The pharmacological profile of norgestimate, a new orally active progestin.

Norgestimate (ORF 10131; d-13β-ethyl-17α-ethynyl-17β-acetoxygon-4-en-3-one oxime) is a new progestin which is being studied clinically in combination with ethinyl estradiol as a new combination oral contraceptive. Norgestimate is a moderately potent progestin, as judged by the classic Clauberg Assay, with an oral potency of about $\text{1}\text{5}$ that of d-norgestrel. It binds to progesterone receptors $\text{in vitro}$ and maintains pregnancy in ovariectomized rats. Norgestimate inhibits ovulation in rats with a potency of at least 800 times that of d-norgestrel. This compound is slightly less androgenic than d-norgestrel. Norgestimate is not estrogenic, i.e., it does not induce vaginal cornification, and it does not bind $\text{in vitro}$ to estrogen receptors. Norgestimate possesses marked antiestrogenic activity when compared to d-norgestrel.     

Preparations of heterospirostanols and their pharmacological activities

(3beta,20S,22S,25R)-22-Thiospirosol-5-en-3-ol (9) and (3beta,20S,22S,25R)-22-seleno-spirosol-5-en-3-ol (11) were prepared from diosgenin (3) via 26-iodopseudodiosgenin (6) as a key intermediate. Diosgenone (15), solasodinone (16), (20S,22S,25R)-22-thio-spirosol-4-en-3-one (17), (20S,22S,25R)-22-selenospirosol-4-en-3-one (18) and (20R,22S,25R)-spirosol-4-en-3-one (19) were prepared by Oppenauer oxidation of 3, solasodine 4, 9, 11 and (3beta,20R,22R,25R)-spirosol-5-en-3-ol 14, respectively. Oxidations of 15 and 16 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) provided corresponding dienone products, (20S,22S,25R)-spirosol-1,4-dien-3-one (20) and (20S,22S,25R)-22-thiospirosol-1,4-dien-3-one (21), respectively, while oxidation of 19 (C-20 diastereoisomer of 15) gave no dienone product but 21-exo vinyl product 22. 26-Thioacetylpseudodiosgenone (24) and 26-cyanoselenopseudodiosgenone (25) were prepared by treatment of 26-iodopseudodiosgenose (23), which was obtained by Oppenauer oxidation of 6, with potassium thioacetate and potassium selenocyanate, respectively. Compounds 15 and 19 exhibited more than 80% inhibitions in INF-gamma productions at 10.0 microM. Compounds 4 and 25 showed cytotoxic activities (IC(50) = 6 and 5 microM, respectively) against cancerous HCT 116 cell lines. Compounds 12 and 25 had antiurease activities (IC(50) = 12.4 and 11.4 microM, respectively), in which only the latter showed an inhibition zone (mean zone diameter = 12.2 mm) formed by Bacillus subtilis 168 trp.     

Adrenomedullin: a new target for the design of small molecule modulators with promising pharmacological activities

Adrenomedullin (AM) is a 52-amino acid peptide with a pluripotential activity. AM is expressed in many tissues throughout the body, and plays a critical role in several diseases such as cancer, diabetes, cardiovascular and renal disorders, among others. While AM is a protective agent against cardiovascular disorders, it behaves as a stimulating factor in other pathologies such as cancer and diabetes. Therefore, AM is a new and promising target for the development of molecules which, through their ability to regulate AM levels, could be used in the treatment of these pathologies.     

Anti-secretory and anti-ulcer activities of some new 2-(2-pyridylmethyl-sulfinyl)-benzimidazoles

A series of substituted sulfinyl benzimidazoles were prepared and tested for gastric anti-secretory activity. Following initial screening, two compounds were tested for anti-ulcer activity. The new compounds showed pharmacological properties different from those of omeprazole 1, since they proved to be weak anti-secretory agents displaying non-specific anti-ulcer activity. Some structural requirements for optimum activity were elucidated.     

