Glucagon releasing activity of a cyclic peptide related to somatostatin

A possible benefit of creating smaller and more rigid active analogs of somatostatin is the discovery of compounds which selectively inhibit the secretion of insulin, glucagon or growth hormone. A series of cyclic tetrapeptide analogs related to somatostatin was synthesized, and one member of this series was found to cause an unexpected stimulation of glucagon secretion while having little if any effect on either insulin or growth hormone secretion. A sustained increase in plasma glucose levels was also observed. Two possible modes of action are proposed.     

DISTANCE LEARNING: THE ROLE OF TELEMEDICINE

Growing awareness of the potential benefits of advanced medicine, emerging democracies, growing middle classes and an ageing population world-wide are significant forces shaping future demand for world-class health care. Coupled with an increased awareness of the potential benefits of advanced modern medical technologies, these factors will have a dramatic impact on medical education systems. Traditional academic institutions might not represent the optimal approach to education in the 21st century. They are expensive to build and run, typically reward academic excellence not exceptional health care delivery, teach matriculating students on site, and tend to perpetuate themselves. The expertise of centres of excellence needs to be disseminated more widely, to a 'student' or client base interacting with the institution only episodically. As relevant geographic distances increase, access to such centres becomes more difficult. To attack this problem on a global basis, we must be able to teach and interact at a distance. Telemedicine is likely to form an essential part of the solution.     

Lability of N-alkylated peptides towards TFA cleavage

Trifluoroacetic acid (TFA) is a common reagent in both solid-phase and solution peptide synthesis. It is used for the deprotection and/or cleavage of the synthesized peptide from the resin. The use of TFA under these standardized conditions is thought to be sufficiently mild, thereby preventing degradation of the desired product. However, peptides of the general structure R¹-(N-alkyl X₁)-X₂-R² are hydrolyzed by standard TFA solid-phase peptide synthesis (SPPS) cleavage/deprotection conditions providing fragments R¹-(N-alkyl X₁)-OH and H-X₂-R². The fragmentation is observed during a TFA cleavage both from the resin and in solution. The hydrolysis is proposed to proceed via an oxazolone-like intermediate in which equilibration of the chiral center of the N-alkylated residue occurs. This mechanism is supported by H/D exchange as observed by MS and NMR in conjunction with HPLC. © Munksgaard 1996.     

Tumors of the Bladder, Kidney, and Intestine of F344 Rats and Liver of B6C3F1 Mice Administered o-Nitroanisole in Feed

Tumors of the Bladder, Kidney, and Intestine of F344 Rats andLiver of B6C3F₁ Mice Administered o-Nitroanisole in Feed. IRWIN,R. D., CHHABRA, R., EUSTIS, S., PINTER, A., AND PREJEAN, J.D. 1996). Fundam. Appl. Toxicol. 30, 1–12. o-Nitroanisole, a mutagenic intermediate used in the manufactureof azo dyes, was administered in feed for 2 years at concentrationsof 0, 222, 666, or 2000 ppm to groups of 60 male and 60 femaleF344 rats. No significant increase in neoplasms occurred inthese groups of rats. Additional (stop exposure) groups of 60male and 60 female F344 rats received diets containing 0, 6000,or 18,000 ppm for 27 weeks followed by maintenance on controldiets for up to an additional 77 weeks. Survival of the stopexposure groups was reduced because of the development of chemicalrelated neoplasms of the urinary bladder. After 13, 28, 40,and 65 weeks on study, 10 rats per group were necropsied andevaluated for the presence of chemical associated lesions. Hyperplasiaof the epithelium of the urinary bladder was significantly increasedat all interim evaluations. A transitional cell carcinoma wasobserved at the 13-week evaluation in one male rat that received18,000 ppm and thereafter transitional cell neoplasms of thebladder were present in male and female rats at each interimevaluation. Adeno matous polyps of the large intestine weresignificantly increased in groups that received 6000 or 18,000ppm. In addition carcino mas of the large intestine were presentin four males and two females that received 18,000 ppm. Hyperplasiaof the transitional epithelium of the renal pelvis was significantlyincreased in groups of rats that received 6000 or 18,000 ppmand transitional cell papillomas were observed in three malesand one female that received 18,000 ppm. Transitional cell carcinomasof the kidney occurred in one male that received 6000 ppm andsix males and one female that received 18,000. Groups of 60male and 60 female B6C3F₁, mice received dietary concentrationsof 0, 666, 2000, or 6000 ppm o-nitroanisole for 2 years. Nostop exposure study was conducted with mice. The only neoplasticresponse observed in mice was in the liver of males; hepatocellularadenomas or carcino mas were increased in groups of male micethat received 2000 or 6000 ppm. No increase in neoplasms associatedwith chemical exposure occurred in female mice.     

Potency of a Complex Mixture of Polychlorinated Dibenzo-p-dioxin, Dibenzofuran, and Biphenyl Congeners Compared to 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Causing Fish Early Life Stage Mortality

