Toxicology and Genetic Susceptibility of Drugs and Pollutant

S21Possibleinvolvementofhereditaryfactors intheriskmodulationofarseniasisintwoethnic clansexposedtoindoorcombustionofhigharse niccoal LINGuo Fang1,DUHui2,CHENJi Gang3,LU Hong Chao2,GUOWei Chao1,ZHANGXin Jiang4,SHENJian Hua1(1.ShanghaiInstituteforBiologicalSciences,Institute ofPlantPhysiologyandEcology,ChineseAcademyof Sciences,Shanghai200032,China;2.Prefecture CenterforDiseasePreventionandControl,Guiyang562400,China;3.MunicipalCenterforDiseasePre ventionandControl,Shang…     

Influence of Type and Level of Water-Soluble Additives on Drug Release and Surface and Mechanical Properties of Surelease® Films

Ethylcellulose in combination with water-soluble additives has been used in the development of microporous membrane-coated dosage forms. In the present study, application of three types of water-soluble additives, namely polyethylene glycols (PEG 400, 3350, and 8000), maltodextrins (Maltrin M150, M100, and M040 in the order of lower to higher average polymer size and molecular weight; dextrose equivalence 16.9, 11.1, and 4.8, respectively), and xylitol, as porosity modifiers in the films of a commercially available aqueous ethylcellulose dispersion (Surelease/E-7-7060 plasticized with glyceryl tricaprylate/caprate) was investigated. The effect of type and level of these additives on drug release characteristics and surface and mechanical properties of the polymeric films was studied. Each additive was incorporated at 20 and 30% levels in the polymeric dispersion based on its solids content. Ibuprofen tablets were coated using the polymeric dispersion with and without additive at 3% w/w coat level in a fluid-bed equipment. The coated tablets were evaluated for their drug release rate, coat reflectivity (gloss), Brinell hardness, and elastic modulus. Differential scanning calorimetric analysis of the films was performed to determine the physico-chemical changes in the applied film-coats. The rate of drug release, hence film porosity, was observed to be dependent on the type and level of the additive added. The molecular weight of the additive and its concentration in the polymeric dispersion had significant influence on the rate of drug release, hardness, and elasticity of the film-coats.     

Synthesis of β-amino carbonyl derivatives of coumarin and benzofuran and evaluation of their biological activity

A series of β-amino carbonyl compounds containing coumarin (4a–h) and benzofuran (6a–i) moieties was synthesized by a three component Mannich reaction of 3-acetyl-2H-chromen-2-one (1) or 1-(1-benzofuran-2-yl) ethanone (5) with p-substituted aromatic aldehydes (2a–g) and aromatic amines (3a–b) in the presence of cerric ammonium nitrate as a catalyst. The newly synthesized compounds were screened for antimicrobial and antioxidant activities. Compounds 4b, 4e, 4f, 6f, 6g, and 6i showed microbial inhibition with minimal inhibition concentration ranging between 0.040 and 0.500 mg/mL, compounds 4b, 4c, 6c, 6e, and 6i showed promising free radical scavenging activity and compounds 4b, 4f, 6c, 6d, and 6h showed good chelating ability with Fe²⁺ ions. The synthesized compounds were studied for docking on the enzyme, glucosamine-6-phosphate synthase to predict the binding affinity and orientation at the active site of the receptor.     

