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OBJECTIVE This study assessed the efficacy/safety of canagliflozin (CANA), a sodium–glucose cotransporter 2 (SGLT2) inhibitor, plus metformin extended-release (MET) initial therapy in drug-naïve type 2 diabetes. RESEARCH DESIGN AND METHODS This 26-week, double-blind, phase 3 study randomized 1,186 patients to CANA 100 mg (CANA100)/MET, CANA 300 mg (CANA300)/MET, CANA100, CANA300, or MET. Primary end point was change in HbA1c at week 26 for combinations versus monotherapies. Secondary end points included noninferiority in HbA1c lowering with CANA monotherapy versus MET; changes in fasting plasma glucose, body weight, and blood pressure; and proportion of patients achieving HbA1c RESULTS From mean baseline HbA1c of 8.8% (73 mmol/mol), CANA100/MET and CANA300/MET significantly lowered HbA1c versus MET (median dose, 2,000 mg/day) by –1.77%, –1.78%, and –1.30% (–19.3, –19.5, and –14.2 mmol/mol; differences of −0.46% and –0.48% [–5.0 and –5.2 mmol/mol]; P = 0.001) and versus CANA100 and CANA300 by –1.37% and –1.42% (–15.0 and –15.5 mmol/mol; differences of –0.40% and –0.36% [–4.4 and –3.9 mmol/mol]; P = 0.001). CANA100 and CANA300 monotherapy met noninferiority for HbA1c lowering and had significantly more weight loss versus MET (–2.8, –3.7, and –1.9 kg [–3.0%, –3.9%, and –2.1%]; P = 0.016 and P = 0.002). Greater attainment of HbA1c CONCLUSIONS Initial therapy with CANA plus MET was more effective and generally well tolerated versus each monotherapy in drug-naïve type 2 diabetes. CANA monotherapy demonstrated noninferior HbA1c lowering versus MET.

The effects of phentolamine and noradrenaline on force development of isolated papillary muscles and on the adenyl cyclase activity of the ventricular myocardium were studied in cats. Phentolamine alone did not influence either force or adenyl cyclase activity. Phentolamine attenuated the increase of both force and adenyl cyclase activity induced by noradrenaline, but did not alter the effects produced by isoprenaline. The present study demonstrates that phentolamine lacks direct positive inotropic effects, but attenuates the effects of noradrenaline.

Three series of investigations were carried out with prazosin (PZN) hydrochloride. In the first, hemodynamic effects of PZN were compared with those of hydralazine (HDZ) in 11 patients with chronic congestive heart failure (CHF). In doses up to 5 mg, PZN increased cardiac output (CO) 20% accompanied by a 20% decrease in pulmonary capillary wedge pressure (LVFP). HDZ increased CO by 50% with little or no effect on LVFP. An additional 12 patients were given multiple 5 mg doses of PZN at 6-hour intervals with measurements of hemodynamic and plasma blood levels. Results suggested an attenuation of the effects of PZN on increasing CO but not on decreasing LVFP. This attenuation of CO was not due to inadequate plasma levels. Acute exercise studies (supine bicycle) were performed in 10 patients with severe CHF before and after the administration of several doses of PZN. There appeared to be a greater effect of PZN during exercise than at rest, with a beneficial increase in CO and reduction in LVFP. These data suggest that, despite hemodynamic attenuation of its effects on CO at rest, PZN may still be beneficial to active patients with CHF. In vitro studies with various vasodilators were performed to evaluate potential intropic effects. Isometric force (cat papillary muscle) increased 2% with 10-4M and 31% with 10-3M HDZ. PZN increased force 4% at 10-6M and 18% at 10-4M. Captopril did not increase force development at any dose level. The doses of HDZ and PZN that increased force development were higher than usual clinical doses.

This study was designed to quantitate the length-tension relations of surgically resected human ventricular aneurysms in order to calculate the degree of paradoxical systolic expansion and mechanical disadvantage produced by various types of aneurysms. The in vitro length-tension relations of the 11 aneurysms studied closely conformed to an exponential equation. In vivo wall stress in each aneurysm was calculated from ventricular pressure and the ventriculogram utilizing the Laplace relation. In the four fibrous aneurysms the calculated increase in circumference averaged 2.4 percent in systole; in five aneurysms with fibrous and muscular tissue, average circumference increased 6.3 percent; in two muscular aneurysms (from patients with acute myocardial infarction and shock), average circumference increased by 14.6 percent. Thus, chronic fibrous aneurysms appear to produce their primary mechanical disadvantage by a loss of contractile tissue since systolic paradox is minimal. An acute muscular aneurysm produces mechanical disadvantage not only by loss of contractile tissue but also by significant paradoxical systolic expansion.

