Effects of long-term glibenclamide administration on gastrointestinal and pancreatic hormones in normal fasting rats.

We previously reported that sulfonylurea treatment reduces insulin (IRI), glucagon (IRG) and somatostatin (SRIF) release following metabolic stimuli from the isolated perfused pancreas of normal rats and that a reduction in IRI, IRG and SRIF pancreatic content was also observed. The present work was undertaken to investigate the effects of long-term glibenclamide treatment on the gastrointestinal content of gut hormones in normal rats. Moreover, the effects of sulfonylurea treatment on IRI, IRG, and SRIF pancreatic content were also analyzed and compared to the peripheral hormone plasma levels. Two groups of male Sprague-Dawley rats received glibenclamide (1 mg/kg/day per os; n = 14) or placebo (distilled water; n = 10) for 5 months, respectively. Tissue contents of IRI, IRG and SRIF in acid-ethanol extracts of pancreas and of gastric inhibitory peptide (GIP), vasoactive intestinal polypeptide (VIP), entero-glucagon (gut-GLI) and SRIF in acid-ethanol extracts of intestine were determined. Blood glucose and plasma pancreatic hormone levels were also measured. Glibenclamide treatment lowered the levels of IRI, IRG and SRIF in the pancreatic tissue; in the same way gut-GLI, SRIF and VIP intestinal concentrations were significantly reduced, whereas no significant inhibition was detected in intestinal GIP content. Blood glucose levels and IRI and SRIF plasma concentrations were similar in the two groups. IRG plasma levels were reduced in the sulfonylurea group. These findings might suggest that sulfonylurea suppresses hormone biosynthesis in a non-specific manner.

Interfering with implantation by postcoital estrogen administration. II. Endometrium epithelial cell ultrastructure.

Secretory human endometrium was studied by electron microscopy after high-dose ethinylestradiol administration, a method used for interception (morning-after pill). Medicated (experimental) cycles were compared to non-medicated (control) cycles in the same volunteers. The nucleolar channel system typically present in the nucleus of the epithelial cell in secretory phase of the human endometrium disappears completely as a result of this treatment, resulting in a nucleolar basket structure. Glycogen deposits were prominent at the basal membrane and in the apex of the cell during the experimental cycle. Giant mitochondria were observed to occur to similar extent during control and treatment cycles. This study confirms the morphological delay found in light microscopic studies, published earlier with diethylstilbestrol and with ethinylestradiol.

PIP: High-dose ethinylestradiol is used as a postcoital contraceptive. Its mechanism of action is to delay the secretory development of the endometrial epithelial cells. This study, using 4 normal volunteers, was undertaken to see the effects of high-dose ethinylestradiol on the ultrastructure of the endometrial cells and on glycogen metabolism during the luteal phase of the menstrual cycle. Ovulation was determined from plasma luteinizing hormone levels, and the subjects were given 5 mg ethinylestradiol for 5 consecutive days thereafter. The nucleolar channel system, which typically appears in the cell during the secretory phase, completely disappeared after treatment with ethinylestradiol. Moreover, the Golgi complexes were enlarged, and large amounts of glycogen accumulated at the basal membrane and in apical vacuoles of the cells. These changes show that large doses of ethinylestradiol given after ovulation interfere with the synthesis and secretion of glycogen in the endometrial epithelial cells.

Cyclosporine plasma levels six hours after oral administration. A useful tool for monitoring therapy.

Clinical evolution and cyclosporine (CsA) monitoring of 65 transplanted patients (55 kidneys, and 10 kidneys and pancreases) treated with CsA were analyzed retrospectively (45 patients) and prospectively (34 patients). Our results showed the following: (1) nephrotoxicity is not uncommon even with low trough plasma levels of CsA; (2) the T6 value of a CsA pharmacokinetic plasma curve (6 hr after oral drug administration) is a valid expression of a full pharmacokinetic study; (3) when T6 was used prospectively as a monitoring tool and dose adjustments made disregarding concomitant serum creatinine levels, the latter decreased when CsA dose adjustments were made to correct toxic (greater than 350 ng/ml) or subtherapeutic (less than 100 ng/ml) T6, P less than 0.01. At present, serum creatinine for all our patients is 180.2 +/- 8 mumol/L, and no patient has needed to be switched to conventional treatment. The validity of trough plasma levels in patients under CsA oral administration once or twice a day seems questionable, and T6 proved to be more useful. Thus nephrotoxicity and CsA undertreatment may be avoided. This new monitoring tool (T6) will allow the utilization of lower doses of CsA and thus contribute to improved long-term graft function.

Effect of use of a measured dispensing device on oral antibiotic compliance.

