Action of prostaglandin,PGF2α, on the uterus of the pregnant rat

Summary The effects of prostaglandin F₂ (PG) have been studied on the transmembrane potentials and contractions in isolated myometrial strips from pregnant rats. The results showed that: 1. The sensitivity of the myometrium to exogenous PG increases from day 19 to day 22 of gestation. 2. The electrical response to PG, at maximally effective doses (10^–6 to 10^–5 M) consists of a slow depolarization which upon reaching threshold initiates spike discharge. 3. These actions are most pronounced t term (day 22) and are due to a direct action of PG on the myometrical cells. 4. D-600 (a methoxy derivative of verapamil) abolishes spike discharge and the phasic contractions induced by PG but has no effect on the slow depolarization and the accompanying increase in tonic tension. 5. The slow depolarization is dependent upon the presence of sodium in the external environment and is unaffected by the removal of calcium. 6. The spikes (and phasic contractions) are dependent upon the presence of calcium in the external environment.This study was supported by USPHS Grant HD-06963-9     

Investigation of the venoconstrictor effect of 8′ hydroxydihydroergotamine,the main metabolite of dihydroergotamine,in man

Summary The time course of the venoconstrictor effect of dihydroergotamine and its main metabolite 8 hydroxy-dihydroergotamine was investigated in a placebo-controlled study in seven healthy male volunteers, after direct local infusion of 0.08 and 0.4 µg into superficial hand veins. Both dihydroergotamine and 8 hydroxy-dihydroergotamine elicited a similar, marked venoconstrictor effect. The time course of the venoconstrictor action was similar for both compounds; about one third of the effect was present at the end of the infusion, which lasted for 10 min, and it took about a further 20 min for the effect to reach its maximum. The effect then remained fairly constant for the rest of the period of observation of 180 min from the start of the infusion. The data indicate that the pharmacological activity of oral dihydroergotamine is due not only to the unchanged drug but also to its main metabolite, 8 hydroxy-dihydroergotamine, which occurs in plasma in concentrations about 5–7 times higher than those of dihydroergotamine itself. The absolute bioavailability of unchanged dihydroergotamine, therefore, does not reflect the markedly higher bioavailability of pharmacologically active drug.     

Combinatorial investigation of the effects of the incorporation of Ti, Si, and Al on the performance of α-Fe2O3 photoanodes

The effect of adding small amounts of Ti, Si, and Al on the photoelectrochemical activity of α-Fe(2)O(3) is investigated using a high-throughput combinatorial method. Quantitative ink jet printing is used to pattern iron oxide and dopant precursors onto conductive glass substrates. Subsequent pyrolysis yields a library of doped iron oxide electrodes that are screened for photoelectrolysis activity by immersing in an electrolyte and scanning a laser over the electrodes to map the photocurrent response. When Si and Al are individually added to iron oxide at the levels we studied, the photoelectrolysis activity decreased whereas low levels of Ti addition enhanced the photocurrents. Synergistic effects were observed resulting in enhanced photocurrents when multiple impurities were added to α-Fe(2)O(3).     

A systematic review of the effects of oleoylethanolamide,a high-affinity endogenous ligand of PPAR-α, on the management and prevention of obesity

