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101.
JACEK PINSKI TETSU YANO TAMAS JANAKY ATTILA NAGY ATTILA JUHASZ LAZARO BOKSER KATE GROOT ANDREW V. SCHALLY 《Chemical biology & drug design》1993,41(1):66-73
A series of new highly potent LH-RH antagonists (T-series) has been synthesized in our laboratory. Among these analogs, antagonists [Ac-d -Nal(2), d -Phe(4Cl)2. d -Pal(3)3, d -Lys(A2pr(Car)2)6, d -Ala10LH-RH (T-140); [Ac-d -Nal(2)1, d -Phe(4Cl)2, d -Pal(3)3, d -Lys(A2pr(Ac)2)6, d -Ala10]LH-RH (T-148); [Ac-d -Nal(2)1, d -Phe(4Cl)2, d -Pal(3)3, d -Lys(A2pr(For)2)6, d -Ala10)]LH-RH (T-151) and [Ac-d -Nal(2)1, d -Phe(4cl)2, d -Pal(3)3, d -Lys(A2bu(For)2)6, d -Ala10]LH-RH (T-159) were the most powerful. Antagonists T-140, T-148 and T-151 produced a complete blockade of ovulation in normal cycling rats at a dose of 1.5 μg/rat and antagonist T-159 at a dose of only 0.75 μg/rat. The inhibitory effects of compounds T-148, T-151 and T-159 on gonadotropin and sex steroid secretion were investigated in male and female rats. To determine their effect on LH levels in castrated male and ovariectomized female rats, T-148, T-151 and T-159 were injected subcutaneously in doses of 0.625 and 2.5 μg/rat. Blood samples were taken at different intervals for 48 h. All three compounds at either dose caused a significant (P< 0.01) decrease in LH levels for more than 6 h. Significant (P <0.01) inhibition of LH lasted for more than 24 h following a dose of 2.5 μg sc of all 3 antagonists in both male and female rats. Serum FSH levels were also suppressed significantly for more than 48 h in castrated male rats by all three antagonists at a dose of 5 μg/rat sc. Serum testosterone levels were measured in intact male rates injected with antagonists T-148, T-151 and T-159 in doses of 50 and 100 pg sc. Both doses produced a dramatic fall in testosterone (P<0.01) to castration levels 6 h after injection. The inhibition of serum testosterone lasted for more than 48 h, but only 100 μg of T-148 maintained testosterone in the castration range for more than 48 h. Antagonists T-148, T-151 and T-159 injected at a dose of 100 μg to intact female rats reduced serum estradiol levels significantly (P<0.01) for more than 48 h, as compared to control animals. In the cutaneous anaphylactoid test (CAT), T-148, T-151 and T-159 proved to have very low histamine releasing activities. These data demonstrate a high efficacy of these new LH-RH antagonists in suppressing the pituitary-gonadal axis in male and female rats. These LH-RH antagonists could possibly be used for treatment of sex-hormone sensitive cancers and other disorders and conditions, in which a reduction in circulating sex steroids would be beneficial. 相似文献
102.
JACEK PINSKI TETSL YANO KATE GROOT JOZSEF ZSIGO ZOLTAN REKASI ANA MARIA COMARU-SCHALLY ANDREW V. SCHALLY 《Chemical biology & drug design》1993,41(3):246-249
Many studies have shown that human GH-RH(1-29)NH2 possesses full intrinsic activity of GH-RH(1-44)NH2in vitro and in vivo. This investigation was performed to evaluate the efficacy of GH-RH(1-29)NH2 given by different routes of administration in stimulating GH release in rats. In each case GH-RH(1-29)NH2 was administered intravenously, subcutaneously, intranasally and by pulmonary inhalation at two different doses to groups of seven male rats. At a dose of 150 μg/kg GH-RH(1-29)NH2, the magnitude of GH response was significantly higher for the pulmonary inhalation group (355 ± 33.2 ng GH/mL) than for the subcutaneous group (246 ± 36ng GH/mL) or for the intranasal group (175 ± 30ng GH/mL). The group injected intravenously with GH-RH(1-29)NH2 at a dose of 2.5 μg/kg showed the highest response, GH levels reaching 877.2 ± 115 ng/mL. A similar pattern of responses was obtained for the superactive GH-RH(1-29) agmatine29 analog, MZ–3-149, at doses that were 50 times lower. Our results indicate a high bioavailability of GH-RH(1-29)NH2 or analog MZ-3-149 administered by a convenient pulmonary inhalation route. The GH-releasing effect of GH-RH(1-29)NH2 or analog MZ-3-149 delivered by pulmonary inhalation is superior to subcutaneous and intranasal administration. 相似文献
103.