Transdermal Penetration of Vasoconstrictors—Present Understanding and Assessment of the Human Epidermal Flux and Retention of Free Bases and Ion-Pairs

Purpose. As reductions in dermal clearance increase the residence time of solutes in the skin and underlying tissues we compared the topical penetration of potentially useful vasoconstrictors (VCs) through human epidermis as both free bases and ion-pairs with salicylic acid (SA). Methods. We determined the in vitro epidermal flux of ephedrine, naphazoline, oxymetazoline, phenylephrine, and xylometazoline applied as saturated solutions in propylene glycol:water (1:1) and of ephedrine, naphazoline and tetrahydrozoline as 10% solutions of 1:1 molar ratio ion-pairs with SA in liquid paraffin. Results. As free bases, ephedrine had the highest maximal flux, Jmax = 77.4 ± 11.7 g/cm²/h, being 4-fold higher than tetrahydrozoline and xylometazoline, 6-fold higher than phenylephrine, 10-fold higher than naphazoline and 100-fold higher than oxymetazoline. Stepwise regression of solute physicochemical properties identified melting point as the most significant predictor of flux. As ion-pairs with SA, ephedrine and naphazoline had similar fluxes (11.5 ± 2.3 and 12.0 ± 1.6 g/cm²/h respectively), whereas tetrahydrozoline was approximately 3-fold slower. Corresponding fluxes of SA from the ion-pairs were 18.6 ± 0.6, 7.8 ± 0.8 and 1.1 ± 0.1 respectively. Transdermal transport of VC's is discussed. Conclusions. Epidermal retention of VCs and SA did not correspond to their molar ratio on application and confirmed that following partitioning into the stratum corneum, ion-pairs separate and further penetration is governed by individual solute characteristics.     

Bioavailability of β-acetyldigoxin after single and repeated doses of tablets and solution

Summary In eight healthy volunteers the bioavailability of -acetyldigoxin solution and tablets was measured after single and multiple doses. Plasma and urine data were used to calculate bioavailability by four different methods. The differences obtained and the interindividual variations suggested that different and independent methods should be employed to assess absolute and true bioavailability. There was no significant difference between the regimens and both preparations had similar bioavailability; mean values (± SD) for the solution were 68.3 ± 8.7 % (single dose) and 68.6±5.9 % (multiple doses), and for the tablets 72.8±7.5 % and 66.1±6.0 %, respectively. For routine measurements, single dose studies with plasma and urine sampling for 24 hours and 48 hours, respectively, were an accurate and practicable procedure.     

Comparative Study of the Pharmacokinetics and Bioequivalence of Meldonium and Mildronate® Preparations

Pharmaceutical Chemistry Journal - Acomparative study of the pharmacokinetics, bioequivalence, and safety of two marketed meldonium dosage forms Meldonium Organika (meldonium, 500 mg capsules,...     

Synthesis and SAR of Benzisothiazole- and Indolizine-β-d-glucopyranoside Inhibitors of SGLT2

d-glucopyranoside inhibitors of human SGLT2 are described. The synthesis of the C-linked heterocyclic glucosides took advantage of a palladium-catalyzed cross-coupling reaction between a glucal boronate and the corresponding bromo heterocycle. The compounds have been evaluated for their human SGLT2 inhibition potential using cell-based functional transporter assays, and their structure−activity relationships have been described. Benzisothiazole-C-glucoside 16d was found to be an inhibitor of SGLT2 with an IC₅₀ of 10 nM.     

Pharmacology and Toxicology of Herbs

S11StudiesontoxicityofChinesemedicines anddecreasedvirulencethroughthecompatibili tyofherbalingredients LIPeng Tao(CST)(BeijingUniversityofTraditionalChineseMedicine,Beijing100029,China)Beginningfromthereportoftherenalinjuryin ducedbyaristolochicacid,thepoisonoussideeffects ofChinesemedicineshaveattractedmoreandmoreat tentions,whichhaveproducedhugeinfluenceontheprogressoftraditionalChinesemedicines.Itbecomesa vitallyimportantissuetounderstandanduseChinese medicinescorrectly.Thetoxicity…     

Pharmacokinetics and Pharmacodynamics of Nitrendipine

ＰｈａｒｍａｃｏｋｉｎｅｔｉｃｓａｎｄＰｈａｒｍａｃｏｄｙｎａｍｉｃｓｏｆＮｉｔｒｅｎｄｉｐｉｎｅＰｈａｒｍａｃｏｋｉｎｅｔｉｃｓａｎｄＰｈａｒｍａｃｏｄｙｎａｍｉｃｓｏｆＮｉｔｒｅｎｄｉｐｉｎｅＭａｒｓｔｅｒ＇ｓＤｅｇｒｅｅＺｈｅｎ－ＬｉＬｉｎＳｕ...     