Along with an increase in overweight and obesity among all age groups, the development of efficacious and safe anti-obesity strategies for patients, as well as health systems, is critical. Oleoylethanolamide (OEA), a high-affinity endogenous ligand of nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-α), plays important physiological and metabolic actions. OEA is derived from oleic acid, a monounsaturated fatty acid, which has beneficial effects on body composition and regional fat distribution. The role of OEA in the modulation of food consumption and weight management makes it an attractive molecule requiring further exploration in obesogenic environments. This systematic review was conducted to assess the effects of OEA on the obesity management, with emphasizing on its physiological roles and possible mechanisms of action in energy homeostasis. We searched PubMed/Medline, Google Scholar, ScienceDirect, Scopus, ProQuest, and EMBASE up until September 2019. Out of 712 records screened, 30 articles met the study criteria. The evidence reviewed here indicates that OEA, an endocannabinoid-like compound, leads to satiation or meal termination through PPAR-α activation and fatty acid translocase (FAT)/CD36. Additionally, the lipid-amide OEA stimulates fatty acid uptake, lipolysis, and beta-oxidation, and also promotes food intake control. OEA also exerts satiety-inducing effects by activating the hedonic dopamine pathways and increasing homeostatic oxytocin and brain histamine. In conclusion, OEA may be a key component of the physiological system involved in the regulation of dietary fat consumption and energy homeostasis; therefore, it is suggested as a possible therapeutic agent for the management of obesity.     

The role of α2-adrenoceptor antagonism in the anti-cataleptic properties of the atypical neuroleptic agent,clozapine, in the rat

1. The mechanism underlying the anticataleptic properties of the atypical neuroleptic agent, clozapine, has been investigated in the rat.
2. The close structural analogues of clozapine, loxapine (0.1 mg kg⁻¹ s.c.) and iso-clozapine (1 and 3 mg kg⁻¹ s.c.) induced catalepsy in rats. In contrast, clozapine and the regio-isomer of loxapine, iso-loxapine (up to 10 mg kg⁻¹ s.c.) did not produce catalepsy, but at a dose of 1 mg kg⁻¹ significantly inhibited catalepsy induced by loxapine (0.3 mg kg⁻¹ s.c.).
3. Radioligand binding assays showed that cataleptogenic potential was most clearly predicted by the D₂/5-HT_1A, D₂/5-HT_1B/1D and D₂/α₂-receptor affinity (K_D) ratios: i.e. 30–100-fold higher ratios were calculated for loxapine and iso-clozapine, whereas the ratios were less than 1 for clozapine and iso-loxapine. The ratios of affinities for D₂ to 5-HT_2A, 5-HT_2C or D₁ did not reflect the grouping of cataleptic and non-cataleptic compounds.
4. Co-treatment with the α₂-adrenoceptor antagonists, yohimbine (1–10 mg kg⁻¹ s.c.), RX 821002 (1–10 mg kg⁻¹ s.c.) and MK-912 (0.3 and 1 mg kg⁻¹ s.c.) dose-dependently inhibited the cataleptic response to loxapine (0.3 mg kg⁻¹). Yohimbine (1–10 mg kg⁻¹ s.c.) also dose-dependently inhibited the cateleptic response to haloperidol (0.3 mg kg⁻¹ s.c.). The α₂-adrenoceptor antagonists had no effect per se.
5. Neither yohimbine (10 mg kg⁻¹) nor RX821002 (3 mg kg⁻¹) altered the cataleptic response to the D₁ receptor antagonist, SCH 23390 (1 mg kg⁻¹ s.c.), while, like clozapine, both compounds abolished the response to the 5-HT_2A receptor antagonist, MDL 100,151 (3 mg kg⁻¹ s.c.).
6. The present data strongly implicate α₂-adrenoceptor blockade in the anticataleptic properties of clozapine and suggest that its lack of extrapyramidal side effects in the clinic may also be a consequence of this property.

     

The inter‐rater reliability of the Japanese version of the Inventory of Depressive Symptomatology, Clinician version

The Inventory of Depressive Symptomatology, clinician version (IDS‐C), was developed by Rush et al. to evaluate the severity of major depressive episodes. The aim of the present study was to establish the inter‐rater reliability of the Japanese version of the IDS‐C. A total of 16 subjects with DSM‐IV major depressive episode were evaluated. Two psychiatrists, who had completed a training session for evaluating the IDS‐C before starting this reliability study, attended systematic interview sessions with each subject to evaluate the IDS‐C independently, using the Japanese version of the structured interview guide for combined rating of the IDS‐C and the Hamilton Depression Rating Scale. The severity of the 30 IDS‐C items assessed by the two raters ranged from 0 to 4 for 27 items and from 0 to 3 for 3 items. The analysis of variance intra‐class correlation inter‐rater reliability values for the individual scale items ranged from 0.874 to 1.000. The present results suggest that the Japanese version of the IDS‐C is a potentially useful rating instrument with high inter‐rater reliability for measuring the severity of depressive symptoms in the hands of psychiatrists with sufficient evaluation training.     

