Tuning in to the ��right�� calcium channel regulation in experimental models of diabetes

Elucidation of cellular and molecular mechanisms underlying vascular disease is of fundamental importance to the development of pharmacological agents to target these pathways. Pinho et al. in this issue of the BJP provide highly compelling evidence that the δ isoform of phosphatidyl inositol 3-kinase (PI3K δ) was upregulated and accounted for the increase in L-type, voltage-gated, Ca channel current in aortic vascular smooth muscle (VSM) cells of a mouse model of type 1 diabetes. There are several key issues of broad fundamental significance to this work. Firstly, what is the ‘right’ answer about calcium channel regulation in diabetes? Conflicting reports of increased and decreased Ca channel current may be due to specificity of the vascular bed and species. Then, the time course of diabetic vasculopathy may influence the expression of contractile versus proliferative phenotypes of VSM. Also the metabolic characterization of diabetes may enlighten or confound any study of diabetic vascular disease. These issues need attention to move forward work in this area.

LINKED ARTICLE

This article is a commentary on Pinho et al., pp. 1458–1471 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2010.00955.x     

Effect of the intraperitoneal administration of salmon-calcitonin on the “in vitro” actions of opioid agonists

• 1.1. The interaction of intraperitoneal administration of salmon-calcitonin with opioids was studied. The study was carried out using guinea pig ileum (μ and κ-opioid receptors), rabbit vas deferens (κ-opioid receptors) and mouse vas deferens (δ-opioid receptors), and selective μ, δ and κ agonists were used in the pertinent tissues.
• 2.2. The treatment with salmon-calcitonin increased, in a dose-dependent manner, the effect of U-50,488H in guinea pig ileum and rabbit vas deferens and the effects of [d-Pen², d-Pen⁵]enkephalin in mouse vas deferens.
• 3.3. The treatment with analgesic doses of salmon-calcitonin enhances the in vitro effects of κ- and δ-opioid agonists. The increase of the effectiveness of the opioid agonists may be one of the mechanisms involved on the analgesia induced by salmon-calcitonin.

     

Gastroprotective activity of α-terpineol in two experimental models of gastric ulcer in rats

BACKGROUND AND THE PURPOSE OF THE STUDY: Several plant essential oils, as well as terpenes present in essential oils, have shown gastroprotective activity. The aim of the present work was to evaluate the gastroprotective activity of α-terpineol, a monoterpene alcohol which is present in essential oils of various plants. METHODS: The gastroprotective activity of α-terpineol was evaluated in rats by assessing the changes in ethanol and indomethacin-induced gastric ulcer scores and on gastric secretory volume and total acidity in pylorus-ligated rats. Alpha-terpineol was administrated orally at the doses of 10, 30, and 50 mg/kg one hour before administration of the ulcer inducing agents by the pylorus ligation procedure. The involvement of endogenous prostaglandins in the protective effect of α-terpineol in ethanol-induced gastric lesions test was assessed by administration of indomethacin (10 mg/kg, s.c.) 30 min before oral administration of α-terpineol at the dose of 50 mg/kg. RESULTS: α-terpineol presented gastroprotective activity against ethanol-induced ulcers at the doses of 10, 30, and 50 mg/kg. Epoxy-carvone at the dose of 10 mg/kg did not present gastroprotective activity against ulcer induced by indomethacin, but at the doses of 30 and 50 mg/kg it attenuated the gastric damages induced by this agent significantly. Pretreatment with indomethacin did not prevent the gastroprotective effect of α-terpineol on ethanol-induced ulcers. Alpha-terpineol also did not affect the gastric secretion in pylorus-ligated rats. MAJOR CONCLUSION: The results suggest that α-terpineol presents gastroprotective action which does not involve either an increase in the synthesis of endogenous prostaglandin or a decrease in the gastric acid secretion.     

