Synthesis and pharmacological activities of 13-dehydro derivatives of primary prostaglandins

13-Dehydro derivatives of prostaglandin E1, E2, E3, F1 alpha and F2 alpha were synthesized. Compared with natural prostaglandins, 13-dehydro analogues were found to exhibit more potent inhibitory activity against human platelet aggregation and relaxation of guinea-pig isolated trachea, while they showed less potent activity of contraction of guinea-pig isolated ileum.     

Pharmaceutical development and specification of stereoisomers

The pharmaceutical development of chiral drugs requires the activities of many different research and development groups. Guidelines which help to coordinate the activities of these groups and assist in the successful development of compounds with either single or multiple chiral centers are outlined and discussed.     

Determination of pharmacological half-life of propranolol in man]

After conservative respectively operative treatment of two exactly comparable patients who suffered from rupture of the long head of the biceps tendon of the arm, the myoelectric activity of both muscle heads was investigated on the injured arm and compared to the uninjured side. There was a significant diminution of activity in the ruptured long head as well as a reactive hyperactivity in the short head after conservative treatment in contrast to the operative treated patient, where these alterations in muscle activity were less marked. The operative treatment therefore shows a better functional result when compared with the conservatively treated rupture.     

The management in clinical trials of pharmacological agents]

A trial of a newly developed experimental model of prostatic cancer showed its convenience in simulating clinical symptoms and response to treatment. The model is effective in the studies of anticancer drugs with various mechanisms of action with special emphasis on immunomodulators as a promising adjuvant modality.     

Synthesis and pharmacological activities of some 2,3,4,5-tetrahydro[1,5]benzo[f]thiazepines

For the purpose of prophylactic treatment of splenic aneurysms, both examinations and treatments should be minimally invasive. Here, we report a case of a patient who underwent three-dimensional arterial computed tomography (CT) and laparoscope-assisted splenectomy with aneurysm resection as a combination of minimally invasive examination and treatment.     

Update on antitumor pharmacology: reality and perspectives in 1998]

Tubulointerstitial changes, characterized by the accumulation of extracellular matrix proteins (ECM) and fibrosis, are often associated with primary glomerular injury. Furthermore, these changes may be better prognostic indicators for decline in renal function than the anatomical changes seen within the glomerulus itself. Although hyperlipidemia and the increased renal accumulation of atherogenic lipoproteins are commonly seen in both human and experimental models of renal disease, the possible role that atherogenic lipoproteins may play in the cellular and molecular events associated with the development of tubulointerstitial injury remains unclear. Since atherogenic lipoproteins have been shown to be mediators of renal injury, we examined the effects of native LDL and oxidatively-modified LDL (ox-LDL, a more atherogenic form of LDL) on fibronectin protein synthesis and gene expression in proximal tubular epithelial cells (TEC). Human LDL was freshly isolated and ox-LDL prepared by incubation of LDL with 100 microM CuS04. Incubation of TEC with LDL or ox-LDL (25-50 micrograms/ml) for 24 h increased the steady-state mRNA expression of fibronectin by 16-135% over control as measured by Northern blot analysis and the effect was greater with ox-LDL than native LDL. Additional studies were done to examine whether the increased fibronectin message in response to lipoprotein activation was translated into TEC protein synthesis. The activation of TEC by LDL or ox-LDL stimulated the synthesis and secretion of fibronectin (52-150%, over control) as measured by Western blot analysis. The data show that LDL and ox-LDL stimulate TEC fibronectin gene message and protein synthesis supporting a pathobiological role for these atherogenic lipoproteins in tubulointerstitial fibrosis.     

Studies on antitumor activities of Basidiomycetes-antitumor activity of polysaccharides and sex factors]

In the dog, pressosensitive endings of the sinus nerve extend along the border between the adventitia and media of the carotid sinus wall. The axon endings, containing a great number of mitochondria, can be divided into small (600-2,000 nm) and large (6,000-8,000 nm) end swellings. In the terminal region the pressosensitive fibers are surrounded by ramified and highly structured Schwann "terminal cells". The topographic location in relation to elastic and collagenous tissue indicates a functional connection between receptors and efferent nerve endings in the immediate surroundings has been discussed in this report. Several axon endings contain variable amounts of glycogen which is regarded as an indication for the inactive metabolic state of the ending. Axonal swellings demonstrate considerable modification in structure, such as loss of structural integrity in mitochondria, the formation of lamellar fields, vesicular irregularities and disintegration of axoplasm, all of which are considered as the morphological expression of "wearing out", degeneration and possibly regeneration.     