Estradiol and testosterone modulate the anesthetic action of the GABA-A agonist THIP,but not of the neurosteroid 3α,5β-pregnanolone in the rat

Rationale As sex steroids modify the number and distribution of brain -aminobutyric acid (GABA)_A receptor subunits, we investigated the potential modulation of anesthesia, induced by agents acting on the GABA_A receptor, by estrogen and androgen.Objectives To assess possible effects of sex and hormonal condition (i.e., intact vs castrate; estradiol vs testosterone treatment) on the anesthetic effect of a GABA_A agonist, THIP (4,5,6,7-tetrahydroisoxazolo[5,4,-c]pyridin-3-ol hydrochloride), and an allosteric modulator of the GABA_A receptor: 3-hydroxy-5-pregnan-20-one (epipregnanolone).Methods The potencies of THIP and epipregnanolone for inducing loss of the righting response were compared between: (a) female and male rats; (b) intact and castrated animals of each sex; (c) untreated castrates and castrates given estradiol or testosterone.Results Sex and endocrine condition influenced sensitivity to i.v. THIP for the induction of anesthesia. ED₅₀ values were: gonadectomized females, 80 mg/kg > intact males, 50 mg/kg > proestrous females, 35 mg/kg > gonadectomized males, 28 mg/kg. Estradiol benzoate (EB; 3 g/day for 5 days) significantly increased THIP sensitivity in gonadectomized females: THIP + EB: ED₅₀=26 mg/kg vs THIP + sesame oil: ED₅₀=94 mg/kg, while testosterone propionate (TP; 10 mg injected 24 h before THIP) decreased THIP sensitivity in orchidectomized males when compared with vehicle-injected animals (ED₅₀=72 mg/kg vs 22 mg/kg, respectively).Conclusions Results suggest that estrogen increases the density or availability of GABA_A receptor subtypes on which THIP acts, while testosterone exerts the opposite effect. Neither sex nor gonadal condition influenced the anesthetic action of epipregnanolone as a similar potency was found in intact and in gonadectomized males and females.     

P20 Deepening the Reform of Pharmacological Experiments, Cultivating the Sense of Innovation in Students

The pharmacological experiment is an important and direct way to improve students＇ practical ability. Through the lab experiments, the students can strengthen their understanding of pharmacological effects or side effects ; learn the basic pharmacological ideas related to drug evaluation and develop their sense of innovation. Thus, we need to reform the design of the experiments.     

Contamination and Biomarkers in the Great Blue Heron, an Indicator of the State of the St. Lawrence River

In 1996–1997, nine breeding colonies of the great blue heron on the St. Lawrence River and its estuary (Québec, Canada) were investigated in the framework of a biomonitoring program. Fledglings from colonies in freshwater were more contaminated with mercury, PCBs and many organic contaminants than those from estuarine colonies. The level of contamination in the St. Lawrence River is generally below the levels of toxicological effects for the great blue heron. The molar ratio of retinol: retinyl palmitate in heron eggs was correlated with total PCBs (r=0.79) and Mirex (r=0.90). In plasma, all biochemical parameters were significantly different between freshwater and marine colonies. Plasma retinol concentrations at the Dickerson and Hérons colonies were significantly lower compared with those at Grande Ile (p<0.05) and Steamboat (p<0.001). Based on retinoid and β-carotene concentrations in eggs, low plasma retinol was not associated with possible dietary deficiency. Plasma retinol was negatively correlated with many PCB congeners, total PCBs (r=−0.78), p,p′-DDE, trans-nonachlor and α-HCH. Similarly, the hormone T3 was correlated with many PCB congeners, total PCBs (r=−0.69) and the same organochlorine chemicals. Plasma LDH concentrations were different among freshwater colonies, Grande Ile and Hérons colonies having LDH values significantly greater than those of Steamboat (respectively, p<0.05 and p<0.01). Globally, the health status of the St. Lawrence great blue heron population was judged to be acceptable, however, several biomarkers indicated positive responses to contaminants.     

