Variable Thyrotropin Response to Thyrotropin-releasing Hormone after Small Decreases in Plasma Free Thyroid Hormone Concentrations in Patients with Nonthyroidal Diseases

Although a normal serum thyrotropin (TSH) concentration is generally considered to be the most important finding to support the clinical impression of euthyroidism in patients with nonthyroidal diseases and decreased serum triiodothyronine (T₃), the regulation of TSH secretion in sick patients has not been studied previously. Accordingly, we studied the regulation of TSH secretion in 23 patients with nonthyroidal diseases; 15 of the patients had decreased serum T₃. TSH regulation was studied by measuring the TSH response to injected thyrotropin-releasing hormone (TRH) before and after effecting a small decrease in serum thyroxine (T₄) and/or T₃ concentrations by iodide treatment, 262 mg daily for 10 d. Iodide treatment significantly decreased (> 10%) the free T₄ index (FT₄-I) and/or free T₃ index (FT₃-I) in all patients. FT₄-I values were correlated (0.611, P < 0.001), with free T₄ concentration determined by equilibrium dialysis. Despite decreased FT₄-I and/or FT₃-I after iodide treatment in all patients, the TSH response to TRH after iodide treatment was augmented in only 8 of 15 patients who had decreased serum T₃ (group 1) and in only 5 of 8 patients who had a normal serum T₃. Mean base-line TSH concentration was increased significantly (P < 0.05) from 0.9±0.1 to 1.5±0.3 μU/ml in group 1 only. Comparison of the mean TSH response to TRH showed that there was no significant difference between groups 1 and 2. Moreover, no significant difference in thyroidal parameters was observed between patients who had augmented TSH response to TRH after iodides and those who had either similar or decreased TSH response irrespective of the initial serum T₃. These studies show that an augmented TSH response to TRH in response to a small reduction in serum T₄ and T₃ concentration occurred in only 57% of the entire group of patients with nonthyroidal diseases and that the presence or absence of a normal TSH response to this stimulus did not seem to be related to the base-line serum T₃ concentration. Because an increase in serum TSH in response to decreased serum T₄ and T₃ did not occur in about one-half of patients with nonthyroidal diseases, normal serum TSH may not be a reliable index of the euthyroid state in these patients.     

Direct Radioimmunoassay of Nuclear 3,5,3′ Triiodothyronine in Rat Anterior Pituitary

Previous tracer studies have suggested that 5′-monodeiodination of l-thyroxine (T₄) in anterior pituitary may contribute a substantial portion of specifically bound nuclear 3,5,3′ l-triiodothyronine (T₃) in this tissue in rats. To evaluate this possibility, a radioimmunoassay for nuclear T₃ in individual anterior pituitaries was developed. Animals received [¹²⁵I]T₃ 60 min before removal of the anterior pituitary and isolation of the nuclei by differential centrifugation. This allowed calculation of the nuclear:serum T₃ ratio and comparison of expected with measured T₃. T₃ was extracted in ethanol, dried, and reconstituted in assay buffer. In untreated hypothyroid rats, anterior pituitary nuclear T₃ was 0.18 ± 0.06 pg/μg DNA which was 0.13 pg/μg DNA greater than expected from the serum T₃ concentration and the pituitary nuclear:serum [¹²⁵I]T₃ ratio. In 10 hypothyroid rats given a single bolus of 400 ng T₃/100 g body wt., the nuclear T₃ by radioimmunoassay was 1.0 ± 0.06 pg/μg DNA, whereas that expected from the T₃ specific activity calculations was 0.85 pg/μg DNA (P < 0.025). Serum T₄ concentrations in these rats were < 0.25 μg/dl but the nuclear T₃ derived from as little as 0.2 μg/dl T₄ could explain a large portion of these small discrepancies between observed and measured nuclear T₃. In 29 normal rats, anterior pituitary nuclear T₃ was 0.63±0.04 pg/μg DNA, whereas that expected from the serum T₃ concentration (55±2 ng/dl) was 0.23±0.02 pg/μg DNA (P < 0.001). Total pituitary T₃ based on this measurement was 92±6 pg. Because the maximal nuclear binding capacity for T₃ in rat anterior pituitary is 0.77 pg/μg DNA, these results suggest there is 82% occupancy of these nuclear receptors. The requirement for normal serum concentrations of both T₄ and T₃ to achieve normal nuclear T₃ saturation in anterior pituitary is in marked contrast to the situation in liver, kidney, and heart muscle which appear to require only a normal serum T₃. As a consequence, the anterior pituitary can monitor both serum T₄ and T₃ and respond appropriately to changes in their concentrations.     

