Effect of vitamin D3 derivatives on calcium concentrations in the serum of rats treated with stannous chloride

Calcium concentrations in the serum of rats were significantly increased by treatment with vitamin D₃ (frsol|25 μg/100 g), but this increase was prevented by a single intraperitoneal administration of tin (Sn²⁺, $\text{3.0 mg}\text{100 g}$). The decrease in serum calcium levels after the administration of Sn²⁺ was reversed by treatment with synthetic 1α-hydroxyvitamin D₃ ($\text{0.25 μg}\text{100 g}$) or 1α,25-dihydroxyvitamin D₃ ($\text{0.25 μg}\text{100 g}$). These results suggest that the decrease in serum calcium levels produced by the administration of Sn²⁺ may be caused by inhibition of metabolism of 25-hydroxyvitamin D₃ to 1α,25-dihydroxyvitamin D₃ in the kidneys.     

The effects of spironolactone on the biliary excretion of mercury,cadmium, zinc,and cerium in rats

The effect of spironolactone (Sp) pretreatment on the biliary excretion of intravenously injected heavy metals (mercury, cadmium, zinc and cerium) was investigated in rats, using five metal compounds (four inorganic metals in chloride form, and methyl mercuric chloride). The oral administration of Sp ($\text{5 mg}\text{100 g}$) 1–3 hr before the bile excretion study increased the biliary recovery of mercury more than ten times over a period of 4 hr in rats injected with mercuric chloride, but did not increase the biliary excretion of the other three metals (Cd, Zn and Ce). Multiple-dose pretreatment (2 doses a day for 3 days) also increased the biliary excretion of mercury but much less than in the acutely treated rats. Cadmium excretion was significantly decreased by multiple dose pretreatment. Sequential nuclear imagings after intravenous injection of ¹⁹⁷HgCl₂, demonstrated clear differences in the tissue distribution of mercury between control and Sp-treated rats.     

Effect of oil of nutmeg on the fertility and induction of meiotic chromosome rearrangements in mice and their first generation

The dose-dependent effects of oil of nutmeg on the fertility and induction of chromosomal translocations in treated mice and their F₁ males were examined. C3H male mice were treated with oil of nutmeg for 8 successive weeks at 60, 80, 100 and 400 $\text{mg}\text{kg}$ body weight. The greatest reduction of fertility occurred in the group treated with 400 $\text{mg}\text{kg}$; chromosomal translocation in directly treated animals was not found. The chromosomal translocations in F₁ males, derived from males treated with oil of nutmeg occurred at dose levels of 60, 80 and 100 $\text{mg}\text{kg}$.     

Effect of spironolactone and pregnenolone-16alpha carbonitrile on bilirubin metabolism and plasma levels in male and female rats

The effect of 5 days of treatment with spironolactone (100 $\text{mg}\text{kg/day}$) or pregnenolone-16α carbonitrile (40 $\text{mg}\text{kg/day}$) on the activity of hepatic bilirubin glucuronyltransferase (EC 2.4.1.17) in 10,000 g supernatant fraction from male and female rats was studied. Bilirubin plasma levels were measured after 5 and 12 days of treatment with spironolactone or pregnenolone-16α carbonitrile. Both spironolactone and pregnenolone-16α carbonitrile significantly increased the rate of bilirubin conjugation in male and female rats after 5 days of treatment. Plasma bilirubin levels were significantly reduced after 5 days of treatment with spironolactone in male rats. Both drugs caused significant decreases in plasma bilirubin levels in male and female rats after 12 days of treatment.     

Effects of physostigmine on brain acetylcholine content and release

The content and release of acetylcholine (ACh) from cat brain and ACh content of rat brain was measured using the frog rectus and leech muscle bioassays before and after physostigmine 100 $\text{μg}\text{kg}$i.v. or i.p. The drug elevates steady state levels of brain ACh of awake animals especially in the neocortex, caudate nucleus and hippocampus but much less so in the lateral geniculate and superior colliculus. Physostigmine was shown to produce neocortical release of ACh through a subcortical mechanism in brainstem transected cats and to decrease ACh neocortical content in pentobarbital anesthetized cats and rats. The neocortical release of ACh seems to be mediated primarily through a subcortical brain mechanism which is activated by physostigmine. It is postulated that the ascending reticular formation is involved. Local application of scopolamine (1 $\text{μg}\text{ml}$) into the collecting cup did not antagonize the effects of 100 $\text{μg}\text{kg}$ of physostigmine i.v. as much as l $\text{mg}\text{kg}$ of scopolamine i.v. On the other hand, 2 $\text{mg}\text{kg}$ of mecamylamine given i.v. not only did not antagonize physostigmine-induced neocortical release of ACh, but seemed to enhance it. The results indicate a complex action of physostigmine on the cholinergic system of the brain.     