Effect of hypophysectomy on the stimulation of liver growth by α-hexachlorocyclohexane,phenobarbital, and partial hepatectomy in the rat

Summary -Hexachlorocyclohexane (-HCH) or phenobarbital (PB) elicit growth and cell multiplication in rat liver.In hypophysectomized rats, -HCH and PB induce an increase in liver mass, but no increase in liver DNA. Hypophysectomy without additional treatment results in a decrease of liver size and RNA, while the DNA content remains unchanged, thereby leading to a relative DNA surplus. 1/3-hepatectomy in hypophysectomized animals leads to a small increase of hepatic DNA only; after 2/3-hepatectomy 75–80% of the original liver DNA are restored. In rats with intact hypophysis losses of liver DNA are known to be restored completely.The findings suggest that the relative DNA surplus in hypophysectomized rats prevents the stimulation of DNA synthesis by weak growth stimuli such as -HCH, PB, and 1/3-hepatectomy. If the relative DNA surplus is eliminated by partial hepatectomy, the inducers do produce DNA multiplication. It is concluded that the induction of liver growth and cell multiplication by -HCH and PB does not require the presence of the hypophysis or one of its hormones.Abbreviations HCH 1,2,3,4,5,6-hexachlorocyclohexane=benzene hexachloride - PB phenobarbital - b.w. body weight - BHT butylhydroxytoluene - STH somatotrophic hormone - ACTH adrenocorticotrophic hormone     

Comparison of the molecular interactions of two antagonists, MEN16132 or icatibant, at the human kinin B₂ receptor

BACKGROUND AND PURPOSE

Icatibant is a well-known kinin B₂ receptor antagonist currently used for angiooedema attacks. MEN16132 is a non-peptide B₂ receptor antagonist, more potent and long lasting than icatibant in different models. Here we studied the reasons for these differences between the two antagonists.

EXPERIMENTAL APPROACH

Rate of reversibility (over about 3 h) of the functional receptor blockade exerted by the antagonists was compared (inositol phosphates accumulation assay) in CHO cells expressing the human B₂ receptor and in human synovial cells. Antagonist pretreated cells were washed with medium and the time taken to restore bradykinin (BK) response measured. Antagonist affinity was measured by radioligand binding to wild type and mutated B₂ receptors.

KEY RESULTS

Recovery of BK-induced responses was slower in cells pretreated with MEN16132 than in those treated with icatibant. The affinity of icatibant (for the [³H]-BK or the B₂ receptor antagonist [³H]-MEN11270 binding site) was compared to that of MEN16132 using a panel of point-mutated receptors with mutations located at the transmembrane regions of the B₂ receptor, previously shown to decrease MEN16132 high affinity interaction. No consistent decrease of icatibant affinity was observed. From the different affinity of MEN16132 derivatives at wild type and W86A (transmembrane 2 region) receptors, and by evaluating its antagonist profile at the D266A/D284A double mutant receptor, a model of the MEN16132-B₂ receptor complex is proposed.

CONCLUSIONS AND IMPLICATIONS

MEN16132 dissociated from the B₂ receptor compartment more slowly than icatibant and interacted at a deeper level in transmembrane regions of the receptor.     

