Affinity profiles of BTM-1086 and BTM-1041 at muscarinic receptor subtypes and at H1- and alpha 1-receptors

The affinities of the (+) and (-) enantiomers of the antimuscarinic benzothiazepinone derivative, cis-2,3-dihydro-3-(4-methyl-1-piperazinylmethyl)-2-phenyl-1,5-benzoth iazepin-4 (5H)-one (BTM-1041 and BTM-1086), for muscarinic receptor subtypes, histamine H1-receptors and alpha 1-adrenoceptors were determined in vitro using isolated organs: field-stimulated rabbit vas deferens (M1-receptors), guinea-pig left atrium (M2-receptors), guinea-pig ileum (M3- and histamine H1-receptors) and rat vas deferens (alpha 1-adrenoceptors). We also assessed the binding profile of BTM-1041 and BTM-1086 at muscarinic receptor subtypes in guinea-pig cortex (M1), heart (M2) and salivary glands (M3) as well as at alpha 1-adrenoceptors in rat cerebral cortex. Functional and binding experiments showed that the (-) enantiomer (BTM-1086) had a high affinity (pA2 = 7.98-8.81; pKi = 8.31-9.15) for the three muscarinic receptor subtypes, whereas the (+) enantiomer (BTM-1041) showed a low antimuscarinic potency (pA2 = 4.87-5.31; pKi = 4.85-5.55). This results in an extremely high stereoselectivity for these optical isomers [-)/(+) ratios = 1023 to 6918). The affinity of the (-) enantiomer BTM-1086 was lower for both histamine H1- and alpha 1-receptors than for muscarinic receptors, whereas the reverse was true for the (+) enantiomer, BTM-1041. Thus, the stereochemical demands for the two optical isomers were most stringent at muscarinic receptors but were inverse and less pronounced at histamine H1- and alpha 1-receptors (stereoselectivity ratios = 0.16-0.22).     

Penetrating chest injuries

The purpose of this paper is to review our experience in the management of penetrating chest injuries and their outcome in spite of the shortage of equipment for thoracic surgery at the Gonder Hospital. The study was based on prospective analysis of 32 cases treated at this hospital between February 1987 and February 1988. About 30% of our cases has associated injuries to other organs. Simple pleural space drainage was done in 19 cases. Only 4 of the patients required immediate or delayed thoracotomy while 3 other cases required laparotomy. Complications occurred in 8 patients, of whom 6 died. In 6 cases only conservative treatment was indicated. About 80% of our patients with penetrating chest chest injuries were treated successfully with no, or only minimal, residual defects. Availability of of simple and effective materials in rural hospitals is recommended.     

The internal sphincter in anorectal malformations: morphologic investigations in neonatal pigs

The knowledge of sphincter anatomy in anorectal malformations is still inadequate and contradictory. Therefore, morphologic investigations were carried out in 33 neonatal piglets with congenital anal atresias. Of the 24 male animals 12 had high anomalies with a rectourethral fistula. The remaining 12 piglets had low anomalies; in nine cases we were able to demonstrate an anocutaneous fistula. Of the nine female animals, six had high anomalies with a rectovaginal fistula. The three female piglets with low anomalies had an anovestibular or an anocutaneous fistula. In all animals we could demonstrate a normal internal sphincter, which surrounded the proximal part of the fistulae. The position of the internal sphincter therefore depended on the localization of the fistula orifice into the rectal pouch. This differed greatly. The form of the internal sphincter also differed greatly. Sometimes the muscle had the form of a tube or an acute-angled funnel as in healthy piglets. However, mostly the internal sphincter was spread out wide and had the form of a disc or a flat dish. The proximal region of the fistulae in anal atresias has most features of a normal anal opening: (1) it is surrounded by an internal sphincter, (2) the rectal pouch in the region of the internal sphincter as well as the fistulae are hypoganglionotic, (3) the proximal fistula region is lined by transitional epithelium, and (4) it contains anal glands. We, therefore, consider that the fistula should be designated as an ectopic anal canal. The most important result was the demonstration of a normal internal sphincter even in high and intermediate anomalies of anal atresias.(ABSTRACT TRUNCATED AT 250 WORDS)     

