Terpenoid biotransformation in mammals IV Biotransformation of (+)-longifolene, (-)-caryophyllene, (-)-caryophyllene oxide, (-)-cyclocolorenone, (+)-nootkatone, (-)-elemol, (-)-abietic acid and (+)-dehydroabietic acid in rabbits

1. The metabolism of (+)-longifolene, (-)-caryophyllene, (-)-caryophyllene oxide, (-)-cyclocolorenone, (+)-nootkatone, (-)-elemol, (-)-abietic acid and (+)-dehydro-abietic acid was studied in rabbits.

2. Each of these sesquiterpenoids was converted to primary, secondary or tertiary alcohols, among which the primary alcohol was predominant.

3. A vinylic methyl group and an exomethylene group were easily hydroxylated and converted to a glycol via an epoxide in many cases.

4. Eight new metabolites were determined by chemical and spectroscopic methods.     

Interacties dopamineantagonisten (metoclopramide, domperidon) en dopamineagonisten (L-dopa, bromocriptine)

Samenvatting Ziekte van Parkinson: L-dopa/bromocriptine met domperidon: gunstige interactie, relatief hoge doseringen L-dopa en bromocriptine worden verdragen zonder dat misselijkheid optreedt; L-dopa/bromocriptine met metoclopramide: ongunstige interactie, door het centrale dopamineantagonistische effect van metoclopramide wordt de werking van L-dopa en bromocriptine verminderd.Hyperprolactinemie: bromocriptine met domperidon of metoclopramide: ongunstige interactie, domperidon en metoclopramide verhogen de prolactinespiegel (dosisafhankelijk).     

In vitro P-glycoprotein-mediated transport of (R)-, (S)-, (R,S)-methadone, LAAM and their main metabolites

Methadone and L-alpha-acetylmethadol (LAAM) are used as treatment for opiate addiction. Using a cellular model, we aimed to determine if methadone, LAAM and their main metabolites are substrates of the human P-glycoprotein transporter (P-gp), which is encoded by the ABCB1 gene, and whether methadone transport exhibits stereoselectivity. Pig kidney epithelial cells (control) and human ABCB1-transfected cells were incubated with methadone, LAAM and their metabolites, and their intra- and extracellular concentrations were measured. The intra- to extracellular ratios of methadone, LAAM and their metabolites were all decreased in ABCB1-transfected cells compared to controls (p < 0.05), thus indicating that they are substrates of P-gp. A weak stereoselectivity in methadone transport was observed towards the (S)-enantiomer. P-gp may therefore affect the pharmacokinetics and pharmacodynamics of methadone and LAAM.     

Final report on the safety assessment of Corylus Avellana (Hazel) Seed Oil, Corylus Americana (Hazel) Seed Oil, Corylus Avellana (Hazel) Seed Extract, Corylus Americana (Hazel) Seed Extract, Corylus Avellana (Hazel) Leaf Extract, Corylus Americana (Hazel) Leaf Extract, and Corylus Rostrata (Hazel) Leaf Extract

These ingredients are all derived from hazelnut trees. The two seed oils are expressed from the nuts of the hazelnut tree of the particular species identified. Most current reported cosmetic uses are of the seed oils. The seed extracts are the extract of the nuts of the identified species tree. There is one current report of use of seed extract in cosmetics. The leaf extracts are the extract from the leaves of the particular species tree. There are no current reports of use of these extracts in cosmetics. Analysis of seed oil from one species identified Oleic Acid, Palmitoleic Acid, Linoleic Acid, Eicosaenoic Acid, Docosenoic Acid, Eicosanoic Acid, Palmitic Acid, Linolenic Acid, Stearic Acid, and Tetraeicosanoic Acid. Little information is available to characterize the extracts, however. The functions of most of these ingredients in cosmetics are not reported. In studies of hazelnuts from Spain and Egypt, aflatoxin was reported as a possible contaminant. Aflatoxins are considered carcinogenic in humans. Virtually no safety test data are available on these ingredients. Negative results in one comedogenicity study using a seed oil are reported. Cross-sensitivity to proteins in peanuts and those in hazelnuts are reported, but the presence or absence of protein in nut extract and plant extract from hazelnut trees is not known. Additional data were provided regarding concentration of use, method of extraction and contaminants, comedogenicity, and ultraviolet (UV) radiation absorption, but these data related to nut oil from only one species, and were not overall sufficient to resolve questions about irritation, sensitization, and photosensitization. Because of the absence of data, it is concluded that the available data are insufficient to support the safety of these ingredients in cosmetic products. Because of the limited information that characterizes any of these oils or extracts, data are needed on each (except that items 1, 2, and 3 below are not needed for Hazel [Corylus Avellana] Nut Oil). The additonal data needs include: (1) current concentration of use; (2) method of extraction/manufacture and quality control (i.e., chemical analyses); (3) contaminants and methods of extraction (especially pesticides and heavy metals); (4) dermal irritation and sensitization; (5) UV absorption; if there is significant absorption, then a photosensitization study will be needed; (6) 28-day dermal toxicity; (7) reproductive and developmental toxicity; and (8) two genotoxicity assays, one in a mammalian system; if positive, then a 2-year dermal carcinogenesis study using National Toxicology Program (NTP) methods may be needed.     

