Degraded and undegraded carrageenans and experimental gastric and duodenal ulceration

The prevention of histamine-induced gastric and duodenal ulceration in the guinea-pig has been examined using a series of undegraded and degraded carrageenans. Undegraded carrageenans were active at lower doses than degraded carrageenans. The high viscosity of the undegraded carrageenans in solution prevented their use in larger doses. Degradation of carrageenan without serious loss of sulphate, gives a product which allows the dose to be increased to an extent that its effect more than offsets the slight loss in activity caused by the degradation. No single feature of carrageenan structure can be related to anti-ulcer activity although degradation, and hence reduction of molecular size, generally reduces activity. Sulphate contents over 30% have little apparent effect on activity; κ-carrageenans were not consistently different in anti-ulcer activity from Λ-carrageenans. This contrasts with the antipeptic activity of carrageenans where κ-carrageenans are less active than their Λ-counter-parts. As with antipeptic activity, the degree of anti-ulcer activity is probably determined by a combination of structural features which includes molecular size and polyanionic properties.     

Affective and Anxiety Disorders and Alcohol and Drug Dependence:

Depression and anxiety frequently coexist in patients with substance use disorders. This clinically-oriented article examiens the relationship between these conditions and emphasizes data showing that substances of abuse can cause signs and symptoms of both depression and anxiety. These substance-related syndromes appear to have a different course and prognosis than uncomplicated, independent anxiety and major depressive disorders, and clinicians should consider the role of alcohol and other drugs in all patients presenting with these complaints. The authors will also outline an approach for diagnosing and managing patients with the combination of a substance use and depressive or anxiety disorder.     

Synthesis and antiradical and antioxidant activity of cycvalon and its analogs

A new approach to the activation of components of the condensation of aromatic aldehydes with cyclohexanone, functioning as a receptor for the CH-acid component, is demonstrated. The condensation was performed in the presence of excess phosphorus oxychloride with heating and formed the corresponding 2,6-dibenzylidenecyclohexanone derivatives at high yield. The antiradical and antioxidant activities of the resulting compounds were assessed and cycvalon was found to have the greatest activity. The reference compound (dibunol) did not quench free radicals and had less antioxidant activity than cycvalon. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 8, pp. 7–10, August, 2007.     

Glucosidase and fucosidase inhibitors and Advances in nucleosides and nucleotides.

The American Chemical Society Symposium "Glucosidase and fucosidase inhibitors" took place on 1 April 1998 and was organized by Professors Zbigniew J Witczak (UConn, School of Pharmacy, CT, USA), Kuniaki Tatsuta (Waseda University, Tokyo, Japan) and Waldemar Priebe, MD (Anderson Cancer Center, University of Texas, USA). Professor Witczak provided introductory remarks including the status of existing glucosidase inhibitors, and chaired the morning session, which consisted of six lectures. The symposium was well received, and was particularly attractive for those interested in networking, as attendance was about sixty. In addition, some participants and attendees presented posters on the subject during the regular poster session organized by the Division of Carbohydrate Chemistry.     

Excretion and biotransformation of alfentanil and sufentanil in rats and dogs

The excretion and biotransformation of alfentanil (ALF) and sufentanil (SUF), two recent analogues of the synthetic opioid fentanyl, were studied after single iv administration of the tritium-labeled drugs in male rats and dogs. The drugs were almost completely metabolized in the two species, which resulted in a large number of metabolites. The excretion of the metabolites was rapid and exceeded 95% within 4 days, except for that of ALF metabolites in dogs (about 85%). For ALF, excretion of the radioactivity with the urine (73% in rats, about 76% in dogs) exceeded that with the feces. For SUF, excretion of the radioactivity with the urine amounted to 38 and 60% and that with the feces to 62 and 40%, in rats and dogs, respectively. Bile-cannulated rats excreted 68% with the bile within 24 hr after SUF dosing, and about 22% of this biliary radioactivity was subjected to enterohepatic circulation. After an ALF dose, the biliary excretion amounted to 24%, and the enterohepatic circulation was minimal. The main metabolic pathways of the two drugs were the oxidative N-dealkylation at the piperidine nitrogen and at the amide nitrogen, oxidative O-demethylation, aromatic hydroxylation, and the formation of ether glucuronides. N-[4-(Hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide (M6) was the main metabolite of both ALF and SUF in rats. In dogs, the glucuronide of N-(4-hydroxyphenyl)propanamide (M5) was the main metabolite of ALF. After SUF dosing in dogs, N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide was more abundant than M5.     