Synthesis and antitumor evaluation of new thiazolo[5,4-b]quinoline derivatives

A new synthesis of 9-hydroxy- and 9-(alkylamino)thiazolo[5,4-b]quinolines by cyclization of 4-(ethoxycarbonyl)-5-(arylamino)thiazoles and 5-(arylamino)-4-carbamoylthiazoles, respectively, is described. In vitro cytotoxicity of a large number of derivatives of these compounds has been tested against several cell lines. The highest activities observed are associated with the presence of a 2-[[(N,N-diethylamino)ethyl]amino] substituent at C-2 and a fluorine atom at the C-7 position of the tricyclic planar heteroaromatic framework. Three structural features seem to be essential for antitumor activities: a positive charge density at carbon C-7, a side chain at position C-2 or C-9 of the thiazoloquinoline skeleton with two basic nitrogens and a pKa value of 7.5-10 in the most basic center, and a conformational flexibility of this basic side chain. These structural requirements must be simultaneously satisfied in order to ensure a significant antitumor activity.     

Synthesis and pharmacological activity of some 3-amino-11H-indolo[3,2-c] [1,8]naphthyridines

The preparation of some 3-amino-11H-indolo [3,2-c]-[1,8] naphthyridines using the Fischer indole synthesis on the appropriate phenylhydrazones is described. Some compounds (IV b, c, d) were effective in inhibiting the reactions of delayed hypersensitivity, but the testing has been discontinued because of toxicity observed.     

Mechanisms of reflex development]

It is generally accepted that psychogenic voice disorder (PVD) is a result of psychosocial stress; however, systematic studies of etiological factors in this condition are few. Furthermore, although immediate effects of therapy are estimated to be good, relapses are frequent, and the long-term effects of therapy are not known. The present prospective and longitudinal study on 30 patients was thus focused on possible etiological factors, the course of therapy, and the long-term results of therapy for PVD. The results indicate that interpersonal conflicts related to family and work are of basic importance in precipitating this condition. PVD is interpreted as a specific disorder of verbal emotional expression. Our therapy model in which vocal exercises are performed, together with training of communicative skills, seems rewarding. Relapses were not reported in 88% of the patients during the followup period of 1.9-8.4 years after therapy.     

Development of new antitumor reagents which block the cell cycle progression]

Most tumor cells have abnormalities in the cell-cycle regulation system. Cyclin-dependent kinases (cdk) are major regulatory molecules for the cell cycle control. Therefore, cell cycle inhibitors, especially cdk-inhibitors, may be a promising new type of antitumor drug. In this review, low-molecular-weight cell-cycle inhibitors isolated from mainly microorganisms are described. As the activation of cdk is caused by the association with cyclins as well as by their phosphorylation and dephosphorylation, kinase inhibitors and phosphatase inhibitors are also candidates for cell cycle inhibitors.     

Synthesis and pharmacological activity of triazolo[1,5-a]triazine derivatives inhibiting eosinophilia

In continuation of our previous work on eosinophilia inhibitors, we synthesized an additional series of inhibitors, which consisted of 5-amino-1-[(methylamino)thiocarbonyl]-1H-1,2,4-triazole derivatives and a newly developed series of 1,2,4-triazolo[1,5-a]-1,3,5-triazine derivatives. We evaluated their inhibitory activity on the airway eosinophilia model, which was induced by the intravenous (iv) injection of Sephadex particles. In the 1,2,4-triazole series with various substituents at the 3 position of the triazole ring such as 2-furyl, pyridyl, and phenoxy, none of derivatives had comparable activity to the previously reported compound GCC-AP0341, 5-amino-3-(4-chlorophenyl)-1-[(methylamino)thiocarbonyl]-1H-1,2, 4-triazole. In the triazolo[1,5-a]triazine series, 2-(4-chlorophenyl)-6-methyl-1,2,4-triazolo[1,5-a]-1,3, 5-triazine-7(6H)-thione (3h) was highly potent, and when given orally it had an ID50 value of 0.3 mg/kg, which is comparable to that of GCC-AP0341. The fact that the structure-activity relationship of these two series was quite similar suggests that a common substructure, such as the 1,2,4-triazole ring with a substituted phenyl ring at the 3 position and a thiocarbonyl moiety at the 1 position, could contribute to the activity. Our selected compound 3h was less active than GCC-AP0341 in the antigen-induced hyper-responsiveness model in guinea pigs; however, we plan to carry out further studies on eosinophil functions, especially on their activation, using our two compounds, 3h and GCC-AP0341.