A series of N-(4-substituted-thiazolyl)oxamic acid derivatives were synthesized and tested for antiallergy activity in the rat PCA model. These compounds were conveniently prepared by treatment of the appropriate acetophenone with thiourea and iodine or by reaction of the chloroacetylbenzene with thiourea to give the corresponding aminothiazoles; subsequent condensation with ethyloxalyl chloride gave the thiazolyloxamates. Many of the analogues showed a 50% inhibition at less than 2 mg/kg po or less than 0.4 mg/kg iv and were significantly more potent than disodium cromoglycate, which in the rat PCA model is orally inactive and gives a 50% inhibition at 1.2 mg/kg iv. Hydrolysis of the oxamates generally resulted in enhanced activities, while substitution of the phenyl ring with a variety of substituents (e.g., 4-F, 4-OEt, and 4-NHCOCH3) did not significantly enhance the activity of the unsubstituted phenyl derivative. One of the ethanolamine salts, N-[4-(1,4-benzodioxan-6-yl)-2-thiazolyl]oxamic acid ethanolamine salt (61, PRH-836-EA), has been selected for further pharmacological evaluation.
Physiologically, the CGIT resulted in a 2-phase curve with positive (hyperglycemic) and negative (hypoglycemic) portions; the positive phase came first (250% of baseline at 1 minute). The descending segment declined linearly to baseline by approximately 30 minutes and to a nadir at 58% of baseline by 75 minutes. After a 35-minute valley, a linear ascent to baseline began. Addition of insulin in the CGIT increased glucose utilization by approximately 4.5 times during the positive phase but not during the negative phase. The diseases' effects and experimental inhibition of insulin secretion with xylazine and stress were detectable by use of the 2 phases of the CGIT. Only a single positive phase resulted from the GTT and a single negative phase from the IST CONCLUSIONS AND CLINICAL RELEVANCE: The CGIT resulted in a consistent, well-defined glycemia profile, which can be disrupted experimentally or by a disease process. The CGIT has clinical potential because it provides integrated information and more information than either the singular GTT or IST.
Dogs diagnosed with sudden acquired retinal degeneration syndrome (SARDS) commonly are presented with concurrent clinical, physical, and historical findings consistent with hyperadreno-corticism (HAC) at the time of vision loss. Thirteen dogs diagnosed with SARDS on the basis of complete ophthalmic examination and extinguished bright-flash electroretinogram were evaluated for steroid hormonal abnormalities. Signalment, case history, physical examination, and clinicopathological findings were recorded. Serum cortisol and sex-hormone concentrations were measured before and after adrenocorticotropic hormone (ACTH) stimulation. Clinical signs of HAC, systemic hypertension, and proteinuria were commonly found in dogs with SARDS. Elevations in one or more sex hormones were found in 11 (85%) of 13 dogs (95% confidence interval [CI] 65% to 100%); cortisol was elevated in nine (69%) of 13 dogs (95% CI 44% to 94%). A minority of dogs (three [23%] of 13; 95% CI 0.2% to 46%) exhibited only an increase in adrenal sex hormones. Only one dog had completely normal ACTH stimulation test results. Symptoms of HAC were associated with abnormal ACTH stimulation results. Routine ACTH stimulation testing to evaluate cortisol and sex hormones, blood pressure screening, and urinalysis are recommended in these animals.
An 11-year-old spayed female Labrador Retriever and a 9-year-old castrated male miniature Poodle were evaluated because of clinical signs of hyperadrenocorticism. Cortisol testing did not support a diagnosis of hypercortisolemia in either dog; however, imaging studies revealed unilateral adrenal tumors in both dogs. Serum concentrations of 17-hydroxyprogesterone, progesterone, and estradiol were high in both dogs, and androstenedione concentrations were also high in 1 dog. It is suspected that sex hormone secretion by the adrenal tumors in these dogs resulted in clinical signs of hyperadrenocorticism. Clinical signs and hormonal abnormalities resolved in the male dog after surgical resection of the tumor. There was no improvement in clinical signs after treatment with mitotane in the female dog, which died 2 months after diagnosis. Histologic evaluation confirmed the presence of adrenocortical carcinoma in both dogs.
Treatment of bovine lateral saphenous vein (cranial branch) and dorsal metatarsal artery with lysergamide (lysergic acid amide), an alkaloid in abundance in tall fescue, resulted in vasoconstriction similar to that previously shown for the ergot alkaloids ergonovine and ergotamine. Preincubation of tissues with lysergamide resulted in partial inhibition of the contractile response induced by the selective adrenergic agents phenylephrine and BHT-920 (P < .05), indicating partial agonist or antagonist activity of lysergamide at these receptors. Bovine vessels were strongly contracted by serotonin, and the response was markedly inhibited (P < .01) when tissues were preincubated with lysergamide. Studies with selective serotonergic agents indicated that lysergamide may have predilection for serotonin-2 receptors (5-HT2). Thus, lysergamide by itself has vasoconstrictor activity and acts as a partial agonist or antagonist at adrenergic and serotonergic receptors. Further studies are needed to establish the exact receptor effects of lysergamide. However, it is evident that this important alkaloid found in tall fescue infested with the endophytic fungus Acremonium coenophialum should be given consideration in studies designed to alleviate the fescue toxicosis syndrome in cattle.
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