MTHFR c.677C>T polymorphism as an independent predictor of peak bone mass in Danish men--results from the Odense Androgen Study

The MTHFR c.677C>T polymorphism has been shown to have significant effects on skeletal health in middle-aged to elderly women and men. Despite an accumulating amount of data on MTHFR genetics and the association between homocysteine levels and fracture, it remains unknown if MTHFR c.677C>T genotype affects bone mineral accretion in youth or bone loss in adulthood. The purpose of this cross-sectional study was to examine the effects of this common allelic polymorphism on peak bone mass and bone turnover. We performed MTHFR genotyping in 780 healthy Danish men, aged 20 to 29 years, participating in the Odense Androgen Study. BMD at the spine, hip and whole-body was measured using a Hologic QDR-4500 densitometer. Genotype frequencies were compatible with Hardy-Weinberg equilibrium. Spine BMD was significantly associated with genotype, with a decrease in BMD of 0.20 SD for each copy of the T-allele. Effects were independent of age, BMI, smoking and serum levels of vitamin D and IGF-I. Associations with BMD of the hip and whole body were short of statistical significance. MTHFR genotype showed no association with the bone turnover markers 1-CTP, bone specific alkaline phosphatase or osteocalcin. In conclusion, significant skeletal effects of this common polymorphism were present at the lumbar spine in men at the age of 25 years.     

Ultralong peripheral nerve block by lidocaine:prilocaine 1:1 mixture in a lipid depot formulation: comparison of in vitro, in vivo, and effect kinetics

BACKGROUND: The aim of this study was to develop stable and easily injectable lipid depot preparations of local anesthetics in which the drug concentration can be varied according to desired duration of action. METHODS: The formulations contained a 2.0, 5.0, 10, 20, 40, 60, 80, or 100% eutectic mixture of lidocaine and prilocaine base in medium-chain triglyceride. Duration of sciatic nerve block and local neurotoxicity was investigated in rats with 2.0% lidocaine:prilocaine HCl solution and 99.5% ethanol as controls. The rate of release of local anesthetic from the site of administration and the possibility to predict in vivo depot characteristics from in vitro release data were investigated for the 20 and 60% formulations. RESULTS: The duration of sensory sciatic block was prolonged 3 times with the 20% formulation and approximately 180 times with the 60% formulation, in comparison with the 2% aqueous solution. With the 80 and 100% formulations, all animals still showed nerve block after 2 weeks. The in vivo release of local anesthetic could be approximately predicted from in vitro data for the 20% but not for the 60% formulation. The formulations of 60% or greater and ethanol showed neurotoxic effects. CONCLUSIONS: The pharmaceutical properties of these formulations compare favorably with those of other depot preparations. The high-percentage ones showed the longest duration of action yet reported for sciatic nerve block in rats. The possibility of using a high-concentration local anesthetic depot formulation as an alternative to ethanol or phenol for long-term nerve blocks in chronic pain merits further investigation.     

Synthesis and Solubility of Collagen in Rats during Recovery after High-dose Cyclophosphamide Administration

Abstract: The metabolism of collagen and mineral was studied during a nine-day postmedicational period in young, male rats receiving high-dose intraperitoneal cyclophosphamide treatment every second day for 12 days. Two days after ending medication the white blood cell counts (WBC) were reduced by about 70%. Both synthesis and solubility of collagen were suppressed by the present medication 2 days after termination of treatment. This suppression continued throughout the 9-day postmedicational period in bones, whereas in connective tissue of porous, ceramic implants both total collagen and the amount of salt soluble collagen regained normal values 9 days after cessation of treatment. Increased mineralization was found 2 days after ending medication and this high degree of mineralization persisted during the postmedicational period studied. Serum albumin levels were reduced and no increases were detected during the postmedicational period. The suggestion is made that the general protein synthesis is affected by high-dose cyclophosphamide administration.     

Elevated blood pressure following LHRH antagonists in rats

LHRH and three potent antagonistic analogs: Z-[Gln¹, des-His², D-Pse⁶, des-Gly¹⁰]-LHRH ethylamide, where D-Pse = threo-D-phenylserine; Z-[Gln¹, des-His², D-Phe⁶, des-Gly¹⁰]-LHRH ethylamide; and Boc-[Ser(Bzl)¹,des-His², D-Trp⁶]-LHRH; were studied for their effects on blood pressure and heart rate in chronically catheterized conscious normotensive and hypertensive rats.All three analogs caused acute increases in blood pressure in normotensive male Sprague-Dawley rats; the Z-Gln-phenylalanine derivative also raised blood pressure in spontaneously hypertensive rats of Kyoto-Wistar origin. LHRH itself had no effect in either normotensive or hypertensive animals. The antagonistic analogs were also associated with acute toxicity.It is concluded that the antagonist analogs of LHRH, unlike LHRH itself, have significant acute cardiovascular effects in rats. Although the mechanism of these effects is not known nor is it known whether they occur in other species, the present data emphasize the need to define further the pharmacological profiles of these potent, biologically active materials.