General pharmacology of S 15261, a new concept for treatment of diabetes

The new compound S 15261 (CAS 159978-02-6) is the I-isomer of 3-[2-[2-[4-[2-(alpha-Fluorenylacetylamino)ethyl]benzoyloxy]ethylam ino]-1- methoxyethyl]trifluoromethylbenzene. The general synthetic pathway used for the preparation of S 15261 and related esters is given in this paper. This compound was selected for its promising therapeutical action on blood glucose, insulin resistance and associated risk factors present in patients with non-insulin-dependent Diabetes mellitus (NIDDM). The general pharmacological profile of S 15261 was investigated. The data given in this paper show that S 15261 has presented a very low acute toxicity (lethal dose in mice greater than 1600 mg/kg orally) and did not induce significant behavioural changes in rats. A poor anorectic effects was observed after acute administration in rats. In guinea pigs S 15261 acutely induced a significant and dose-dependent hypoglycaemic effect (ED25 = 40 mg/kg orally). Biogenic amines and their metabolites in different structures of the brain were only slightly affected after acute administration of S 15261. Chronic administration of this compound (2.5 mg/kg bid for 14 days p.o.) did not cause significant alterations in the brain amines content, with the exception of an increase of serotonin (19%) in the striatum, a result not confirmed by the dose-effect study (from 1 mg/kg to 12.5 mg/kg bid for 14 days p.o.). In vitro binding assays with 31 different receptors did not show significant affinity of S 15261 for any of them. The rat arterial blood pressure was decreased (12 mmHg) after acute (25 mg/kg i.v.) or repeated administration (2.5 mg/kg bid for 14 days p.o.) without any dose-dependent effect. We therefore conclude that S 15261 may not have significant adverse effect even at doses higher than the pharmacological effective range of doses. Although the mechanism of action of this new class of compounds was not fully understood, other pharmacological data suggest that S 15261 acts at both the liver (intraportal infusion) and skeletal muscle (microdialysis studies) at least in part to enhance insulin sensitivity. For all these activities S 15261 may be useful to treat patients with NIDDM or insulin resistance known to be the major risk for onset of NIDDM.     

A new concept for the pathogenesis and treatment strategies for oral lichen planus

Mounting evidence points out to the immunologic basis of lichen planus (LP). Tumour necrosis factor (TNF-alpha) is a cytokine with multiple biologic activities, some of which may be relevant to the pathogenesis of LP. The present study was thus conducted to assess its production by peripheral blood leucocytes in patients with active lesions of oral lichen planus (OLP) compared to age matched healthy control volunteers. For the assessment, the quantitative immunometric sandwich technique was employed. Significantly greater amounts of TNF-alpha were found in serum samples of OLP patients compared to healthy individuals, suggesting a possible association between this cytokine and the pathogenesis of OLP and pointing out to the primary initiative role played by altered keratinocytes. This pointed out the beneficial effect of anti-TNF drugs in the management of OLP.     

Fluorescence cross-correlation: a new concept for polymerase chain reaction

Infusion of sodium selenite to the occipital cortex of the rat was used for the specific tracing of zinc-rich pathways. Large numbers of labeled somata were found ipsilaterally in the visual, orbital and frontal cortices, and contralaterally in homotopic and heterotopic visual areas. Labeled neurons were also found ipsilaterally in the retrosplenial, parietal, sensory-motor, temporal and perirhinal cortex. In contrast to the cortico-cortical connections, ascending afferents to the visual cortex were not zinc-rich except for a few labeled neurons in the claustrum. Additional injections showed reciprocal zinc-rich connections between the visual cortex and the orbital and frontal cortices. The latter cortices also received ascending zinc-rich afferents from the claustrum. Selenite injections revealed the layered distribution and the morphology of these labeled neurons in the neocortex. Zinc-rich neurons were found in layers II-III, V and VI. However, none was found in layer IV. Zinc-rich somata appeared as pyramidal and inverted neurons. The contrasting chemical properties of cortical and subcortical visual afferents may account for the functional differences between these systems.     

