A sensitive and specific radioimmunoassay for cis (Z)-flupenthixol in human serum

The injection of cis (Z)-7-carboxy-flupenthixol covalently bound to bovine serum albumin into a sheep has produced an antibody serum which can be used in a very high dilution. This antibody serum and tritium labelled cis (Z)-flupenthixol of high specific activity have been used for a radioimmunoassay for cis (Z)-flupenthixol. The radioimmunoassay has a limit of sensitivity of about 0.3 ng/ml serum or plasma. Some cross-reactivity was seen with trans(E)-flupenthixol, flupenthixol metabolites and cis (Z)-flupenthixol esters, but this did not influence the estimation of cis (Z)-flupenthixol to any significant degree. A series of drugs structurally related to flupenthixol showed varying degrees of cross-reactivity depending on the closeness of their relationship to flupenthixol. Compounds of other therapeutic groups, which structurally are un-related to flupenthixol, showed very little cross-reactivity. The standard deviation was 6–7 per cent when a series of identical samples of pooled patient sera was estimated. Oral administration of cis (Z)-flupenthixol to human volunteers indicates a rather slow absorption with maximum serum level 6 hours after administration. Intramuscular injection of flupenthixol decanoate in Viscoleo to patients gives serum concentration curves, which show maxima 7 days after injection and a factor of two fluctuation in serum level in a two weeks dosage interval.     

Immediate and Prolonged Effects of Drugs on Rhythm's Characteristics: Relevance to Chronochemotherapy

Four groups of mice were injected with vincristine, each at a different time, for ten successive days. Mortality and daily pattern of peripheral white blood cells (WBC) count were monitored immediately and at various times after the last injection. The results demonstrated that (1) drug administration time dependency was observed in rate of death, recorded for 80 days following the injections; (2) the time of drug administration affected the parameters of WBC count rhythm, and (3) there were differences between immediate effects upon the rhythm parameters (monitored one day after the last injection) to those measured at succeeding times (on days 8 and 15 after injections cessation). The results emphasize the need to consider continuous post administration rhythm changes, especially when scheduling repeated chronotherapeutics, where variables which serve for toxicity-diagnosis are rhythmic in nature.     

Immediate and Prolonged Effects of Drugs on Rhythm's Characteristics: Relevance to Chronochemotherapy

Four groups of mice were injected with vincristine, each at a different time, for ten successive days. Mortality and daily pattern of peripheral white blood cells (WBC) count were monitored immediately and at various times after the last injection. The results demonstrated that (1) drug administration time dependency was observed in rate of death, recorded for 80 days following the injections; (2) the time of drug administration affected the parameters of WBC count rhythm, and (3) there were differences between immediate effects upon the rhythm parameters (monitored one day after the last injection) to those measured at succeeding times (on days 8 and 15 after injections cessation). The results emphasize the need to consider continuous post administration rhythm changes, especially when scheduling repeated chronotherapeutics, where variables which serve for toxicity-diagnosis are rhythmic in nature.     

Effects on the murine mononuclear phagocyte system of chronic administration of liposomes containing cytotoxic drug or lipid A compared with empty liposomes

In experiments designed to examine the adverse effects of chronic liposome administration in vivo on the mononuclear phagocyte system (reticuloendothelial system), the presence of drug entrapped in the liposomes may increase the level of reticuloendothelial impairment. We have compared the effects on the mononuclear phagocyte system in mice of chronic administration of empty liposomes with the effects of liposomes containing the anti-leishmanial drug meglumine antimoniate. We have also examined the effect on the mononuclear phagocyte system of continued injections of liposomes containing lipid A, a component of bacterial lipopolysaccharide, which is responsible for macrophage activation. Ten intravenous injections of multilamellar liposomes composed of dipalmitoylphosphatidylcholine and cholesterol (1:0.75 M ratio) were given to ICR mice over a 25-day period. Two individual groups of mice received endotoxin-free liposomes in which meglumine antimoniate was either present or absent. One addition group received liposomes containing lipid A derived from Escherichia coli lipopolysaccharide. A control group received sterile saline injections. In each group, a depression of the phagocytic index, as measured by reduction of uptake of particulate carbon, was observed among some of the individual animals 24 h after the first injection. In many mice a marked splenomegaly was observed. A depressed phagocytic index and splenomegaly were most marked for mice receiving lipid A liposomes. However, there was a large individual variability among mice receiving these preparations and some mice in each group had normal spleen size and a nearly normal phagocytic index. Tissue distribution of liposomes containing [14C]dipalmitoylphosphatidylcholine as a phospholipid marker was examined in all groups in mice 24 h after the last injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thermoregulatory (core, surface and metabolic) responses of unrestrained rats to repeated POAH injections of beta-endorphin or adrenocorticotropin