丹参的化学成分和药理活性研究概况(综述)

目的:对中药丹参的化学成分和药理活性进行综述.方法:查阅文献.结果:丹参为中医活血化瘀代表药,含多种化学成分、具有多种药理活性.结论:丹参的进一步研究开发具有广阔前景.     

Antioxidant activities of various fruits and vegetables produced in Taiwan

Fruits and vegetables have been known to contain a variety of antioxidant components. It has been suggested that antioxidants may protect biomolecules from oxidative damage and therefore be associated with reduced risks of cardiovascular disease and certain cancer. The antioxidant abilities of various parts of eight common fruits and vegetables produced in Taiwan were investigated, including tomato, guava, squash, tangerine, wax gourd, pineapple, chayote, and eggplant. Squash, wax gourd, tomato, and guava seeds showed the highest antioxidant activities in thiobarbituric acid assay. Wax guard and squash seeds showed the highest antioxidant activities in iodometric assay. At the level of 1 g fresh sample, low-density lipoprotein peroxidation was inhibited by at least 90% by tomato meat, guava meat, squash seed, wax gourd meat, core, and seed, and eggplant skin. The total phenolic content was significantly correlated with antioxidant activities measured by thiobarbituric acid (r=0.715, P<0.01) and iodometric (r=0.749, P<0.01) assays. The results of this study could be used for development of merchandise with potential health benefits from agricultural products.     

Antioxidant activities of various fruits and vegetables produced in Taiwan

Fruits and vegetables have been known to contain a variety of antioxidant components. It has been suggested that antioxidants may protect biomolecules from oxidative damage and therefore be associated with reduced risks of cardiovascular disease and certain cancer. The antioxidant abilities of various parts of eight common fruits and vegetables produced in Taiwan were investigated, including tomato, guava, squash, tangerine, wax gourd, pineapple, chayote, and eggplant. Squash, wax gourd, tomato, and guava seeds showed the highest antioxidant activities in thiobarbituric acid assay. Wax guard and squash seeds showed the highest antioxidant activities in iodometric assay. At the level of 1 g fresh sample, low-density lipoprotein peroxidation was inhibited by at least 90% by tomato meat, guava meat, squash seed, wax gourd meat, core, and seed, and eggplant skin. The total phenolic content was significantly correlated with antioxidant activities measured by thiobarbituric acid (r=0.715, P<0.01) and iodometric (r=0.749, P<0.01) assays. The results of this study could be used for development of merchandise with potential health benefits from agricultural products.     

Synthesis and pharmacological evaluation of new 1,2-dithiolane based antioxidants

Molecules containing a dithiolane moiety are widely investigated due to their antioxidant properties. The archetypal representative of this class of compounds is lipoic acid and indeed the lipoic acid-dihydrolipoic acid couple is part of the antioxidant defence system of the cell. In the course of a program aiming to find improved antioxidants effective in vivo, we designed, synthesised and pharmacologically investigated new lipoic acid analogs. The salient feature of these structures is the connection, via a thioamide or a thiocarbamate, of a 1,2-dithiolane moiety bearing a carbon chain and a N-alkyl-substituted morpholine ring. It was expected that the antioxidant and chelating properties of these functional groups combined with the basicity of the morpholine ring will impact on the antioxidant as well as on the partition and solubility characteristics of the compounds. Indeed in vitro and in vivo pharmacological investigation showed that these new molecules and especially those containing a thiocarbamate linker possess superior antioxidant properties compared with alpha-lipoic acid and to the amide or carbamate linker analogs. In particular, some of these compounds efficiently cross the blood brain barrier (BBB) thus providing efficient protection from lethality in a situation of induced oxidative stress. Moreover the absence of the 1,2-dithiolane moiety does not completely abolish antioxidant effects thus demonstrating that these compounds are distinct new chemical entities and not merely lipoic acid prodrugs. The chemical and pharmacological features of these new antioxidants are presented and discussed in the following paper.     

Synthesis and pharmacological activity of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine. Part 1. Synthesis and pharmacological activity of chain derivatives of 1-aryl-2-iminoimidazolidine containing urea moiety.