Terpenoid biotransformation in mammals. IV Biotransformation of (+)-longifolene, (-)-caryophyllene, (-)-caryophyllene oxide, (-)-cyclocolorenone, (+)-nootkatone, (-)-elemol, (-)-abietic acid and (+)-dehydroabietic acid in rabbits

The metabolism of (+)-longifolene, (-)-caryophyllene, (-)-caryophyllene oxide, (-)-cyclocolorenone, (+)-nootkatone, (-)-elemol, (-)-abietic acid and (+)-dehydroabietic acid was studied in rabbits. Each of these sesquiterpenoids was converted to primary, secondary or tertiary alcohols, among which the primary alcohol was predominant. A vinylic methyl group and an exomethylene group were easily hydroxylated and converted to a glycol via an epoxide in many cases. Eight new metabolites were determined by chemical and spectroscopic methods.     

Synthesis,characterization, and solvolysis of mono- and bis-S-(glutathionyl) adducts of methylene-bis-(phenylisocyanate) (MDI)

Bifunctional isocyanates are highly reactive compounds that undergo nucleophilic attack by a variety of functional groups available in the biological system. While the etiology of the respiratory disease caused by diisocyanates is not fully understood, a great deal of research has been performed to elucidate the chemical mechanisms involved in the direct and indirect effects of these compounds. Since adducts of isocyanates are found not only to proteins along the entire respiratory tree but also to proteins in the circulatory system, it is likely that a transport mechanism for the isocyanate from the respiratory to the circulatory system exists. The initial reaction of isocyanates with cellular thiols to form thiocarbamates, which are known to release the isocyanate under physiological conditions, is believed to provide a possible carrier mechanism for the isocyanate functional group. Previous work with aliphatic mono-isocyanates and the aromatic diisocyanate toluene diisocyanate has demonstrated the feasibility of this mechanism. Adding to this database, the products of the reaction of the highly water-insoluble, low vapor pressure, methylene-bis-(phenylisocyanate) (MDI) with glutathione were synthesized, and their chemical stability under various pH and buffer conditions was tested. Novel synthetic routes were developed for both the mono- and bis-S-(glutathionyl) adducts with MDI that yielded each compound in analytically pure form. Both compounds were found to be unstable under mild basic conditions (phosphate-buffered saline, pH 7.4, and NaHCO(3), pH 8.2), however to a different degree. Furthermore, a significant influence of the pH value (the rate of degradation increases with pH) and the concentration of free glutathione (increasing thiol stabilizes the adduct) on the stability was observed, indicating a base-catalyzed mechanism of the degradation/formation of the thiocarbamate bond. Unlike the monoadduct, which forms almost exclusively the polyurea upon degradation, a variety of products were formed upon degradation of the bis adduct. Though the disappearance of the bis adduct was complete as measured by HPLC, (1)H NMR spectra showed the existence of residual thiocarbamate bonds in the final mixture. In both cases, no evidence of the free methylene-bis-phenylamine (MDA) could be detected under the applicable conditions.     

Thermosensitive poly-(d,l-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly-(d,l-lactide-co-glycolide) hydrogels for multi-drug delivery