Circulating endothelial cell/leucocyte adhesion molecules in ischaemic heart disease 总被引:6,自引:0,他引:6
ANDREW D. BLANN JEAN AMIRAL & CHARLES N. MCCOLLUM 《British journal of haematology》1996,95(2):263-265
Increased levels of the endothelial markers soluble E-selectin ( P = 0.011), soluble thrombomodulin ( P = 0.0001) and von Willebrand factor (VWF, P < 0.0001) were found in 116 patients with ischaemic heart disease compared to an equal number of age- and sex-matched asymptomatic controls. In a multivariate analysis of the markers versus the major risk factors for atherosclerosis, VWF correlated with total cholesterol ( P = 0.002) and E-selectin with sex (lower in women, P = 0.004) and triglycerides ( P = 0.007). The data point to profound differences in the release mechanisms of these three endothelial cell products and suggests that further studies into the roles of these molecules in coronary artery disease are warranted. 相似文献
104.
ANDREW J. BURGER M.D. PRAVEEN JADHAV M.D. MASOOR KAMALESH M.D. 《Echocardiography (Mount Kisco, N.Y.)》1997,14(6):589-595
Objectives: The purpose of our investigation was to describe the echocardiographic characteristics of an atrial septal aneurysm (ASA) and associated cardiac abnormalities, to determine whether any echocardiographic characteristics are associated with cerebrovascular events, and to compare the cerebrovascular risk of ASA when it is an isolated and incidental finding with ASA associated with other cardiac abnormalities and diagnostic indications, including a cardiac source of embolus. Methods: In 1605 consecutive patients referred for transesophageal echocardiography during open heart surgery, we identified 78 patients with ASA as an incidental finding (Group I). During the same period, this anomaly was found in 39 of 8014 consecutive patients referred to the echocardiographic laboratory for various diagnostic reasons (Group II). The frequency of cerebrovascular events and ASA characteristics was compared between these two groups. Results: A total of 117 patients with ASA was included in the study: 60 males and 57 females with a mean age of 66.7 ± 9.1 years. There were no significant differences in the echocardiographic characteristics of ASA or associated cardiac abnormalities between these two groups; no intracardiac or ASA associated thrombi were detected in either group. While only 6.4% of Group I had a clinical event, 23% of patients in Group II had a stroke or transient ischemic abnormality. Conclusions: The morphological characteristics of ASA and associated cardiac abnormalities do not distinguish patients at risk for cerebrovascular events. Although the presence of ASA may be a risk factor for embolic strokes, this risk is lower than previously thought . 相似文献
105.
A computer-assisted and cross-reference literature search identifiedtrials of therapy for alcohol withdrawal symptoms. Those witha randomized, double-blind placebo-controlled design were systematicallyassessed for quality of methodology. Fourteen studies were identifiedinvestigating 12 different drugs. The quality of methodologicaldesign, even among this highly selected group of published studies,was often poor. Study populations were generally under-defined,most studies excluded severely ill patients, control groupswere poorly matched, and the use of additional medication mayhave confounded results in some studies. Twelve different ratingscales were used to assess severity of symptoms. All 12 compoundsinvestigated were reported to be superior to placebo, but thishas only been replicated for benzodiazepines and chlormethiazole.Further research using better methods is required to allow comparisonof different drugs in the treatment of alcohol withdrawal symptoms.On the evidence available, a long-acting benzodiazepine shouldbe the drug of first choice. 相似文献
106.
107.
108.