EEG-synchronizing effect of gamma-hydroxybutyrate and 1-hydroxy-3-amino-pyrrolidone-2 (HA-966) in relation to dopaminergic brain function.

The earlier finding that γ-hydroxybutyrate and HA-966-induced depression of the central nervous system was associated with the increase of dopamine concentration and block of its release, prompted this study of the influence which the monoaminergic system may have upon the electrocorticogram in rats.The synchronization induced by α-methyl-p-tyrosine began earlier than the decrease of the duration of arousal, indicating different sensitivities to the depressive drug action of structures responsible for synchronizing and for arousal.Five $\text{mg}\text{kg}$ HA-966 in diethyldithiocarbamate desynchronized animals increased the amplitude but the duration of arousal was unchanged. p-Chlorophenylalanine treatment of rats did not influence the synchronizing effect of HA-966 (10–20 $\text{mg}\text{kg}$) or the inhibitory effect upon the duration of arousal. Haloperidol (100 μg-4 $\text{mg}\text{kg}$) potentiated the synchronizing effect of y-hydroxybutyrate and HA-966. The number of phasic discharges in the electrocorticogram induced by treatment with anaesthetic doses of γ-hydroxybutyrate were increased by the low dose of haloperidol (100 $\text{μg}\text{kg}$), while the higher dose (4 $\text{mg}\text{kg}$) was ineffective.Animals with intact and lesioned substantia nigra compacta responded equally to the synchronizing activity of HA-966 and γ-hydroxybutyrate. Therefore, it is concluded that their effect is not due to the accumulation of dopamine in the nigrostriatal system.     

Carbon disulphide tetratogenicity and postnatal effects in rat

Pregnant albino rats were exposed to carbon disulphide vapour in concentrations of 50, 100 or 200 $\text{mg}\text{m}{}^3$throughout gestation. Two successive generations (F₁ and F₂) were studied.Concentration levels of 100 and 200 $\text{mg}\text{m}{}^3$ produced marked dose-related impairment in the prenatal development of the F₁ progeny, with increase of early embryonal lethality, reduction in foetal weight and a high incidence of malformations affecting mostly the brain and limbs. Postnatal viability, body weight, lipid and energy metabolism and behaviour were also impaired. Behavioral deviations were observed even at 50 $\text{mg}\text{m}{}^3$.After reaching sexual maturity the F₁ rats were mated within their experimental groups, but no further carbon disulphide exposure was applied. The adverse effects on progeny were still detectable in the F₂ generation. Structural abnormalities of the same type as those found in the F₁ at 100 and 200 $\text{mg}\text{m}{}^3$ exposure were observed in their progeny and, postnatally, statistically significant behavioral changes were observed in the progeny of all test groups.     

Toxicity of N-(phosphonomethyl)glycine to chick embryo

The LD₅₀ values, 12.88 $\text{mg}\text{100 g egg}$ and 13.22 $\text{mg}\text{100 g egg}$, obtained when the N-phosphonomethyl derivative of glycine was injected into the air sacs of White Rock and White Leghorn eggs respectively, were significantly lower (P < 0.01) than the values, (24.72 $\text{mg}\text{100 g egg}$ for White Rocks and 25.44 $\text{mg}\text{100 g egg}$ for White Leghorns) obtained by injection into the yolk sac. These findings suggest that the toxicity of N-(phosphonomethyl)glycine (PMG) to the chick embryo depends on the route of injection.     

Decrease of phosphorylase activity in the liver of rats orally administered stannous chloride

The serum glucose concentration, hepatic glycogen concentration, and hepatic glucose-6-phosphatase activity in fed rats were not significantly altered by the oral administration of tin (Sn²⁺, 3.0 $\text{mg}\text{100 g}$) 6 times at 12-h intervals. The hepatic phosphorylase activity in fed rats was significantly decreased by the oral administration of tin. This decrease was. dose dependent. The present results suggest that the decrease of hepatic phosphorylase activity produced by the oral administration of tin may cause the reduction of glycogenolysis in the liver of fed rats.     