Total and free triiodothyronine in human serum

A reliable method has been developed for the determination of total serum T3, dialyzable fraction (DFT3), and absolute concentration of free T3 (AFT3). Total T3 values (mean ± SD) were: healthy euthyroid subjects, 0.33 ± 0.07 μg per 100 ml; hyperthyroid patients, 0.71 ± 0.1 μg per 100 ml; hypothyroid, 0.10 ± 0.03 μg per 100 ml. Values (mean ± SD) for DFT3 in these groups were 0.46 ± 0.14%, 0.78 ± 0.17%, and 0.16 ± 0.08%, respectively. Calculated values for AFT3 were: 1.51 ± 0.4 mμg per 100 ml, 5.00 ± 0.6 mμg per 100 ml and 0.24 ± 0.1 mμg per 100 ml, respectively. Dilution of serum before dialysis lowered estimated DFT3 values. Enrichment of serum with labeled T3 in the range examined did not affect DFT3. However, DFT3 was increased by addition of Merthiolate to serum in concentration 1: 10,000 due to displacement of T3 from thyroxine-binding globulin to albumin. The data suggest that triiodothyronine may play a considerably more important role in normal and pathological physiology, as evidenced by kinetic analysis using these data. A metabolic role for T3 equal to that of T4 is indicated.     

Acute release of thyrotropin in the newborn

Measurements of serum thyrotropin (TSH) concentrations were conducted in maternal and fetal blood during labor and delivery and the early postnatal and neonatal periods. Mean TSH concentration was significantly higher in cord blood (9.5 μU/ml) than maternal blood (3.9 μU/ml), a finding suggesting a fetal-maternal TSH gradient at term. Serum TSH concentration in the newborn increased rapidly to mean levels of 60 μU/ml at 10 min and 86 μU/ml at 30 min of age. Between 30 min and 3-4 hr serum levels decreased rapidly, then fell more gradually to a mean concentration of 13 μU/ml at 48 hr. The half-time of the decrease in serum TSH concentration between 30 and 90 min was 77 min, a value slightly greater than the half-time of disappearance of radioiodinated TSH measured in adults. This indicates that the early high rate of TSH secretion in the newborn ceases by 30 min, and that the rapid rise and fall in serum TSH concentrations may represent release of stored pituitary TSH. A more chronic TSH hypersecretion persisted throughout the first 24-48 hr of extrauterine life. Measurements of serum PBI concentrations were conducted in a separate group of maternal and cord blood samples and in the newborn infants during the first 48 hr of extrauterine life to relate the TSH and serum hormonal iodine concentration changes. Serum protein-bound iodine (PBI) concentrations were similar in maternal and cord blood, increased significantly by 4 hr of age in the newborn, and peaked at about 24 hr, presumably in response to the TSH hypersecretion. The pattern of TSH hypersecretion was similar in infants delivered vaginally and by caesarean section. Maternal serum TSH concentrations were stable throughout the perinatal period. Warming the infants at 99-103°F during the first 3 hr of life did not prevent the early, acute release of thyrotropin. Cooling of warm infants at room temperature (72-78°F) between 3 and 4 hr resulted in a decrease in mean rectal temperature of 3.3°F and produced a significant increment in serum TSH concentration. These data suggest that the mechanism of the early, acute release of thyrotropin in the newborn may involve a potent stimulus other than cooling. However, the increase in serum TSH stimulated by delayed (3-4 hr) cooling indicates that neonatal hyperthyroxinemia is, at least, augmented by extrauterine cooling. Thus, cold exposure is capable of increasing TSH secretion in humans.     

Daptomycin Pharmacokinetics in Adult Oncology Patients with Neutropenic Fever

Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant Staphylococcus aureus. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means ± standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (C_max) was 49.04 ± 12.42 μg/ml (range, 21.54 to 75.20 μg/ml), the 24-h plasma concentration was 6.48 ± 5.31 μg/ml (range, 1.48 to 29.26 μg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 ± 523.53 μg·h/ml (range, 164.64 to 3155.11 μg·h/ml), the volume of distribution at steady state was 0.18 ± 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 ± 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 ± 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 ± 20.66 h (range, 7.00 to 121.73 h), and the median time to C_max was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 ± 0.02. All patients achieved C_max/MIC and AUC from time zero to 24 h (AUC_0-24)/MIC ratios for a bacteriostatic effect against Streptococcus pneumoniae. Twenty-seven patients (93%) achieved a C_max/MIC ratio for a bacteriostatic effect against S. aureus, and 28 patients (97%) achieved an AUC_0-24/MIC ratio for a bacteriostatic effect against S. aureus. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for S. pneumoniae and 90% of patients for S. aureus. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.     