Repeated preoptic-anterior hypothalamic (POAH) injections of saline and 10 or 25 micrograms/microliters of beta-endorphin or ACTH were given to groups of male Sprague-Dawley rats. One hr after the fifth injection of beta-endorphin or ACTH, each rat received a POAH injection of naloxone HCl (10 micrograms/microliters). Core (Tre-rectal) and surface (Tt-tail) temperatures, metabolic (VO2) and behavioral responses were recorded 30 min before and 60 min after each drug injection. The initial POAH injection of either dose of beta-endorphin produced a hyperthermia. Peak hyperthermia was reduced in the group given 10 micrograms/microliters of beta-endorphin repeatedly. TtS rose after each beta-endorphin injection but temporally lagged Tre increases. Metabolic rate (VO2) was increased with repeated POAH injections of beta-endorphin. Naloxone reduced the elevated Tre seen with beta-endorphin by increasing Tt's further and reducing VO2. POAH administration of ACTH evoked only a slight hyperthermic Tre response, but elevated TtS and VO2S, due to enhanced grooming and explorative behavior. With repeated ACTH injections, TreS did not change from those on the first day as TtS and VO2 remained enhanced. Naloxone reduced VO2 and TtS of the ACTH-treated rats but TreS still were unchanged. Results suggest that the hyperthermia of unrestrained rats given an acute as opposed to repeated POAH beta-endorphin injections is mediated by different effector mechanisms. With the doses used, the slight and unchanging TreS seen with ACTH occurred because this peptide increased heat production due to locomotor activation yet also exaggerated heat loss by vasodilating the peripheral vasculature.     

Mechanism of induction of micronuclei and chromosome aberrations in mouse bone marrow by multiple treatments of methotrexate.

Methotrexate (MTX), an inhibitor of dihydrofolate reductase (DHFR), slightly induced micronuclei and this induction of micronuclei was enhanced by multiple treatments with the drug (Yamamoto et al., 1981; Hayashi et al., 1984; CSGMT/JEM.MMS, 1990). More micronuclei and chromosomal aberrations in mouse bone marrow cells were induced by multiple than by single treatment. The MTX level in mouse plasma and bone marrow showed little (or no) differences between single and quadruple treatments several hours after the injection(s). On the other hand, the DHFR activity in bone marrow cells 3 h after one and four injections was decreased to approximately 38 and 0%, respectively, of that in non-treated mice. Furthermore, the intracellular MTX level in the bone marrow cells (but not in total bone marrow) after four injections was about 10-fold higher than that after one injection. The amount of MTX bound to protein 3 h after four injections, as assayed by gel filtration (Sephadex G-25), was approximately 8-fold greater than after one injection. Therefore, the multiple-dose effects of MTX on the induction of micronuclei and chromosomal aberrations may be explained by the intracellular accumulation of MTX resulting in an enhancement of enzyme inhibition.     

Isolation versus grouped housing in rats: Differential effects of low doses of heroin in the place preference paradigm

Male Long Evans rats were reared from weaning (21–23 days) either in isolation or in groups of four for 40 days. Animals were then individually introduced to a testing apparatus consisting of two distinct chambers. A modified place preference paradigm was used consisting of 3 phases: (1) An habituation phase (4 days) during which rats were allowed free access to the entire test apparatus for 15 min. periods daily; (2) A conditioning phase (4 days) during which rats were confined to their non-preferred side for 15 minutes each day immediately following subcutaneous injection of 0, 20, 40 and 80 μg/kg of heroin HCl; (3) A test phase (1 day) during which rats were again allowed free access to the testing chamber following injection of vehicle. The difference in time spent on the conditioned side during habituation and test periods was determined. The group-reared rats showed similar effects for all doses of heroin whereas the same magnitude of drug effect was attained only at the highest dose used in the isolated rats. This differential sensitivity to heroin in the place preference paradigm is discussed in terms of the modification of behavioral effects of opiates by environmental influences.     