Paraldehyde and methylpentynol and ganglionic transmission

Paraldehyde and methylpentynol blocked transmission of nerve impulses through the superior cervical ganglion of the cat when the drugs were administered intra-arterially to the ganglion or intravenously using the nictitating membrane as an indicator. Electrical studies showed that concentrations of methylpentynol and paraldehyde which blocked transmission in the isolated rat superior cervical ganglion were without action on the preganglionic nerve fibre. In amounts which blocked transmission in the isolated rat ganglion, paraldehyde had no depolarizing activity directly on the ganglion cells and did not interfere with the depolarizing activity of added acetylcholine. The results suggest that the block in transmission of the impulse could be accounted for by a decrease in the release of acetylcholine from the preganglionic nerve terminals. In both species the block was reversible.     

成骨细胞的功能与损伤和骨质疏松的防治

骨质疏松是一种全身性骨骼疾病,导致骨折风险增加。成人的骨量通过破骨细胞的骨吸收和成骨细胞的骨形成作用来维持动态平衡,治疗骨质疏松症的理想策略是抑制破骨细胞的骨吸收和/或增强成骨细胞的骨形成功能。目前针对保护成骨细胞及增强其功能的骨质疏松疗法相对较少。因此,本文针对成骨细胞相关功能蛋白、各种细胞损伤机制（内质网应激、氧化应激、机械过载、微小RNA和长链非编码RNA的影响等）及骨质疏松的治疗与预防作一综述,以期为针对增强成骨细胞功能的骨质疏松治疗策略提供新思路。     

Cellular and multicellular form and function

Engineering artificial tissue constructs requires the appropriate spatial arrangement of cells within scaffolds. The introduction of microengineering tools to the biological community has provided a valuable set of techniques to manipulate the cellular environment, and to examine how cell structure affects cellular function. Using micropatterning techniques, investigators have found that the geometric presentation of cell-matrix adhesions are important regulators of various cell behaviors including cell growth, proliferation, differentiation, polarity and migration. Furthermore, the presence of neighboring cells in multicellular aggregates has a significant impact on the proliferative and differentiated state of cells. Using microengineering tools, it will now be possible to manipulate the various environmental factors for practical applications such as engineering tissue constructs with greater control over the physical structure and spatial arrangement of cells within their surrounding microenvironment.     

Antiinfective and encrustation-inhibiting materials--myth and facts

Catheters, urethral and ureteral stents and other urological implants are frequently affected by encrustration and infection due to their permanent contact with urine. Indwelling urinary catheters provide a haven for microorganisms and thus require extensive monitoring. Several surface modification techniques have been proposed to improve the performance of devices including the immobilization of biomolecules, the incorporation of hydrophilic grafts to reduce protein adsorption, the creation of hydrophobic surfaces, the creation of microdomains to regulate cellular and protein adhesion, new polymers and antimicrobial coatings. Physico-chemical explanation to elucidate the mechanism of such encrustation or infection inhibiting materials is still not available. Our series of experiments showed a marked decrease of silver-activity in biological fluids which corresponds with the controversial clinical results obtained with silver coated urinary catheters. Rifampicin/minocycline coated catheters had very low activity against Gram-negative rods, enterococci and Candida spp., the main causing organisms of urinary catheter infection. Surface engineered materials and antimicrobial drug delivery systems will be the next generation of sophisticated urinary catheters and stents, if both efficacy as well as efficiency has been proved clinically.     