Intracellular time course, pharmacokinetics, and biodistribution of isoniazid and rifabutin following pulmonary delivery of inhalable microparticles to mice

Intracellular concentrations of isoniazid and rifabutin resulting from administration of inhalable microparticles of these drugs to phorbol-differentiated THP-1 cells and the pharmacokinetics and biodistribution of these drugs upon inhalation of microparticles or intravenous administration of free drugs to mice were investigated. In cultured cells, both microparticles and dissolved drugs established peak concentrations of isoniazid (~1.4 and 1.1 μg/10⁶ cells) and rifabutin (~2 μg/ml and ~1.4 μg/10⁶ cells) within 10 min. Microparticles maintained the intracellular concentration of isoniazid for 24 h and rifabutin for 96 h, whereas dissolved drugs did not. The following pharmacokinetic parameters were calculated using WinNonlin from samples obtained after inhalation using an in-house apparatus (figures in parentheses refer to parameters obtained after intravenous administration of an equivalent amount, i.e., 100 μg of either drug, to parallel groups): isoniazid, serum half-life (t_1/2) = 18.63 ± 5.89 h (3.91 ± 1.06 h), maximum concentration in serum (C_max) = 2.37 ± 0.23 μg·ml⁻¹ (3.24 ± 0.57 μg·ml⁻¹), area under the concentration-time curve from 0 to 24 h (AUC_0-24) = 55.34 ± 13.72 μg/ml⁻¹ h⁻¹ (16.64 ± 1.80 μg/ml⁻¹ h⁻¹), and clearance (CL) = 63.90 ± 13.32 ml·h⁻¹ (4.43 ± 1.85 ml·h⁻¹); rifabutin, t_1/2 = 119.49 ± 29.62 h (20.18 ± 4.02 h), C_max = 1.59 ± 0.01 μg·ml⁻¹ (3.47 ± 0.33 μg·ml⁻¹), AUC_0-96 = 109.35 ± 14.78 μg/ml⁻¹ h⁻¹ (90.82 ± 7.46 μg/ml⁻¹ h⁻¹), and CL = 11.68 ± 7.00 ml·h⁻¹ (1.03 ± 0.11 ml·h⁻¹). Drug targeting to the lungs in general and alveolar macrophages in particular was observed. It was concluded that inhaled microparticles can reduce dose frequency and improve the pharmacologic index of the drug combination.     

Chronic Hyperglycemia Reduces Surface Active Material Flux in Tracheal Fluid of Fetal Lambs

I tested the hypothesis that chronic hyperglycemia alters fetal lung maturation by continuous infusion of glucose (14±2 mg/kg per min, mean±SE) from 112 up to 145 d gestation into six chronically catheterized fetal lambs from which tracheal fluid could be collected. Serum glucose levels (32±2 mg/dl) and serum insulin levels (38±4 μU/ml) in these glucose-treated fetuses were significantly higher than serum glucose levels (18±2 mg/dl, P < 0.001) and serum insulin levels (12±3 μU/ml, P < 0.001) in six chronically catheterized control fetuses of the same gestational ages. Glucose infusion to the fetuses did not alter maternal serum glucose (60±3 mg/dl) or serum insulin levels (35±5 μU/ml). Arterial blood gases (pH 7.34±0.01, Po₂ 24.3±0.5 mmHg, Pco₂ 41.5±0.9 mmHg), oxygen saturation (73±2%), hematocrit (31±1%), and tracheal fluid flow (2.4±0.1 ml/g per h) in the glucose-treated fetuses were not significantly different from controls. Among the control fetuses, surface active material (SAM) began to appear in tracheal fluid at 123 d gestation and was present in all six fetuses by 129 d gestation, whereas SAM did not appear at all in tracheal fluid of four of the glucose-treated fetuses, and appeared in two at low levels after 142 d gestation. SAM flux in the glucose-treated fetuses (<1 μg/g per h) was statistically lower than SAM flux in the control fetuses (60±9 μg/kg per h, P < 0.001). Between 130 and 140 d gestation, tracheal fluid phospholipid content rose fourfold, mixed lecithin content rose ninefold, disaturated phosphatidylcholine content rose fourfold in the control fetuses, whereas little or no increase in these measurements occurred in the glucose-treated fetuses (all differences significant). I conclude that chronic hyperglycemia with secondary hyperinsulinemia reduces SAM flux in tracheal fluid of fetal lambs. The reduction in SAM flux is attributed to low surface active phospholipid content of the SAM. A similar mechanism may operate in utero to cause respiratory distress in infants of diabetic mothers whose maternal glucose homeostasis is poorly controlled.     