Conditioned place preference from intra-accumbens but not intra-caudate amphetamine injections

Rats received injections of d-amphetamine sulphate (10 micrograms in 0.5 ul) in nucleus accumbens and were placed into one of two (randomly assigned) distinctive environments. The next day the rats were placed into the other environment and received either a saline injection or no treatment. This procedure was repeated six times. When the rats were allowed a free choice between the two environments they showed a significant preference for the one that had been paired with amphetamine. This finding suggests that amphetamine-stimulated release of dopamine in nucleus accumbens can increase the incentive value of neutral stimuli with which it is paired. When the same procedure was carried out with a group of rats that received amphetamine injections in the dorsolateral caudate nucleus, no preference for the side paired with the drug was evident. This suggests that there is functional differentiation between different parts of the dopaminergic terminal system.     

Protective effect of ellagic acid and pumpkin seed oil against methotrexate-induced small intestine damage in rats

Gastrointestinal toxicity is one of the most serious side effects in the methotrexate (MTX) treatment. This study was designed to investigate whether ellagic acid (EA) and/or pumpkin seed oil (PSO) had a protective effect on MTX-induced small intestine damage. Forty albino rats were randomized into five groups of 8 rats each. Group I served as a normal control group. In Group II, MTX was administered as a single dose (20 mg/kg) intraperitoneally. Groups III, IV and V were pre-treated respectively with either PSO (40 mg/kg), EA (10 mg/kg) or 0.2% DMSO (vehicle control) orally every day by gavage for 5 days and then they received MTX. All animals were sacrificed 5 days after the intraperitoneal injection of MTX for histopathological examination, estimation of serum prostaglandin E2 (PGE2) level, assay of tissue malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (NO) levels and myloperoxidase (MPO), xanthine oxidase (XO) and adenosine deaminase (AD) activities. Administration of EA and/or PSO decreased the intestinal damage, PGE2, MDA and NO levels and MPO, XO and AD activities and increased GSH level. These results suggest that EA and PSO protect the small intestine of rats from MTX-induced damage through their antioxidant and anti-inflammatory effects and thus have potential as a promising drug in the prevention of undesired side effects of MTX.     

Effect of the administration of 5,6-dihydroxytryptamine to the amygdala and dorsal raphe nucleus on plasma renin activity

The effect of injections of 5,6-dihydroxytryptamine, a potent and selective neurotoxic of serotonin neurons, into amygdala and dorsal raphe mesencephalic nucleus on the plasma renin activity has been studied in male Wistar rats. Plasma renin activity was estimated on 2nd, 4th, Tth and 14th day after injections in both areas. The administration of 5,6-dihydroxytryptamine in amigdala produced a significant decrease in plasmatic renin activity between 2nd and 4th day, but the inverse effect between 7th and 14th day. Similar effects were found after injections in dorsal raphe nucleus. The contents of cerebral 5-HT were simultaneously evaluated in the entire brain when the drug was implanted in dorsal raphe, and only in amygdaloid tissue when the injection was restricted to this area. A significant decrease in serotonin content was produced 7th day in both places, while partial recuperation was found toward 14th day. The results, especially the ones related to the chemical lesion of dorsal raphe nucleus, suggest that serotoninergic brain systems are involved, as stimulators, in the control of the dynamics of renin-angiotensin system.     

Effect of a single botulinum toxin injection on bone development in growing rabbits

Intramuscular injections with botulinum toxin A (BTX-A) lead to a rapid decrease in muscle mass and force, but the effect of this drug on bone development is unclear. In the present pilot study we evaluated the effect of a one-time injection of BTXA in growing rabbits. Twelve young (weight 1.5 kg) New Zealand rabbits were randomly assigned to receive either BTX-A (total dose 8 units per kg body weight) or sodium chloride 0.9% injections into the left quadriceps and gastrocnemius muscles. Both groups continued to gain weight in a similar manner following the injection. However, when the animals were sacrificed at five weeks after the injection, the group receiving BTX-A had a significant deficit (of 10%) in gastrocnemius muscle mass on the injected side, whereas no significant side-difference was found for the quadriceps. BTX-A injections did not affect the length of the tibia. Nevertheless, bone mineral content of the whole tibia, as measured by dual-energy X-ray absorptiometry, was 7% lower in the BTX-A injected side than on the contralateral side. Peripheral quantitative computed tomography showed that this bone mass deficit was larger in the metaphysis than in the epiphysis or diaphysis. In the diaphysis, the bone mass deficit was due to a reduction in cross-sectional bone dimensions, which equally affected the cross-section of the entire bone, the cortical compartment and the marrow space. BTX-A injections did not have a detectable effect on cortical bone mineral density. The bone mass deficit in the diaphysis thus appeared to be caused by a lack of periosteal bone apposition rather than increased endocortical or intracortical resorption. These preliminary data suggest that intramuscular BTX-A injections can have a deleterious effect on the development of bones that are loaded by the injected muscles.     