The synthesis and physicochemical properties of new carbonyl derivatives of 1-aryl-2-iminoimidazolidine are presented. Isomeric 1-(1-arylimidazolidine-2-ylidene)-3-arylureas (series A) and 1-aryl-2-imine-3-arylaminocarbonylimidazolidines (series B) were obtained after the condensation reaction of 1-aryl-2-iminoimidazolidines and arylisocyanates. 1-Aryl-2-iminoimidazolidines were synthesised in a two-step reaction from the respective anilines. The molecular structure of 1-(1-phenylimidazolidine-2-ylidene)-3-(4-chlorophenyl)urea (A2) has been determined by X-ray crystallography. The representatives of both investigated series were evaluated in behavioural animal tests. They exhibited significant, especially analgesic, activity on the animal central nervous system (CNS). They displayed substantial effect on the serotonine and catecholamine neurotransmission as well, at very low toxicity (LD(50) over 2000 mg kg(-1) i.p.). In the binding affinity tests they exhibited moderate affinity (on the micromolar level) toward opioid (mu) and serotonine (5HT(2)) receptors. The derivatives of series A had moderate affinity toward benzodiazepine (BZD) receptor as well. Distinctive differences observed in their activity spectra can be connected with the presence of particular structural features such as relative orientation of the two aromatic rings and the carbonyl moiety.     

Synbiotic effect of various prebiotics on in vitro activities of probiotic lactobacilli

In the present study, five Lactobacillus strains were evaluated for their viability in presence of different prebiotics viz. inulin, oligofructose, lactulose, raftilose, and honey. The viability of lactobacilli was observed before and after 5 weeks of refrigerated storage. The doubling time varied from 5.2 hrs to 9.6 hrs. The lowest doubling time was for Lactobacillus plantarum M5 followed by L. plantarum Ch1 with inulin. Viability of lactobacilli was greatest with inulin. The growth and viability in presence of prebiotics were found to be strain-specific. Hence, it could be concluded that the addition of prebiotics have a significant effect on probiotics, and hence, a combination of suitable Lactobacillus strain(s) with a specific prebiotic could be a viable probiotic-based functional food approach in administering the beneficial bacteria in-vivo.     

Effect of mirex on the activities of various rat hepatic mixed-function oxidases

Mirex (dodecachlorooctahydro-1,3,4-metheno-2H-cyclobuta[cd]pentalene) was orally administered to male and female rats at daily dosages of 5, 10, 25, and 50 mg/kg for 5 days and its effects on aniline hydroxylas,p-nitroanisoleO-demethylase, ethyl morphine-N-demethylase, and UDP-glucruonyltransferase activities in the liver were studied. Liver-to-body weight ratios show significant increases at all of the doses tested, reaching maximum of 206 and 230 per cent of controls at a dose of 25 mg/kg for males and females, respectively. Metabolism of each of the substrates is altered by each dose of mirex fed. Aniline hydroxylase activity is decreased at all levels tested and the reduction is progressive with the dose. The Mirex content of rat liver microsomes is, by analysis, 9.69, 14.75, and 36.73 µg per 0.2gram-equivalents of liver microsomes from male rats treated at 10, 25, and 50 mg/kg, respectively. Aniline hydroxylase activity is not affected by addition of up to 400 µg of mirex to the reaction mixtures, using liver preparations from untreated animals.p-Nitroanisole demethylation activity is induced to a maximum in animals treated at 5 mg/kg. Ethyl morphine demethylase is induced to a maximum by 10 mg/kg in male and 25 mg/kg in female rats. Higher doses manifest a reversal ofp-nitroanisole-and ethyl morphine demethylase activities in both the sexes. Although the UDP-glucuronyl transferase specific activity is unaffected by mirex pretreatment, total activity in the liver increases to a maximum of 173 and 149 percent of controls at 25 mg/kg in males and females, respectively. Thus, it appears that chronic low doses of mirex seriously alter hepatic mixed-function oxidase systems of exposed animals, although mirex is not a substrate for any of these enzymes.     

