke little, if any. additional effect. The induction period for the diphenylhydantoin effect was short (less than 1 hr), whereas a relative latency was associated with the phenobarbital effect. Simultaneous alterations in cortex and plasma concentrations of several amino acids were detected. Dose-related increases in cortex leucine. isoleucine and valine levels occurred after treatment with either drug. Cortex glycine concentrations were elevated only in response to the largest doses administered. Plasma leucine. isoleucine and valine levels were also elevated, but there was no change in plasma glycine concentration at any dose of either drug. The results indicate that diphenylhydantoin and phenobarbital inhibit the incorporation in vivo of radioactive leucine in the rat cortex when plasma drug levels have been attained that are therapeutically rational in the human, and substantial inhibitions would probably occur after much lower doses in the rat. The relationship of the altered amino acid levels to the effects on protein metabolism remains uncertain.     

Physalaemin,a new potent antidipsogen in the rat

In this paper the effect on water intake of intracerebroventricular administration of the naturally occurring endecapeptide physalaemin is reported. Drinking was induced by intracerebroventricular injection of angiotensin II (100 ng/rat) or carbachol (300 ng/rat), water deprivation or NaCl load. Physalaemin produced a dose-dependent inhibition of water intake induced by angiotensin II. The inhibition was virtually complete at the dose of 500 ng/rat. The minimum dose employed (50 ng/rat) produced a 6% drinking inhibition. Physalaemin inhibited drinking induced by carbachol. The threshold dose was 125 $\text{ng}\text{rat}$. A virtually complete inhibition was produced by physalaemin, 1μg. The effect was dose-dependent.In water deprived rats 10 μg, but not lower doses, of the peptide produced a significant inhibition of water intake. The effect was short-lasting and ceased 30 min after the injection. Physalaemin was completely ineffective in sodium chloride-loaded rats, in spite of the very large doses employed (up to 5 mg/rat).The results of these experiments demonstrate that physalaemin is a potent antidipsogenic agent, but do not allow any conclusion to be made about the mechanism of its inhibitory effect. However, it is reasonable to propose that the effect is specific to the CNS and not simply due to the very marked vascular activity of the peptide.     

Drugs and the liver. I. Effects of glutethimide and phenobarbital on hepatic bilirubin clearance, plasma bilirubin turnover and carbon monoxide production in man

The effects of glutethimide and phenobarbital on the plasma unconjugated bilirubin concentration, hepatic bilirubin clearance (C_BR) and plasma bilirubin turnover (BRT) were determined in 19 patients with mild chronic unconjugated hyperbilirubinemia (Gilbert's syndrome) and 11 normal volunteers. C_BR and BRT were calculated from plasma radio-bilirubin disappearance curves obtained both before and during drug administration. The response to both drugs was essentially identical. During drug administration, the patients with Gilbert's syndrome attained a new steady state in which the plasma unconjugated bilirubin concentration $\text{(}\text{BR}\text{)}\text{was}\text{30 ± 2\% (}\text{mean}\text{±}\text{S.E.M.}$) and C_BR 314 ± 25% of baseline. In the normal volunteers, $\text{BR}$ fell to 65 ± 6%, while C_BR increased to 135 ± 9% of baseline during the period of drug administration. Although neither total red cell volume nor the half-life of ⁵¹Cr-labeled erythrocytes was altered by either agent, daily plasma bilirubin turnover fell significantly (P < 0.05) to 87 ± 4% of baseline in the 30 subjects studied, and endogenous carbon monoxide production, which provides an independent estimate of the rate of heme degradation and bilirubin formation, was 93 ± 5 % of control (0.2 > P > 0.1). These studies indicate that both accelerated hepatic bilirubin clearance and reduced plasma bilirubin turnover contribute to the reduction in bilirubin concentration observed during administration of phenobarbital and glutethimide. The methods employed provided no evidence that these agents produce an increase in the rates of heme catabolism, bilirubin production or carbon monoxide formation.     