Effect of food abundance on larval lake whitefish, Coregonus clupeaformis Mitchill, growth and survival

The effect of food ration on larval lake whitefish, Coregonus clupeaformis , growth and survival was determined in the laboratory using brine shrimp as the test prey. In replicate experiments, larval whitefish were fed one of seven different rations of brine shrimp over a 25 day period. Statistically significant differences were found between larval growth and survival at each feeding level. Larvae fed to excess were 1.33 times as long and 2.80 times as heavy as those on the 1.8 zooplankton/fish (z/f) ration. No mortality was recorded until after day 15 of the experiment by which time all larvae had resorbed their yolk sac. Total mortality followed within 1 week for all feeding densities with the exception of the three highest (18 z/f, 32 z/f and excess rations) where total mortality equalled 90%, 12% and 0%, respectively.     

Intramuscular beta2-agonist administration enhances early regeneration and functional repair in rat skeletal muscle after myotoxic injury.

Systemic administration of beta(2)-adrenoceptor agonists (beta(2)-agonists) can improve skeletal muscle regeneration after injury. However, therapeutic application of beta(2)-agonists for muscle injury has been limited by detrimental cardiovascular side effects. Intramuscular administration may obviate some of these side effects. To test this hypothesis, the right extensor digitorum longus (EDL) muscle from rats was injected with bupivacaine hydrochloride to cause complete muscle fiber degeneration. Five days after injury, half of the injured muscles received an intramuscular injection of formoterol (100 mug). Muscle function was assessed at 7, 10, and 14 days after injury. A single intramuscular injection of formoterol increased muscle mass and force-producing capacity at day 7 by 17 and 91%, respectively, but this effect was transient because these values were not different from control levels at day 10. A second intramuscular injection of formoterol at day 7 prolonged the increase in muscle mass and force-producing capacity. Importantly, single or multiple intramuscular injections of formoterol did not elicit cardiac hypertrophy. To characterize any potential cardiovascular effects of intramuscular formoterol administration, we instrumented a separate group of rats with indwelling radio telemeters. Following an intramuscular injection of formoterol, heart rate increased by 18%, whereas systolic and diastolic blood pressure decreased by 31 and 44%, respectively. These results indicate that intramuscular injection can enhance functional muscle recovery after injury without causing cardiac hypertrophy. Therefore, if the transient cardiovascular effects associated with intramuscular formoterol administration can be minimized, this form of treatment may have significant therapeutic potential for muscle-wasting conditions.     

A single amino acid residue contributes to distinct mechanisms of inhibition of the human multidrug transporter by stereoisomers of the dopamine receptor antagonist flupentixol.

Both cis and trans isomers of the dopamine receptor antagonist flupentixol inhibit drug transport and reverse drug resistance mediated by the human multidrug transporter P-glycoprotein (Pgp) with a stereoselective potency. The rate of ATP hydrolysis by Pgp and photoaffinity labeling of Pgp with the substrate analogue [125I]iodoarylazidoprazosin ([125I]IAAP) are modulated by each isomer in an opposite manner, suggesting different mechanisms for the inhibitory effect on drug transport. In this study we demonstrate that substitution of a single phenylalanine residue at position 983 (F983) with alanine (F983A) in putative transmembrane (TM) region 12 selectively affects inhibition of Pgp-mediated drug transport by both isomers of flupentixol. In F983A the stimulatory effect of cis(Z)-flupentixol and the inhibitory effect of trans(E)-flupentixol on ATP hydrolysis and [125I]IAAP labeling were significantly altered. This indicates that F983 contributes to inhibition of drug transport by both isomers of flupentixol and plays an important role in stimulation and inhibition of ATP hydrolysis and [125I]IAAP labeling by cis(Z)- and trans(E)-flupentixol, respectively. The near-wild-type level of drug transport by the F983A Pgp mutant dissociates susceptibility to inhibition by flupentixol from drug translocation, indicating the allosteric nature of the flupentixol interaction. The inhibitory effects of cyclosporin A on drug transport, drug-stimulated ATP hydrolysis, and [125I]IAAP labeling as well as the stimulatory effect of verapamil on ATP hydrolysis by Pgp were minimally affected by substitution of F983, suggesting no global alteration in the structural and functional integrity of the mutant. Taken together, our data suggest that distinct mechanisms of inhibition of Pgp-mediated drug transport by the cis and trans isomers of flupentixol are mediated through a common site of interaction.     