Different roles of PKC and PKA in effect of interferon-γ on proliferation and collagen synthesis of fibroblasts

AIM: To study the signal roles of protein kinase C (PKC) and protein kinase A (PKA) in the influence of interferon-gamma (IFN-gamma) on proliferation and collagen synthesis of fibroblasts derived from hypertrophic scar (HS-FB) and normal skin (NS-FB). METHODS: HS-FB and NS-FB were cultured and passaged in Dulbecco modified Eagles medium (DMEM). Activity of PKC and PKA were assayed by transferring phosphorus (32P) into substrate after treatment with IFN-gamma 1000 kU/L at 10, 30, 60, and 120 min. Cell proliferation was determined with MTT assay. The collagen synthesis was measured with [3H]proline incorporation and Type III pre-collagen was determined with radioimmunoassay. RESULTS: After exposure to IFN-gamma 1000 kU/L for 30 min, PKC activity of HS-FB and NS-FB increased from 2.57 +/- 0.14 and 2.13 +/- 0.12 nmol x min(-1) x g(-1) of control to 3.75 +/- 0.19 and 3.36 +/- 0.16 nmol x min(-1) x g(-1), respectively (P < 0.05). After exposure to IFN-gamma 1000 kU/L for 60 and 120 min, PKA activities of HS-FB increased gradually from 0.82 +/- 0.04 nmol x min(-1) x g(-1) of control to 1.03 +/- 0.05 and 1.23 +/- 0.06 nmol x min(-1) x g(-1), respectively (P<0.05). The PKA activities of NS-FB also increased from 0.52 +/- 0.03 nmol x min(-1) x g(-1) of control to 0.68 +/- 0.03 and 0.89 +/- 0.05 nmol x min(-1) x g(-1), respectively (P<0.05). The proliferation and collagen synthesis were enhanced by PKC activator (containing phosphatidylserine, diacylglycerol and Ca2+) and PKA inhibitor [H(7)250 micromol/L, 1-(5-isoquinolinylsulfonyl)-2-methyl piperazine], and inhibited by PKC inhibitor (GF109 250 micromol/L) and PKA activator (cAMP 25 micromol/L) (P<0.01). GF109 abrogated increased proliferation and collagen synthesis by IFN-gamma but it did not affect the inhibitory effects of IFN-gamma. At 120 min H7 reversed the inhibitory functions of IFN-gamma. CONCLUSION: IFN-gamma transiently increased proliferation and collagen synthesis of HS-FB and NS-FB by activation of PKC and subsequently inhibited proliferation and collagen synthesis by activation of PKA.     

Bifendate treatment attenuates hepatic steatosis in cholesterol/bile salt- and high-fat diet-induced hypercholesterolemia in mice

Effects of bifendate, a synthetic intermediate of schisandrin C (a dibenzocyclooctadiene derivative), on liver lipid contents were investigated in experimentally-induced hypercholesterolemia in mice. Hypercholesterolemia was induced by either chronic administration of cholesterol/bile salt or feeding a high-fat diet containing cholesterol and/or bile salt. Hepatic and serum total cholesterol levels were significantly increased (42-268% and 23-124%, respectively) in cholesterol or high-fat diet-treated mice, when compared with control animals receiving vehicle or normal diet. Hepatic triglyceride level was increased (up to 108%), but serum triglyceride level was significantly reduced by 23-63% in hypercholesterolemic mice. Daily administration of bifendate (0.03-1.0 g/kg, i.g.) for 4 days decreased hepatic levels of total cholesterol (9-37%) and triglyceride (10-37%) in hypercholesterolemic mice. Supplementing the high-fat diet with bifendate (0.25%, w/w) caused decreases in hepatic total cholesterol (25-56%) and triglyceride (22-44%) levels following 7 or 14 days of experiment, respectively, when compared with animals fed with high-fat diet not supplemented with bifendate. While fenofibrate treatment decreased both hepatic and serum lipid levels in hypercholesterolemic mice, bifendate treatment did not reduce serum lipid levels. Bifendate and fenofibrate caused an increase (10-41% and 59-98%, respectively) in hepatic index of hypercholesterolemic mice. The results indicate that bifendate treatment can invariably decrease hepatic (but not serum) lipid levels in various mouse models of hypercholesterolemia.     