Concentrations of nitrate in normal human urine and the effect of nitrate ingestion

A method suitable for the analysis of nitrate in human urine was developed. Normal urinary concentrations of nitrate in urine of human volunteers in Dade County, Florida, where the drinking water contains negligible amounts of nitrate, averaged 47.6 ppm of $\text{NO}{}_3{}^{\mathrm{?}}$ (SD = 17.3). On a vegetable and preserved-meat-free diet, the nitrate concentration was reduced (10 to 30 ppm of $\text{NO}{}_3{}^{\mathrm{?}}$), but, on nitrate-supplemented drinking water, the urinary concentration rose to a range of 34–87 ppm of $\text{NO}{}_3{}^{\mathrm{?}}$. A high vegetable diet resulted in peak urinary nitrate concentrations of 270–425 ppm. These results indicated that nitrate in drinking water is a factor in determining urinary nitrate concentration, but that vegetable ingestion is of greater significance.     

Studies on carbon tetrachloride-ethanol interactions in mice

Male C57BL/6J (C57) and DBA/2J (DBA) inbred mice were dosed with either corn oil or carbon tetrachloride (CCLQ in corn oil 24 h before a $\text{3.25}\text{g}\text{kg}$ i.p. dose of ethanol. The CCL₄ doses were increased in approximate half-log intervals ($\text{5, 15, 50, 150}\text{or}\text{500}\text{μl}\text{kg}$, intragastrically (i.g.)). Blood acetaldehyde concentrations were significantly increased l, 2, 3 and 4 h after ethanol administration at Ccl₄ doses of $\text{15}\text{μl}\text{kg}$ and higher, with DBA and C57 mice exhibiting similar dose-response effects up to the $\text{150}\text{μl}\text{kg}$ dose. A CCl₄ dose of $\text{500}\text{μl}\text{kg}$ produced differences in blood acetaldehyde elevation between the two inbred strains (DBA—5-fold, C57—3-fold). Associated with the elevation of blood acetaldehyde content was a decrease in the rate of elimination of ethanol from blood. Using male genetically heterogeneous stock (HS) mice it was shown that phenobarbital pretreatment potentiated the CCl₄-induced decrease in in vivo acetaldehyde oxidation. An equimolar dose of CHCl₃ ($\text{0.5}\text{mmol}\text{kg}$) was without effect in either control or phenobarbital-pretreated mice. Mice pretreated with $\text{0.5}\text{mmol}\text{kg}$, i.g., 1,2-dichloroethane, 1,1,2-trichloroethylene or bromobenzene did not exhibit significant interaction with ethanol. These data show that in vivo acetaldehyde oxidation is inhibited by very low doses of CCl₄ ($\text{15}\text{μl}\text{kg}$, i.g.) and that this inhibition is enhanced by the cytochrome P-450-inducing agent phenobarbital.     

The effect of inorganic lead on hepatic biochemical and ultrastructural changes produced by phenobarbital

Lead acetate ($\text{105}\text{μmol}\text{kg}$, i.p.) decreased rat hepatic cytochrome P-450 to 57% and 63% of control values when measured 24 and 48 h after lead administration, respectively. A large increase in urinary delta-aminolevulinic acid (U-ALA) was observed after lead treatment, indicating a depression of heme synthesis. In addition, lead treatment produced dilated cisternae of the smooth endoplasmic reticulum (SER).Phenobarbital ($\text{100}\text{mg}\text{kg}$, i.p.) produced an induction of cytochrome P-450, proliferation of the SER, and did not alter U-ALA content.Simultaneous lead and phenobarbital treatment produced a delayed but robust induction of cytochrome P-450, only a moderate rise in U-ALA, and a reduced proliferation of the SER of hepatocytes. Therefore, phenobarbital, an inducer of heme synthetic enzymes, is apparently capable of reversing lead-induced inhibition of heme synthesis as measured by hepatic cytochrome P-450 induction and U-ALA content.     

