Aliphatic and heterocyclic analogues of arecaidine propargyl ester. Structure-activity relationships of mono- and bivalent ligands at muscarinic M1 (M4), M2 and M3 receptor subtypes.

The pharmacological profiles of tertiary and quaternary monovalent (1b-6b) and bivalent ligands (7a-12b), closely related to arecaidine propargyl ester (CAS 35516-99-5, APE, 1a), were evaluated at muscarinic receptors in rat superior cervical ganglia (M1), rabbit was deferens (M1/M4-like), guinea-pig atria (M2) and guinea-pig ileum (M3). In the monovalent ligand series (1a-6b) APE (1a) displayed the highest potency at all three muscarinic receptors [M2 (-log EC50 = 8.12) > or = M3 (-log EC50 = 7.77) = M1/M4 (-log EC50/vas deferens = 7.72)], whereas in the bivalent ligand series (7a-12b) arecaidine 2-butyne-1,4-diyl bisester (bisABE, 7a) was the most potent agonist with functional selectivity for M1/M4 (-log EC50/vas deferens = 6.94) and M2 receptors (-log EC50 = 7.10) over M3 receptors (-log EC50 = 6.27). On ganglia bisABE elicited M2 receptor-mediated hyperpolarisations, which were followed by long-lasting pirenzepine-sensitive depolarisations. However, the potency at M1 receptors in ganglia of APE (-log EC50 = 6.96) and bisABE (-log EC50 = 5.69) was lower than that in rabbit vas deferens. All bivalent molecules exhibited decreased potencies when compared with their monovalent analogues. However, a change in potency profiles was often obtained. The quaternary isonicotinic acid 2-butyne-1,4-diyl bisester (10b) displayed some functional selectivity for M2 receptors (-log EC50 = 5.78) [6- to 9-fold over M1/M4 (-log EC50/vas deferens = 5.03) and M3 receptors (-log EC50 = 4.83)] without showing nicotinic effects.(ABSTRACT TRUNCATED AT 250 WORDS)

WAL 2014--a muscarinic agonist with preferential neuron-stimulating properties.

The ability of WAL 2014 to elicit muscarinic responses was investigated in various in vitro and in vivo models. In CHO cells transfected with human m1- or m3- receptor genes, WAL 2014 was clearly more effective in stimulating the M1-mediated PI response. In isolated tissue preparations, WAL 2014 exhibited full agonist properties in the rabbit vas deferens (putative M1 receptor) and behaved like a partial agonist at M2 receptors in the atrium and M3 receptors in the ileum of guinea-pigs. In the pithed rat, in which the increase in blood pressure is mediated through a stimulation of M1 receptors in sympathetic ganglia, WAL 2014 produced a full dose response curve, whereas the reference compounds RS 86 and arecoline exhibited a bell-shaped behaviour. This is in accord with the view that WAL 2014 selectively activates M1 receptors in sympathetic ganglia, whereas conventional agonists in the same dose range stimulate both ganglionic M1 and vascular M3 receptors. The preferential neuron-stimulating properties were confirmed by EEG recording in the rabbit, in which muscarinic activation occurred at doses similar to those for ganglionic stimulation in the pithed rat. On the other hand, higher doses of WAL 2014 were needed to elicit muscarinic effects in peripheral effector organs, i.e. bradycardia, urinary bladder contraction and increase in airway resistance. It is concluded that WAL 2014 due to its preferential neuronal activity is a promising candidate for a cholinergic substitution therapy in Alzheimer's disease.

[A case of anaerobic emphysematous cholecystitis with a subhepatic abscess]. / Prípad anaerobní emfyzematózní cholecystitidy s podjaterním abscesem.

The authors describe their own observation of a complicated course of emphysematous cholecystitis caused by anaerobic microorganisms. An extensive subhepatic abscess was involved which developed as a results of emphysematous cholecystitis diagnosed by sonographic and CT examination. After two operations on account of the abscess and a phlegmon of the abdominal wall the patient recovered. The authors emphasize that early diagnosis and adequate treatment calls for collaboration of clinicians, microbiologists and roentgenologists.

Computed tomography of bones and joints.

The monograph sums up the problem of CT diagnosis of bones and joints making use of predominantly the authors' own experience based on CT tests of more than 45,000 patients examined at the Department of Radiology, Charles University Medical Faculty of Hygiene teaching hospital in Prague in the years 1980-1988. Specific scans of the skeleton were made in 4,500 patients, mostly for suspicion or closer assessment of neoplasms (43.5%), the radicular lumbosacral syndrome (34.5%), and injuries (12%). The opening chapters sum up basic facts about the principle of computed tomography, the apparatus in use, the evaluation of CT images, CT radiation doses, and the patients' preparation for CT scanning. The use of contrast media is discussed with regard to the possible hazards involved and to the need to hear allergological opinion first. For spinal canal visualization non-ionogenic contrast media are used exclusively. The management of side reactions to contrast medium application is also reviewed. Indications for bone and joint computed tomography now comprise a whole series of traumatological, orthopaedic, oncological, rheumatological, neurological and rehabilitation conditions, each of which is discussed in detail in a separate chapter. CT anatomical studies offer the advantage of being applicable even in patients examined for other than bone or articular diseases. The option of simultaneous soft tissue assessment represents another advantage. The authors describe different anatomical structures in terms of CT images, some of them complete with dimensional and density values. The chapter on anomalies and developmental variants stresses the relevance of computed tomography for precise characteristics of clefts of the spinal column and facial bones and for the diagnosis of anomalies and dysplasias of the spinal column and the chest. A rare case of cephalothoracopagus is demonstrated. As for traumatology, computed tomography is found useful in diagnosing fractures of the orbit and facial bones in general, the atlas, axis and pelvis and in tracing vertebral fragments displaced into the spinal canal. Computed tomography occupies a monopoly position in the diagnosis of post-injury haematomas of intracranial but also thoracic, pelvic and abdominal localization. There is a wealth of illustrations to document a wide range of traumatic conditions. The chapter on degenerative diseases is focused mainly on computed tomography in the lumbosacral radicular syndrome, one of the most frequent and also most effective indications for CT. Protrusion and herniation of the intervertebral disk and sequestra in the spinal canal are all absolute indications for CT scanning where surgical treatment is contemplated.(ABSTRACT TRUNCATED AT 400 WORDS)