Effect of repeated nicotine exposure on core temperature and motor activity in male and female rats

Comparatively little is known about the thermoregulatory effects of single and repeated administration of nicotine. Nicotine is a relatively fast acting drug that induces transient changes in core temperature (T_c) of rodents. The development of radio telemetry allows one to detect subtle and rapid changes in T_c that otherwise are difficult to measure with conventional colonic probe techniques. To this end, T_c and motor activity (MA) were monitored by radio telemetry in male and female Sprague-Dawley rats following five daily injections of saline or nicotine tartrate (0.5 mg/kg; sc). The first injection of saline led to a transient increase in T_c that was attributed to the handling and injection procedures. Rats dosed with nicotine for the first time were hypothermic for approximately 2 h after injection. The hypothermia was attributed to an impaired increase in T_c from handling and injection. A transient hyperthermic response began to develop with each successive injection of nicotine. After the fourth injection of nicotine, T_c of male rats increased by 0.5°C above controls; T_c of females increased by 0.25°C above controls after the fifth injection. MA also increased transiently with each injection of saline and nicotine. The MA response of females was significantly greater than the males for the second through fifth injections of nicotine. Overall, the thermoregulatory system develops sensitization with 4–5 repeated injections of nicotine. The mediation of a hyperthermic response to a systemically administered cholinergic agonist is a novel effect. It may aid in understanding the delayed hyperthermic response to organophosphate pesticides. The sensitization of the thermoregulatory system to nicotine may shed light on the neuropharmacological mechanisms of this drug.     

Effects of diurnal loading on the transport of charged antibiotics into intervertebral discs

The objective of this study was to quantitatively analyze the effect of diurnal loading on the transport of various charged antibiotics into negatively charged human intervertebral disc (IVD). Transport of charged antibiotics into a human lumbar disc was analyzed using a 3D finite element model. The valence (z) of the electrical charge of antibiotics varied from z = +2 (positively charged) to z = −2 (negatively charged). An uncharged antibiotic (z = 0) was used as a control. Cases with transient antibiotic concentration at disc boundaries [to mimic intravenous (IV) infusion] were simulated. Our results showed that diurnal compression increased the concentrations in the nucleus pulposus (NP) region, but degreased the concentrations in the annulus fibrosus (AF) region for all charged or non-charged drugs. The overall concentration (averaged over disc) increased with diurnal compression. The diurnal compression had more effects on negatively charged antibiotics than positively charged ones. For example, at day 5 with diurnal compression, the diurnal compression increased the concentration of negatively charged drug (z = −1) in NP by 18.3%, but only by 6.6% for positively charged one (z = +1). In AF, diurnal compression decreased the concentration by 13.2% for negatively charged drug (z = −1) versus 1.2% for positively charged one (z = +1). Note these percentages are the averaged values over day 5. This study provides quantitative information on understanding the mechanisms of charged drug transport in human IVDs.     

Effect of adrenalectomy and corticosterone on cocaine-induced sensitization in rats.

Effects of adrenalectomy (ADX) and corticosterone (CORT) on the development and expression of sensitization to the locomotor effect of cocaine (COC) were studied in rats. Sensitization was evoked by 5 daily injections of COC (10 mg/kg) and measured after a challenge dose of the drug (10 mg/kg) after a 5-day withdrawal (on day 10 of the experiment). ADX, performed before the start of COC administration, completely blocked the manifestation of COC-induced sensitization. In contrast, ADX performed on animals already sensitized to COC did not affect the sensitized locomotor activity response to a challenge dose of COC (on day 18). Pretreatment with CORT, 10 mg/kg, but not 5 mg/kg, before each of the 5 daily COC injections facilitated the development of COC sensitization, tested after a 5-day withdrawal. When pretreated with CORT alone (10 mg/kg), the challenge dose of COC administered on day 10 induced cross-sensitization to CORT. CORT (10 mg/kg) injected acutely before COC on day 10, potentiated the expression of COC sensitization. When given alone, on day 10 CORT (5-10 mg/kg) induced an increase in the locomotor activity of rats pretreated daily (5 injections) with COC. No drug treatment induced conditioned locomotion, as measured after saline challenge on day 8. Our results indicate that CORT facilitates the development and expression of COC sensitization, while ADX blocks the initiation of the behavioral phenomenon only. Moreover, there takes place cross-sensitization between CORT and COC, which indicates a close relationship between the drug-related mechanism and behavioral sensitization.     