We studied 56 right ventricular papillary muscles isolated from cats to determine whether the direct mechanical effects of contrast media are due to their pharmacologic action or to the hyperosmolality caused by them. A 10% solution of Renografin-76 abruptly decreased force 22% below control, then slowly increased it to 22% above control. To elucidate these changes we also studied: (1) Renografin-60 (lower concentration of diatrizoate); (2) meglumine and diatrizoate; (3) meglumine alone; (4) diatrizoate sodium; (5) ethylene diamine tetra-acetic acid (EDTA) (same concentration as in Renografin-76); (6) sucrose to increase osmolality; and (7) Amipaque (metrizamide), a contrast medium without meglumine or diatrizoate. All solutions containing meglumine, and EDTA alone decreased force. Diatrizoate sodium also decreased force initially, presumably due to the high sodium concentration. Meglumine alone decreased force abruptly and substantially. In contrast, metrizamide and 100 mmol sucrose only increased force. Thus, the abrupt decrease in force was caused by the pharmacologic action of meglumine, EDTA, or high sodium in the contrast media, whereas the slow increase in force was caused by hyperosmolality.

We investigated the hemodynamic and inotropic effects of the new class III antiarrhythmic drug melperone. In eight pentobarbital-anesthetized dogs, the effects of intravenous melperone 0.5, 2.5, and 12.5 mg/kg-1 were tested. During atrial pacing we measured cardiac output (CO), mean aortic blood pressure (MAP), right (RV) and left (LV) ventricular pressures, and LV dP/dt. In six RV papillary muscles isolated from cats and suspended in a muscle bath containing Krebs-Henseleit solution, we studied the direct effects of melperone 10(8)-5 X 10(-5) M. Administration of melperone decreased total peripheral resistance, MAP, RV and LV systolic and end-diastolic pressures, while CO remained unchanged. Melperone increased LV dP/dtmax. The contractile force (F) and dF/dtmax of the isolated ventricular muscle preparations increased slightly with increasing concentrations of melperone, up to 10(-5) M. In conclusion, melperone has vasodilator and slight positive inotropic effects in addition to its class III antiarrhythmic effect.

The direct myocardial depressant effects of lidocaine, ajmalin, propranolol and quinidine were determined in vitro in isolated right ventricular papillary muscles and spontaneously beating right atria of the cat. In concentrations similar to therapeutically effective serum levels, the average depression in contractile force produced by each drug was: lidocaine 1%, ajmalin 1.9%, Propranolol 3.5%, and quinidine 8.3%. Similarly, the reduction in spontaneous atrial rate was: ajmalin 4.5%, Propranolol 5%, and quinidine 11%. The minimal depressive effects of lidocaine and ajmalin confirm their relative safety in patients as compared to quinidine. The combination of the direct myocardial depressant effects and beta blocking effects of propranolol suggest that this drug, as well as quinidine, must be used with caution in patients with heart failure.

The present study was undertaken to reevaluate the effects of preload on maximum velocity of shortening at zero load, V max , relative to the length-tension curve. Force-velocity relations were measured from afterloaded isotonic contractions and were calculated from isometric contractions of isolated cat papillary muscles. Results were interpreted in the light of three alternative mechanical models of muscle. V max was obtained by mathematical extrapolation of each force-velocity relation to zero load using a hyperbolic least-squares analysis performed on an IBM 360 computer. With the application of all three muscle models to isotonic force-velocity relations, V max was relatively constant at low preloads but was reduced substantially as muscle length approached L max (the length at the peak of the active length-tension curve). In force-velocity relations from isometric contractions, similar results were obtained with the two-element and Voigt models of muscle. With the Maxwell model, V max remained more nearly constant near L max . Peak developed force (isometric contraction), maximum dP/dt, peak calculated velocity of the contractile element (V CE ), and V max were compared in terms of their dependence on preload and length over the entire length-tension curve (using the Maxwell model). Peak V CE and V max were similar and were less dependent on preload than maximum dP/dt or developed force.