Antioxidant activities of various extracts of lotus (Nelumbo nuficera Gaertn) rhizome

Lotus rhizome powder was extracted with solvents of different polarities. Antioxidant activities of the extracts were evaluated by a 2, 2'-diphenylpicrylhydrazyl (DPPH) assay and a beta-carotene bleaching assay, and compared with that of butylated hydroxyanisole (BHA) and ascorbic acid. Methanol showed the highest extract yield among all of solvents. Although acetone extract had the highest total phenolics content, methanol extract had the highest total phenolics recovery from lotus powder (20.1 mg catechin equivalents/100g lotus powder). Extract of either methanol or acetone demonstrated the highest DPPH scavenging activity at both 66.7 mg/L and 133.3 mg/L. All extracts exhibited higher antioxidant activity coefficient (AAC) than that of ascorbic acid, furthermore, dichloromethane and petroleum extracts had comparable AAC with BHA by the beta-carotene bleaching assay. The properties of the extracting solvents significantly affected the yield, total phenolics content and antioxidant activity of lotus rhizome extracts.     

Evaluation of interaction potential of certain concurrently administered drugs with pharmacological and pharmacokinetic profile of centchroman in rats

Centchroman (Ormeloxifene) is a nonsteroidal, selective estrogen receptor modulator, oral contraceptive and anticancer agent, and is intended for long-term use by women. In view of its vast clinical application and the interaction of steroidal oral contraceptives with certain commonly used therapeutic agents, evaluation of interaction of certain concomitantly administered therapeutic agents (ibuprofen, rifampicin, diazepam, salbutamol, nifedipine, paracetamol, haloperidol, and tetracycline), in terms of both the postcoital contraceptive efficacy and pharmacokinetic profile, with centchroman was undertaken in female Sprague-Dawley rats. Among the representatives from each commonly used therapeutic category, interaction (pharmacokinetic) was observed with ibuprofen (60 mg/kg, twice daily), haloperidol (0.7 mg/kg, twice daily), and tetracycline (140 mg/kg, twice daily) coadministration on Days 1 through 5 postcoitum. Of these three therapeutic agents, only tetracycline interfered with the contraceptive efficacy of centchroman. It reduced the bioavailability of centchroman and its active metabolite by increasing their excretion through bile and feces. Increased metabolite excretion on tetracycline coadministration indicates the enterohepatic recirculation of the metabolite, not the parent drug. However, the effect of tetracycline was negated by the inclusion of lactic acid bacillus spores in the regimen.     

Synthesis and pharmacological evaluation of new 4-2-(7-heterocyclemethoxynaftalen-2-ylmethoxy)ethylbenzoic acids as LTD(4)-antagonists

A group of new 4-[2-(7-heterocyclemethoxynaftalen-2-ylmethoxy)ethyl]benzoic acids have been synthesized and pharmacologically evaluated as LTD(4)-antagonists. Thiazole derivatives, especially 4-[2-[7-(4-cyclobutylthiazole-2-ylmethoxyl)naphthalen- 2-ylmetho-xy]et hyl]benzoic acid, present considerable activity and improved pharmacokinetic profiles in comparison with our quinoline containing lead molecule confirming the interest of our compounds as potentially oral antiasthmatics and that the 4-alkylthiazole system can be considered as bioisosteric of the quinoline ring at least in our series of compounds.     

The trace element profile in children from various goiter-endemic areas of the Arkhangelsk Region

The paper presents the results of studying the trace element status in residents from various goiter-endemic areas of the Arkhangelsk Region. It is concluded that endemic goiter in the study areas is determined by not only iodine deficiency, but also by the imbalance of thyroid-specific elements. Goiter endemic is caused by the decreased content of Se, Co, Cr, Fe, and the elevated level of Si. Moreover, an iodine-sufficient area is characterized by the lower levels of Ca, Mg, and Mn. Trace element imbalance is accounted for by the biogeochemical features of the areas under study.