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Twenty two preterm infants were prospectively evaluated to assess the need for dose adjustment when converting enteral and parenteral routes of methylxanthine administration.Serum theophylline concentrations remained unchanged in 18 infants after conversion from intravenous aminophylline to theophylline by mouth without dose reduction, as is currently recommended [corrected]. Intravenous aminophylline and theophylline by mouth may therefore be prescribed at equivalent doses, with a possible reduction in drug errors, and improved stability of serum concentrations.
It was hypothesized that the exercise-induced changes in glucoregulatory hormones and glucose production (Ra) occur as a result of a small deficit in glucose availability. To test this, 18-h fasted dogs performed 150 min of treadmill exercise with either the liver as the sole source of glucose (controls, n = 5) or with glucose infused from 0 to 50 min (period 1) and from 100 to 150 min (period 3) at rates designed to track the glucose utilization (Rd) response (ExoGlc, n = 5). The liver alone supplied glucose from 50 to 100 min (period 2). Isotopic and arteriovenous methods were used to assess Ra, Rd, and gluconeogenesis (GNG). Variable [3H]glucose infusion and frequent sampling were used to facilitate Ra measurements. Arterial glucose declined by -3.1 +/- 1.4, -4.3 +/- 2.9, and -6.4 +/- 3.7 mg/dl in periods 1-3 in controls (changes are mean values during each of the 50-min periods; P < 0.05). In ExoGlc, arterial glucose did not deviate from basal in periods 1 (+0.1 +/- 1.8 mg/dl) and 3 (+1.5 +/- 4.5 mg/dl) but fell from basal (P < 0.05) by the same amount as controls in period 2 (-5.7 +/- 2.1 mg/dl). Matching the Rd response with exogenous glucose led to increases in arterial and portal vein plasma insulin levels (P < 0.05) but did not affect glucagon, norepinephrine, epinephrine, and cortisol levels. Ra was elevated by 3.1 +/- 0.5, 4.0 +/- 1.1, and 4.7 +/- 1.1 mg.kg-1.min-1 in periods 1-3 in controls (P < 0.05). In ExoGlc, Ra rose by 0.0 +/- 0.4, 4.1 +/- 1.4 (P < 0.05), and 0.4 +/- 0.7 mg.kg-1.min-1, respectively, in periods 1-3. The rise in Ra was reduced in periods 1 and 3 of ExoGlc compared with controls (P < 0.02). GNG rose to approximately 250% basal in controls and did not respond with any significant difference in ExoGlc. In summary, the exercise-induced increases in counterregulatory hormones and GNG are present even when a deficit in glucose supply is eliminated by an exogenous glucose infusion. In contrast, the fall in insulin and the rise in hepatic glycogenolysis are greatly attenuated. The regulatory components affected by exogenous glucose predominate at the liver as deviations in plasma glucose of approximately 4% correspond to approximately 60% changes in Ra.(ABSTRACT TRUNCATED AT 400 WORDS)
Clindamycin phosphate (C-PO4) must be hydrolyzed to the active antibiotic, but whether this occurs within the peritoneal cavity during peritoneal dialysis is unknown. Therapeutic peritoneal levels are difficult to achieve after intravenous administration, so direct intraperitoneal instillation is preferred in treating dialysis-associated peritonitis. Therefore, the activation of C-PO4 in peritoneal dialysate was investigated. Fresh and 'uremic' peritoneal dialysates of 1.5 and 4.25% dextrose concentrations at pHs of 5.1 and 7.4 did not activate C-PO4. Clindamycin hydrochloride in this same fluid was active, ruling out uremic deactivators. A patient with peritonitis was treated with intraperitoneal C-PO4, and therapeutic (greater than 5 micrograms/ml) serum and peritoneal levels were achieved. Infected (exudative) peritoneal dialysate drained from another patient with peritonitis activated C-PO4 in vitro. Commercial alkaline phosphatase added to uremic dialysate also activated C-PO4 in vitro. C-PO4 was instilled into the peritoneal cavities of 10 noninfected patients. Exposure to the peritoneal membrane at two concentrations resulted in a 3% activation of C-PO4. From these observations it is clear that C-PO4 is only partially activated intraperitoneally. Uremia or uremic products in the dialysate do not deactivate the antibiotic. Exudative material (bacteria, white blood cells and proteins) in infected dialysate contribute to activation of C-PO4. The peritoneal membrane further assists in activation. We recommend that C-PO4 be administered at a concentration of 167 mg/l of dialysate to ensure therapeutic peritoneal levels of the active antibiotic, especially after the exudative phase clears.