Dietary vitamin E and selenium and toxicity of nitrite and nitrate

Nitrites and nitrates are important antimicrobial and flavoring/coloring agents in meat and fish products. However, nitrites and nitrates may cause methemoglobinemia and other illness, and may react with certain amines to form carcinogenic nitrosamines. The nutritional status of vitamin E and selenium has long been associated with nitrite and nitrate toxicity, although the mechanism involved is not yet clear. Information available recently shows that nitrites and nitrates are both oxidation products and ready sources of nitric oxide (NO*), that NO* reacts rapidly with superoxide to form highly reactive peroxynitrite (ONOO-), and that vitamin E may mediate the generation and availability of superoxide and NO*. Increased formation of ONOO- resulting from nitrite treatment and low intake of vitamin E and selenium may thus be the critical event leading to tissue damage and animal mortality observed previously. The protection against the adverse effects of nitrites/nitrates by vitamin E is attributed to its ability to reduce ONOO- formation, while selenium exerts its protective effects via seleno-enzymes/compounds, which reduce ONOO- formed.     

Melanocortins and their receptors and antagonists

The melanocortins are a group of small protein hormones derived by post-translational cleavage of the proopiomelanocortin (POMC) gene product. The known melanocortin hormones include alpha-melanocyte stimulating hormone (MSH), beta-MSH, gamma-MSH and adrenocorticotropic hormone (ACTH). Five melanocortin receptors (MCIR through to MC5R) have been identified and most of these show tissue-specific expression patterns, as well as different binding affinities for each of the melanocortin hormones. The central melanocortin system consists of alpha-MSH, agouti-related protein (AGRP), MC3R and MC4R. AGRP and alpha-MSH are believed to be the natural antagonist and agonist respectively of MC3R and MC4R. This central melanocortin system is thought to play a fundamental role in the control of feeding and body weight. Knock-out mice models and genetic studies have pointed to the importance of the melanocortins in complex human pathways such as pigmentation, lipolysis, food intake, thermogenesis, sexual behaviour, memory and inflammatory response. Recently the melanocortins and their receptors have been the target for drug-based treatment of human physiological processes. MC3R and MC4R are likely targets for controlling body weight; MCIR may be used in the treatment of inflammation and MC2R for the treatment of glucocortical deficiency. A role for MCSR still remains unclear, but the evidence suggests an exocrine gland function.     

Modelling and simulation of variability and uncertainty in toxicokinetics and pharmacokinetics

Two important methodological issues within the framework of the variability and uncertainty analysis of toxicokinetic and pharmacokinetic systems are discussed: (i) modelling and simulation of the existing physiologic variability in a population; and (ii) modelling and simulation of variability and uncertainty when there is insufficient or not well defined (e.g. small sample, semiquantitative, qualitative and vague) information available. Physiologically based pharmacokinetic models are especially suited for separating and characterising the physiologic variability from the overall variability and uncertainty in the system. Monte Carlo sampling should draw from multivariate distributions, which reflect all levels of existing dependencies in the intact organism. The population characteristics should be taken into account. A fuzzy simulation approach is proposed to model variability and uncertainty when there is semiquantitative, qualitative and vague information about the model parameters and their statistical distributions cannot be defined reliably.     

2,2 and 1,2-Bisaralkylmercapto- and -aralkylsulfonylpropanes

2,2- and 1,2-Bisaralkylmercapto- and -aralkylsulfonyl-propanes Condensation of aralkyl mercaptans 2 with acetone by means of hydrogen chloride affords 2,2-bismercapto-propanes 1 , which undergo cleavage to mercaptans 2 and isopropenyl sulfides 3 when heated in the presence of oxygen. Dependent on starting materials and reaction conditions 2 and 3 add together again to give 2,2-bismercapto-propanes 1 or 1,2-bismercapto-propanes 4 , which can be identified by n.m.r. spectroscopy or via the sulfones 5 and 8 , respectively. The addition of mercaptans to isopropenyl sulfides 3 or 9 also allows the preparation of different substituted 2,2- and 1,2-bismercapto-propanes, which can be oxidized to the corresponding dissulfones 10 – 17 .     