Serum enzyme activities and hepatic triglyceride levels in acute and subacute acetaminophen-treated rats

The dose- and time-related hepatotoxic effects of acetaminophen were investigated in rats using biochemical parameters as indices of hepatotoxicity supplemented by the histophatological examination of the livers. The acute or subacute (twice daily for 7 days) administration of 0.25 g/kg acetaminophen did not produce any noticeable heptocellular damage. On the other hand, dose-dependent elevations in serum enzyme glutamic-oxaloacetic transminase (GOT), glutamic-pyruvic transaminase (GPT) and sorbitol dehydrogenase (SDH) activities and hepatic triglyceride (TG)_levels were observed following the administration of single doses of 0.5 and 1 g/kg acetominophen. Maximal hepatic damage occured 12–18 h after acute dosing, while the hepatic function returned to control levels by 48–72 h.In contrast with the acutely treated rats, the serum enzyme activities and the hepatic TG levels remained unchanged following 7-day treatment with 0.5 or 1 g/kg acetomiophen. Also, histopathologically the degree of acetaminophpen-induced hepatic necrosis was found to be far lee extensive in rats given 0.5 to 1 g/kg acetiminophen twice daily for upt to one week, as compared with the animals sacrified 18 h after administering single equivalent doses of this drug. The results suggest that the function in intensity of acetaminophen-induced hepatotoxicity becomes less severe after repeated exposure to this hepatotoxin.     

薯藤多糖降血脂作用实验研究

目的:观察薯藤多糖(STDT)在高脂动物模型上的降血脂作用。方法:SD大鼠、新西兰家兔采用高脂饲料喂养法、ICR小鼠采用腹腔注射蛋黄乳法复制高脂模型,分别灌胃给予不同剂量的STDT,测定给药前或给药后不同时间血清TC、TG、高密度脂蛋白胆固醇(HDL-C)和低密度脂蛋白胆固醇(LDL-C)等指标。结果:STDT250、500、1000mg/kg剂量灌胃给药4周可明显抑制食糜性高脂大鼠血清TC、TG以及LDL-C的升高;100、200、400mg/kg剂量灌胃给药4周,能明显降低食糜性高脂家兔的血脂水平,使其血清TC、TG、LDL-C明显下降;STDT400、800、1600mg/kg剂量给药3d,对腹腔注射蛋黄乳所致的高脂模型小鼠血脂也有一定的降低趋势。结论:STDT无论是预防给药或是治疗给药,对多种高脂模型动物均体现出一定的降脂作用。     

Schisandrin B from Schisandra chinensis reduces hepatic lipid contents in hypercholesterolaemic mice

The effects of schisandrin B (Sch B) on liver and serum lipid contents were investigated in mice with experimentally-induced hypercholesterolaemia. Hypercholesterolaemia was induced either by oral administration of a cholesterol/bile salts mixture (2/0.5 g kg(-1)) for four days or by feeding a high fat/cholesterol/bile salts (10/1/0.3%, w/w) diet for seven days. Daily co-administration of Sch B (50-200 mg kg(-1), i.g.) for four or six days, respectively, decreased hepatic total cholesterol (TC) and triglyceride (TG) levels (by up to 50% and 52%, respectively) in hypercholesterolaemic mice. Sch B treatment also increased hepatic indices (14-84%) in hypercholesterolaemic mice. The results indicated that Sch B treatment could decrease hepatic TC and TG levels, and increase liver weight, in mouse models of hypercholesterolaemia. Fenofibrate treatment (100 mg kg(-1)) produced effects similar to those of Sch B on the hepatic index and lipid levels of hypercholesterolaemic mice.     

