Pharmacological analysis of the participation of the catecholaminergic system in the development of the abstinence syndrome in rats

The behavioural activity of rats in "the open field" was studied. It was revealed that rats alcoholized for 8 months do not practically differ in their behavioural indicators from the intact ones. After the discontinuation of alcohol marked disturbances appear in their behaviour, that are arrested by apomorphine (0,1 mg/kg). In intact animals dopamine (50 mkg into the brain ventricles) induces behavioural disorders similar to those in rats during abstinence. Noradrenaline does not induce similar disorders. A conclusion is made on the dopaminergic nature of disorders in the behaviour of rats in the state of alcohol abstinence.     

Microdialysis in the study of drug transporters in the CNS

Quantitative microdialysis in the central nervous system (CNS) has recently provided evidence for the existence of transporters as they relate to the brain distribution of a variety of drugs. Support for the existence of drug transporters in the blood-brain barrier (or in the blood-CSF barrier) comes from investigations that have found: unbound drug concentrations in brain fluids that are lower than corresponding levels in plasma; saturability of transport clearances across the blood-brain barrier and; the regulation of transport by putative inhibitors. Additional confirmatory evidence for the existence of active transport or carrier-mediated processes has also been derived from models that relate observed drug levels in the CNS with those in plasma or blood. The conclusion that reduced drug levels in brain fluids generally indicate the existence of active efflux transport is questioned. In the case of relatively polar compounds with modest blood-brain barrier permeability, lower unbound concentrations in brain may be a consequence of dilution by turnover of brain fluids. This review summarizes recent reports (grouped by class of compounds) where investigators have used microdialysis to examine the distribution of therapeutic agents to the CNS, and have reached conclusions regarding the functional presence of drug transporters in the brain.     

The role of setting in the oral self-administration of alcohol in the rat

Rationale  

We have previously found that rats that were kept at all times in the self-administration (SA) chambers (resident group) self-administered more heroin than rats that were transferred to the SA chambers immediately before testing (Non-Resident group). Alcohol resembles heroin in its ability to produce, at recreational doses, mood elevation, euphoria, drowsiness, and sedation. Furthermore, alcohol presents some similarities with the mechanisms of action of heroin at the levels of the mesostriatal circuitry. Therefore, we predicted that, as for heroin, alcohol intake would be greater in the Resident than in the Non-Resident group.     

The role of the gut flora in the reduction of sulphinpyrazone in the rat

Sulphinpyrazone underwent both reduction to a sulphide and oxidation to a sulphone after parenteral administration to normal Wistar rats. Oral administration was associated with a bioavailability of about 75% and with a 3-fold greater formation of the sulphide. However, no sulphide was detected in the plasma after oral administration of sulphinpyrazone to germ-free (BD/X) rats or normal rats treated with oral antibiotics. In vitro studies showed that the major site of reduction of sulphinpyrazone was the contents of the hind gut with little activity detected in the liver or other tissues. The sulphide was oxidised in vivo to sulphinpyrazone and small amounts of sulphone, while the latter underwent only slight reduction to sulphinpyrazone, but did not give detectable levels of the sulphide. These data suggest that the gut microflora are the main site of reduction of sulphinpyrazone in the rat in vivo.     

Glucuronidation and sulfation in the rat in vivo. The role of the liver and the intestine in the in vivo clearance of 4-methylumbelliferone

The role of the liver in the conjugation of 4-methylumbelliferone (4MU), mainly glucuronidation, was investigated in the rat in vivo. The liver extracted 4MU almost completely (97%) during steady-state infusion, as measured by the difference between 4MU concentration in portal and hepatic venous blood. Previously, it was shown that the intestinal region extracts 40% of the 4MU of the incoming arterial blood. The liver and the gastrointestinal region are so efficient that their conjugation activity can account for total body clearance of 4MU (50-60 ml/min per kg). These results and other evidence on extrahepatic conjugation of phenolic substrates suggest that glucuronidation may be limited to the liver, (the kidney) and the gastrointestinal region, while sulfation may occur more widespread throughout the body. Protein binding studies showed the sulfate conjugate to be even more protein-bound than unconjugated 4MU, while 4MU glucuronide was much less bound to rat plasma proteins.     