Acute administration of typical and atypical antipsychotics reduces EEG γ power, but only the preclinical compound LY379268 reduces the ketamine-induced rise in γ power

A single non-anaesthetic dose of ketamine, a non-competitive NMDA receptor (NMDAR) antagonist with hallucinogenic properties, induces cognitive impairment and psychosis, and aggravates schizophrenia symptoms in patients. In conscious rats an equivalent dose of ketamine induces key features of animal models of acute psychosis, including hyperlocomotor activity, deficits in prepulse inhibition and gating of auditory evoked potentials, and concomitantly increases the power of ongoing spontaneously occurring gamma (30-80 Hz) oscillations in the neocortex. This study investigated whether NMDAR antagonist-induced aberrant gamma oscillations could be modulated by acute treatment with typical and atypical antipsychotic drugs. Extradural electrodes were surgically implanted into the skull of adult male Wistar rats. After recovery, rats were subcutaneously administered either clozapine (1-5 mg/kg, n=7), haloperidol (0.05-0.25 mg/kg; n=8), LY379268 (a preclinical agonist at mGluR2/3 receptors: 0.3-3 mg/kg; n=5) or the appropriate vehicles, and 30 min later received ketamine (5 mg/kg s.c.). Quantitative measures of EEG gamma power and locomotor activity were assessed throughout the experiment. All three drugs significantly reduced the power of baseline EEG gamma oscillations by 30-50%, an effect most prominent after LY379268, and all inhibited ketamine-induced hyperlocomotor activity. However, only pretreatment with LY379268 attenuated trough-to-peak ketamine-induced gamma hyperactivity. These results demonstrate that typical and atypical antipsychotic drugs acutely reduce cortical gamma oscillations, an effect that may be related to their clinical efficacy.     

Chronic Δ9-tetrahydrocannabinol administration affects serotonin levels in the rat frontal cortex

Adult rats were subjected to chronic treatment with the cannabinoid agonist, Δ⁹-tetrahydrocannabinol, or with vehicle, and their brains used to analyze the contents of serotonin (5HT) and of its intraneuronal metabolite, 5-hydroxyindolacetic acid (5HIAA). 5HT and 5HIAA contents were not affected by chronic cannabinoid administration in most of the brain regions analyzed. We found a marked increase in 5HT contents in the frontal cortex that was accompanied by no changes in 5HIAA contents. This originated a decrease in 5HIAA/5HT ratio, which suggests a possible reduction in the activity of serotoninergic terminals reaching this cortical area. This effect was not seen after an acute injection of this cannabinoid. The relevance of these observations was that they occurred in a region where changes in serotoninergic transmission have been implicated in the development of depression; therefore, our data support the theory that the cannabinoid system might be a potential target for the treatment of this neuropsychiatric disease.     

Effects of acute and chronic imipramine administration on conflict behavior in the rat: a potential “animal model” for the study of panic disorder?

Although numerous animal procedures have been employed in the study of generalized anxiety and agents effective in treating generalized anxiety, an analogous behavioral model for the study of panic disorder does not exist. In the present study, the effects of imipramine were examined in a potential animal model for panic disorder, the conditioned suppression of drinking (CSD) paradigm. In daily 10-min sessions, water-deprived rats were trained to drink from a tube that was occasionally electrified (0.5 mA). Electrification was signalled by a tone. Imipramine was administered both in an acute (3.5–20 mg/kg, IP) and a chronic (2.5 mg/kg, IP, twice daily for 5 weeks) regimen. Acute administration of imipramine resulted in a decrease in the number of shocks accepted and a decrease in water intake. In contrast, chronic administration of imipramine resulted in a gradual increase in the number of shocks received in CSD sessions over the course of several weeks of testing. This time-dependent increase in punished responding in the CSD observed during chronic imipramine treatment parallels the time-dependent reduction in the severity and frequency of panic attacks in panic disorder patients receiving chronic imipramine. Thus, the CSD paradigm might serve as an animal model for the study of panic disorder and potential anti-panic agents.     