GLUTATHIONE ALTERATIONS IN RAT LIVER AFTER ACUTE AND SUBACUTE ORAL ADMINISTRATION OF PARACETAMOL

1. The effect on hepatic glutathione was studied in rats pretreated orally with various dosages of paracetamol (acetaminophen) for varying time intervals. 2. Paracetamol caused a dose-dependent depletion of hepatic glutathione, the maximum depletion occurring 3 h after acute dosing, the levels returning to normal by 12 h after low doses (0.1 or 0.25 g/kg, p.o.) and by 72 h after the hghest doses (1 g/kg, p.o.). 3. Before returning to normal, the liver glutathione levels became significantly greater than the control values (35–40%) at 24 and 48 h in 0^.5 and 1 g/kg paracetamol-treated rats, respectively, suggesting thereby a ‘glutathione rebound action’ of paracetamol-pretreatment. 4. In contrast with the acutely treated rats, the liver glutathione content remained unchanged when 0–5 g/kg paracetamol was administered twice daily for 7 consecutive days. 5. Fasting caused a significant reduction in hepatic glutathione, the glutathione stores were replenished within 6 h after feeding. 6. The results suggest that the hepatic glutathione levels are reversibly depleted by single large doses of paracetamol, while the glutathione depletory effect appears to decrease after the repeated administration of this hepatotoxic agent.     

Glutathione depletion and recovery after acute ethanol administration in the aging mouse

Glutathione (GSH) plays an important role in the detoxification of ethanol (EtOH) and acute EtOH administration leads to GSH depletion in the liver and other tissues. Aging is also associated with a progressive decline in GSH levels and impairment in GSH biosynthesis in many tissues. Thus, the present study was designed to examine the effects of aging on EtOH-induced depletion and recovery of GSH in different tissues of the C57Bl/6NNIA mouse. EtOH (2-5 g/kg) or saline was administered i.p. to mice of ages 6 months (young), 12 months (mature), and 24 months (old); and GSH and cyst(e)ine concentrations were measured 0-24h thereafter. EtOH administration (5 g/kg) depleted hepatic GSH levels >50% by 6h in all animals. By 24h, levels remained low in both young and old mice, but recovered to baseline levels in mature mice. At 6h, the decrease in hepatic GSH was dose-dependent up to 3g/kg EtOH, but not at higher doses. The extent of depletion at the 3g/kg dose was dependent upon age, with old mice demonstrating significantly lower GSH levels than mature mice (P<0.001). Altogether these results indicate that aging was associated with a greater degree of EtOH and fasting-induced GSH depletion and subsequent impaired recovery in liver. An impaired ability to recover was also observed in young animals. Further studies are required to determine if an inability to recover from GSH depletion by EtOH is associated with enhanced toxicity.     

Markers of experimental acute inflammation in the Wistar Han rat with particular reference to haptoglobin and C-reactive protein