Is ecstasy MDMA? A review of the proportion of ecstasy tablets containing MDMA, their dosage levels, and the changing perceptions of purity

Aims Not every tablet sold as ecstasy contains MDMA (3,4-methylenedioxymethamphetamine). The historical origins and evolution of this mismatch will be reviewed, in order to estimate the proportions of ecstasy tablets containing MDMA at different periods over the past 30 years.Methods Surveys into the pharmacological constituents of ecstasy tablets, dosage levels, and empirical reports of their perceived purity, provide the main data for this review.Results During the 1980s and early 1990s there were few problems with the purity of ecstasy tablets, and the biochemical evidence shows that they nearly always contained MDMA. During the mid-1990s, the majority of ecstasy tablets continued to contain MDMA, while many others comprised MDA (3,4-methylenedioxyamphetamine), MDEA (3,4-methylenedioxyethylamphetamine), or amphetamine drug mixtures. However, a small proportion (4–20% according to survey, time and place), comprised non-amphetamine drugs such as caffeine, ephedrine, ketamine, paracetamol, or placebo. During the late 1990s, the proportion of ecstasy tablets containing MDMA increased to around 80–90%. The latest reports suggest that non-MDMA tablets are now very infrequent, with purity levels between 90% and 100%. Dosage levels of tablets are also highly variable, with low dose tablet often encountered during the mid-1990s, and high dose tablets now seen more frequently. The theoretical and practical implications of these findings will be debated.Conclusions The ecstasy purity problem was predominantly a phenomenon of the mid to late 1990s, when many tablets contained substances other than MDMA. Before and since then, the proportion of ecstasy tablets containing MDMA has been very high.     

Recent progress in understanding of structure, ligand interactions and the mechanism of activation of the β₂-adrenergic receptor

The understanding of β?-adrenergic receptor (β?AR) interactions with ligands as well as the mechanism of receptor activation changed radically from 2007, when the first crystallographic structure of the receptor was reported. Since then numerous crystallographic studies described interactions with all main classes of β?AR ligands and with G proteins, which provided a great insight into the molecular structure of the receptor. However, molecular mechanisms of receptor activations remain to be determined. Functional research supported the concept of ligand-directed signaling at β-adrenoceptors. Agonist can activate alternative signaling pathways with different capacities and trigger cellular effects. It indicates that agonists nominally belonging to the same class may bind to and/or stabilize different active conformations of the receptor which are selectively recognized by signaling proteins in the allosteric manner.     

Zinc,among a ‘cocktail’ of metal pollutants,is responsible for the absence of the terrestrial isopod Porcellio scaber from the vicinity of a primary smelting works

Porcellio scaber Latreille (Crustacea: Isopoda) of one month in age were reared for a year on leaf litter of field maple (Acer campestre) contaminated in the laboratory with a range of concentrations of cadmium, copper, lead or zinc. The metals were applied topically to the leaves as nitrates. Growth and survival, numbers of live offspring produced by females that matured, and concentrations of metals in adult isopods at the end of the experiment were measured.Critical concentrations of metals in food at which all the isopods died before producing offspring were 100 g Cd g^–1, 100 g Cu g^–1, 2000 g Pb g^–1 and 1000 g Zn g^–1 (on a dry weight basis). The relative toxicities of the four metals in the laboratory were compared with concentrations of cadmium, copper, lead and zinc in surface leaf litter in the vicinity of a primary smelting works at Avonmouth, South West England. The results support the hypothesis that the absence of Porcellio scaber from sites in the immediate vicinity of the factory is due to zinc poisoning. Although cadmium is approximately ten times more toxic to isopods than zinc in the laboratory, zinc is most likely to be killing isopods in the field because its concentration is always at least 30 times higher than cadmium in Avonmouth leaf litter, and more than 100 times higher at most sites.Populations of Porcellio scaber survive in field sites where surface leaf litter contains up to 5000 g Zn g^–1. This is at least five times higher than the critical concentration in laboratory experiments. Thus, the methodology for assessing metal toxicity described in this paper, exaggerates the potential effects of metals to isopods in the field. Such differences between laboratory and field toxicities of metals should be taken into account when environmental protection levels for metals are being proposed for soil invertebrates based on ecotoxicological tests conducted in the laboratory.     