Preparation of novel cisplatin-conjugated hollow gold nanospheres for targeting cervical cancer

Cervical cancer is a deadly gynecological malignancy in need of innovative treatment strategies. Emerging preclinical data has suggested the benefits of nanocarriers over the traditional chemotherapy for cancer treatment. In particular, gold nanoparticles are gaining popularity due to gold's inert nature, limited side effects, good cytocompatibility, and flexibility in preparation/modification. We conjugated polyethylene glycol (PEG) with hollow gold nanospheres (HGNs) and loaded the pegylated HGNs with an anticancer drug, cisplatin to target cervical cancer. HGNs were irradiated with noninfrared laser to increase the penetration of drug into tumor tissue and improve the delivery of cisplatin. We investigated the comparative characterization studies of prepared cisplatin loaded pegylated HGNs (cis PEG-HGNs), free cisplatin, cisplatin loaded HGNs (cis-HGNs), cis PEG-HGNs without laser, and cis PEG-HGNs with laser and its effects over cervical cancer cells. Transmission electron microscopy photomicrographs confirmed the integrity of prepared HGNs. While no significant difference was observed between encapsulation efficiency and drug loading of cis-HGNs (84.6%) and cis PEG-HGNs (86.7%), the encapsulation efficiency increased almost twice in HGNs, compared with control gold nanoparticles (GNs) because of the hollow cavity in HGNs. In-vitro cytotoxicity was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using HeLa cells. With irradiation, HGNs induced much elevated cytotoxicity. Not only HGNs were internalized by HeLa cells, they were retained in the cellular compartment. We also tested formulations in vivo and observed that the irradiated cis-HGNs and cis PEG-HGNs were most effective in regressing tumors in mice.     

The role of ovarian steroid hormones in the regulation of basal and stress induced absence seizures

Ovarian hormones play an important role in the regulation of absence seizures in patients as well as in animal models. The present study examined whether chronic progesterone exposure would induce tolerance for the occurrence of absence seizures and whether reduction in gonadal steroids (via ovariectomy) would alter the number of basal and stress induced absence seizures in WAG/Rij rats, a genetic model for absence epilepsy.

Methods

In Experiment 1, female WAG/Rij rats equipped with EEG electrodes received progesterone (P) (20 mg/kg) or cyclodextrin (CD, solvent) i.p. injections once a day for 3 days while a third group received CD injections on Days 1 and 2 and P on Day 3. The EEG was recorded on the day preceding the injections and at each day after injections. In Experiment 2, female WAG/Rij rats equipped with EEG electrodes, were ovariectomized (OVX) or sham operated. EEG recordings were made before and at the 4th, 8th, 10th, 20th, and 35th day after surgery. Rats were then exposed to three series of 10 foot-shocks (FS, 1.5 mA, 1 s) over 3 days. The EEG was recorded 1 h before and 2 h after each FS series.

Results

Tolerance developed after a single P injection and the effect of P on SWDs was facilitated by two preceding control injections. No differences were found between OVX and sham-operated females in the occurrence of SWDs either in resting conditions or after acute FS exposure. However, OVX females showed a more prominent day-to-day aggravation in SWDs after repeated FS administration.

Conclusions

The data suggest an important interaction between hormones of the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes in seizure control. On the one hand, stress interferes with and facilitates the acute effects of progesterone on the occurrence of SWDs and, on the other hand, rats with an intact hypothalamo-pituitary-gonadal axis can better regulate the stress response and develop tolerance to the stressor.     

顺,反铂配合物诱导生物合成金属硫蛋白的研究

给家兔皮下注射不同结构的铂配合物溶液、对肝、肾组织的可溶性组分进行凝胶和离子交换层析分离,研究了它们诱导金属硫蛋白合成的性质,发现顺铂只选择性地诱导肝脏合成ＭＴ,反铂对肝,肾都不诱导,Ｋ２ＰｔＣｌ４同时可在肝和肾脏中诱导ＭＴ的合成。并通过用Ｚｎ（ＮＯ３）２预先诱导肝和肾中合成ＭＴ,然后每日以２、４、４和８ｍｇＰｔ／ｋｇ的剂量连续皮下注射４天顺铂或反铂溶液后,在肝和肾中分离出大量的铂化硫蛋白,且用反