Pharmacokinetics and safety of TCMCB07, a melanocortin-4 antagonist peptide in dogs.

The melanocortin-4 receptor (MC4R) antagonistic peptide TCMCB07 was developed for the treatment of cachexia. The objectives of this study were to examine pharmacokinetics and safety of TCMCB07 administered subcutaneously to healthy dogs. Dogs were treated with high- (2.25 mg kg-1 ) (n = 5) and low-dose TCMCB07 (0.75 mg kg-1 ) (n = 5) once daily for 28 days with a 14-day washout period between groups. Histamine levels, complete blood count, chemistry panel, blood pressure, 24-hour Holter recording, and pharmacokinetic parameters were monitored in the high-dose group. Physical examination changes were limited to weight gain and darkening of the coat color. There was no elevation of plasma histamine within 24 hours of injection but there was a significant elevation of plasma histamine across time. An approximately doubled eosinophil count and an approximately 25% increase, and then 25% decrease back to pre-treatment plasma phosphorous were also found, although both remained within the reference interval. Serial blood pressure and 24-hour Holter monitors revealed no clinically relevant changes. A difference was found in the AUC between dosing groups and a significant effect of dose, time, and interaction was noted for Vd . Low-dose TCMCB07 had a Cmax of 2.1 ug ml-1 at day 28, compared to high-dose TCMCB07 which had a Cmax 3.6 ug ml-1 at day 28. Once-daily subcutaneous administration of TCMCB07 was well-tolerated for up to 28 days in dogs when administered at doses one and three times (0.75 mg kg-1 and 2.25 mg kg-1 ) the predicted therapeutic dose and pharmacokinetic parameters are described. SIGNIFICANCE STATEMENT: Melanocortin-4 receptor (MC4R) antagonistic peptide TCMCB07 is safe at both low and high doses in dogs. Therapy was tolerated well as determined by physical examination, clinical pathology, and cardiovascular parameters; darkening of the coat was noted with treatment and resolved with discontinuation. Pharmacokinetics are described and further study in the naturally occurring canine model is warranted.

Echocardiographic assessment of hemodynamic changes produced by two methods of inducing fluid deficit in dogs.

BACKGROUND: Hydration status is important to the cardiovascular system because of its effects on preload. Decreased preload can alter echocardiographic measurements of systolic and diastolic function, potentially confounding interpretation of results. HYPOTHESIS/OBJECTIVES: Mild fluid deficits are associated with measurable echocardiographic changes that are validated by physical and biochemical markers of decreased intravascular volume. ANIMALS: Twenty-five healthy staff/student-owned dogs with no evidence of cardiac or renal disease. METHODS: Prospective, interventional laboratory study. Dogs were randomly assigned to water deprivation (WD) alone for 8 hours (n = 13) or to furosemide treatment (FTx, 2.5mg/kg IV) followed by WD for 8 hours (n = 12). Echocardiograms, biochemical sampling, and physical parameters were measured at baseline, and after 4 and 8 hours. RESULTS: Both protocols induced fluid deficit as indicated by significant (P < .00001) decreases in weight at 4 hours (WD, 1.1%; FTx, 3.7%) and 8 hours (WD, 2.7%; FTx, 4.5%). Furosemide significantly decreased left ventricular end-diastolic volume (54.3 +/- 19.3-42.1 +/- 17.3 mL, P < .0001), cardiac index (4.2 +/- 1.1-2.9 +/- 0.9 L/min/M2, P < .0001), and mitral valve E wave velocity (0.79 +/- 0.2-0.66 +/- 0.2 m/s, P = .0004). These changes were accompanied by significant increases in blood urea nitrogen concentration (13.8 +/- 2.6-14.8 +/- 2.7 mg/dL, P = .04), vasopressin concentration (1.4 +/- 1.2-3.3 +/- 1.9 pg/mL, P = .045), and PCV (49.8 +/- 4.5-53.2 +/- 6.5%, P = .006). Effects of water deprivation alone were similar, but less pronounced. CONCLUSIONS AND CLINICAL IMPORTANCE: Mild fluid deficits have measurable hemodynamic effects in dogs. Hydration status should be considered when evaluating cardiac function by echocardiogram.