The substitution of a syringe in place of a teaspoon for the delivery of oral medications has become routine in some pediatric practices for reasons that are not clear. Although a syringe would measure dosages more accurately, most oral medications have a broad acceptable dose range. A possible advantage of syringes is that parents who receive these may be more impressed with the importance of treatment than those prescribed medications by teaspoon. To test this hypothesis, 72 patients below 24 months of age with otitis media were randomly divided into a group that received a prescription indicating amoxicillin should be given by teaspoon and a group that received a labeled syringe for this purpose. The qualitative presence of the antibiotic in urine at seven-day follow-up visit was 56 per cent among the teaspoon users and 67 per cent among syringe users, while return rates for one week appointments were 51 per cent and 32 per cent, respectively. Neither difference was significant. Use of a measured oral dispensing syringe did not improve compliance in administration of medication or return for follow-up and therefore, was judged not to be cost effective.

A tethering system for intravenous and intragastric drug administration in the baboon.

A system for minimally restraining adult baboons with chronic intravenous (IV) or intragastric (IG) catheters for long term pharmacological and behavioral studies is described. The system consists of an adjustable foam-padded backplate and harness which is custom-fitted to each animal. A flexible stainless-steel cable connects the backplate to a liquid swivel through which the drugs are administered. Methods for the preparation and surgical implantation of IV and IG catheters are also described. Intravenous catheters were sequentially implanted in the internal jugular, femoral, axillary and external jugular veins. Catheters have remained patent for as long as 45 months, and catheter life appears to be conjointly determined by both site and number of successive implantations. The advantages of the harness/tether system over previously used chair-restraint procedures include greater freedom of movement, fewer restraint-related health problems, and longer experimental life of the animals.

Antihypertensive effect of the new oral angiotensin converting enzyme inhibitor "MK-421".

The effects of the new oral converting enzyme inhibitor "MK-421" on blood pressure, plasma renin activity, plasma angiotensin II, aldosterone, and angiotensin converting enzyme were assessed in 16 hypertensive patients. Maximum (maintenance) doses ranged from 2.5 mg-40 mg daily. Blood pressure decreased from 177 +/- 7/111 +/- 4 mm Hg to 145 +/- 6/94 +/- 3 mm Hg supine and from 174 +/- 7/177 +/- 4 mm Hg to 142 +/- 6/101 +/- 3 mm Hg upright (mean +/- SEM, p less than 0.001 for both). Heart rate did not change significantly. Plasma renin activity rose during treatment, whereas plasma angiotensin II, aldosterone, and angiotensin converting enzyme remained suppressed at 24h after the maximum dose. Magnitude of blood pressure reduction after the maximum dose did not correlate with baseline plasma renin activity levels. No side-effects were noted during the 2-10 week observation period. MK-421 is similar to its predecessors in efficacy and clinical and biochemical correlates, the main difference being its higher potency and longer duration of action.

Can food influence the absorption of methotrexate in children with acute lymphoblastic leukaemia?

Serum levels of methotrexate (MTX) were measured in 10 children with acute lymphoblastic leukaemia over a 4 hour period after oral administration. The drug was given to each child on three occasions: first, with no food, then with a milky meal, and finally with a citrus meal. Peak serum MTX levels were significantly reduced by the milky meal and both meals delayed drug absorption in most children. The area under the absorption curve was also significantly reduced by the milky meal. Thus, for maximum serum levels, MTX should not be given with food, and if patients are to be grouped on the basis of their MTX absorption profile this should be determined under standard conditions in relation to meals.

Uracil mustard in the treatment of thrombocytosis.

Uracil mustard was used for the treatment of thrombocytosis in 14 patients, eight who had polycythemia vera and six who had essential thrombocytosis. Intermittent treatment with 1 to 2 mg/day for 14 days was used for most patients, and continuous treatment was used for three patients. The nadir of the platelet count occurred during a mean period of five to seven weeks, and the mean duration between courses was seven months. The drug selectively depressed the platelet count, with a minimal effect on leukocytes and erythrocytes. Uracil mustard is an effective drug for the control of thrombocytosis.

[Histamine H-2 receptor antagonists and medical treatment of Zollinger-Ellison syndrome]. / Antagonistes des récepteurs H2 a l'histamine et traitement médical du syndrome de Zollinger-Ellison.

Cimetidine was studied in 8 cases of Zollinger-Ellison syndrome. The average dose was 1,2 g a day for 14 to 195 days. The treatment was remarkably effective in 2 cases, but only partial or temporary improvement was noted in 3 other cases. The last 3 patients failed to respond to treatment. The possibility of a rebound phenomenon requires strict clinical and biological supervision.

Esophageal cannulation for oral drug administration in the sub-human primate.

A technique of esophageal cannulation used in rats was adapted for use in the sub-human primate. Cannulation of the esophagus requires general surgical skills and a very short postoperative recovery period. No interference in eating habits or tendency toward vomiting was noted following cannulation. This technique allows the investigator an effective method for oral dosing of drugs with minimal physical and emotional stress to the animals and is quite appropriate for oral drug self-administration studies.