The purpose of this study was to determine the relaxant effects in vitro of two nitric oxide donors, glyceryl trinitrate and sodium nitroprusside, which are currently available for use in vivo, on contractions of non-labouring myometrium from pregnant women. Since nitric oxide also mediates relaxation by increasing the concentration of cGMP, sensitivity to 8-bromo-cGMP (a cGMP analogue) was also determined. The effects of the K(+)-channel opener lemakalim and of the Ca(2+)-channel blocker nifedipine were studied for comparison. After the addition of glyceryl trinitrate (0.1-100 mumol l-1), sodium nitroprusside (0.1-100 mumol l-1) or 8-bromo-cGMP (0.001-3 mmol l-1), the spontaneous rhythmic contractility of myometrial strips was inhibited in a concentration-dependent manner: the maximum inhibition produced by the highest tested concentration of each drug was 40 +/- 7%, 53 +/- 8% and 39 +/- 8% of the original degree of contraction, respectively. Myometrial contractions were completely abolished by lemakalim and by nifedipine and verapamil at concentrations of > or = 10(-5) mol l-1. The nitric oxide donors, glyceryl trinitrate and sodium nitroprusside, attenuate myometrial contractions and are therefore useful as tocolytic agents. However, at equimolar concentrations in vitro, the ability of glyceryl trinitrate and sodium nitroprusside to attenuate myometrial contractions is less than that of lemakalin, nifedipine and verapamil. Controlled trials are required to determine the side-effects and clinical efficacy of each of these agents in vivo.
Although corticosteroids (CS) cause nitrogen wasting in healthy humans, it is not known whether the salutary antiinflammatory and appetite-stimulating effects of CS in inflammatory diseases mitigate this effect. We measured nitrogen balance before, during, and after 3 d of high-dose methylprednisolone therapy in nine patients with flare-ups of rheumatoid arthritis. There was evidence of preexisting somatic protein and fat depletion in seven of nine subjects. Patients were allowed to eat freely on a metabolic ward. Nitrogen balances were -0.89 +/- 1.38 g/d (means +/- SEM) before CS therapy, -5.77 +/- 1.30 g/d during therapy (P less than 0.001), and -3.54 +/- 1.38 g/d after therapy (P less than 0.01) despite increased energy and nitrogen intake and clinical resolution of inflammation during and after the pulse therapy. We conclude that patients with rheumatoid arthritis are often cachectic and high-dose CS cause nitrogen wasting in these patients despite an antiinflammatory and appetite-stimulatory benefit.
Rates of progression of chronic renal failure were compared in patients receiving alternately an amino acid supplement (AA) and a ketoacid supplement (KA) to a very low protein (0.3 g/kg), low phosphorus (7 to 9 mg/kg) diet. The first supplement was randomly chosen. Bias due to carryover effects was minimized by delaying the regression analysis until one month after starting or changing supplements. In order to minimize possible bias caused by initiating the two supplements at differing levels of severity, a multiple crossover design was used (ABA, BAB, ABAB, or BABA) with at least four GFR's in each treatment period (except for three GFR's in one instance). Sixteen patients completed the protocol; five dropped out. Average starting GFR's were nearly identical for the two supplements (15.4 and 15.9 ml/min). For each patient, mean progression on KA was compared with mean progression on AA. Thirteen out of 16 patients progressed more slowly on KA than AA. On the average, progression on KA was significantly slower (95% confidence limits = -0.36 to 0.09 ml/min/month) than on AA (-0.91 to -0.41 ml/min/month; P = 0.024). There was no significant difference in estimated protein intake, phosphate excretion, or mean arterial pressure between KA and AA periods. Serum triglyceride concentration was significantly lower on KA (P = 0.0026). 17-hydroxycorticosteroid excretion was also lower (P = 0.031). We conclude that KA slow progression, relative to AA, independently of protein or phosphorus intake, in patients on this regimen.
Progression of chronic renal failure during 35 treatment periods in 27 patients was measured as the rate of change of bimonthly radioisotope GFR for an average of 15 months. Treatments were comprised of: (1) mild protein restriction; (2) more severe protein and phosphorus restriction plus essential amino acids; or (3) the same diet plus ketoacids. Progression was significantly (P less than 0.025) correlated with urinary 17-hydroxycorticosteroid excretion in all three treatment groups; overall r was 0.78 (P less than 0.0001). Multiple regression analysis showed that the following factors were not additional significant determinants of progression: urea N excretion, phosphate excretion, protein excretion, serum calcium times phosphorus product, serum alkaline phosphatase, serum uric acid, serum triglycerides, serum cholesterol, etiology, mean arterial pressure, or enalapril treatment. However, when urinary 17-hydroxycorticosteroid excretion was factored by GFR (with which it was correlated), additional significant regressors appeared: serum triglycerides and polycystic kidney disease, which tended to be associated with more rapid progression, and ketoacid treatment, which tended to be associated with slower progression. Mean 17-hydroxycorticosteroid excretion differed significantly between the three treatment groups, in the order (1) greater than (2) greater than (3) (though not when factored by GFR). Changing from essential amino acids to ketoacids (or vice versa) without change in diet was associated with lower 17-hydroxycorticosteroid excretion on ketoacids (but not when factored by GFR).(ABSTRACT TRUNCATED AT 250 WORDS)
Twelve patients with chronic renal failure who exhibited a progressive decline in 24-hour creatinine clearance, despite being given for 2 to 10 months a diet containing 0.3 g per kg ideal weight of protein and 7 to 9 g mg per kg ideal weight of phosphorus, supplemented with vitamins, CaCO3, and 10 g per day of essential amino acids, were changed to a supplement containing predominantly ketoacids. In six patients whose serum creatinine was 7.5 mg/dl or greater at changeover, progression continued unabated. In six patients with serum creatinine levels at changeover of 6.6 to 7.4 mg/dl, one was non-compliant with the diet and progressed to dialysis. In the other five, progression, measured as the rate of change of a bimonthly radioisotope clearance, has been undetectable during the ensuing one to two years. There has been no change in urea appearance, blood pressure, phosphaturia or proteinuria. Nutrition has been maintained. Thus this ketoacid supplemented regimen apparently halted the progression of moderately-severe chronic renal failure for at least a year in a small group of patients in whom restriction of protein and phosphate intake without ketoacids failed to halt progression. In more severe renal failure, no effect on progression was seen.
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