Preparation and opioid activities of N-methylated analogs of [D-Ala2, Leu5]enkephalin

Analogs of opioid pentapeptide [D-Ala², Leu⁵]enkephalin were prepared using two kinds of N-methylation reactions, namely quaternization and amide-methylation. Quaternization reaction with CH³I-KHCO³ in methanol was applied to the deprotected N-terminal group of the pentapeptide derivatives affording trimethylammonium group-containing analogs. [Me₃⁺ Tyr¹,D-Ala², Leu⁵]enkephalin and its amide were found to show opioid activity on guinea pig ileium assay only slightly lower than the parent unmethylated peptides. Application of amide-methylation reaction using CH₃I-Ag₂O in DMF to the protected pentapeptide yielded a pentamethyl derivative in which all of the five N atoms were methylated. Deprotection of the derivative gave pentamethyl analogs of [D-Ala², Leu⁵]enkephalin, which showed no significant activity on the guinea pig ileum assay and opiate-receptor binding assay.     

An Attempt to Assess the Replacement Dose of Human Growth Hormone in the Treatment of Growth Hormone Deficient Children

Hibi, I., Tanaka, T., Yano, H., Umezawa, S., Kagawa, J., Tanae, A. and Ishikawa, E. (National Children's Medical Research Center, Tokyo, the National Children's Hospital, Tokyo and the Department of Biochemistry, Miyazaki Medical College, Miyazaki, Japan). Acta Paediatr Scand [Suppl] 337:87, 1987.
In 25 patients with hGH deficiency, who had been treated long-term with hGH, the mode of hGH administration was switched from the conventional method (0.3–0.5 IU/kg/week, in two or three divided doses, intramuscularly) to daily subcutaneous injection at 1900–2100 hours with a dose of 0.46 ± 0.07 IU/kg/week (equivalent to 14.7 ± 2.0 IU/m²/week). After 1–3 months of this new mode of hGH administration, blood and urine were sampled at 0900 hours after overnight fasting. Blood glucose, plasma insulin, plasma IGF-1 and plasma total IGF (after extraction) were analysed in blood samples. IGF-1 and hGH were measured in urine samples. These measurements indicated that the dose studied was close to a replacement one, but might be slightly higher than the exact replacement dose.     

AN AUTOPSY CASE OF DIPROSOPUS

A case of diprosopus, a very rare malformation belonging to dupli-citas, of a female newborn is reported. This diprosopus monauchenos tetrophthalmus triotus dioris was delivered from a 33 years old multipara. Autopsy revealed duplication of cerebral hemispheres, 1st, 2nd and 3rd cranial nerves, hypophysis, intracranial internal carotid arteries, basilar artery and tip of tongue. This diprosopus had also congenital cardiac and great vessel anomalies consisting of double outlet right ventricle without pulmonary stenosis, coarctation of aorta (infantile type), ventricular septal defect, patent ductus arteriosus, patent foramen ovale and thick right ventricular wall. Except for mesenterium commune, the organs in the chest and abdomen, and the extremities were normal in position, shape and number. ACTA PATH. JAP. 20: 239–249, 1970.     

Potentiated Embryotoxicity of Pyrimethamine by Folic Acid in Mice

ABSTRACT Effects of folic acid (FA) and folinic acid (FNA) on the embryotoxicity of pyrimethamine (PYR), an antifolate drug, were examined in mice. PYR and FA were administered orally, and FNA was injected intraperitonially for 7 days from day 9 to 15 of pregnancy. The incidence of embryotoxicity including intrauterine deaths and malformations, was 33.5 % in the PYR 50 mg/kg/day group. However, all the fetuses were resorbed in the PYR 50 + FA 50 mg/kg/day group, and FA potentiated the embryotoxicity of PYR. On the contrary, FNA reduced the embryotoxicity of PYR (PYR 50 + FNA 10mg/kg/day; 8.5%). Plasma concentrations of PYR and 5-methyltetrahydrofolic acid (5MF), a principal form of folate in plasma, were determined after single oral administration of PYR 50 mg/kg with or without FA 50 mg/kg to non-pregnant mice. Plasma 5MF concentration decreased drastically in the group receiving PYR with FA, compared with the PYR alone group. The pharmacokinetics of PYR were not affected by co-administration of FA. Therefore, we consider that the potentiated embryotoxicity of PYR by oral FA results from a decrease of plasma 5MF concentration in dams.     

Cough-reflex sensitivity to inhaled capsaicin in COPD associated with increased exacerbation frequency

Background and objective:   The causes of exacerbations in COPD patients are poorly understood. This study examined the association between cough-reflex sensitivity in patients with stable COPD and the frequency of subsequent exacerbations.
Methods:   The sampling frame for cases and controls for this study was patients attending a hospital outpatient clinic. cough-reflex sensitivity was evaluated using the log concentration of capsaicin causing five or more coughs (log C₅). Subsequent COPD exacerbations were identified prospectively via symptom-based diaries over a 12-month period.
Results:   The study group comprised 45 COPD subjects and 10 controls. Mean log C₅ was lower in the COPD group than in the control group (0.97 (95% confidence interval (CI): 0.76–1.18) versus 1.26 (95% CI: 0.81–1.71), P  = 0.095). In the COPD group, log C₅ was negatively correlated with serum CRP level ( r  = −0.36, P  = 0.02) and significantly associated with the exacerbation frequency ( r  = −0.38, P  = 0.01). Stepwise multiple regression analysis showed that cough-reflex sensitivity was significantly associated with exacerbation frequency ( r ² = 0.15, P  = 0.01).
Conclusions:   Hypersensitivity of the cough reflex to inhaled capsaicin might reflect airway inflammation in stable COPD patients, which predisposes to frequent exacerbations.     

Effects of Folic Acid and Folinic Acid on Pyrimethamine Teratogenesis in Rats

ABSTRACT  The effects of folic acid (FA) and folinic acid (FNA) on the tera-togenicity of the antifolate drug pyrimethamine (PYR) were examined in rats. PYR and FA were orally administered with mashed feed. FNA was intraperitoneal-ly injected. The drugs were administered for 5 days of day 11–15 of gestation. Six groups were made; G-I PYR 1.6 (mg/kg/day), G-II PYR 3.6, G-HI PYR 1.6 + FA 50, G-IV PYR 3.6 + FNA 12, G-V FA 50, G-VI control. No malformations were found in G-I, IV, V and VI. All fetuses in G-II and HI had malformations. Main malformations in G-II and III were cleft palate and brachygnathia. Accordingly it might be demonstrated that the teratogenicity of PYR was potentiated by concurrent FA in rats.     

Primary gastric lymphoma with arterial bleeding

We experienced a case of primary gastric lymphoma with arterial bleeding. The case was an 88‐year‐old‐man who was admitted to our hospital with hematemesis. Gastroduodenal endoscopy revealed a gastric ulcerating tumor with arterial bleeding in the posterior wall of the angular gastric region, and a distal subtotal gastrectomy with lymph node dissection was performed. The resected tumor measured 7.0 × 3.0 cm in size with a blood vessel visible in the bottom of the ulcer. Pathologic examination confirmed a diagnosis of B‐cell malignant lymphoma of the diffuse large cell type. Metastasis was detected in nos 3 and 5 lymph nodes. According to the Ann Arbor and Naquvi classifications, the lymphoma was stage IIE and II, respectively. One year and 10 months after the operation, a computed tomography scan revealed a few swollen lymph nodes around the abdominal aorta. Recurrence of lymphoma was confirmed and chemotherapy comprising cyclophosphamide, doxorubin, vincristine and predonisolone was given at half the ordinary adult dose.