Intra-articular administration of tachykinin NK₁ receptor antagonists reduces hyperalgesia and cartilage destruction in the inflammatory joint in rats with adjuvant-induced arthritis

Persistent pain associated with inflammatory arthritis is an aggravating factor that decreases patients' quality of life. Current therapies for joint pain have limited effectiveness and produce unwanted negative side effects. Although the involvement of substance P and its cognate tachykinin receptor, NK(1), in joint inflammation has been extensively documented through animal experiments, the development of oral tachykinin NK(1) receptor antagonists against arthritis-induced pain has been unsuccessful in humans to date. To explore the possibility of using tachykinin NK(1) receptor antagonists as local therapeutic agents for inflammatory arthritis, we examined the effects of tachykinin NK(1) receptor antagonists administered into the rat ankle joint on hyperalgesia in complete Freund's adjuvant (CFA)-induced inflammatory monoarthritis. Administration of the tachykinin NK(1) receptor antagonist WIN 51708 or GR 82334 into the affected ankle joint at day 3 following intra-articular CFA injection reduced the mechanical hyperalgesia 12 h after the tachykinin NK(1) receptor antagonist injection and their analgesic effects persisted for at least 2 days. Histological examinations revealed that intra-articular WIN 51708 reduced the CFA-induced destructive changes in the cartilage. These findings suggest that intra-articular injection of tachykinin NK(1) receptor antagonists is a promising strategy for relieving the hyperalgesia that occurs in inflammatory arthritis.     

Metabolic mapping of the time-dependent effects of Δ9-tetrahydrocannabinol administration in the rat

RATIONALE: Delta(9)-Tetrahydrocannabinol (THC) has a long duration of action. Studies have shown that effects on some behavioral endpoints can persist for as long as 24 h after exposure, but the neural substrates underlying these long-lasting effects have not yet been determined. OBJECTIVES: The purpose of the present study was to identify the neuroanatomical substrates associated with the temporal course of the effects of the acute administration of moderate to high doses of THC using the quantitative autoradiographic 2-[(14)C]deoxyglucose (2DG) method. METHODS: Male Sprague-Dawley rats ( n=4-5 per group) were administered THC (0.0, 2.5 or 10 mg/kg, intraperitoneally), and the 2DG procedure was initiated 15 min, 6 h, or 24 h after treatment. To establish the behavioral profile of THC administration, locomotor activity and core body temperature were measured at corresponding time points. RESULTS: The administration of THC produced widespread dose-dependent reductions in rates of cerebral metabolism when the 2DG method was applied 15 min after treatment. A more limited set of structures was affected when the 2DG method was applied 6 h after THC administration, closely paralleling the effects of THC on locomotor activity and core body temperature. However, 24 h after administration, glucose utilization remained depressed within mesolimbic and amygdalar regions. CONCLUSIONS: These data demonstrate that the functional consequences of acute administration of THC follow a distinct temporal course that is regionally specific. That functional activity remains depressed in areas involved in the processing of motivational and emotional information suggests that behaviors subserved by these structures (e.g. anxiety, stress, and reward) may remain altered for as long as 24 h after a single exposure to THC.     

Insight into the pharmacokinetic behavior of tanshinone IIA in the treatment of Crohn’s disease: comparative data for tanshinone IIA and its two glucuronidated metabolites in normal and recurrent colitis models after oral administration

1.?Previous reports implied that tanshinone IIA (TSA) may offer potential benefits for Crohn’s disease (CD). However, the detailed pharmacokinetic behavior of TSA in the treatment of colitis remain unclear. Herein, a recurrent trinitrobenzene sulfonic acid (TNBS)-colitis mouse model was used to investigate whether TSA possesses favorable pharmacokinetic and colonic distribution profiles to serve as a candidate drug.

2.?Although the systemic TSA exposures were low (AUC_0–t approximately 330?ng*h/ml) in both the normal and colitis models after oral administration TSA 20?mg/kg, high levels of TSA were found in the gastrointestinal tract (GI). Such a GI exposure of TSA in colitis mice is adequate to exert anti-inflammatory effects as observed in various in vitro studies.