HACCP在学校集体食堂卫生管理中的应用研究

目的 通过HACCP在学校集体食堂管理中的应用,提高食品卫生水平,保障学生的身体健康。方法 HACCP原则。结果 食品卫生达到较高水平,极大地减少了食物中毒的发生。结论 提示HACCP原则可在学校集体食堂的卫生管理中发挥有效作用。     

Role of methotrexate in the treatment of bullous pemphigoid in the elderly

Bullous pemphigoid (BP) is an autoimmune blistering disease that commonly occurs in the elderly. Immunosuppressive medications are effective at controlling the disease in the majority of cases. Mortality can occur as a consequence of severe disease or as a result of the therapies that are frequently employed as treatment. Commonly employed therapies include systemic corticosteroids, azathioprine and mycophenolate mofetil. In a small subset of patients, these first- and second-line therapies do not control disease or are not tolerated by the patients. Optional therapies include nicotinamide (niacinamide), tetracycline, intravenous immunoglobulin, cyclophosphamide, dapsone and methotrexate. The majority of BP patients are elderly, and several considerations need to be taken into account before a specific therapy is chosen. Methotrexate provides several advantages in the elderly population in terms of practicality, cost and tolerability. Several retrospective and prospective studies have evaluated its effectiveness in the treatment of BP in the elderly population. The results of these studies indicate that methotrexate is an effective therapy for BP and is a reasonable option for treatment in the elderly population, although maybe not as a first- or second-line therapy.     

Differences in N-acetylation of the experimental antitumor agent batracylin in the mouse and the rat

Summary Batracylin (NSC-320846) is a quinalzolineone recently evaluated as a potential antitumor agent by the National Cancer Institute. The analog was active against a number of murine tumors, including colon adenocarcinoma 38 and multidrug resistant sublines of P-388 leukemia. Preclinical toxicity studies revealed that batracylin was much more toxic when administered orally to rats than to mice. The combined sex LD₁₀ in mice was 5,655 mg/m² while 576 mg/m² was lethal to all rats treated at that dose. We determined that following oral administration of batracylin, systemic exposure of parent drug to the rat was only 14.9% of that to the mouse. It was subsequently noted that systemic exposure of a relatively non-polar metabolite was approximately 9 times greater in the rat than in the mouse. The metabolite was identified as N-acetylbatracylin by TLC, HPLC and mass spectral analyses. Observations by the National Cancer Institute that N-acetylbatracylin was not toxic following oral administration to mice or rats prompted evaluation of systemic exposure following oral administration to rats. Following oral administration of N-acetylbatracylin to rats, systemic exposure was almost nil. Indeed, exposure of rats to N-acetylbatracylin was several orders of magnitude greater following oral administration of six-fold lower doses of the parent drug, batracylin. Thus, N-acetylation may play a role in the toxicity of batracylin despite the lack of toxicity observed following oral administration of N-acetylbatracylin. In addition, further metabolism of the N-acetyl conjugate, analogous to that of other aromataic amines, may be involved in the pharmacology of batracylin and similar analogs.     

Orexins in the regulation of the hypothalamic-pituitary-adrenal axis

Orexin-A and orexin-B are hypothalamic peptides that act via two G protein-coupled receptors, named orexin type 1 and type 2 receptors (OX1-Rs and OX2-Rs). The most studied biological functions of orexins are the central control of feeding and sleep, but in the past few years findings that orexin system modulates the hypothalamic-pituitary-adrenal (HPA) axis, acting on both its central and peripheral branches, have accumulated. Orexins and their receptors are expressed in the hypothalamic paraventricular nucleus and median eminence and orexin receptors in pituitary corticotropes, adrenal cortex, and medulla. Whereas the effects of orexins on adrenal aldosterone secretion are doubtful, compelling evidence indicates that these peptides enhance glucocorticoid production in rats and humans. This effect involves a 2-fold mechanism: 1) stimulation of the adrenocorticotropin-releasing hormone-mediated pituitary release of adrenocorticotropin, which in turn raises adrenal glucocorticoid secretion; and 2) direct stimulation of adrenocortical cells via OX1-Rs coupled to the adenylate cyclase-dependent cascade. The effects of orexins on catecholamine release from adrenal medulla are unclear and probably of minor relevance, but there are indications that orexins can stimulate in vitro secretion of human pheochromocytoma cells via OX2-Rs coupled to the phospholipase C-dependent cascade. Evidence is also available that orexins enhance the growth in vitro of adrenocortical cells, mainly acting via OX2-Rs. Moreover, findings suggest that the orexin system may favor HPA axis responses to stresses and play a role in the pathophysiology of cortisol-secreting adrenal adenomas.     