Calcifying tendinitis: a new concept of its pathogenesis

To elucidate the pathogenesis of calcifying tendinitis, clinical and morphological investigations were done on 46 surgically treated cases. Contrary to the prevalent concept of degeneration preceding dystrophic calcification, we found no evidence for an active or a healed degenerative process. The affected tendon was transformed into fibrocartilage with a predilection for calcification. The formative phase of calcification was followed in course of time by a resorptive phase during which the deposits were surrounded by phagocytosing cells. There was a concomitant proliferation of vascular channels. We found a significant correlation between severe pain and histological signs of resorption. The pathogenetic mechanism of calcifying tendinitis should be reassessed as a unique disorder of the musculotendinous cuff.     

Allograft "acceptance" and tolerance: a new concept

Discovery of microchimerism in kidney and liver transplantation provided an important framework for a better understanding of allograft acceptance, for analysis of management problems and for therapeutically oriented transplanted research. In these new concept correlations with infectious diseases caused by non cytopathic microorganisms, previous enigmas, immunologic reaction, counter argument and general immunologic implications are discussed.     

Viscosupplementation: a new concept in the treatment of sacroiliac joint syndrome: a preliminary report of four cases

OBJECTIVE: To evaluate the modulatory effects of interleukin (IL)-1beta and prostaglandin (PG)E2 on the PGE2 receptor subtype EP1 in amnion cell cultures. METHODS: Amnion cell cultures were incubated in increasing concentrations of (IL)-1beta or PGE2. Cultures were also incubated in high concentrations of IL-1beta and PGE2 in combination. Changes in EP1 receptor levels were evaluated by western and northern blot analysis. Culture fluid PGE2 levels were measured by enzyme-linked immunosorbent assay. RESULTS: EP1 receptor protein levels decreased with increasing levels of PGE2 (r = -0.82, P < .05). EP1 receptor protein (r = 0.95, P < .05), EP1 mRNA (r = 0.95, P < .01), and culture fluid PGE2 levels (P < .01) were all increased after IL-1beta administration. EP1 receptor levels also increased approximately fourfold in response to IL-1beta incubation even in the presence of high agonist (PGE2) concentrations (P < .01). CONCLUSION: The results of this study show that IL-1beta might be involved in infection-induced preterm labor by interfering with the normal regulation of EP1 receptor levels and with the promotion of increased PGE2 production in amnion tissue.     

Stepwise concept for treatment of complex anal fistulas

Most anal fistulas can be easily dealt with by simple fistulotomy. So called complex fistulas-in-ano need a differentiated, individually tailored surgical approach in order to avoid recurrence and sphincter incompetence. Complex fistulas comprise either tracks with high trans-, supra-, or extrasphincteric extension or fistulas that are complicated by multiple side branches, chronic inflammatory disease, previous operations etc. Prior to treatment a thorough preoperative diagnostic work-up is warranted. A precise intraoperative evaluation is paramount to allow radical excision of all inflamed tissue, often necessitating anal sphincter division with subsequent reconstruction. The treatment plan involves staged operations over a period of many months, usually with the (laparoscopic) fashioning of a protective stoma at the primary operation. Analysing our patients in the study period from 1/95 to 12/96 our different surgical approaches and their results are presented and discussed. During this period 96 patients with a fistula-in-ano were operated upon in the Department of Surgery at Würzburg University Hospital, of which 11 (11.5%) had complex disease. We encountered one early and one late recurrence as well as a parastomal hernia and a stoma prolapse. Anal continence was re-assessed three months following reversal of colostomy. All patients (n = 7) who had perfect continence preoperatively remained unchanged. Preoperatively, four patients were incontinent for gas and liquid stool. Two of these were fully continent, one remained unchanged at re-assessment. The fourth patient did not undergo stoma reversal as yet, because all examinations revealed an incompetent sphincter. This patient is therefore fully incontinent. Successful treatment of complex anal fistulas needs an individual approach and planning over a lengthy period of time, requiring a high level of motivation on the part of both patient and surgeon.     