益生菌与肿瘤防治

益生菌广泛存在于自然界中,通过维持宿主体内菌群平衡、影响肠屏障功能和调节免疫应答等作用,提高宿主健康水平,被公认为"肠道健康卫士".一些益生菌可以增强机体的免疫功能,抑制致癌物质,影响肿瘤细胞的基因表达,对肿瘤具有拮抗作用.大量研究表明,益生菌在未来的肿瘤防治中有很好的应用和发展前景.     

Convulsant and anticonvulsant cyclopentanones and cyclohexanones

The convulsant and/or anticonvulsant activity of unsubstituted and mono-alkyl-substituted cyclopentanones and cyclohexanones were examined by testing the ability of these compounds to produce seizures or to inhibit seizures induced by pentylenetetrazol and maximal electroshock in CF-1 mice. In addition, these compounds were tested for their ability to bind to the picrotoxin receptor. The unsubstituted compounds, cyclopentanone and cyclohexanone, prevented both pentylnetetrazol- and maximal electroshock-induced seizures. Cyclopentanones and cyclohexanones with small (less than 3 carbon atoms) alkyl substituents in the 2-position were also anticonvulsant; all of these compounds, except 2-ethylcyclohexanone, blocked both pentylenetrazol- and maximal electroshock-induced seizures. 2-Ethylcyclohexanone was very effective against pentylenetetrazol seizures but did not prevent maximal electroshock seizures. Cyclohexanones with larger alkyl substituents in the 2-position, 2-propylcyclohexanone and 2-t-butylcyclohexanone, caused clonic seizures following injection into mice. Of the cyclopentanones and cyclohexanones with alkyl substitutions in the 3-position that were studied, one was an anticonvulsant (3-methylcyclopentanone), one was a mixed convulsant/anticonvulsant (3-ethylcyclohexanone), and the other two (3-ethylcyclopentanone and 3-t-butylcyclohexanone) were convulsants. Finally, two cyclohexanones with alkyl substituents in the 4-position were studied. Both 4-ethylcyclohexanone and 4-t-butylcyclohexanone produced convulsions when injected into mice. All the neuroactive cyclopentanones and cyclohexanones competitively displaced [35S]t-butylbicyclophosphorothionate, a ligand specific for the picrotoxin receptor, from rat brain membranes. The convulsant compounds were generally more potent than the anticonvulsants. The cyclohexanones were more potent than their corresponding cyclopentanones and the binding potency of both increased as the size of the alkyl substituent increased. These results suggest that cyclopentanone, cyclohexanone, and their alkyl-substituted derivatives act at the picrotoxin receptor to increase or decrease neuronal activity. Thus, they appear to have sites and mechanisms of action similar to those of the neuroactive gamma-butyrolactones and gamma-thiobutyrolactones.     

Membrane potential and ion content in cat and guinea-pig myometrium and the response to adrenaline and noradrenaline