The correction of disorders in the pharmacodynamics of drugs metabolized in the liver in the postnatal ontogeny of rats with acute hepatitis]

It has been established in experiments on 30 day albino rats that in acute hepatitis, the pharmacodynamics of the test drugs hexenal, amidopyrine and ethylmorphine metabolized in the liver is considerably potentiated. In contrast to silibor, phytin and zixorine, experimental therapy with benzonal brings about a complete recovery of the pharmacodynamics of the drugs under study. It is believed that benzonal holds promise in pediatrics as a remedy that restores the detoxifying potency of the liver.     

Involvement of the cAMP-dependent pathway in the reduction of epileptiform bursting caused by somatostatin in the mouse hippocampus

The cyclic AMP pathway is major signal transduction system involved in hippocampal neurotransmission. Recently, the peptide somatostatin-14 (SRIF) has emerged as a key signal that, by activating its receptors, inhibits epileptiform bursting in the mouse hippocampus. Little is known on transduction mechanisms, which may mediate SRIF function in native cell/tissues. Using a well-established model of epileptiform activity induced by Mg²⁺-free medium with 4-aminopyridine [0 Mg²⁺/4-aminopyridine (4-AP)] in mouse hippocampal slices, we demonstrated that protein kinase A (PKA)-related signaling is upregulated by hippocampal bursting and that treatment with SRIF normalizes this upregulation. We also demonstrated that the SRIF-induced inhibition of PKA impairs phosphorylation of the NMDA receptor subunit NR1. Extracellular recordings of the 0 Mg²⁺/4-AP-induced hippocampal discharge from the CA3 region demonstrated that treating slices with compounds, which interfere with PKA activity, prevent SRIF inhibition of epileptiform bursting. Our results suggest that SRIF modulation of hippocampal activity may involve PKA-related signaling.     

Characterization of the enzymes involved in the in vitro metabolism of amrubicin hydrochloride

The in vitro metabolism of amrubicin by rat and human liver microsomes and cytosol was examined. The main metabolic routes in both species were reductive deglycosylation and carbonyl group reduction in the side-chain. In vitro metabolism of amrubicinol by rat and human liver microsomes and cytosol was also examined and the main metabolic route of this active metabolite was reductive deglycosylation. Metabolism of amrubicin in human liver microsomes was inhibited by TlCl(3) and that in human liver cytosol was inhibited by dicumarol and quercetin. Generation of amrubicinol was inhibited only by quercetin. The results indicate that metabolism of amrubicin is mediated by NADPH-cytochrome P450 reductase, NADPH:quinone oxidoreductase and carbonyl reductase. In addition, generation of amrubicinol is mediated by carbonyl reductase. Metabolism of amrubicinol in human liver microsomes was inhibited by TlCl(3) and that in human liver cytosol was inhibited by dicumarol. The results indicate that metabolism of amrubicinol is mediated by NADPH-cytochrome P450 reductase and NADPH:quinone oxidoreductase. To investigate the influence of cisplatin on the metabolism of amrubicin and amrubicinol, human liver microsomes and cytosol were pre-incubated with cisplatin. This did not change the rates of amrubicin and amrubicinol metabolism in either human liver microsomes or cytosol.     

Characterization of the enzymes involved in the in vitro metabolism of amrubicin hydrochloride