3.?Interestingly, colonic TSA exposure in the colitis mouse model was much lower than that in the normal mice, which may be explained by a significant upregulation of colonic UDP-glucuronosyltransferase (Ugt)1a9 expression and a higher plasma concentration of TSA glucuronides in the model mice at 0.5, 1 and 2?h after TSA administration.

4.?Together, these results reveal high accumulation at the site of inflammation and minimal systemic concentration of TSA, which are favorable pharmacokinetic behaviors to meet the requirements for CD treatment.     

Lung tumors in mice induced by “whole-life” inorganic arsenic exposure at human-relevant doses

In mice, inorganic arsenic in the drinking water in the parts per million range via the dam during in utero life or with whole-life exposure is a multi-site carcinogen in the offspring. However, human arsenic exposure is typically in the parts per billion (ppb) range. Thus, we studied “whole-life” inorganic arsenic carcinogenesis in mice at levels more relevant to humans. Breeder male and female CD1 mice were exposed to 0, 50, 500 or 5,000 ppb arsenic (as sodium arsenite) in the drinking water for 3 weeks prior to breeding, during pregnancy and lactation, and after weaning (at week 3) groups of male and female offspring (initial n = 40) were exposed for up to 2 years. Tumors were assessed in these offspring. Arsenic exposure had no effect on pregnant dam weights or water consumption, litter size, offspring birthweight or weight at weaning compared to control. In male offspring mice, arsenic exposure increased (p < 0.05) bronchiolo-alveolar tumor (adenoma or carcinoma) incidence at 50-ppb group (51 %) and 500-ppb group (54 %), but not at 5,000-ppb group (28 %) compared to control (22 %). These arsenic-induced bronchiolo-alveolar tumors included increased (p < 0.05) carcinoma at 50-ppb group (27 %) compared to controls (8 %). An increase (p < 0.05) in lung adenoma (25 %) in the 50-ppb group compared to control (11 %) occurred in female offspring. Thus, in CD1 mice whole-life arsenic exposure induced lung tumors at human-relevant doses (i.e., 50 and 500 ppb).     

Chronic administration of ethanol on pituitary and hypothalamic β-endorphin in rats and golden hamsters

The effect of chronic exposure to ethanol on hypothalamic and pituitary endorphin levels of rats and golden hamsters was studied. In rats, chronic ethanol consumption caused a decrease in the level of immuno-reactive (i.r.) β-endorphin (β-EP) in the pituitary but an increase of i.r. β-EP in the hypothalamus. The Met-enkephalin level in the hypothalamus of ethanol-treated rats remained the same as the control. The body weights, as well as food and liquid intake, of ethanol-treated rats were observed to be lower than the controls. In golden hamsters, i.r. β-EP level in the hypothalamus and pituitary remained unchanged with chronic ethanol consumption. The body weight and liquid intake of golden hamsters also remained the same as the controls. Since the changes of pituitary and hypothalamic β-EP after ethanol administration were found only in rats but not in golden hamsters, it is likely that the effects of ethanol observed in rats are not specific.     

Examination of environmentally friendly “green” logistics behavior of managers in the pharmaceutical sector using the Theory of Planned Behavior

Background

Logistics activities play a prominent role in enabling manufacturers, distribution channels, and pharmacies to work in harmony. Nowadays these activities have become increasingly striking in the pharmaceutical industry and seen as a development area for this sector. Additionally, green practices are beginning to be more attracting particularly in decreasing costs and increasing image of pharmaceutical companies.