Quantification of facial morphology using stereophotogrammetry--demonstration of a new concept

OBJECTIVES: The purpose of this study was to introduce stereophotogrammetry as a three-dimensional registration method for quantifying facial morphology and detecting changes in facial morphology during growth and development. METHODS: Using stereophotogrammetry, three-dimensional (3-D) co-ordinates for the bilateral landmarks Exocanthion and Cheilion and the midsagittal landmark Pronasale were determined in 10 subjects to ascertain the reproducibility of the method, and in 59 children to detect changes in facial morphology due to growth and development. Linear and angular measurements were calculated by means of the 3-D co-ordinates in order to quantify facial morphology. Significant differences were determined by means of analyses of variance (MANOVA). RESULTS: During the observation period, significant (P < 0.01) changes in facial morphology were determined for the linear measurements. Advantages and disadvantages of current registration methods are discussed. CONCLUSION: It is concluded that stereophotogrammetry is a suitable 3-D registration method for quantifying and detecting developmental changes in facial morphology.     

Results of a standardized treatment concept in primary hyperparathyroidism

BACKGROUND AND OBJECTIVE: Primary hyperparathyroidism (PHPT) is being diagnosed ever more frequently. After diabetes mellitus, ovarian dysfunction and metabolic disorders it is now among the most frequent metabolic disease. Its surgical treatment has become standardized with increasing experience. A prospective study was undertaken to clarify to what extent our own standardized diagnostic and therapeutic measures conform to current standards in literature. PATIENTS AND METHODS: During 10 years (1. 1. 1987-31. 12. 1996) 478 patients with PHPT were treated surgically (solitary adenoma: 317 (76.5%), multiple lobe hyperplasias 66 (15.9%), double adenoma 28 (6.8%), and carcinoma 4 (0.8%). PHPT was part of the MEN (multiple endocrine neoplasia) syndrome in 20 patients. Typical symptoms of PHPT had been present in 400 patients (83.7%), while 78 (16.3%) had no manifest symptoms. Ultrasound examination of the soft tissues was the only preoperative test of localization. More extensive preoperative diagnosis was practised only before reoperations. All patients had bilateral exploration of the neck to try and demonstrate all four epithelial bodies. RESULTS: A primary operation normalized the calcium level in 405 of 414 patients (97.8%). In 64 previously unsuccessfully operated patients who were reoperated for persisting HPT the elevated calcium levels could be normalized in 90.6%. Hypercalcaemia was finally abolished in all 478 patients. Average follow-up duration for 319 patients was more than 4.8 (0.5-8.5) years. The perioperative mortality rate was 0.8 (4 of 478), with 41 deaths during the later follow-up period. Permanent recurrent laryngeal nerve palsy occurred in 6 patients (1.8%). Long-term calcium substitution was necessary postoperatively in four patients (1.2%). CONCLUSION: Our findings support a liberal policy towards indication for bilateral surgical exploration of the neck in PHPT.     

Lack of effectiveness of bed rest for sciatica

BACKGROUND AND METHODS: Bed rest is widely advocated for sciatica, but its effectiveness has not been established. To study the effectiveness of bed rest in patients with a lumbosacral radicular syndrome of sufficient severity to justify treatment with bed rest for two weeks, we randomly assigned 183 subjects to either bed rest or watchful waiting for this period. The primary outcome measures were the investigator's and patient's global assessments of improvement after 2 and 12 weeks, and the secondary outcome measures were changes in functional status and in pain scores (after 2, 3, and 12 weeks), absenteeism from work, and the need for surgical intervention. Neither the investigators who assessed the outcomes nor those involved in data entry and analysis were aware of the patients' treatment assignments. RESULTS: After two weeks, 64 of the 92 patients in the bed-rest group (70 percent) reported improvement, as compared with 59 of the 91 patients in the control (watchful-waiting) group (65 percent) (adjusted odds ratio for improvement in the bed-rest group, 1.2; 95 percent confidence interval, 0.6 to 2.3). After 12 weeks, 87 percent of the patients in both groups reported improvement. The results of assessments of the intensity of pain, the bothersomeness of symptoms, and functional status revealed no significant differences between the two groups. The extent of absenteeism from work and rates of surgical intervention were similar in the two groups. CONCLUSIONS: Among patients with symptoms and signs of a lumbosacral radicular syndrome, bed rest is not a more effective therapy than watchful waiting.