The in vitro metabolism of amrubicin by rat and human liver microsomes and cytosol was examined. The main metabolic routes in both species were reductive deglycosylation and carbonyl group reduction in the side-chain. In vitro metabolism of amrubicinol by rat and human liver microsomes and cytosol was also examined and the main metabolic route of this active metabolite was reductive deglycosylation. Metabolism of amrubicin in human liver microsomes was inhibited by TlCl₃ and that in human liver cytosol was inhibited by dicumarol and quercetin. Generation of amrubicinol was inhibited only by quercetin. The results indicate that metabolism of amrubicin is mediated by NADPH-cytochrome P450 reductase, NADPH:quinone oxidoreductase and carbonyl reductase. In addition, generation of amrubicinol is mediated by carbonyl reductase. Metabolism of amrubicinol in human liver microsomes was inhibited by TlCl₃ and that in human liver cytosol was inhibited by dicumarol. The results indicate that metabolism of amrubicinol is mediated by NADPH-cytochrome P450 reductase and NADPH:quinone oxidoreductase. To investigate the influence of cisplatin on the metabolism of amrubicin and amrubicinol, human liver microsomes and cytosol were pre-incubated with cisplatin. This did not change the rates of amrubicin and amrubicinol metabolism in either human liver microsomes or cytosol.     

Gender-linked differences in the expression of physical dependence in the rat

In earlier studies, it was shown that there were gender differences in several aspects of the pharmacological profile of morphine, including its antinociceptive activity, discriminative stimulus properties and its reinforcing effects. The purpose of the present studies was to examine whether there might also be gender-related differences in the development of physical dependence, as reflected in the expression of an opiate withdrawal syndrome upon cessation of chronic morphine administration. We found that a more severe spontaneous withdrawal syndrome was produced by chronic morphine injections or morphine pellet implantation in male rats than in females. The duration of the withdrawal syndrome was also longer. In contrast to our observations with spontaneous withdrawal, we found no gender differences in the naloxone-precipitated withdrawal syndrome induced by chronic morphine administration. These observations suggest that there are gender differences only in the expression of the spontaneous withdrawal syndrome, but not in the neuro-adaptive changes associated with the generation of physical dependence as reflected by naloxone-precipitated withdrawal.     

白三烯调节剂在哮喘治疗中的应用

白三烯包括半胱氨酰白三烯（cysteinyl leukotrienes, CysLT）和白三烯B4（leukotriene B4, LTB4）等,是哮喘的主要炎症介质,参与哮喘发病的多种病理生理机制。白三烯调节剂已用于哮喘治疗,其中CysLT受体-1（CysLT receptor-1, CysLT1）拮抗剂可口服、单药治疗轻度持续性哮喘,但疗效通常不如吸入糖皮质激素。重症哮喘患者联合使用CysLT1拮抗剂和吸入糖皮质激素既能有效控制哮喘,又能减少吸入糖皮质激素的剂量。确定对CysLT1拮抗剂治疗反应良好的哮喘患者亚群有助于更好地发挥CysLT1拮抗剂的作用。CysLT1拮抗剂还有抗重塑作用,可防止哮喘患者的气道结构改变。本文主要就白三烯调节剂在哮喘治疗中的应用作一综述。     

A Comparison of the Standard Approach and the NONMEM Approach in the Estimation of Bioavailability in Man

There has recently been concern about confidence intervals calculated using the standard error of parameter estimates from NONMEM, a computer program that uses a non-linear mixed-effects model to calculate relative bioavailability (F), because of possible downward bias of these estimates. In this study an alternate approach, the log-likelihood procedure, was used to calculate the confidence intervals for F from NONMEM. These were then compared with those calculated using the standard error of the parameter estimates, the traditional NONMEM approach, and the standard model-independent method, to determine whether bias exists. By use of data from a single dose, open cross-over study of ibuprofen using 14 healthy male volunteers, NONMEM was shown to give results consistent with those obtained using the standard model-independent method of analysis and could be a useful tool in the determination of F where conditions for using the standard method of analysis are not optimum. The width of the confidence interval for F using the log-likelihood procedure was narrower and non-symmetrical when compared with that obtained using the traditional NONMEM approach. The width of the confidence interval obtained using the traditional NONMEM method was similar to that from the standard approach, however the parameter estimate for F was higher than that obtained from the standard method. This could have been because of an outlier in the data set to which the standard approach is more sensitive. No downward bias was found in the confidence intervals from NONMEM. The bioavailability data set was of relatively low variability and more research with highly variable data is necessary before it can be concluded that the confidence intervals calculated from NONMEM can be used for hypothesis testing.     