Ciomodulatory activities and gerontological pharmacologyof Chinese herbal drugs in the neuroendocrine-immunesystem in experimental models and aged animals

<正> The aging process in man and experimental animals has been subjected to numerous investigations in recent years in China as well as in many other countries. In the past 10 years, we have been interested in the evaluation of Chinese herbal products in the prevention and restoration of senile changes in the immune and related physiological systems, such as the     

Effects of the administration of miconazole by different routes on the biomarkers of the “steroidal module” of the Athlete Biological Passport

This article reports the results obtained from the investigation of the influence of miconazole administration on the physiological fluctuation of the markers of the steroid profile included in the “steroidal module” of the Athlete Biological Passport. Urines collected from male Caucasian subjects before, during, and after either systemic (i.e., oral and buccal) or topical (i.e., dermal) treatment with miconazole were analyzed according to validated procedures based on gas chromatography coupled to tandem mass spectrometry (GC–MS/MS) (to determine the markers of the steroid profile) or liquid chromatography coupled to MS/MS (LC–MS/MS) (to determine miconazole urinary levels). The results indicate that only after systemic administration, the markers of the steroid profile were significantly altered. After oral and buccal administration, we have registered (i) a significant increase of the 5α-androstane-3α,17β-diol/5β-androstane-3α,17β-diol ratio and (ii) a significant decrease of the concentration of androsterone, etiocholanolone, 5β-androstane-3α,17β-diol, and 5α-androstane-3α,17β-diol and of the androsterone/etiocholanolone, androsterone/testosterone, and 5α-androstane-3α,17β-diol/epitestosterone ratios. Limited effects were instead measured after dermal intake. Indeed, the levels of miconazole after systemic administration were in the range of 0.1–12.5 μg/ml, whereas after dermal administration were below the limit of quantification (50 ng/ml). Significant alteration started to be registered at concentrations of miconazole higher than 0.5 μg/ml. These findings were primarily explained by the ability of miconazole in altering the kinetic/efficacy of deglucuronidation of the endogenous steroids by the enzyme β-glucuronidase during the sample preparation process. The increase of both incubation time and amount of β-glucuronidase was demonstrated to be effective countermeasures in the presence of miconazole to reduce the risk of uncorrected interpretation of the results.     

Discriminative stimulus effects of ethyl-β-carboline-3-carboxylate at two training doses in rats

Rationale and objectives: The role of benzodiazepine (BZ) receptor mechanisms in modulating the stimulus effects of the BZ partial inverse agonist ethyl-β-carboline-3-carboxylate (β-CCE) are not well understood. The purpose of the present experiments was to assess the role of BZ and non-BZ receptor stimulation in the discriminative stimulus effects of β-CCE in rats. Methods: Adult male rats were trained to discriminate either a relatively high dose (10 mg/kg, n=8) or a relatively low dose (5.0 mg/kg, n=7) of β-CCE from saline under a fixed-ratio 10 schedule of food presentation. Results: Under the high-dose training condition, β-CCE engendered an increase in responding on the drug-paired lever up to 100% drug-lever responding, with no decrease in response rate. Diazepam, pentobarbital, flumazenil, (+)-amphetamine, and morphine did not share stimulus effects with 10 mg/kg β-CCE up to doses that suppressed rate of responding. The BZ full inverse agonist dimethoxy-4-ethyl-β-carboline-3-carboxylate also did not engender ≥80% β-CCE-lever responding up to doses that suppressed response rate and produced seizures in some animals. The BZ partial inverse agonists Ro 15-4513 and sarmazenil fully reproduced the stimulus effects of β-CCE. Flumazenil antagonized the effects of β-CCE with an in vivo apparent pA₂ value of 6.1 (slope=–0.86). Under the low-dose condition, β-CCE engendered an increase in drug-lever responding, with no changes in response rate. In contrast to the high-dose condition, diazepam, pentobarbital, and (+)-amphetamine engendered high levels of β-CCE-lever responding (up to 77, 96, and 75%, respectively), whereas flumazenil and morphine did not engender full β-CCE- lever responding. Conclusions: These results indicated that the stimulus effects of the high dose of β-CCE appeared consistent with mediation by the drug’s partial inverse agonist effects at BZ receptors. The discriminative stimulus effects of β-CCE at the lower training dose, however, appeared to be relatively non-specific. Received: 12 November 1998 / Final version: 15 March 1999