SANDOR BAJUSZ VALER J. CSERNUS TAMAS JANAKY LAZARO BOKSER MATYAS FEKETE ANDREW V. SCHALLY 《Chemical biology & drug design》1988,32(6):425-435
Modifications of the previously described LHRH antagonists, [Ac-d -Nal(2)1, d -Phe(4Cl)2, d -Trp3, d -Cit6, d -Ala10]LHRH and the corresponding d -Hci6 analogue, have been made to alter the hydrophobicity of the N-terminal acetyl-tripeptide portion. Substitution of d -Trp3 with the less hydrophobic d -Pal(3) had only marginal effects on the antagonistic activities and receptor binding potencies of the d -Cit/d -Hci6 analogues, but it appeared to further improve the toxicity lowering effect of d -Cit/d -Hci6 substitution. Antagonists containing d -Pal(3)3 and d -Cit/d -Hci6 residues, i.e. [Ac-d -Nal(2)1, d -Phe(4Cl)2, d -Pal(3)3d -Cit6, d -Ala10]LHRH (SB-75) and [Ac-d -Nal(2)1, d -Phe(4Cl)2, d -Pal(3)3, d -Hci6, d -Ala10]LHRH (SB-88), were completely free of the toxic effects, such as cyanosis and respiratory depression leading to death, which have been observed in rats with the d -Trp3, d -Arg6 antagonist and related antagonists. Replacement of the N-acetyl group with the hydrophilic carbamoyl group caused a slight decrease in antagonistic activities, particularly in vitro. Introduction of urethane type acyl group such as methoxycarbonyl (Moc) or t-butoxycarbonyl (Boc) led to analogues that showed LHRH-potentiating effect. The increase in potency induced by these analogues, e.g. [Moc-d -Nal(2)1, d -Phe(4Cl)2, d -Trp3, d -Cit6, d -Ala10]LHRH and [Boc-d -Phe1, d -Phe(4Cl)2, d -Pal(3)3, d -Cit6, d -Ala10]LHRH, was 170-260% and persisted for more than 2 h when studied in a superfused rat pituitary system. 相似文献
109.
JAMES SAMANEN GLYNN WILSON PHILIP L. SMITH CHAO-PIN LEE WILLIAM BONDINELL THOMAS KU GERALD RHODES ANDREW NICHOLS 《The Journal of pharmacy and pharmacology》1996,48(2):119-135
This review discusses both tools and strategies that may be employed as approaches towards the pursuit of orally active compounds from peptidergic molecules. Besides providing a review of these subjects, this paper provides an example of how these were utilized in a research programme at SmithKline Beecham involving the development of orally active GPIIb/IIIa antagonists. The tools for studying oral drug absorption in-vitro include variants of the Ussing chamber which utilize either intestinal tissues or cultured epithelial cells that permit the measurement of intestinal permeability. Example absorption studies that are described are mannitol, cephalexin, the growth hormone-releasing peptide SK&F 110679 and two GPIIb/ IIIa antagonist peptides SK&F 106760 and SK&F 107260. With the exception of cephalexin, these compounds cross the intestine by passive paracellular diffusion. Cephalexin, on the other hand, crosses the intestine via the oligopeptide transporter. Structure-transport studies are reviewed for this transporter. The tools for studying oral drug absorption in-vivo involve animals bearing in-dwelling intestinal or portal vein catheters. A study of the segmental absorption of SK&F 106760 is provided. The review concludes with two chemical strategies that may be taken towards the enhancement of oral bioavailability of peptidergic molecules. The first strategy involves the chemical modification of peptides which enhance intestinal permeability, specifically the modification of amide bonds. The second strategy involves the design of compounds bearing nonpeptide templates, which are more amenable to the discovery of compounds with oral activity, from peptide pharmacophore models. An example is given regarding the discovery of SB 208651, a potent orally active GPIIb/IIIa antagonist, designed from the peptides SK&F 106760 and SK&F 107260. 相似文献
110.
Profound suppression of cellular proliferation mediated by the secretions of nematodes 总被引:8,自引:1,他引:7
Loss of T lymphocyte proliferation and the emergence of a host response that is dominated by a Th2-type profile are well-established features of human filarial infection. Downregulation and modulation of host T cell responses during lymphatic filariasis has been investigated by implantation of parasite stages into inbred mice. Adherent peritoneal exudate cells (PEC) from mice transplanted with adult or larval Brugia malayi parasites are profoundly anti-proliferative but do not prevent antigen-specific cytokine production by T cells. We demonstrate here that the excretory/secretory (E/S) products of the adult parasite are sufficient to induce PEC that block proliferation if injected daily into mice. We have previously shown that in vivo production of host IL-4 is required for the generation of suppressive cells. Because the induction of host IL-4 is characteristic of infection with nematodes, we asked whether E/S from two other nematode parasites, Nippostrongylus braziliensis and Toxocara canis were also capable of generating a suppressor cell population. Injection of E/S from these two parasites also led to a reduction in T cell proliferation suggesting that this mechanism of down-regulating host responses is a feature common to nematode parasites . 相似文献