Some pharmacokinetic parameters of doxycycline in east African goats after intramuscular administration of a long-acting formulation

A compartmental and non-compartmental study was carried out on five adult goats following intramuscular administration of doxycycline at 20 mg/kg bodyweight. The concentration of the drug in serum was determined by a microbiological assay employing Bacillus cereus var mycoides (ATCC 11778) as the test organism. The mean serum concentration (Cmax) and the time of maximum concentration (Tmax) were 1.87 micrograms/ml and 0.85 h, respectively. Using compartmental analysis, the plasma concentration-time curve of doxycycline best fitted a three-compartment open model with first-order absorption. A three-phase disposition of doxycycline was found, the terminal elimination half-life being approximately 40 h. The statistical moment theory was mainly used for non-compartmental analysis. The value obtained for the mean residence time (MRT) was 16.4 h. The mean values for the volume of distribution at steady state (Vdss), determined by compartmental and non-compartmental analyses, were 8.73 and 13.19 L/kg, respectively. There were no statistically significant differences when the major pharmacokinetic parameters were compared. It was concluded that the pharmacokinetic behaviour of doxycycline in goats after intramuscular administration is characterized by a three-compartment model with a slow terminal elimination phase. Based on current knowledge, this could be due to enterohepatic recycling and/or flip-flop kinetics. The study indicated that a single intramuscular administration of 20 mg/kg of doxycycline may only provide therapeutic concentrations for up to 24 h owing to slow absorption at the injection site.     

Collapse behavior evaluation of hybrid thin-walled member by stacking condition

The recent trend of vehicle design aims at crash safety and environmentally-friendly aspect. For the crash safety aspect, the energy absorbing members should absorb collision energy sufficiently but for the environmentally-friendly aspect, the vehicle structure must be light weight in order to improve the fuel efficiency and reduce the tail gas emission. Therefore, the light weight of vehicle must be achieved in a securing safety status of crash. An aluminum or carbon fiber reinforced plastics (CFRP) is representative one of the light-weight materials. Based on the respective collapse behavior of aluminum and CFRP member, the collapse behavior of hybrid thin-walled member was evaluated. The hybrid members were manufactured by wrapping CFRP prepreg sheets outside the aluminum hollow members in the autoclave. Because the CFRP is an anisotropic material whose mechanical properties, such as strength and elasticity, change with its stacking condition, the effects of the stacking condition on the collapse behavior evaluation of the hybrid thin-walled member were tested. The collapse mode and energy absorption capability of the hybrid thin-walled member were analyzed with the change of the fiber orientation angle and interface number.     

A rare and little known variant of hypospadias

Hypospadia is a congenital defect presenting as different variants of dysplasia of the distal urethra with ectopy of the urethral external orifice and distortion of the penis. A variant of hypospadia not yet described in Russian medical literature was observed in a newborn boy. He had normal penis and scrotum, but on the under-side of the penis there was a site of thin skin protruding as a resonance bag in urination. At the site of the thin skin the back urethral wall was absent with a cavity covered by the thin skin. In urination urine filled the cavity blowing up the skin above it to the form of the resonance bag. This variant of hypospadia was designated as segmental urethral hypoplasia.     

Cocaine-induced activation of striatal neurons during focused stereotypy in rats

As psychomotor stimulants, both amphetamine and cocaine elicit episodes of repetitive motor activation (focused stereotypy) known to involve the mesostriatal dopamine system. During amphetamine-induced focused stereotypy, motor-related neurons in the striatum respond with either an excitation or inhibition, depending on dose and behavioral pattern, whereas nonmotor-related units are inhibited. To assess striatal activity during the focused stereotypy induced by cocaine, both types of striatal units were recorded in ambulant rats. Either 20 or 40 mg/kg cocaine caused highly focused sniffing and head bobbing, which occurred in conjunction with activation of both motor- and nonmotor-related neurons. The activation of motor-related units was evident even when firing rate was compared during periods of matched pre- and post-drug behavior, arguing against movement as the sole basis for the drug-induced neuronal excitation. Subsequent administration of haloperidol (1.0 mg/kg) reversed but did not completely block the neuronal activation, while the behavioral response shifted away from focused stereotypy toward an increase in ambulation. Thus, the level of activation of both motor- and nonmotor-related striatal neurons may play a critical role in the behavioral response pattern induced by cocaine.     

Fine needle aspiration cytology in a rural setting

OBJECTIVE: To compare, contrast and analyze the value and limitations of fine needle aspiration (FNA) cytology and core biopsy (CB) in a rural setting. STUDY DESIGN: Retrospective analysis of 100 FNA cytology and 100 CB results of mass lesions from 193 patients matched for age, sex and body organs, and referred for FNA or CB in rural New South Wales, Australia, between September 1990 and May 1996. RESULTS: FNA cytology and CB results from 193 patients were analyzed, based on anatomic location and cytologic criteria. Sites included lung, retroperitoneum, liver, breast, kidney, pancreas and ovary. The FNA group contained 6 inadequate, 14 benign, 3 atypical, 6 suspicious and 71 malignant cases, whereas the CB group had 1 inadequate, 24 benign and 75 malignant conditions. The inadequate samples in both groups were due to technical difficulty in obtaining representative material. The indeterminate (atypical and suspicious) group, which was the main pitfall of FNA, contained 4 low grade carcinomas, 3 low grade non-Hodgkin's lymphomas and 2 fibrocystic breast changes. The benign FNA group comprised 8 cysts, 5 inflammatory/reactive conditions and 1 benign tumor/hamartoma, whereas the benign CB group contained 11 cysts, 9 inflammatory/reactive conditions and 4 benign tumors. CONCLUSION: FNA was comparable to CB at most anatomic sites. CB occasionally offered additional information. This slight advantage was due to the availability of tissue from the first and often the only pass for assessment of architecture and performance of ancillary tests, which obviated the need for further sampling. On-site assessment of the core imprints at the time of the procedure by the highly skilled and experienced interventional cytopathologist was responsible for limiting the number of attempts to one core in most of the instances, therefore minimizing complications. Pathologists are encouraged to become more familiar with the criteria of aspiration cytology, which has proven its validity in the new cost-conscious environment. Despite the recent surge in the popularity of core biopsy, FNA cytology, when practiced in a multidisciplinary setting, with involvement of pathologists, radiologists and clinicians, is an extremely accurate test with very high sensitivity, which approaches that of surgical pathology, and specificity very similar to that of frozen section. FNA has a positive predictive value for a malignant diagnosis of almost 100%. FNA is a well-tolerated, relatively noninvasive test with a very low risk of complications.     

Development of orally active oxytocin antagonists: studies on 1-(1-[4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2- methoxybenzoyl]piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines

The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.