Pharmacokinetics of a new histamine H2-receptor antagonist,Z-300, in rat and dog

1. The plasma level of Z-300 reached a maximum (C_max) at 30?min after the oral administration of Z-300 to dog, and disappeared from the systemic circulation with a halflife of 8-9 h. The bioavailability of Z-300 was 52% after the oral administration of Z-300, 3?mg/kg. At doses ranging from 3 to 30?mg/kg, C_max and AUC (area under the plasma concentration-time curve) were proportional to the dose. 2. The plasma level of Z-300 reached C_max at 10?min after the oral administration of Z-300 to rat, and disappeared from the systemic circulation with a half-life of 0.8-1.6 h. The bioavailability of Z-300 was 39% after the oral administration of Z-300, 10?mg/kg, and there was a non-linear relationship between the plasma level-time profile of Z-300 and the administered dose (3-50?mg/kg). 3. The binding of Z-300 to plasma protein was 92% in man, 65% in dog and 25% in rat. It is suggested that these species differences were due to the content of α₁-acid glycoprotein (α₁-AG), because Z-300 bound more strongly to α₁-AG than to albumin.     

Cyclic peptides

In order to investigate the role of the L-2-hydroxy-3-methylbutanoic acid residue at position 2 of AM-toxin I (cyclic tetradepsipeptide) on necrotic activity for apple leaves, two analogs, [L-lactic acid²] AM-toxin I and [L-2-hydroxy-4-methylpentanoic acid²] AM-toxin I, were synthesized by the conventional method for peptide synthesis. The toxic activity of the former analog was much weaker than that of the natural AM-toxin I and the latter analog. CD spectra of AM-toxin I and these analogs were correlated to those toxic activities, indicating that bulkiness of the side chain at position 2 is important for the maintenance of active conformation and the induction of necrotic activity.     

[13C]-pantoprazole breath test to predict CYP2C19 phenotype and efficacy of a proton pump inhibitor, lansoprazole

Background  ¹³CO₂ is produced on metabolism of ¹³C-labelled-pantoprazole ([¹³C]-pantoprazole) by CYP2C19.
Aim  To investigate whether the [¹³C]-pantoprazole breath test can predict CYP2C19 status and efficacy of proton pump inhibitors (PPIs) in Japanese.
Methods  We classified 110 healthy volunteers as rapid metabolizers (RM), intermediate metabolizers (IM) or poor metabolizers (PM) of CYP2C19 by genotyping. Breath samples were collected at 10-min intervals for 60 min after dosing with 100 mg [¹³C]-pantoprazole. Changes in the carbon isotope ratios (¹³CO₂/¹²CO₂) in carbon dioxide in breath samples were measured and expressed as a delta-over-baseline (DOB) ratio (‰). Of the 110 subjects, twenty-two randomly selected subjects underwent intragastric pH monitoring on day 7 of dosing with 30 mg of lansoprazole.
Results  The DOB values of RMs were the highest and those of PMs the lowest of the three groups. Statistically significant differences were observed in the area-under-the-curve ( AUC )_20–60 min of DOB among the three groups. The mean 24-h intragastric pHs attained by lansoprazole 30 mg for 7 days were inversely correlated with the AUC _20–60 min of DOB.
Conclusions  [¹³C]-pantoprazole breath test can easily estimate the individual activity of CYP2C19 and predict the efficacy of a PPI (i.e. lansoprazole). This test would be useful for individualized medicine with a PPI.     

A Case of Pneumatosis Cystoides Intestinalis Associated with Trichlor-oethylene Developing Typical Features during the Follow-up of Undetermined Sigmoid Lesions

Abstract: A 64-year-old male lens grinder with a 43-year history of occupational exposure to trichloroethylene (TCE) visited Shinshu University Hospital in December 1988 complaining of distention of the lower abdomen. A barium enema study and endoscopic examination showed rosary-like semilunar folds and edematous mucosa of undetermined etiology in the sigmoid colon. Three months later, the patient visited the hospital again complaining of blood in the stool. An endoscopic examination performed at this time revealed numerous broad-based, smooth-surfaced, protruding lesions in the sigmoid colon. A diagnosis of pneumatosis cystoides intestinalis (PCI) associated with TCE was made. After 4-days treatment with 50% oxygen given by inhalation, the patient's symptoms were completely relieved, and a colonoscopy revealed no evidence of PCI. He returned to his job at the factory which involved dealing with TCE and because of adequate ventilation and a shorter work-day he has been free of recurrence during a year follow-up period. The finding of rosary-like semilunar folds, as demonstrated by the initial endoscopic and barium enema studies in our patient, is a peculiar one in the incipient stage of PCI.     

Changes in work performances in obstructive sleep apnea patients after dental appliance therapy

Abstract The effects of dental appliances on work performances of obstructive sleep apnea syndrome (OSAS) is not well examined. This study evaluated the polysomnographic and psychological findings before and after therapy. Nine patients were diagnosed OSAS by nocturnal polysomnography. The psychological battery was performed from 13:00 to 14:00, which consisted of Uchida-Kraepelin psychodiagnostic test (U-K's test) and Bourdon's cancellation test (Bourdon's test). Approximately 3 months after the treatment, the examinations were performed. Apnea and desaturation index decreased significantly after the therapy. In addition, sleep architecture improved after the therapy compared with that before the therapy. Dysfunction of task performances, such as mean level of work amounts in U-K's test, mean error, mean performance time and mean deviation in Bourdon's test improved after therapy. We conclude that dental appliances therapy is effective not only to apnea but also to work performance in OSAS.     

Interaction of lipophilic peptides derived from mastoparan with phospholipid vesicles

Various kinds of lipophilic peptides were prepared by acylation of an ct-helical peptide, mastoparan, to investigate the effects of acyl groups on the interaction of peptides with phospholipid membranes. α-Helicity of the peptides was increased by introduction of long acyl groups. Acyl peptides showed different membrane-perturbation activities for neutral and acidic phospholipid vesicles, whereas a peptide with a dialkycarbamoyl group always exhibited a strong activity. High hemolytic activities were observed for the peptides with long acyls (single or double chain). These results indicate that lipophilic groups introduced to mastoparan contribute greatly to the interaction of the peptide with phospholipid membranes with lengthening of the acyl chain and that the structural character of the lipophilic group also influences the conformation of the peptide.     

Interaction of α-helical peptides with phospholipid membrane: effects of chain length and hydrophobicity of peptides

To investigate the interaction of amphiphilic α-helical peptides with phospholipid membranes, we synthesized Ac-(Leu-Ala-Arg-Leu)₃-NHcH₃ (4₃) and three derivatives, in which the chain length and the size of the hydrophobic region of the peptides were different from each other. These peptides formed an α-helical structure in the presence of vesicles. In the membrane-perturbation measurement, only 4₃ showed a strong membrane-perturbation activity below phase-transition temperature (25°C), but above phase-transition temperature (50°C), most peptides showed similar strong activities. On the other hand, in membrane-fusion measurement the long peptides, e.g., Ac-(Leu-Ala-Arg-Leu)₃-(Leu-Arg-Ala-Leu)₃-NHCH₃, had strong activities at low peptide concentrations at 25°C. The present study indicated a parallel relationship did not always exist between membrane fusion and perturbation caused by peptides.