Drug interactions with misonidazole: Effects of dexamethasone and its derivatives on the pharmacokinetics and toxicity of misonidazole in mice

Misonidazole [1-(2-nitroimidazol-1-yl)-3-methoxypropan-2-ol; Ro 07-0582] selectively sensitizes hypoxic cells to radiation and is undergoing clinical trial in the radiation treatment of solid tumours. It has been suggested that the glucocorticoid hormone dexamethasone may reduce the incidence of neurotoxicity, the dose-limiting side effect of misonidazole in man. Here it is shown that the absorption and elimination of misonidazole (1 $\text{g}\text{kg}$ i.p.) in C3H mice are unaffected by pretreatment (i.p. for 5 days) with dexamethasone (10$\text{mg}\text{kg}$/day), dexamethasone acetate (10 $\text{mg}\text{kg}\text{day}$) and dexamethasone phosphate (0.5, 10, 25 and lOO $\text{mg}\text{kg}\text{day}$). The apparent half-life of misonidazole in blood and area under the curve (AUC) of misonidazole concentration × time were unaltered. Likewise O-demethylation was unaffected. In contrast, phenobarbitone pretreatment (80 $\text{mg}\text{kg}\text{day}$) increased misonidazole clearance through induction of demethylation. Dexamethasone phosphate pretreatment increased pentobarbitone sleeping-time and slightly decreased liver weight, whereas phenobarbitone did the opposite. Dexamethasone phosphate (25 $\text{mg}\text{kg}$) given as an i.v. bolus injection immediately before misonidazole also had no effect on the systemic pharmacokinetics of misonidazole. Broadly, pretreatment with dexamethasone derivatives had little effect on brain misonidazole and desmethylmisonidazole. But after 100 $\text{mg}\text{kg}\text{day}$ dexamethasone phosphate the 6 hr misonidazole concentration was reduced 36 per cent. Simultaneous dexamethasone phosphate (25 $\text{mg}\text{kg}$) reduced the concentration at 1 hr by 15 per cent and the brain AUC_(0–6hr) by 14 per cent. Dexamethasone phosphate pretreatment reduced the acute LD₅₀ for misonidazole by up to 19 per cent whereas phenobarbitone increased it by 16 per cent. Simultaneous dexamethasone phosphate had no effect. The drug had little effect on misonidazole-induced hypothermia. The significance of these findings for the putative role of dexamethasone in the protection of misonidazole neurotoxicity is discussed.     

Toxicological studies on 4-(hexadecylamino)benzoate (PHB), an agent with anti-atherosclerotic properties,in the rat

The subacute oral toxicity of sodium 4-(hexadecylamino)benzoate (PHB) was studied in male and female Sprague-Dawley rats. The animals were given PHB 0, 10, 30, 100 or 300 $\text{mg}\text{kg}$ body weight as a 3% gum arabic suspension for 13 weeks. During PHB administration all animals on the highest dose level died or were killed because of loss of weight: there were deaths also in the 100 $\text{mg}\text{kg}$ group. PHB caused a leukocytopenia which was significant only at the highest dose level. The hemoglobin decreased in the two lowest dose groups. In the highest dose group the histological liver pictures were pathological. Acidophilic bodies and karyorrhexis indicating severe liver cell damage occurred at this level. In the groups receiving 30, 100 and 300 $\text{mg}\text{kg}$ there were foci with poorly distinguishable liver cells, mono-nuclear cells and some neutrophiles. PHB had no noticeable toxic effects on the other organs or parameters measured.     

Prediction of ftorafur disposition in rats and man by a physiologically based pharmacokinetic model

A physiologically based pharmacokinetic model including fourteen compartments (artery, vein, and twelve tissues) was used to predict plasma and tissue ftorafur concentrations in rats after a 100 $\text{mg}\text{kg}$ i.v. dose. Fairly good agreement was obtained between the predicted and observed time courses of ftorafur concentrations in plasma and tissues. This model was also used to predict plasma ftorafur concentrations for man. Fairly good agreement was again obtained between the predicted and observed plasma ftorafur concentrations. Additionally, it was ascertained that the ratio of body weight (kg) to distribution volume (liter) of ftorafur was approximately 1:1 in man, rat, monkey, dog and rabbit, and the ratio of body weight (kg) to total body clearance ($\text{ml}\text{min}$) was the same in all cases except rabbit.     