Binding of the antiretroviral drug, d-aspartate-β-hydroxamate on the NMDA receptor

d-Aspartate-β-hydroxamate (d-A β H) exhibits antiretroviral properties in vitro and in vivo. It has glutamate agonist properties at the N-methyl-d-aspartate (NMDA) receptor in neuronal cell cultures. This study characterizes its binding properties to the NMDA receptor by measuring its stimulating effect on N-(1-(2-thienyl)[(3)H]cyclohexyl)piperidine ([(3)H]TCP) binding to the ionic channel in rat brain membranes. d-A β H stimulated [(3)H]TCP binding in a dose-dependent manner but to a lower extent than glutamate, suggesting only partial glutamate agonist properties. In the presence of antagonists of the different effector sites of the NMDA receptor the affinity of d-A β H was competitively decreased by CGS-19755 and 7-chlorokynurenate and unaffected by arcaine. Among several d-A β H analogues VHS.125 behaved as a full NMDA agonist, but l- or d-glutamate γ-monohydroxamate (d-GH or l-GH) were without effect. This study shows that d-A β H has potential neurotoxic effects due to its direct interaction with the NMDA receptor and that analogues such as d-GH or l-GH may rather be used in humans.     

Pilot study,in a rental retirement village,of an “AdherenceCheck” on the management of medicines by the older-aged

Background The older-aged living in a low socioeconomic, rental, retirement village have a low adherence to medicines and a poor understanding of their illnesses. MedsChecks are commonly used in Australian pharmacies in an attempt to improve the management of medicines. There is no published evidence that MedsChecks, or similar brief/single, interventions improve the management of medicines in the older-aged. Objective The objective of our study was to determine the effect of an AdherenceCheck, which is similar to a MedsCheck, but is performed in the home of the older-aged, had on the ongoing management of medicines by the older-aged living independently. Both a MedsCheck and an AdherenceCheck involves forming an individual Action Plan. Setting Rental retirement village. Method After interviewing the older-aged in the village about their management of medicines, they were given an AdherenceCheck and an Action Plan. Six months later their management of medicines and the Action Plan were (re-)evaluated. Main outcome measure Present and ongoing adherence to medicines. Results Only 15 of the original 23 participants completed the study. The AdherenceCheck with Action Plan did not significantly change the adherence to medicines of these older-aged living in the rental retirement village. Pre- to post-AdherenceCheck, there was a reduction in the percentage of participants with a good knowledge of their illnesses, and thus a corresponding significant increase in the percentage with no knowledge of their illnesses, and this may have been age related. Only 11 of the 15 participants remembered receiving an Action Plan, as part of the AdherenceCheck, and 7 of these considered that the Action Plan helped them manage their medicines. Conclusion An AdherenceCheck may not improve the management of medicines by the older-aged living in a rental retirement village. As there are no peer-reviewed publications as to whether the commonly used MedsChecks, which have some similarities to the AdherenceCheck, improve the management of medicines, it is suggested that these MedsChecks should also be formally evaluated.     

A comparison of the central actions of prostaglandins A1, E1, E2, F1α, and F2α in the rat

The effect of prostaglandins (PGs) A₁, E₁, E₂, F₁, and F₂ administered intraventricularly at doses of 0.02–4.0 g/rat were studied in some behavioral, antinociceptive and anticonvulsant tests in rats. Exploratory and locomotor activity were decreased by all PGs except A₁ and F₂ which had no effect on locomotor activity. All PGs studied, except A₁, induced hyperthermia and afforded protection in the hot-plate analgesic test and against maximal electroshock seizures.