Abstract

A current treatment strategy for peritoneal ovarian cancer is a combination of peritoneal surgery and multi-drug-based chemotherapy that often involves intraperitoneal (IP) injection. A thermosensitive poly-(d,l-lactide-co-glycolide)-block-poly(ethylene glycol)-block-poly-(d,l-lactide-co-glycolide) (PLGA-b-PEG-b-PLGA) hydrogel platform (thermogels) enabled gel loading of poorly work-soluble paclitaxel (cytotoxic agent), 17-allylamino-17-demethoxygeldanamycin (17-AAG, heat shock protein inhibitor), and rapamycin (mammalian target of rapamycin protein inhibitor). PLGA-b-PEG-b-PLGA thermogels (15%) carrying paclitaxel, 17-AAG, and rapamycin (named Triogel) made a successful transition from a free-flowing solution below ambient temperature to a gel depot at body temperature. Triogel gradually released paclitaxel, 17-AAG, and rapamycin at an equal release rate in response to the physical gel erosion. In an ES-2-luc ovarian cancer xenograft model, a single IP injection of Triogel (60, 60, and 30?mg/kg of paclitaxel, 17-AAG, and rapamycin, respectively) significantly reduced tumor burden and prolonged survival of ES-2-luc-bearing nude mice without notable systemic toxicity relative to those delivered by poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-b-PLA) micelles in solution via IP or intravenous (IV) injection route. These results show a great potential of a biodegradable thermogel platform carrying multi-drugs for IP chemotherapy in peritoneal ovarian cancer.     

Human papillomavirus quadrivalent (types 6, 11, 16, 18) recombinant vaccine (Gardasil)

Human papillomavirus (HPV) quadrivalent recombinant vaccine is a mixture of virus-like particles derived from the L1 capsid proteins of HPV types 6, 11, 16 and 18. It is administered intramuscularly in a three-dose regimen, with the initial injection followed by subsequent doses at months 2 and 6. The vaccine is indicated for use in the prevention of cervical cancer, vulvar and vaginal precancer and cancers, precancerous lesions and genital warts associated with HPV types 6, 11, 16 or 18 infection in adolescents and young women. The quadrivalent vaccine has demonstrated good immunogenicity in young women (16-26 years) and male and female adolescents (aged 9-15 years), inducing high and persistent anti-HPV antibody titres. In a randomised phase III trial designed to bridge efficacy in young women to adolescents (using immunogenicity as a surrogate), the quadrivalent HPV vaccine in adolescents was at least as immunogenic as that in young women. In randomised, double-blind, placebo-controlled trials in >20 000 young women (aged 16-26 years), the vaccine was highly effective in preventing cervical dysplasia of any grade and external genital lesions related to HPV types 6, 11, 16 and 18 infection. These women were followed up for an average of 2 years.black triangle The vaccine was well tolerated, with injection-site reactions and fever being the most common vaccine-related adverse events.     

Polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) in the Grenlandfjords (Norway)--disposition, levels, and effects

Polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) are regarded as highly toxic. Their lipophilicity and persistence also render them subject to bioaccumulation. The Grenlandfjords (southern Norway) have long been polluted by PCDD/Fs through the magnesium production at Her?ya (1951-2002). Therefore, extensive environmental monitoring was performed in the area, and the project "Dioxins in the Grenlandfjords--DIG" was launched to study abiotic mass balances, biotic processes and ecological risk. This article describes some results from DIG on the dispositions of PCDD/Fs in the food web and biological effects. Furthermore, data from the Norwegian monitoring of the Grenlandfjords are described. Differences in cod liver PCDD/F levels were found between stations, with the highest concentrations in the inner fjord (the Frierfjord), closest to the pollution source. Furthermore, considerable decreases in the concentrations followed the large discharge reductions (1975 and 1990). Contrary to earlier food web studies on other organochlorines, it was found that the concentrations of PCDD/Fs decline with higher trophic level. Higher chlorinated congeners also constituted a lower percentage of sigmaPCDD/Fs higher in the food chain. The results indicated a limited bioaccumulation of PCDD/Fs, especially of higher chlorinated congeners, likely due to reduced membrane permeability (high molecular size), and possibly slow transport through intestinal aqueous phases. Hepatic cod 7-ethoxyresorufin O-deethylase (EROD) activities differed between the Frierfjord and the Eidangerfjord, showing the different PCDD/F exposure in the two fjords. Furthermore, seasonal variations in cytochrome P-450 (CYP) 1A activity were shown, with different responses between genders. The differences were likely linked to the reproductive cycle of the fish.     

Acedicon-Vergiftung,chronische, medizinale (Acediconismus)

Ohne Zusammenfassung     

Molecular analysis of beta(2)-adrenoceptor coupling to G(s)-, G(i)-, and G(q)-proteins