A conditioned taste aversion induced by alpha-methyl-p-tyrosine

Rats treated with either four 50 $\text{mg}\text{kg}$ or 100 $\text{mg}\text{kg}$ injections of alpha methyl-p-tyrosine (α-MPT) spaced 12 hr apart acquired an aversion to a 0.1% saccharin solution in a two-bottle choice with water. Rats treated with either saline or four injections of 100 $\text{mg}\text{kg}$ of α-MPT without saccharin present exhibited a complete preference for the saccharin solution. In a subsequent experiment, the saccharin aversion induced by the four 100 $\text{mg}\text{kg}$ α-MPT injection procedure was found to persist after telencephalic norepinephrine had returned to normal levels. Thus, α-MPT was found to be a highly effective drug for inducing a taste aversion at dose levels which did not produce obvious signs of toxicity.     

The distribution of beta-phenylethylamine in discrete regions of the rat brain and its effect on brain noradrenaline, dopamine and 5-hydroxytryptamine levels

β-Phenylethylamine (100 $\text{mg}\text{kg}$) injected interperitoneally into rats 1 hr before death, caused a significant depletion of whole brain levels of noradrenaline and dopamine, but not of 5-hydroxytryptamine. An investigation of discrete regions of the brain showed that the same dose of phenylethylamine caused significant depletion of dopamine in the cerebellum, corpus striatum, midbrain, and cortex, but not in the hypothalamus or medulla oblongata-pons region. All regions were depleted of noradrenaline, while only the midbrain and cortex were significantly depleted of 5-hydroxytryptamine. Administration of [4-T]-β-phenylethylamine, 100 $\text{mg}\text{kg}$, showed that the distribution of labelled phenylethylamine in various regions of the brain was significantly correlated with the distribution of dopamine (both in controls and after 100 mg $\text{β-phenylethylamine}\text{kg}$). These results and their significance are discussed.     

Plasma cyclic AMP in the morphine-tolerant rat

Effects of morphine on plasma cyclic AMP leveis in the rat were investigated. Morphine (20 $\text{mg}\text{kg}$, s.c. + 4 $\text{mg}\text{kg/hr}$, i.v.) produced an increase in plasma cyclic AMP concentrations at 1hr and sustained elevated levels for several hours, but the levels returned to normal levels at 48 hr. the 48 hr increase in plasma cyclic AMP elicited by morphine (20 $\text{mg}\text{kg}$, s.c.) was far smaller than that of 1 hr; the plasma concentration of morphine was at the same level as the 1 hr. This indicated the development of tolerance to the morphine induced increase in plasma cyclic AMP. At 48 hr an epinephrine challenge increased plasma cyclic AMP to the same extent as in naive rats. Therefore, desensitization of peripheral tissues as being responsible for the increase in the plasma cyclic AMP could be ruled out. the development of tolerance by the sympatho-adrenal reflex elicited by morphine was suggested. In naioxone-precipitated abstinence, plasma cyclic AMP showed a 4-fold increase but. on spontaneous withdrawal, it showed on a slight but significant increase. It was concluded that plasma cyclic AMP is a sensitive index of tolerance to and dependence on morphine.     

Effect of diazepam on the spontaneous and harmaline-induced electrical activity of Purkinje cells at the cerebellium of the rat and rabbit

The effect of diazepam and harmaline upon spontaneous simple spike (SS) and complex spike (CS) activity of cerebellar Purkinje cells (PC) was studied in unanaesthetized and curarized rats and rabbits. Diazepam (5 $\text{mg}\text{mg}$) markedly decreased the SS activity of the Purkinje cells tested without any modification of the CS frequency. Harmaline (5–15 $\text{mg}\text{mg}$ i.v.) induced a rhythmical activity of CS at 6–12 Hz, associated with a remaining SS activity that was also rhythmically organized in most of the Purkinje cells recorded. In rabbits the rhythmical CS discharges elicited by harmaline were suppressed by diazepam administration but only transiently (10 min). In rats diazepam did not prevent or suppress the rhythmical CS activity. These results suggest that the inhibition of harmaline-induced tremor by diazepam (Mao, Guidotti and Costa, 1975a) is not due to an inhibition of rhythmical CS activity of Purkinje cells.     

