RESUMEN
The present study investigated the effects of telmisartan, a selective AT1 receptor antagonist, on renal function in dogs. Conscious female dogs were treated with (i) vehicle (controls) and three doses of telmisartan (0.03 mg/kg, 0.1 mg/kg and 0.3 mg/kg) administered intravenously; (ii) vehicle and three doses of telmisartan (0.3 mg/kg, 1.0 mg/kg and 3.0 mg/kg) administered orally; or (iii) 1.0 mg/kg per day telmisartan orally for 12 days. Eight dogs were used for each experiment. Each of the four treatments in (i) and (ii) was administered 7 days apart. During the 6 h after intravenous administration, urine volume was significantly higher in dogs treated with telmisartan 0.1 mg/kg (8.5 +/- 1.6 ml/kg) and 0.3 mg/kg (7.0 +/- 0.9 ml/kg) than controls (2.7 +/- 0.3 ml/kg; P < 0.05), and renal sodium excretion was increased significantly with telmisartan 0.03 mg/kg (803 +/- 124 micromol/kg), 0.1 mg/kg (1039 +/- 213 micromol/kg) and 0.3 mg/kg (966 +/- 161 micromol/kg) versus controls (159 +/- 21 micromol/kg; P < 0.05). Oral telmisartan at doses of 1.0 mg/kg and 3.0 mg/kg also produced significant increases in urine volume (7.2 +/- 1.1 ml/kg and 6.6 +/- 1.2 ml/kg, respectively) and renal sodium excretion (599 +/- 146 micromol/kg and 555 +/- 131 micromol/kg, respectively) compared with controls (2.8 +/- 0.5 ml/kg and 80 +/- 33 mciromol/kg; P < 0.05) over the 6-h post-dose period. Telmisartan at all intravenous doses and at 3.0 mg/kg orally increased the urinary excretion of chloride significantly over the 6-h post-dose period compared with vehicle alone. The excretion of potassium and creatinine were unchanged by any treatment. Telmisartan 1.0 mg/kg administered orally for 12 days produced similar results. In conclusion, acute intravenous or oral as well as subchronic oral administration of telmisartan to conscious dogs promotes diuresis and natriuresis without affecting potassium or creatinine excretion.
Asunto(s)
Bencimidazoles/farmacología , Benzoatos/farmacología , Riñón/efectos de los fármacos , Animales , Diuresis/efectos de los fármacos , Perros , Relación Dosis-Respuesta a Droga , Riñón/fisiología , TelmisartánRESUMEN
The effects of telmisartan and hydrochlorothiazide (HCTZ) alone and in combination on blood pressure (BP) and renal excretory function were investigated in male spontaneously hypertensive rats (SHR) after oral administration for five consecutive days. Four treatments were studied: vehicle (0.5% Natrosol), telmisartan 3 mg/kg, HCTZ 10 mg/kg, and telmisartan 3 mg/kg+HCTZ 10 mg/kg. The effects on BP and heart rate were studied in 40 SHRs (10 animals per group) using an implanted telemetry device. Renal excretory function was assessed in 76 SHRs (18 animals per group, of which nine were used for urine sampling and nine for blood sampling). The telmisartan/HCTZ combination produced the greatest reductions in trough DBP (-44+/-1.5 mmHg), SBP (-60+/-1.9 mmHg) and mean BP (mBP; -53+/-1.7 mmHg) after five days of therapy (p<0.05 vs. vehicle and vs. telmisartan). Telmisartan monotherapy also decreased DBP, SBP and mBP significantly (p<0.05), but only minor BP fluctuations occurred in SHRs receiving HCTZ or vehicle. Telmisartan/HCTZ elevated heart rate by approximately 12 beats per minute (p<0.05 vs.control). Significant increases in urine volume and Na+, Cl, K+, creatinine and glucose excretion were observed with HCTZ treatment (p<0.01). Telmisartan/HCTZ also promoted renal water and electrolyte excretion (p<0.01); the diuretic effect appeared to be greater with the combination than with HCTZ alone, and there was some attenuation of urinary K+ loss. Elevated blood urea nitrogen levels were observed only in HCTZ-treated SHRs. These results indicate that the antihypertensive efficacy of telmisartan in SHRs is augmented by co-administration with HCTZ. The combination did not affect renal excretory function, with the exception of an increase in blood urea nitrogen and a possible amelioration of HCTZ-related K+ depletion.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Bencimidazoles/farmacología , Benzoatos/farmacología , Presión Sanguínea/efectos de los fármacos , Hidroclorotiazida/farmacología , Riñón/fisiología , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Animales , Diuréticos , Quimioterapia Combinada , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Riñón/efectos de los fármacos , Masculino , Ratas , Ratas Endogámicas SHR , Telmisartán , OrinaRESUMEN
