Intestinal Absorption of Stable Cyclic Dipeptides by the Oligopeptide Transporter in Rat

Intestinal absorption of four cyclic dipeptides was studied in the everted small intestine of the rat. Cyclic seryltyrosine (cyclo(Ser-Tyr)) was stable enough to be transported whereas linear seryltyrosine was not. The absorption clearance of cyclo(Ser-Tyr) was concentration-dependent, and for cyclo(Ser-Tyr) at 125 μM decreased in the presence of glycylsarcosine (10 mM) or cephalexin (10 mM), which were reported to be absorbed by oligopeptide transporter. The absorption clearance was also reduced at 4°C and in the presence of 1 mM dinitrophenol. Kinetic analysis of cyclo(Ser-Tyr) absorption showed that K_m and V_max were 19.8 μM and 0.295 nmol min^?1 cm^?1, respectively. It was also suggested that cyclic aspartylphenylalanine and cyclic histidylphenylalanine were absorbed by oligopeptide transporters, but cyclic histidylproline was not. The absorption clearance of cyclo(Ser-Tyr) in the control was much higher than the value of the correlation line representing a plot of passive transport (which was obtained from the absorption clearance of cyclic peptides in the presence of glycylsarcosine (10 mM)) against hydrophobicity (oil-water partition coefficient). These results indicate that cyclo(Ser-Tyr) is absorbed by the oligopeptide transporter.     

Inhibition of Nifedipine Metabolism in Dogs by Erythromycin: Difference between the Gut Wall and the Liver

The purpose of this study was to evaluate possible interaction of nifedipine with erythromycin or rokitamycin in the intestinal mucosa. Male beagle dogs were orally administered nifedipine (10 mg), with or without oral pre-medication with erythromycin (300 mg), and 300 mg erythromycin or rokitamycin twice a day for 3 days. The experiments were of randomized cross-over design with a two-week wash-out period between dosing regimens. Erythromycin pre-medication for 3 days resulted in a significant increase in the area under the serum nifedipine concentration-time curve (AUC), whereas the curve for one nifedipine metabolite (M-2) decreased significantly. When the effects of erythromycin on the metabolism of nifedipine were studied using dog liver microsomes it was found that erythromycin significantly inhibited formation of M-2 but not of the metabolite M-1. These results indicate that formation of M-2 from M-1 in the liver might be reduced by erythromycin premedication. To avoid possible metabolism in the gut, the dogs were then administered 8 mg nifedipine into the peritoneal cavity, with or without multiple dose pre-treatment with erythromycin for 3 days. After intraperitoneal administration of nifedipine, the maximum concentration (C_max) of nifedipine increased significantly. After pre-administration of erythromycin the relative bioavailability of nifedipine after oral administration was increased compared with injection into the peritoneal cavity. In-vitro study using rat intestinal microsomes and the in-vivo rat intestinal loop technique also showed that pre-administration of erythromycin inhibits nifedipine metabolism in the small intestine.     

Enhancement of J–ST-Segment Elevation by the Glucose and Insulin Test in Brugada Syndrome

NOGAMI, A., et al. : Enhancement of J–ST-Segment Elevation by the Glucose and Insulin Test in Brugada Syndrome. The effects of glucose and insulin on J–ST-segment elevation were evaluated in seven men   (mean age 45 ± 10 years)   with Brugada syndrome. Six patients had been reanimated from VF and one patient had experienced syncope. The effects of intravenous (1) pilsicainide 50 mg, (2) glucose 50 g, and (3) glucose 50 g plus regular insulin 10 IU on the precordial ECG leads were examined. Pilsicainide significantly enhanced J-ST elevation in all patients and induced VF in 1 patient. A significant accentuation of the abnormal J-ST configuration was observed in all patients at a mean of   51 ± 40   minutes after glucose and insulin infusion. Changes in blood glucose and serum potassium concentration were   111 ± 158 mg/dL   and   −0.30 ± 0.48 mEq/L   , respectively. These changes were not directly related to the ECG changes. Glucose infusion without insulin caused a subtle increase in J-ST elevation. In conclusion, the administration of glucose and insulin safely unmasked or accentuation the J–ST-segment elevation in Brugada syndrome. Blood glucose and insulin concentrations may be factors modulating the circadian or day-to-day ECG variations in this syndrome. (PACE 2003; 26[Pt. II]:332–337)     

Retroperitoneal haematoma due to ruptured microaneurysm of the pancreaticoduodenal artery

A case of retroperitoneal haematoma due to a ruptured microaneurysm of the posterior superior pancreaticoduodenal artery in a 61 year old man is described. Ultrasonography and computed tomography revealed cystic masses near the gall-bladder. Selective coeliac angiography disclosed a microaneurysm of the posterior superior pancreaticoduodenal artery. Surgical extirpation of the cystic masses was performed, and the histological finding was an encapsulated old haematoma.     