Use of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) toxicity equivalentsconcentration (TEC) assumes that polychlorinated di benzo-p-dioxins(PCDDs), dibenzofurans (PCDFs), and biphenyls (PCBs) act additivelyand via a common mechanism to cause toxicity. To test theseassumptions, 11 TCDD-like congeners and three non-TCDD-likecongeners were combined at ratios typically found in Lake Michiganlake trout. The potency of the mixture, expressed as TEC basedon fish-specific toxic equivalency factors, was compared toTCDD for producing lake trout and rainbow trout early life stagemortality. Signs of toxicity following exposure of newly fertilizedeggs to the mixture or to TCDD were indistinguishable; sac frymortality associated with blue-sac disease, and slopes of thedose-response curves for percentage sac fry mortality versusegg TEC or versus egg TCDD were parallel. However, the mixturedose-response curves were significantly shifted to the rightof the TCDD dose-response curves by 1.3- to 1.8-fold as illustratedby LD₅₀ values. Following exposure to the mixture or TCDD, LD₅₀sfor lake trout early life stage mortality were 97 (89–110)pg TE/g egg and 74 (70–80) pg TCDD/g (LD₅₀, 95% fiduciallimits) and for rainbow trout were 362 (312–406) pg TE/gegg and 200 (148–237) pg TCDD/g egg. These data suggestthat TCDD-like congeners act via a common mechanism to causetoxicity during trout early development, but may not act strictlyadditively when combined in a mixture of TCDD- and non-TCDD-likecongeners at ratios found in Great Lakes fish. The deviationfrom additivity, however, is less than current safety factorsof 10-fold commonly applied in ecological risk assessments,providing support for the continued use of a TE additivity modelfor assessing risk posed by complex mixtures of PCDDs, PCDFs,and PCBs to fish.     

The Inhalation Toxicology, Genetic Toxicology, and Metabolism of Difluoromethane in the Rat

Difluoromethane (HFC32) is under development as a replacementfor chlorofluorocarbons (CFCs) in some refrigeration applications.It has been evaluated by standard studies of toxicity, developmentaltoxicity, and genotoxicity. In addition, the metabolism anddisposition of HFC32 was investigated and a physiologicallybased pharmacokinetic (PB-PK) model constructed. Inhalationof HFC32 (up to 50,000 ppm) caused no organ-specific effects,but resulted in slight maternal toxicity to the pregnant ratand rabbit and some fetotoxicity to the rat. HFC32 did not sensitizethe heart to adrenaline. The pharmacokinetics of [¹⁴C]difluoromethane(10,000 to 50,000 ppm/6 hr) revealed that about 2.1% of theinhaled HFC32 was absorbed and that steady state blood levelswere achieved within 2 hr and were proportional to dose. Carbondioxide was the major metabolite of HFC32 at all exposure levels.Carbon monoxide was not detected. The in vivo data were usedto validate a PB-PK model to describe the uptake and metabolismof HFC32. Absorption and distribution are adequately describedusing rat blood:air and tissue:air partition coefficients. Metabolism,which was linear across the dose range, was described by a firstorder rate constant (K_f=8.98 hr^–1). Of the absorbed HFC32,about 63% was metabolized at all doses; however, when metabolismwas expressed as a percentage of the inhaled dose it was muchlower, being about 1.4% of the HFC32 entering the airways. Overall,the results indicate that HFC32 is of very low toxicity andshould be an acceptable alternative to CFCs.     

Retinoid-Induced Hypertriglyceridemia in Rats Is Mediated by Retinoic Acid Receptors

Retinoids in clinical use today are known to induce hypertriglyceridemiaas one of their major side effects. The purpose of the presentstudy was to determine, in an appropriate animal model, if retinoid-inducedhypertriglyceridemia is mediated by retinoic acid receptors(RARs) and/or by retinoid X receptors (RXRs). Oral gavage ofmale Fischer rats with 13-cis-retinoic acid for 6 days causeda rapid and sustained increase in serum triglycerides that wasreversible within 4 days posttreatment In subsequent experiments,rats were treated by gavage once daily for 3 days with variousretinoids, and serum triglyceride levels were determined 24hr after the last treatment without fasting. All-trans-and 13-cis-retinoicacid, which can be converted to both RAR and RXR agonists, and9-cis-retinoic acid, an RAR/RXR pan-agonist, caused dose-dependentincreases in serum triglycerides at doses that did not causeweight loss or mucocutaneous toxicity. Ro 13–6298 andAGN 190121, two RAR-specific agonists, caused dose-dependentincreases in serum triglycerides, although Ro 13–6298only induced hypertriglyceridemia at weight-suppressive doses.Two RXR-selective agonists, LG100268 and AGN 191701, failedto induce hypertriglyceridemia or weight loss up to the highestdoses tested. A structural isomer of AGN 190121 that does notactivate RARs or RXRs, AGN 190727, did not induce hypertriglyceridemia.Hypertriglyceridemia induced by AGN 190121 was significantlyinhibited by co-treatment with an RAR-selective antagonist,AGN 193109. Taken together, these data provide strong evidencethat retinoid-induced hypertriglyceridemia is mediated, at leastin part, by RARs. These data also suggest that RXR-specificagonists may have reduced potential to induce hypertriglyceridemiarelative to RAR-active retinoids.     

Carcinogenic Potential of Gasoline and Diesel Engine Oils

Used gasoline engine oils are carcinogenic in mouse skin andmutagenic in Salmonella. The toxicity of fresh gasoline engineoils and that of fresh and used diesel engine oils are lesswell defined. The present studies examined the dermal carcinogenicpotential of a series of fresh and used oils from both gasolineand diesel engines. The used oils represented a variety of operatingconditions. The objective of the study was to assess the potentialcarcinogenic hazards associated with exposure to these materials.The majority of the used gasoline engine oils tested were carcinogenicalthough one oil, collected after a relatively short drainageinterval, was inactive in the dermal carcinogenesis bioassay.Additionally, polycyclic aromatic hydrocarbon (PAH) concentrationswere elevated in the used oils in comparison to the fresh oils.The fresh gasoline engine oils and both the fresh and used dieselengine oil samples were noncarcinogenic, and there was littleevidence of elevated PAH levels in the used diesel engine oils.The carcinogenic potency of used oils from gasoline engineswas related to drainage interval, but other factors such ascontribution of the fuel due to blowby and driving cycle mayalso have been important. The used diesel engine oils were notcarcinogenic even after extended use.