The beta(2)-adrenoceptor (beta(2)AR) couples to the G-protein G(s) to activate adenylyl cyclase. Intriguingly, several studies have demonstrated that the beta(2)AR can also interact with G-proteins of the G(i)- and G(q)-family. To assess the efficiency of beta(2)AR interaction with various G-protein alpha-subunits (G(xalpha)), we expressed fusion proteins of the beta(2)AR with the long (G(salphaL)) and short (G(salphaS)) splice variants of G(salpha), the G(i)-proteins G(ialpha2) and G(ialpha3), and the G(q)-proteins G(qalpha) and G(16alpha) in Sf9 cells. Fusion proteins provide a rigorous approach for comparing the coupling of a given receptor to G(xalpha) because of the defined 1:1 stoichiometry of receptor and G-protein and the efficient coupling. Here, we show that the beta(2)AR couples to G(s)-, G(i)-, and G(q)-proteins as assessed by ternary complex formation and ligand-regulated guanosine 5'-O-(3-thiotriphosphate) (GTPgammaS) binding. The combined analysis of ternary complex formation, GTPgammaS binding, agonist efficacies, and agonist potencies revealed substantial differences in the interaction of the beta(2)AR with the various classes of G-proteins. Comparison of the coupling of the beta(2)AR and formyl peptide receptor to G(ialpha2) revealed receptor-specific differences in the kinetics of GTPgammaS binding. We also detected highly efficient stimulation of GTPgammaS dissociation from G(salphaL), but not from G(qalpha) and G(16alpha), by a beta(2)AR agonist. Moreover, we show that the 1:1 stoichiometry of receptor to G-protein in fusion proteins reflects the in vivo stoichiometry of receptor/G-protein coupling more closely than was previously assumed. Collectively, our data show 1) that the beta(2)AR couples differentially to G(s)-, G(i)-, and G(q)-proteins, 2) that there is ligand-specific coupling of the beta(2)AR to G-proteins, 3) that receptor-specific G-protein conformational states may exist, and 4) that nucleotide dissociation is an important mechanism for G-protein deactivation.     

Phosphor-Vergiftung,akute (Selbstmerdversuch)

Ohne Zusammenfassung     

Valeroform-Vergiftung,akute (Selbstmordversuch)

Zusammenfassung Nach dem Gebrauch von angeblich 20 Tabletten des Pr?parates Valeroform durch ein im 8. Monat schwangeres M?dchen traten bei ihr eine mindestens 24 Stunden, wahrscheinlich erheblich l?nger, andauernde Bewu?tlosigkeit und eine Kreislaufschw?che ein, die durch gro?e Mengen von Herzmitteln (Coramin, Hexeton, Coffein, Cardiazol) erfolgreich behoben wurde. Erst am vierten Tage war die Patientin wieder ganz klar und konnte ohne Folgeerscheinungen entlassen werden.     

2-Chloro-N(6)-cyclopentyladenosine,adenosine A(1) receptor agonist,antagonizes the adenosine A(3) receptor

The potent adenosine A(1) receptor agonists, N(6)-cyclopentyladenosine (CPA) and 2-chloro-N(6)-cyclopentyladenosine (CCPA), were studied in Chinese hamster ovary (CHO) cells expressing the human adenosine A(3) receptor. CPA, but not CCPA, induced phosphoinositide turnover. CPA inhibited forskolin-stimulated cyclic AMP production (EC(50) value of 242+/-47 nM). CCPA competitively antagonized the effects of agonist Cl-IB-MECA (2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarbamoyladenosine) with K(B) value of 5.0 nM. CPA competition curves versus the A(3) antagonist radioligand [3H]PSB-11 (8-ethyl-4-methyl-2-phenyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo[2.1-i]purin-5-one) were right-shifted four-fold by 100 microM GTP, which had no effect on binding of CCPA or the antagonist MRS 1220 (N-[9-chloro-2-(2-furanyl)[1,2,4]triazolo[1,5-c]quinazolin-5-yl]benzene-acetamide). Thus, CCPA is a moderately potent antagonist (K(i)=38 nM) of the human A(3) adenosine receptor.     

Cefoperazone (Cefobid, Pfizer)

Cefoperazone is a new beta-lactam antibiotic that possesses a broad spectrum of activity against gram-positive and gram-negative organisms. Cefoperazone differs from all previous cephalosporins in that it has exceptional activity against P. aeruginosa. The other distinguishing feature of cefoperazone is its high rate of biliary excretion, which will allow for treatment of biliary tract infections. Renal elimination accounts for only 20 percent of the agent's elimination; dosage modification is not necessary in decreased renal function. The clinical response rate of infections to cefoperazone is similar to that of moxalactam, cefotaxime, or the cephalosporins in general. The overall incidence of side effects was 14 percent in U.S. trials, with skin rash, fever, or urticaria occurring in 1 percent; phlebitis and injection-site pain in 2 percent; and diarrhea in 5 percent. As with the other third-generation cephalosporins, cefoperazone requires close scrutiny because of its expected high cost and the lack of comparative trials with standard antibiotic regimens.