Effects of turpentine oil pretreatment on β-blocker pharmacokinetic parameters in rats

Abstract— Turpentine oil treatment (0·2 mL kg^?1, s.c.) was used to increase the plasma concentration of α₁-acid glycoprotein (0·13 mg mL^?1 in control rats) to 1·72 mg mL^?1 after 2 days, and allow assessment of its effects on the pharmacokinetics and stereoselective binding of three β-blockers. Racemates (5 mg kg^?1) were administered intravenously to control and turpentine oil-pretreated rats and the plasma concentrations were determined up to 90 min. Stereoselective analysis showed the apparent distribution volume and the area under plasma concentration-time curves (AUC) of R-(+)-propranolol to be, respectively, one-quarter and twice those of the S-(–)-enantiomer and differences in pharmacokinetic parameters between the two were magnified by turpentine oil pretreatment. Pharmacokinetic parameters of oxprenolol enantiomers were essentially similar for the controls but after turpentine oil pretreatment, a higher affinity of the R-(+)-enantiomer for plasma was observed. Acebutolol enantiomers behaved non-stereospecifically throughout. These results were consistent with predictions from the in-vitro stereospecific binding properties of these agents to purified rat α₁-acid glycoprotein.     

The Effect of Biliary Pressure on Antibiotic Excretion into Bile

Abstract: Biliary obstruction has been recognized to inhibit excretion of antibiotics into bile. In the present study, using cefpirome sulfate (CPR), we sought to determine the effect of biliary pressure on antibiotic transfer into bile in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Thirty-six patients with a variety of biliopancreatic diseases (free of renal disease or hypoproteinemia) received a single intravenous dose of CPR (1 g) prior to ERCP. Under fluoroscopy a diagnostic catheter with a metal ball tip was advanced into the middle portion of the extrahepatic bile duct or, in cases of common bile duct obstruction, above the obstruction. Biliary pressure was measured via the same catheter using duodenal pressure as a reference. Subsequently, bile was aspirated, and blood was withdrawn simultaneously. The mean interval between CPR administration and the bile and blood samplings was 67±12 minutes. The bile CPR concentration and the bile/serum ratio of CPR concentrations showed a significant inverse correlation with biliary pressure, but the serum CPR concentration did not. The bile CPR concentration and the bile/serum ratio of CPR concentrations differed significantly between the group with normal biliary pressures, below 10 mmHg, and that with biliary pressures exceeding 10 mmHg. The serum CPR concentrations of the two groups were similar. These results suggest that biliary pressure plays an important role in determining antibiotic transfer into bile.     

Acquired total immunoglobulin G deficiency in a patient with primary biliary cirrhosis

Abstract. A 38-year-old Japanese woman was hospitalized for susceptibility to respiratory tract infections. Clinical examinations revealed asymptomatic primary cholestasis, abnormally elevated immunoglobulin M (IgM) and antimitochondrial antibody, being consistent with asymptomatic primary biliary cirrhosis. Three years later her serum immunoglobulin G (IgG) decreased remarkably, whereas other immunoglobulins were unchanged. Immunological examinations on the peripheral blood lymphocytes demonstrated spontaneous over-synthesis of serum IgM and decreased synthesis of IgG due to abnormal function of both T and B cells. Our case suggests a new possible association between primary biliary cirrhosis and IgG deficiency.     

Testosterone administration promotes regeneration of chemically impaired spermatogenesis in rats

AIM: It has been proposed that gonadotropin-releasing hormone (GnRH) analog administered after testicular damage stimulates the recovery of spermatogenesis. However, GnRH analogs suppress the function of sex accessory organs. In this study, we investigated whether testosterone also stimulates the regeneration of rat spermatogenesis after exposure to busulfan. METHODS: Male Fisher rats were divided into three groups of five each and all rats were treated with busulfan, 25 mg/kg, intraperitoneally at week 0. Group A served as the control. The other two groups received testosterone enanthate, 8 mg/kg, subcutaneous injections at 3 week intervals two times before (group B) or three times after (group C) busulfan. States of spermatogenesis were evaluated by histology and by the number of spermatid nuclei per testis at week 25. RESULTS: The mean percentage of 'recovered' seminiferous tubules plus or minus standard deviation was 10.3 +/- 7.8% in group A and 2.1 +/- 1.2% in group B. In both groups, more than 80% of the tubules remained degenerated. However, testes of group C rats showed an improvement of up to 37.1 +/- 20.5% (P < 0.05). The significant recovery of spermatogenesis was also demonstrated in group C by counting the number of spermatid nuclei per testis ([78.8 +/- 57.5] x 106). However, the count was only (7.6 +/- 13.5) x 106 and (0.52 +/- 1.0) x 106 in group A and B, respectively. CONCLUSIONS: Testosterone administration after severe testicular damage enhanced the regeneration of spermatogenesis in rats. We assumed that supplementary doses of testosterone would be more practical for clinical application than GnRH analogs, because exogenous testosterone maintains androgenicity.