Effects of clophen A50, 3-methylcholanthrene,pregnenolone-16α-carbonitril and phenobarbital on the hepatic microsomal cytochrome P-450-dependen monooxygenase system in rainbow trout, Salmo gairdneri, of different age and sex

Four groups of rainbow trout (mature male and female, $\text{1}\text{2}\text{-}\text{year-old}$ juvenile, and $\text{1}\text{1}\text{2}\text{-}\text{year-old}$ juvenile) were injected ip at Days 0 and 3 with 20 mg/kg 3-methylcholanthrene (3-MC), 500 mg/kg Clophen A50 (Cl A50), 40 mg/kg pregnenolone-16α-carbonitrile (PCN), respectively, and examined at Day 14. Further, one group of $\text{1}\text{1}\text{2}\text{-}\text{year-old}$ juvenile was injected ip daily with 80 mg/kg phenobarbital (PB) and examined at Day 14. Only 3-MC and Cl A50 markedly elevated the total amount of cytochrome P-450 and the cytochrome P-450-dependent metabolism of paranitroanisole (PNA) and benzo(a)pyrene in the fish liver, whereas no such elevation were observed by PCN or PB. In order to characterize the hepatic cytochrome P-450-dependent metabolism, the Michaelis-Menten kinetic constants of PNA-O-demethylase and the responses of the reactions to α-naphtoflavone, metyrapone, and SKF 525A, in vitro, were studied. These studies (A) showed PCN to significantly elevate apparent K_m of PNA metabolism, whereas no alterations of apparent K_m were seen by 3-MC or Cl A50, (B) indicated the hepatic reactions to be mediated by several species of cytochrome P-450, (C) indicated the formation of alternative form(s) of cytochrome P-450 species in 3-MC- or Cl A50-induced fish when compared to control fish, (D) showed 3-MC- and Cl A50-induced reactions to be similar in character. The presence of differences due to age and sex in the response to the inducers and in the response to the inhibitors, in vitro, is indicated.     

Biliary excretion of cadmium in the rat,rabbit, and dog

The fecal elimination of cadmium is more important than urinary elimination. Within 1 week after iv administration of cadmium to the rat (1 mg/kg), 17% is excreted into the feces and less than 0.5% into the urine. However, of the amount excreted into the feces in 1 week, 85% is excreted within 2 days. The disappearance of ¹⁰⁹Cd from the plasma and its excretion into bile were measured for 2 hr after the iv administration of 0.1, 0.3, 1.0, and 3.0 mg/kg of cadmium to rats. The bile/plasma concentration ratio of cadmium was highly dose dependent; at the lowest dose, it was 2.6, and, at the highest dose, it was 133. The bile/plasma ratio was greater than 1 because the concentration of cadmium in the liver was 100 to 700 times higher than in the plasma. However, the bile concentration of cadmium was equal to or much lower than that in the liver; at the lowest dose (0.1 mg/kg), the concentration of cadmium in the bile was less than 1% of that in the liver. The relationship of the dose of cadmium to its biliary excretion was also reflected in the percentage of cadmium excreted into the bile within 2 hr, which ranged from 0.23 to 9% as the dose was increased from 0.1 to 3 mg/kg. The biliary excretion of cadmium was increased approximately four times as the temperature of the rat was increased from 30 to 40°C. The effect of 4 days of pretreatment with phenobarbital, spironolactone, pregnenolone-16α-carbonitrile, or 3-methylcholanthrene on the biliary excretion of cadmium was measured; only phenobarbital significantly increased its excretion. Marked species variation in the biliary excretion was observed. Rabbits excreted cadmium at a rate of about $\text{1}\text{6th}$, and dogs excreted cadmium at a rate of about $\text{1}\text{300th}$ of that observed in the rat. These results suggest that, while biliary excretion is the main route for cadmium elimination, the rate at which it is excreted appears to be highly dependent on the time after administration, the dose, and the species employed. This rate is not as responsive to alteration in the temperature of the animal or to administration of microsomal enzyme inducers as is that of some other metals.     