Evaluation of pimobendan and N-terminal probrain natriuretic peptide in the treatment of pulmonary hypertension secondary to degenerative mitral valve disease in dogs.

BACKGROUND: Pimobendan is a positive inotrope and vasodilator that may be useful in the treatment of pulmonary hypertension (PHT) secondary to degenerative mitral valve disease. HYPOTHESIS: Pimobendan decreases the severity of PHT measured echocardiographically and improves quality-of-life scores. Changes in N-terminal probrain natriuretic peptide (NT-proBNP) concentrations will reflect improvement in severity of PHT. ANIMALS: Ten client-owned dogs with peak tricuspid regurgitant flow velocity (TRFV) > or =3.5 m/s. METHODS: Prospective short-term, double-blinded, crossover design, with a long-term, open-label component. Short term, dogs were randomly allocated to receive either placebo or pimobendan (0.18-0.3 mg/kg PO q12 h) for 14 days. After a 1-week washout, they received the alternative treatment for 14 days, followed by pimobendan open-label for 8 weeks. RESULTS: Short-term comparison: peak TRFV decreased in all dogs on pimobendan compared with placebo from a median of 4.40 (range, 3.2-5.6) to 3.75 (range, 2.4-4.8) m/s (P < .0001). NT-proBNP concentration decreased after treatment with pimobendan from a median of 2,143 (range, 450-3,981) to 1,329 (range, 123-2,411) pmol/L (P= .0009). All dogs improved their quality-of-life score (P= .006). In the long-term comparisons, peak TRFV decreased in all dogs from a median of 4.28 (range, 3.5-5.7) to 3.52 (range, 2.4-5.0) m/s (P < .0001). No significant changes in NT-proBNP or quality-of-life scores were detected. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan lowered severity of measurable PHT, improved quality-of-life scores, and decreased NT-proBNP concentrations short-term. Long term, only the reduction in TRFV was maintained.

Hemodynamic and biochemical alterations in dogs with lymphoma after induction of chemotherapy.

BACKGROUND: Doxorubicin is a common antineoplastic agent with dose-dependent cardiotoxic adverse effects, and pre-existing myocardial dysfunction is a contraindication to its use. OBJECTIVES: To systematically define the hemodynamic and biochemical alterations in dogs undergoing chemotherapy for newly diagnosed lymphoma and assess the reversibility of these alterations with fluid administration. ANIMALS: Twenty-one client-owned dogs with newly diagnosed lymphoma were evaluated 1 week after induction of chemotherapy. Underlying degenerative valve disease was exclusionary. Eighteen healthy age- and weight-matched dogs were used as controls. METHODS: Physical examination, blood pressure by Doppler, echocardiography, and biochemical evaluation (routine serum biochemistry, plasma renin activity and aldosterone concentrations, plasma and urine osmolalities, and urine electrolyte concentrations) were measured in dogs with lymphoma and compared to controls. Dogs with lymphoma received crystalloids IV at 6 mL/kg/h for 24 hours. All variables were reassessed at 4 and 24 hours. Deuterium oxide dilution and bromide dilution were used to determine total body water and extracellular water space, respectively. RESULTS: Baseline echocardiograms showed significantly smaller chamber dimensions in dogs with lymphoma compared to controls. These changes were reversed by fluid administration. Systolic blood pressure and urine sodium concentration were significantly increased, and bromide dilution space, PCV, urine specific gravity, and urine potassium concentration were significantly decreased compared to controls. CONCLUSION AND CLINICAL IMPORTANCE: Echocardiographic and biochemical abnormalities in dogs with lymphoma appear consistent with volume depletion, and may be the result of systemic hypertension and subsequent pressure natriuresis.