Proposed Changes in the Classification of Carcinogenic Chemicals in the Work Area

Carcinogenic chemicals in the work area are currently classified into three categories in Section III of the GermanList of MAK and BAT Values.This classification is based on qualitative criteria and reflects essentially the weight of evidence available for judging the carcinogenic potential of the chemicals. It is proposed that these Categories—IIIA1, IIIA2, and IIIB—be retained as Categories 1, 2, and 3, to conform with EU regulations. On the basis of our advancing knowledge of reaction mechanisms and the potency of carcinogens, it is now proposed that these three categories be supplemented with two additional categories. The essential feature of substances classified in the new categories is that exposure to these chemicals does not convey a significant risk of cancer to man, provided that an appropriate exposure limit (MAK value) is observed. It is proposed that chemicals known to act typically by nongenotoxic mechanisms and for which information is available that allows evaluation of the effects of low-dose exposures be classified in Category 4. Genotoxic chemicals for which low carcinogenic potency can be expected on the basis of dose–response relationships and toxicokinetics and for which risk at low doses can be assessed will be classified in Category 5. The basis for a better differentiation of carcinogens is discussed, the new categories are defined, and possible criteria for classification are described. Examples for Category 4 (1,4-dioxane) and Category 5 (styrene) are presented. The proposed changes in classifying carcinogenic chemicals in the work area are presented for further discussion.     

Changes in the metabolism of hypothalamic norepinephrine associated with the onset of maternal behavior in the nulliparous rat

Both norepinephrine (NE) and its major metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), were assayed both in the hypothalamus of nulliparous rats that had behaved maternally toward foster young and in the hypothalamus of those that had failed to behave maternally. It was found that the maternally-behaving animals had both lower concentrations of NE and higher concentrations of MHPG as compared with their nonresponding counterparts. These data parallel those reported for the puerperal female and suggest that the onset of material behavior may be mediated by increased transmission across hypothalamic noradrerergic synapses.     

The role of the pituitary in the development of electroacupuncture analgesia in rats

In order to investigate the involvement of pituitary beta-endorphin in electroacupuncture analgesia (EAA), the effects of hypophysectomy, dexamethasone (Dex) and adrenalectomy on the analgesia and the increase in plasma corticosterone (Cort) and ACTH levels produced by electroacupuncture (EA) were studied in male SD rats. In saline-treated and Dex-treated rats, plasma Cort levels were correlated with plasma ACTH levels. In non-treated rats, the time course of EA-induced increase in pain threshold was similar to that of EA-induced elevation of plasma Cort levels. In the hypophysectomized rats, EAA was significantly reduced and the EA-induced increase in plasma Cort was also abolished. Single administration of a large dose of Dex tended to reduce EAA and significantly reduced the EA-induced increase in plasma Cort and ACTH. Further suppression of pituitary functions by 4 days-treatment with Dex resulted in further reduction of EAA and the EA-induced increase in plasma Cort and ACTH. On the other hand, hind-paw pressure test without EA produced an increase in plasma Cort and ACTH to the same extent as that produced by EA and produced no analgesia. In the adrenalectomized rats, EAA was reduced, and the plasma ACTH level, which was sixteen times higher than that of nonoperated rats, was further elevated 2-fold higher by EA. No correlation between plasma ACTH levels and the increase in pain thresholds was observed in individual rats of the saline-treated and Dex-treated groups. Control pain thresholds were not influenced by hypophysectomy, Dex or adrenalectomy. These results suggest that pituitary beta-endorphin may not be mainly involved in EAA.     

Adenosine mechanisms in the regulation of breathing in the rat

The central respiratory effects of various adenosine (A) analogues were studied in halothane-anesthetized rats. Intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) injections of the A analogues (2-Cla, L-PIA, CHA and NECA) reduced minute ventilation (VE) due to decreases in respiratory frequency (f) as well as tidal volume (VT). Dose-dependent effects were seen after i.c.v. L-PIA in both normal and vagotomized rats. Analysis of the A-induced changes using the occluded breath technique revealed an increase in expiratory time (TE) as well as a decrease in inspiratory drive. NECA, a relatively specific A2 agonist seemed to be somewhat more potent in eliciting respiratory depression than a relatively specific A1 agonist like L-PIA. Pretreatment with the methylxanthine theophylline completely antagonized the respiratory depression induced by L-PIA. It is concluded that central A receptors are involved in the central regulation of breathing and that A interacts with the respiratory control system mainly by decreasing inspiratory neural drive and prolonging expiratory time.