The general pharmacologist in the pharmaceutical industry is challenged to generate physiologically relevant data on possible safety liabilities or on secondary therapeutic uses as early as possible in drug development. This implies the need for efficient use of usually only small supplies of test article. For this reason, we have developed a new animal model combining various elements to provide a broad spectrum of data focussing on the so-called vital physiological functions: cardiovascular, respiratory, and central nervous system. This system uses rats chronically implanted with transmitters for the measurement of arterial pressure, ECG, and body temperature. Modification of the transmitters also allows for the simultaneous assessment of locomotor activity. Studies are performed with these rats in plethysmographs placed directly over the antenna units thus allowing for the additional assessment of respiratory function in the same studies. Using this system, we can generate simultaneously a wide range of relevant physiological parameters in conscious rats with a modest requirement for test article. Such an approach is highly useful for getting early safety readouts of potential drug development candidates as well as for detecting possible secondary therapeutic actions of a drug.
Asunto(s)
Fenómenos Fisiológicos , Pletismografía/métodos , Telemetría/métodos , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Anfetamina/farmacología , Animales , Presión Sanguínea/fisiología , Temperatura Corporal/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Calibración , Estimulantes del Sistema Nervioso Central/farmacología , Electrocardiografía , Frecuencia Cardíaca/fisiología , Masculino , Nifedipino/farmacología , Ratas , Mecánica Respiratoria/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacologíaRESUMEN
OBJECTIVE AND DESIGN: Two structurally related compounds, meloxicam (Mel) and its structural 4'-isomer (4'-Mel), were compared to examine the role of a slightly different chemical structure on cyclooxygenase (COX) selectivity in in vitro and in vivo experimental models. MATERIAL OR SUBJECTS: In vitro studies were performed using human whole blood obtained from healthy volunteers, in vivo studies were performed in rats. TREATMENT: A concentration-response curve was obtained in the whole blood assay for Mel, 4'-Mel, indomethacin, piroxicam and diclofenac. These were used to calculate the respective IC50 values of either prostaglandin E2 (PGE2) or thromboxane B2 (TxB2). Similarly, a dose-response curve was obtained for Mel, 4'-Mel and piroxicam when measuring in vivo prostaglandin production, anti-inflammatory activity and gastric tolerance to determine the dose resulting in a 50% reduction of the each parameter. METHODS: COX selectivity was investigated in vitro using a human whole blood assay. PGE2 synthesis in vivo was measured in inflammatory exudate, in the stomach and kidneys of rats. Anti-inflammatory effects were measured in an adjuvant arthritis model and gastric tolerance was tested in an ulcerogenicity model in vivo in rats. RESULTS: In the human whole blood assay, the ratio of IC50 values for COX-1 vs. COX-2 inhibition was 13 for Mel and 1.8 for 4'-Mel. In inflammatory exudate in rats, Mel and 4'-Mel inhibited PGE2 synthesis to a similar extent, ID50 values approximately 0.3 mg/kg. In contrast, Mel was a weaker inhibitor of PG synthesis than 4'-Mel in the rat stomach and in the rat kidney. Paw swelling was reduced by 50% with 0.1 and 0.2 mg/kg for Mel and 4'-Mel, respectively, in the rat adjuvant arthritis model. Gastric tolerance (UD50) was 2.4 mg/kg for Mel and 0.4 mg/kg for 4'-Mel. CONCLUSIONS: These data demonstrate that the in vitro and in vivo pharmacological profile of meloxicam is structurally dependent and that minor structural changes can lead to significant differences in the selectivity for COX-1 and COX-2 in vitro and to different profiles in vivo suggesting different therapeutic potential.