Cyst infection in patients with autosomal-dominant polycystic kidney disease (ADPKD) is often refractory to therapy, in part because of the limited entry of commonly used antibiotics into cyst fluid. To study the efficacy of trimethoprim-sulfamethoxazole in cyst infection, cyst fluid was obtained by percutaneous aspiration or at surgery from eight patients with ADPKD receiving trimethoprim-sulfamethoxazole. Cysts were categorized as nongradient or gradient by cyst-fluid sodium concentration. Trimethoprim-sulfamethoxazole concentrations within cysts were determined and cyst fluid inhibitory and bactericidal titers were assessed in vitro against Escherichia coli, Proteus mirabilis and Streptococcus fecalis. The mean cyst fluid trimethoprim and sulfamethoxazole concentrations were 15.2 micrograms/ml and 42.5 micrograms/ml, respectively. Preferential accumulation of trimethoprim was observed in gradient cysts, exceeding serum levels more than eightfold. Sulfamethoxazole penetrated cysts to a lesser extent, with concentrations ranging from 10 to 70 percent of the serum level. Cyst fluid sampled prior to trimethoprim-sulfamethoxazole administration (control) demonstrated no antibacterial activity, while cyst fluid inhibitory and bactericidal titers following antibiotic administration were 1:32 or greater in most instances. These studies indicate that trimethoprim-sulfamethoxazole is likely to be efficacious in the treatment of cyst infection in polycystic kidneys.
Chronic administration of LHRH agonist analogs to humans reduces gonadal function through pituitary desensitization. Serum immunoreactive gonadotropin levels are modestly reduced, whereas serum bioactive LH levels are drastically suppressed. The effects on bioactive FSH levels, however, are not known. In this study, serum bioactive FSH was measured using an in vitro granulosa cell aromatase bioassay in four normal men given a LHRH agonist, [D-Trp6,Pro9-NEt]LHRH (LHRHA; 500 micrograms/day for 16 weeks), by sc infusion and testosterone enanthate (TE; 100 mg, im every 2 weeks) and in five men given 500 micrograms/day LHRHA by daily sc injection for 20 weeks and TE (100 mg every 2 weeks) from weeks 10 through 20. During the first study, serum immunoreactive FSH levels (IR-FSH) decreased by 56.5 +/- 4.8% (+/- SEM), and serum bioactive FSH (Bio-FSH) level decreased by 57.6 +/- 6.4%. The ratio of Bio-FSH to IR-FSH did not change. During the second study, both serum IR-FSH and Bio-FSH levels followed a triphasic pattern, decreasing slightly but not significantly immediately after initiation of LHRHA administration, progressively increasing to a peak (P less than 0.5 vs, baseline) at week 10, and then, after addition of TE to this regimen, decreasing slightly again. The Bio-FSH to IR-FSH ratio, as in the first study, did not change. When serum obtained at week 10 during the second study, just before initiation of TE, was chromatographed on a Sephadex G-100 column, IR-LH eluted in two distinct peaks, while IR-FSH eluted as a single peak. These results demonstrate that in normal men chronic LHRHA administration alone for up to 10 weeks or LHRHA plus TE for up to 16 weeks does not alter the qualitative characteristics of secreted FSH, since there was no dissociation between serum IR- and Bio-FSH levels.
Calcium bioavailability was defined as either retention of 45Ca in tibias (Experiment 1) or retention of 47Ca in carcasses (Experiment 2). In Experiment 1, rats (age 21, 40 or 100 d) were fed purified meals extrinsically labeled with 45Ca. The meals contained either 0.5% Ca (control) or 1% Ca [control supplemented with CaCO3, calcium citrate-malate (CCM), milk or cheese] and either no lactose or 20% lactose. Lactose increased Ca bioavailability (P less than 0.05) from the control and milk meals in all age groups. Increases from CCM and CaCO3 were significantly only in the 21-d-old group. Lactose did not affect bioavailability from cheese. In Experiment 2, suckling rats (age 7, 12 or 17 d) were gavaged with 47Ca-labeled milk (fluid skim or lactose-hydrolyzed fluid skim) or an aqueous CaCl2-casein mixture (containing either no sugar, glucose + galactose, or lactose). Bioavailability from milk was higher than from lactose-hydrolyzed milk in all age groups. Lactose and glucose + galactose increased bioavailability over the sugar-free CaCl2-casein mixture in all age groups. Data from these experiments show that lactose enhances Ca bioavailability at several stages of development and the effect is not markedly diminished by high Ca diets. Lactose increases Ca bioavailability from a variety of sources but the magnitude of the effect may vary among sources.