C-reactive protein (CRP), haptoglobin (Hp) and fibrinogen (Fbgn) are acute phase reactants (APRs), the blood levels of which increase during acute inflammation. However, although the levels of these APRs are used to monitor inflammation in man, their usefulness and sensitivity as markers of inflammation in rodents are less clear. We therefore wished to evaluate, in a comparative fashion, a prototype immunoassay for serum CRP, a commercial assay for serum Hp, and an automated assay for Fbgn, using a model of acute inflammation in the rat. Additionally, pro-inflammatory cytokines and serum protein fractions were also measured. The model of inflammation used was the intraperitoneal injection of Freund's complete adjuvant (FCA). In a concluding experiment, findings with Hp in the FCA rat model were validated in a toxicologically relevant study involving the induction of acute hepatic inflammation using the model hepatotoxicant carbon tetrachloride (CCl(4)). Female Wistar Han rats were treated with a single injection of FCA in a dose-response study (1.25-10.0 ml/kg, sampling at 36 h) and two time-course studies (over 40 h and 21 days). In a final experiment, rats were dosed with CCl(4) at 0.8 ml/kg and sampled over a 17-day period. In FCA and CCl(4) experiments, serum/plasma was prepared and tissues taken at autopsy for histological assessment (CCl(4) study only). In the dose-response study, serum CRP, Hp and plasma Fbgn were increased at all FCA dose levels at 36 h post-dosing. Serum alpha(2) and beta(1) globulin fractions were also increased, while albumin levels were decreased. In the 40-h time-course study, CRP levels peaked at 25-40 h post-dosing, to approximately 120% of control (as 100%). Hp levels increased to a maximum at 25 and 40 h post-dosing with values greater than 400% of control, and alpha(2) and beta(1) globulin fractions peaked at 30 and 40 h post-dosing to 221 and 187% of control, respectively. Increased serum interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) levels peaked at 20 h (11-fold) and 25 h (19-fold), respectively. In a 21-day time-course study, no increased CRP levels were measured despite elevated levels of Hp, which peaked at 36 h (approximately 7-fold above control), and remained elevated up to 21 days. IL-6 and IL-1beta levels peaked at 12 h (19-fold) and 24 h (28-fold), respectively. Liver histopathology of animals treated with CCl(4) showed centrilobular hepatocellular degeneration and necrosis (most significant at 36 h) with an inflammatory response (most significant at 48 h). Resolution of the lesion was complete by 4 days post-dosing. Serum alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase levels peaked at 36 h post-dosing. Hp levels increased maximally at 48 h (426% of control). We conclude that serum CRP is a poor marker of acute inflammation in the rat in comparison with serum Hp and plasma Fbgn. Between Hp and Fbgn, serum Hp is shown to be the most sensitive and useful marker of acute inflammation.     

The effects of temik and sumicidin and their mixture on Nubian goats

The administration of single oral doses of a mixture of 0.25 mg temik/kg and 112.5 mg sumicidin/kg to Nubian goats caused severe clinical signs. Death occurred within 10 h after redosing on day 7. Lesions were correlated with clinical chemistry changes. Goats which received single oral doses of 0.25 mg temik/kg or 112.5 mg sumicidin/kg alone has slight clinical changes and recovered 5 h post-dosing.     

Comparative induction of hepatic zinc-thionein and increase in tissue calcium by bacterial endotoxin in endotoxin-sensitive (C3H/HeN) and endotoxin-resistant (C3H/HeJ) mice

Induction of zinc-thionein (Zn-Th) by endotoxin was studied in mice using an endotoxin-sensitive C3H/HeN strain and an endotoxin-resistant C3H/HeJ strain to find a relation between the sensitivity of these strains to endotoxin and the inducibility of hepatic Zn-Th by the endotoxin. Both strains of female mice were injected with endotoxin at two doses and the increase in hepatic Zn-Th levels was examined after 24 h. At the lower dose (0.25 mg/kg body weight), C3H/HeJ mice induced Zn-Th at a markedly lower level than C3H/HeN mice. However, both strains exhibited a comparable amount of Zn-Th when a higher dose (10 mg/kg body weight) of endotoxin was used. A parallel increase in hepatic calcium concentration was observed with the induction of hepatic Zn-Th in both strains. The injection of a spleen supernatant fraction from C3H/HeJ mice into C3H/HeN mice did not reduce the Zn-Th induction by endotoxin in C3H/HeN mice.