Inhalation studies on the biotransformation and elimination of [14C] trichlorofluoromethane and [14C] dichlorodifluoromethane in beagles

The possible biotransformation of trichlorofluoromethane (FC-11) and dichlorodifluoromethane (FC-12) was investigated in 4 male and 2 female adult Beagles after a short (6- to 20-min) inhalation. Dogs were anesthetized with ketamine and succinylcholine, intubated, and ventilated artificially. Trichlorofluoromethane (1000–5000 ppm, $\text{v}\text{v}$) or dichlorodifluoromethane 38000–12,000 ppm, $\text{v}\text{v}$) containing up to 180μ Ci of $\text{[}{}^{14}\text{C}\text{]}\text{fluorocarbon}$ was delivered from 110-liter Teflon bags, and all exhalations were collected via a nonrebreathing valve in similar bags for 1 hr. Venous blood samples were withdrawn at appropriate times and assayed for fluorocarbon-associated radioactivity. Exhalation bags were assayed for $\text{[}{}^{14}\text{C}\text{]}\text{fluorocarbon}$ and ¹⁴CO₂. Urine was collected for up to 3 days and assayed for ${}^{14}\text{C}$ metabolites as nonvolatile radioactivity. In some experiments animals were sacrificed 24 hr after exposure and tissues were removed for determination of nonvolatile radioactivity. Essentially all of the administered (inhaled) fluorocarbon was recovered in the exhaled air within 1 hr. Only traces of radioactivity were found in urine or exhaled carbon dioxide. All tissues contained measurable concentrations of nonvolatile radioactivity 24 hr after exposure but together represented less than 1% of the administered dose. It is not possible to determine if these trace levels are associated with metabolites of the fluorocarbons or with the unavoidable radiolabeled impurities present in the administered gas mixture. Neither phenobarbital pretreatment (60 mg/day for 3 days) nor prolonged exposure (50–90 min) produced any alteration of these results. Thus, it can be concluded that FC-11 and FC-12 are relatively refractory to biotransformation after a short inhalation exposure and that they are rapidly exhaled in their unaltered chemical form.     

The lack of effects of pretreatment with phenobarbital and chlorpromazine on the acute toxicity of benzene in rats

Female CD rats were injected ip daily for 3 days with either phenobarbital (75 mg/kg) or chlorpromazine (15 mg/kg). On the fourth morning the animals were either subjected to a 4-hr inhalation exposure of benzene or given an ip injection of 50% ($\text{v}\text{v}$) of benzene and mineral oil. Animals were injected with doses of 1, 2, 3 and 4 g benzene/kg body weight. In the inhalation studies, animals were exposed to 6 levels of benzene ranging from 11,500 to 15,500 ppm. The LD50 for animals injected with benzene and the LC50 for animals inhaling benzene were calculated for control groups and those pretreated with either phenobarbital or chlorpromazine. Neither the LD50 or the LC50 were affected by any of the treatment protocols. In order to determine that the pretreatment was stimulating benzene metabolism, a method for measuring benzene metabolism has been developed using [¹⁴C]benzene. These studies have shown that phenobarbital and 3-MC do induce benzene metabolism in the liver, that chlorpromazine slightly induces benzene metabolism in the lung, and that pretreatment by these compounds does not affect the acute inhalation toxicity or the ip toxicity of benzene.     

Organometal-induced antinociception: A time- and dose-response comparison of triethyl and trimethyl lead and tin

