Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01185 (vasopressin)
 23,126 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cornerstone of treatment for syndrome of inappropriate antidiuretic hormone secretion (SIADH) is fluid restriction. Demeclocycline is sometimes used but its efficacy is based solely on laboratory endpoints. This drug also has the adverse effects shared by all tetracyclines. Tolvaptan antagonises receptors for arginine vasopressin, a hormone that regulates blood sodium levels by stimulating renal water resabsorption. Tolvaptan is now authorised in the European Union for the treatment of hyponatraemia due to SIADH. Clinical evaluation of tolvaptan in this setting is based on two comparative double-blind placebo-controlled trials including a total of 448 patients with SIADH or hyponatraemia from various other causes. The two trials were combined for analysis. However, because of major methodological flaws, no firm conclusions can be drawn concerning the efficacy in SIADH patients. It remains to be shown that tolvaptan improves symptoms of hyponatraemia (especially neuropsychiatric disorders) or even that it corrects hyponatraemia in these patients. The adverse effects observed in clinical trials were predictable, given the mechanism of action, and included thirst and dry mouth (respectively 16% and 8.4% of patients), hypernatraemia (1.7%), pollakiuria and polyuria. Tolvaptan is metabolised by the cytochrome P450 isoenzyme CYP 3A4, hence a high risk of pharmacokinetic interactions. In summary, there is no reason to use tolvaptan to treat the syndrome of inappropriate antidiuretic hormone secretion: its efficacy on symptoms or even on sodium levels has not been demonstrated, and its adverse effect profile is poorly documented. It is better to concentrate on non-drug management.
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PMID:Tolvaptan: any evidence of efficacy in SIADH? 2118 Mar 68

Binding of vasopressin to its type 2 receptor in renal collecting ducts induces cAMP signaling, transcription and translocation of aquaporin (AQP)2 water channels to the plasma membrane, and water reabsorption from the prourine. Demeclocycline is currently used to treat hyponatremia in patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Demeclocycline's mechanism of action, which is poorly understood, is studied here. In mouse cortical collecting duct (mpkCCD) cells, which exhibit deamino-8-D-arginine vasopressin (dDAVP)-dependent expression of endogenous AQP2, demeclocycline decreased AQP2 abundance and gene transcription but not its protein stability. Demeclocycline did not affect vasopressin type 2 receptor localization but decreased dDAVP-induced cAMP generation and the abundance of adenylate cyclase 3 and 5/6. The addition of exogenous cAMP partially corrected the demeclocycline effect. As in patients, demeclocycline increased urine volume, decreased urine osmolality, and reverted hyponatremia in an SIADH rat model. AQP2 and adenylate cyclase 5/6 abundances were reduced in the inner medulla but increased in the cortex and outer medulla, in the absence of any sign of toxicity. In conclusion, our in vitro and in vivo data indicate that demeclocycline mainly attenuates hyponatremia in SIADH by reducing adenylate cyclase 5/6 expression and, consequently, cAMP generation, AQP2 gene transcription, and AQP2 abundance in the renal inner medulla, coinciding with a reduced vasopressin escape response in other collecting duct segments.
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PMID:Demeclocycline attenuates hyponatremia by reducing aquaporin-2 expression in the renal inner medulla. 2415 96


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