Glucose homeostasis in men fasted for 84 h was assessed using isotopes, indirect calorimetry and forearm balance techniques during a basal period and three sequential hyperinsulinaemic euglycaemic clamps each lasting for 150 min. Two protocols (n = 12 in each) were used: subjects were either allowed to develop hypoaminoacidaemia or received a commercial solution of L-amino acids while maintaining near-basal plasma leucine levels. Insulin infusions resulted in 3-, 35- and 650-fold increases in plasma insulin levels in both protocols. The infusion of amino acids produced a rightward shift in the dose-response curve of insulin's effect on suppressing hepatic glucose production, indicating decreased sensitivity in addition to blunting of the maximal responsiveness. Total body glucose rate of disappearance was progressively increased with escalating insulin doses, but was 22% lower at the intermediate and highest insulin doses in the group that was infused with amino acids (3.44 +/- 0.53 vs 4.82 +/- 0.71 and 7.72 +/- 1.01 vs 10.36 +/- 1.08 mg.kg-1.min-1, respectively; p less than 0.05). Forearm balance data confirmed the isotopic data, since amino acid infusions blunted the insulin-mediated increase in net forearm glucose utilization (by 50-83%). Furthermore, the infusion of amino acids resulted in marked reductions in the rate of carbohydrate oxidation and storage as assessed by indirect calorimetry. The data indicate that the amino acid-mediated suppression of glucose utilization and carbohydrate oxidation is exerted on the responsive component of insulin action.
To assess the means by which peripheral metabolism facilitates the transition to a gluconeogenic state, dogs were studied during 150 min of moderate treadmill exercise. Metabolism in the working hindlimb was assessed with arteriovenous difference and isotopic techniques (n = 9). In a separate group (n = 6), hepatic metabolism was assessed using arteriovenous differences. Limb glucose uptake (LGU) and oxidation (GOX) rose from 33 +/- 10 and 5 +/- 2 to 101 +/- 20 and 54 +/- 15 mumol/min at 10 min of exercise. LGU continued to rise (151 +/- 21 mumol/min at 150 min), while GOX declined. Nonoxidative glucose metabolism (GNOX) was 28 +/- 10 mumol/min at rest and 47 +/- 24 and 108 +/- 16 mumol/min at 10 and 150 min of exercise. Limb nonglycemic (predominantly glycogen) pyruvate formation rose from 52 +/- 22 to 198 +/- 54 and 242 +/- 74 mumol/min at 10 and 150 min of exercise. The gradual increase in GNOX and the high glycogenolytic rate were paralleled by accelerated lactate, pyruvate, and glutamine releases. Limb glycerol release rose promptly and remained elevated during exercise. Plasma nonesterified fatty acids (NEFAs) rose gradually and paralleled the gradual rise in GNOX (r = 0.93). The resulting rise in hepatic NEFA delivery was highly correlated to hepatic O2 uptake (r = 0.87), hepatic vein lactate-to-pyruvate ratio (r = 0.90), and intrahepatic gluconeogenic efficiency (r = 0.96). In summary, during exercise, 1) the primary fate of the added glucose consumed by the working limb is initially oxidation, but becomes GNOX as exercise duration progresses; 2) glycogenolysis rises promptly, but attains its highest rate at the end of exercise; 3) the late increases in GNOX and glycogenolysis relate to an increased gluconeogenic precursor release from the working limb; 4) although lipolysis increases promptly and is sustained, circulating NEFAs rise only gradually; and 5) the gradual rise in plasma NEFAs is highly correlated to the shift from GOX to GNOX and the adjustments in hepatic metabolism that are necessary for the full gluconeogenic response.