Recent reports have demonstrated that organolead and -tin compounds can alter behavioral reactivity to noxious stimuli. To further define the dose response and temporal characteristics of these neurobehavioral effects, male Fischer 344 rats were injected sc with either one-fourth, one-half, or three-fourths the acute LD50 of triethyl lead (TEL), triethyl tin (TET), trimethyl lead (TML), trimethyl tin (TMT), or distilled water and tested on a 57.5°C hot plate 1, 7, 14, 21, and 28 days after dosing. All four organometals altered hot plate latencies, but the magnitude and time course of these effects differed among the compounds. TEL produced a dose-related increase in latencies which was maximal 1 and 7 days postdosing and had dissipated by 28 days. In contrast, the group administered TML ($\text{3}\text{4}$ LD50) exhibited a late developing antinocioception which became evident 14 days after dosing and persisted throughout the period of testing. The intermediate dose of TMT ($\text{1}\text{2}$ LD50) also produced a delayed increase in response times which was observed 21 and 28 days post-treatment. The $\text{3}\text{4}$ LD50 dose of TMT produced increased hot plate latencies on all post-treatment test days except Day 14. TET ($\text{1}\text{2}$ LD50) produced increased hot plate latencies 1, 7, 14, and 21 days postdosing and also induced a reversible ataxia and akinesia. Higher doses of TET proved lethal to 80% of the animals and lower doses failed to alter response times in the hot plate. These data demonstrate that trialkyl lead and tin compounds can produce time- and dose-related increases in hot plate latencies.     

Properties of enzyme systems involved in the formation of catechol estrogen glutathione conjugates in rat liver microsomes.

The properties of enzyme systems involved in the formation of the glutathione 1- and 4-thioethers of catechol estrogen from estradiol, 2-hydroxy-3-deoxyestradiol, or 2-hydroxyestradiol in rat liver microsomes have been investigated. Molecular oxygen was essential and NADPH was preferable as a cofactor to obtain the maximum activity with the three substrates. The presence of carbon monoxide suppressed the formation of the thioethers where the $\text{CO}\text{O}{}_2$ ratios needed for 50 per cent inhibition of the bioconversion were 2.1 to 3.6. This inhibitory effect was reversed almost completely by illumination with white light. SKF-525A inhibited considerably the formation of the glutathione conjugates. Pretreatment with phenobarbital stimulated the formation of the thioethers from the three substrates by 100–220 per cent, whereas administration of 3-methylcholanthrene did not exert any significant influence. The storage of frozen microsomes resulted in a marked decrease in the enzyme activity: the initial activity was depressed to 50 per cent at 24 hr for catechol estrogen and at 4–5 days for phenol estrogens. The NADH-dependent enzyme activities were also inhibited by both SKF-525A and CO; the CO inhibition was reversed by light irradiation. It is evident from these data that cytochrome P-450 participated in both NADPH- and NADH-dependent formation of 2-hydroxyestradiol glutathione thioethers and two different enzyme systems are involved in this biotransformation between phenol estrogens and catechol estrogen.     

The relative ethylumbelliferone dealkylase activity characterizing the effect of different inducers on the hydroxylase system in the liver musomes of female mice

d,l-Camphor was detected as a new inducer of hydroxylase in the liver musomes of female mice. After a 2-day inhalation of d,l-camphor, cyt. P-450 and the ethylumbelliferone dealkylase were increased by 250 per cent and the NADPH-cyt. P-450 reductase by 350 per cent. The product [NADPH-cyt. P-450 reductase activity × cyt. P450 concentration] was shown to be a suitable reference parameter for the ethylumbelliferone dealkylase activity in the liver musomes during the treatment with four different inducers. The relative dealkylase activity Q was much decreased during inhalation of cyclohexane or d,l-camphor.

$\text{Q =}\text{mU ethylumbelliferone dealkylase}\text{mU NADPH-cty. P-450 reductase × nmoles cty. P-450/mg protein}$

Obviously these two inducers preferably enhanced cyt. P-450 species with a low dealkylase activity. The Q-values were reproducible. Q was increased by 100 per cent during induction of a MC-sensitive mouse strain with 3-methylcholanthrene, but it was only moderately decreased by induction with phenobarbital. Corresponding to this, methylcholanthrene is known to selectively induce a cyt. P-448 with high dealkylase activity whereas phenobarbital is known to change the hydroxylase specificity in the liver musomes not very much.     