Apomorphine-induced inhibition of neostriatal activity is enhanced by lesions induced by 6-hydroxydopamine but not by long-term administration of amphetamine

Single-unit activity was recorded in the neostriatum of locally-anesthetized, immobilized rats which had received either a unilateral injection of 6-hydroxydopamine (6-OHDA) into the nigroneostriatal dopamine pathway, or repeated injections (twice daily for 6 days) of saline, 1.0, 5.0 or 10.0 $\text{mg}\text{kg}$ (+)-amphetamine. A staircase regimen of apomorphine was administered intravenously to each rat to determine if the long-term administration of amphetamine changed the sensitivity of postsynaptic dopamine receptors in a way comparable to that produced by 6-hydroxydopamine. In all groups, the most frequent response to apomorphine was inhibition of neostriatal activity. In saline-treated rats, most units were moderately excited by small doses of apomorphine (0.0025–0.02 $\text{mg}\text{kg}$) and then inhibited by doses exceeding 0.04 $\text{mg}\text{kg}$. In rats with lesions induced by 6-hydroxydopamine, apomorphine caused significantly more inhibition than in saline-treated animals. By contrast, neuronal responses in amphetamine-treated rats were not significantly different from those of saline controls. These results indicate that the long-term administration of amphetamine produces an augmentation of behavior by some mechanism other than an increase in the sensitivity of postsynaptic dopamine receptors.     

Effects of acute inorganic lead administration on in vivo drug metabolism and cytochrome P-450 in the rat

An acute dose of inorganic lead acetate (4.0 $\text{mg}\text{kg}$ i.p.) prolonged rat methohexital-induced narcosis while doses of 1.5 and 2.0 $\text{mg}\text{kg}$ i.p. did not. The in vivo metabolism of methohexital was tested 24 h after the administration of the lead. Hepatic cytochrome P-450 content was decreased 12 to 24 h following the administration of 4.0 $\text{mg}\text{kg}$ i.p. lead acetate. Hepatic microsomal protein and cytochrome B₅ content did not change 12 or 24 h following lead treatment.     

Arachidonate-induced thrombosis in vitamin E-deficient rabbits

Dutch male rabbits with an average plasma tocopherol level of only 2.5 $\text{μg}\text{ml}$ following administration of a ration low in vitamin E were injected intravenously with sodium arachidonate (4 $\text{mg}\text{kg b.w.}$): all died or were sacrificed in moribund condition with pronounced thrombotic lesions in the pulmonary vasculature.Control rabbits with an average plasma tocopherol level of 20 $\text{μg}\text{ml}$ were injected with the same dose of sodium arachidonate: the only response observed was slight respiratory distress that disappeared within a few minutes.     

A TRH analog (DN-1417): Motor stimulation with rearing related to catecholaminergic mechanisms in rats

The effect of an analog of TRH, γ-butyrolactone-γ-carbonyl-histidyl-prolinamide citrate (DN-1417) on motor activity was studied in rats. Peripheral administration of DN-1417 (0.2–20 $\text{mg}\text{kg}$, i.p.) caused a significant, dose-dependent increase in total spontaneous motor activity, with a definite increase in rearing behaviour. Both increases in spontaneous motor activity and rearing behaviour were markedly inhibited by pretreatment with chlorpromazine (1, 5 $\text{mg}\text{kg}$, i.p.), haloperidol (0.1, 0.5 $\text{mg}\text{kg}$, i.p.), pimozide (1 $\text{mg}\text{kg}$, i.p.) or α-methyltyrosine (250 $\text{mg}\text{kg}$, i.p.). Only stimulation of rearing behaviour was selectively attenuated by phenoxybenzamine (5 $\text{mg}\text{kg}$, i.p.) or FLA-63 (25 $\text{mg}\text{kg}$, i.p.) at doses producing no significant effect on spontaneous motor activity. Although propranolol (10 $\text{mg}\text{kg}$, i.p.) and methysergide (10 $\text{mg}\text{kg}$, i.p.) had no effect, atropine (10 $\text{mg}\text{kg}$, i.p.) and mecamylamine (10$\text{mg}\text{kg}$, i.p.) respectively potentiated and counteracted the effects of DN-1417. Concerning the stimulation of spontaneous motor activity, the nucleus accumbens and lateral hypothalamic area were most sensitive to DN-1417, and the lateral hypothalamic area was the most sensitive site for the stimulation of rearing. Furthermore, DN-1417 (5 × 10^?5 M) significantly enhanced the spontaneous release of [³H]dopamine from the rat nucleus accumbens slices in vitro. These findings indicate that the motor stimulatory action of DN-1417 appears to be mediated primarily via a dopaminergic mechanism by enhancing the release of dopamine from nerve terminals, including the nucleus accumbens in the mesolimbic dopamine system, and, in turn, the rearing may be mediated via noradrenergic mechanism.