Selective antagonists provide evidence that M1 muscarinic receptors may mediate carbachol-induced drinking in the rat

The present study served to investigate the ability of seven selective muscarinic antagonists to inhibit carbachol-induced drinking in the rat. The muscarinic antagonists were given by intracerebroventricular (i.c.v.) injection 1 min before the i.c.v. injection of carbachol (1 microgram/rat). The M2 antagonist, methoctramine, was inactive up to 80.3 nmol/rat. The M3 antagonist, p-fluoro-hexahydro-sila-difenidol, elicited a modest (42%) but statistically significant inhibition of drinking only at 80 nmol/rat. On the other hand, the selective M1 antagonists, (R)-trihexphenidyl, o-methoxy-sila-hexocyclium and pirenzepine, produced a marked and dose-dependent inhibition of carbachol-induced drinking, their ID50 values being 0.51, 7.36 and 9.31 nmol/rat. Also the M1/M3 antagonists, 4-diphenylacetoxy-N-methylpiperidine methiodide and hexahydro-sila-difenidol, were potent inhibitors of carbachol-induced drinking, their ID50 values (0.28 and 11.09 nmol/rat) being related to their pA2 values for M1 receptors in rabbit vas deferens. These data suggest that carbachol-induced drinking may be mediated by activation of muscarinic M1 receptors.     

A study comparing biopharmaceutic characteristics of four once daily controlled release diltiazem preparations

Summary— In the present study we have compared the steady state biopharmaceutic characteristics of four diltiazem once daily controlled release capsules: Mono-Tildiem LP 300® (300 mg), Adizem® XL (300 mg)¹, Cardizem® (300 mg) and Dilacor® (240 mg). Sixteen healthy male volunteers (aged 22.9 ± 3.3 years, range 19–31 years) completed an open label, multiple oral dose, randomized, four-period crossover study without a washout period in between. The volunteers received each diltiazem formulation once daily for four days. Trough diltiazem and metabolites plasma concentrations were determined on days 3 and 4. The 24-h plasma concentration-time profiles were assessed after the dose on day 4 of each period. The following steady state pharmacokinetic parameters for diltiazem were calculated: the minimum plasma concentration (c_min), the maximum plasma concentration (c_max), the time to reach that concentration (t_max), the time interval during which the plasma concentration exceeds 50% of c_max (t₅₀), the area under the plasma concentration-time curve (AUC_72–96) and the peak-to-trough fluctuation (PTF). For the metabolites of diltiazem, N-mono-desmethyl-diltiazem (NDM) and desacetyldiltiazem (DAD), AUC_72–96 (AUC_NDM and AUC_DAD) and the ratio metabolite/parent compound were calculated. Steady state was achieved on day 3. Except one, all controlled release formulations have satisfactory controlled release properties allowing once daily administration. However, significant (P < 0.05) differences were found between the pharmacokinetic characteristics which do not allow exchange of the various formulations. Concentrations well below 50 ng·mL^-1 in the morning hours were observed for Dilacor® (240 mg) and Adizem® XL (300 mg), which could be a disadvantage of these formulations as it is well-known that ischaemic events occur at a higher rate during that part of the day. The plasma concentration profiles of NDM and DAD, the major circulating metabolites, parallel the plasma concentration profiles for the parent compound. From a clinical point of view, all treatments were well tolerated.     

Segmental intestinal muscular thinning: a possible cause of intestinal obstruction in the newborn

Intestinal obstruction proximal to a transition zone without an interposed physical barrier usually indicates Hirschsprung disease. The authors report one case of focal small bowel muscular thinning just distal to a transition zone that produced clinical and radiographic findings that simulated long-segment Hirschsprung disease in a 2-day-old infant.