Carcinogenicity study of rifampicin in mice and rats

Rifampicin was administered in the drinking water to C3Hf and $\text{BALB}\text{c}$ mice at three dose levels (0.01, 0.03, and 0.06%) for 60 weeks and to Wistar rats at two dose levels (0.03 and 0.06%) for 104 weeks. After completion of the treatment period, C3Hf and $\text{BALB}\text{c}$ mice and the rats were observed until 114, 120, and 144 weeks of age, respectively. The treatment had no adverse effects on body growth and survival rate. Various types of tumors were observed in all groups. Statistically significant excesses of hepatomas were found in C3Hf female mice treated with rifampicin and in one control group of $\text{BALB}\text{c}$ male mice. Also an excess of Harderian gland tumors was observed in one control group of $\text{BALB}\text{c}$ male mice. No significant differences in tumor incidence were found among the rat groups.     

The effects of ethanol ingestion and repeated benzene exposures on benzene pharmacokinetics

Two groups of $\text{C57B1}\text{6J}$ mice were exposed to 300-ppm benzene vapor, 6 hr/day, 5 days/week for 20 exposures. One group received 10% ethanol (EtOH) in the drinking water commencing 20 hr prior to the initial exposure and continuing 5 days/week throughout the study. The second group received tap water. The uptake and clearance of benzene was followed in the blood during and after the 1st and 20th exposures. During the first benzene exposures, the mean steady state benzene concentrations in benzene/EtOH-treated mice and benzene/water-treated mice were 5.2 and 10.7 μg/ml, respectively. The mean elimination rate constants for the benzene/EtOH- and benzene/water-treated groups were 0.124 and 0.042 min^?1, respectively. By 20 exposures, the benzene/EtOH group showed no change in mean blood steady state concentration (Css); however, the Css of the benzene/water group was reduced to 7.9 μg/ml. The mean elimination rate constants for the two groups were not different after the 20th exposure. The benzene/water mice exhibited a shift from mono- to biexponential clearance between the 1st and 20th exposures. Monoexponential clearances were observed for the benzene/EtOH group at both time points. These results indicate that 1 day of 10% EtOH consumption causes dramatic effects on benzene kinetics. After 20 days of treatment, the benzene/water and benzene/EtOH animals are kinetically similar. These changes in kinetics can be explained by the ability of ethanol and benzene to alter benzene metabolism.     

The effects of 1-(1-phenylcyclohexyl) piperidine HCL (Sernylan) on bulbo-spinal and spinal reflexes.

We have investigated the effects of Sernylan, a dissociative anaesthetic, on both the bulbo-spinal and spinal reflexes of cats. Cats decerebrated at the precollilcular level were used to investigate the interaction of bulbo-spinal with spinal reflexes. Conditioning stimuli were delivered to the contralateral dorsal root, reticular formation, or medial longitudinal fasciculus and their effect on the amplitude of the test monosynaptic reflex at L7 was recorded. Sernylan (2 $\text{mg}\text{kg}$, i.v.) decreased the amplitude of the test monosynaptic reflex and decreased or totally eliminated both the facilitation and the inhibition phases of the spino-bulbo-spinal response pattern, but had little effect at this dosage on bulbo-spinal interactions with the monosynaptic reflex (whether conditioning was delivered to the reticular formation or medial longitudinal fasciculus). Spinal reflexes were investigated in cats made spinal at T10. Sernylan (1–2 $\text{mg}\text{kg}$) in spinal animals also decreased the amplitude of the monosynaptic reflex (20–50% of controls). Sernylan decreased both the spontaneous and stimulus driven response of interneurones located in the dorsal horn of L7. Neither Renshaw cell activity nor Renshaw cell inhibition of the monosynaptic reflex was affected. Focal stimulation of the spinal cord in the motoneurone pool indicated that the response of motoneurones to direct electrical stimulation was unaffected by the drug, whereas the response attributed to antidromic stimulation of Ia afferent fibres was decreased by Sernylan (1–2 $\text{mg}\text{kg}$). It appears that Sernylan has its major effect on the spino-bulbo-spinal reflex at the input side (spino-bulbo). It also appears that the drug does not affect the monosynaptic reflex by tonic inhibition or disfacilitation of the motoneurones or by the mechanism of presynaptic inhibition, but by direct action on the membrane of Ia fibres or at the Ia- α motoneurone synapse.