1. Cats, virgin and 17 days pregnant, and guinea-pigs, virgin and 14-60 days pregnant, or treated for 1-8 days with oestradiol+progesterone, were used. The response of the uterus to adrenaline and noradrenaline was observed and, in pieces from the same tissues, the resting and active membrane potentials were recorded and the ionic content was determined.2. Adrenaline and noradrenaline relaxed the virgin cat uterus, adrenaline being 20-100 times more potent in vivo and about 10 times or less in vitro.3. Adrenaline and noradrenaline caused contraction of the early pregnant cat uterus, the ratio of potency being about 1.4. Adrenaline and noradrenaline had a biphasic effect on the guinea-pig uterus in all conditions. The ratio of potency was about 1.5. The mean membrane potential was 48 mV in virgin cat uterus and 64 mV on the seventeenth day of pregnancy.6. In guinea-pigs the average membrane potential increased from 38 mV in the virgin uterus to 58 mV on the thirtieth day of pregnancy. A similar increase was produced by eight daily injections of 5 mug oestradiol and, on the last 4 days, additional 1.5 mg progesterone.7. In the cat, no significant change in K and Na content was observed during pregnancy. The intracellular chloride content, however, rose from 51.5 m-moles/1. fibre water in the virgin uterus to 89 m-moles in the early pregnant uterus. As a result, the calculated chloride equilibrium potential changed from - 25 mV in virgin uterus to - 11 mV in pregnant uterus.8. In the guinea-pig no significant change in ion content was observed and the calculated potassium and chloride equilibrium potentials remained both unaltered during pregnancy.9. In contrast to guinea-pig uterus in all conditions, and to virgin cat uterus, early pregnant cat uterus was not spontaneously active and excess calcium caused no hyperpolarization.10. The reversal of the uterine response to adrenaline as a result of pregnancy is discussed in relation to the increase of the intracellular chloride content which was only observed in the cat.     

Metabolism and disposition of cyproheptadine and desmethylcyproheptadine in pregnant and fetal rats

The tissue distribution of unchanged drug and metabolites in pregnant rats was studied following oral administration of cyproheptadine (CPH) or its N-demethylated metabolite, desmethylcyproheptadine (DMCPH). A high performance liquid chromatographic (HPLC) method was developed for analysis of CPH and its metabolites in maternal and fetal tissues. In pregnant rats given CPH (11 mg/kg) during the final 2 or 8 days of gestation, the unchanged drug, DMCPH and desmethylcyproheptadine-10,11-epoxide (DMCPH-epoxide) were detected in various maternal and fetal tissues, including pancreas, liver, lung, kidney and placenta. DMCPH and DMCPH-epoxide were also present in fetal tissues after 8 oral doses of DMCPH (11 mg/kg) to pregnant rats. Tissue concentrations of unchanged CPH and its metabolites, after each treatment regimen, were highest in the lung. Except for pancreas and brain, the levels of CPH, DMCPH, or DMCPH-epoxide in tissues at early times after completing CPH treatment were 3- to 10-fold higher in the dam than in the fetus. Brain levels of CPH metabolites were higher in the fetus than in the maternal animal. The metabolite DMCPH-epoxide appeared in fetal pancreas in concentrations equal to those in the maternal pancreas. In separate experiments designed to examine the metabolic capability of the fetus (day 20 of gestation), it was found that fetally administered CPH was not demethylated and, instead, epoxidated to form cyproheptadine-10,11-epoxide (CPH-epoxide). Administration of the metabolite DMCPH to the fetus showed that it was also readily converted to an epoxide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Self-stimulation and amphetamine: Tolerance to d and l isomers and cross tolerance to cocaine and methylphenidate

The effects of the d and l isomers of amphetamine on self-stimulation responding were tested following acute and chronic administration. Tolerance and post-drug depression of responding occurred in tests with both isomers, indicating no role for p-hydroxynorephedrine (PHN) which is one of the metabolites of d-amphetamine. In the second experiment, d-amphetamine, methylphenidate and cocaine all produced quantitatively and qualitatively similar effects on self-stimulation responding following acute administration. Following chronic administration of d-amphetamine, animals showed tolerance to all three drugs, indicating cross-tolerance among them. These data are consistent with an hypothesis that tolerance and post-drug depression following chronic amphetamine treatment are the result of decreases in postsynaptic receptor sensitivity, which would lead to a decreased effectiveness of all three drugs, regardless of their pre-synaptic mechanisms.