3,3′-Diiodothyronine Production, a Major Pathway of Peripheral Iodothyronine Metabolism in Man

3,3′-Diiodothyronine (3,3′-T₂) has been detected in human serum and in thyroglobulin. However, no quantitative assessment of its clearance rate (CR), production rate (PR), or of the importance of extrathyroidal sources of 3,3′-T₂ relative to direct thyroidal secretion is yet available. This study examines these parameters in seven euthyroid subjects, and in eight athyreotic subjects (H) eumetabolic due to thyroxine therapy (HT₄) (n = 5) or triiodothyronine replacement (HT₃) (n = 3). A highly specific radioimmunoassay for the measurement of 3,3′-T₂ in whole serum was developed. Serum 3,3′-T₂ concentrations were (mean ± SD) 6.0±1.0 ng/100 ml in 13 normal subjects, 9.0±4.6 ng/100 ml in 25 hyperthyroid patients, and 2.7±1.1 ng/100 ml in 17 hypothyroid patients. The values in each of the latter two groups were significantly different from normal. 3,3′-T₂ was detected regularly in normal concentrations in 11 hypothyroid patients eumetabolic by treatment with synthetic T₄, in 10 eumetabolic patients suffering from nonthyroidal systemic illness, and in 2 subjects with elevated serum T₄-binding globulin. The 3,3′-T₂ CR was assessed from data acquired from the ¹²⁵I-3,3′-T₂ constant infusion technique. The 3,3′-T₂ PR was calculated from CR and serum concentration of 3,3′-T₂ determined by radio-immunoassay. In the HT₄ subjects the 3,3′-T₂ CR averaged 840±377 liters/day and 3,3′-T₂ PR 33.9±12.5 μg/day. These results were not significantly different from those in the control group: 3,3′-T₂ CR 628±218 liters/day and 3,3′-T₂ PR 39.8±19.8 μg/day (all corrected to 70 kg body wt). In addition to 3,3′-T₂ PR, T₃, and reverse triiodothyronine (rT₃) PR were determined in three of the HT₄ subjects. In each case studied, the 3,3′-T₂ PR was close to the combined triiodothyronine (T₃ + rT₃) PR. The mean molar ratio of T₂ PR/(T₃ + rT₃) PR was 1.08±0.10. The results obtained in the HT₄ subjects indicate that the production of 3,3′-T₂ is a major route of T₄ metabolism. The combined studies of 3,3′-T₂, T₃ and rT₃ PR in the HT₄ subjects indicate that both T₃ and rT₃ are major precursors of 3,3′-T₂. In the HT₃ subjects, the conversion of T₃ to 3,3′-T₂, determined as the molar ratio of 3,3′-T₂ PR to T₃ PR, ranged from 0.36 to 0.92, providing further evidence that T₃ is a precursor of 3,3′-T₂. From the close agreement between the mean values for 3,3′-T₂ PR in the euthyroid and HT₄ group it is concluded that most, if not all of the 3,3′-T₂ produced in normal humans is derived by extrathyroidal conversion from T₃ and rT₃.     

Pharmacokinetics of Antituberculosis Drugs in HIV-Positive and HIV-Negative Adults in Malawi

Limited data address the impact of HIV coinfection on the pharmacokinetics (PK) of antituberculosis drugs in sub-Saharan Africa. A total of 47 Malawian adults underwent rich pharmacokinetic sampling at 0, 0.5, 1, 2, 3, 4, 6, 8, and 24 h postdose. Of the subjects, 51% were male, their mean age was 34 years, and 65% were HIV-positive with a mean CD4 count of 268 cells/μl. Antituberculosis drugs were administered as fixed-dose combinations (150 mg rifampin, 75 mg isoniazid, 400 mg pyrazinamide, and 275 mg ethambutol) according to recommended weight bands. Plasma drug concentrations were determined by high-performance liquid chromatography (rifampin and pyrazinamide) or liquid chromatography-mass spectrometry (isoniazid and ethambutol). Data were analyzed by noncompartmental methods and analysis of variance of log-transformed summary parameters. The pharmacokinetic parameters were as follows (median [interquartile range]): for rifampin, maximum concentration of drug in plasma (C_max) of 4.129 μg/ml (2.474 to 5.596 μg/ml), area under the curve from 0 to 24 h (AUC_0–∞) of 21.32 μg/ml · h (13.57 to 28.60 μg/ml · h), and half-life of 2.45 h (1.86 to 3.08 h); for isoniazid, C_max of 3.97 μg/ml (2.979 to 4.544 μg/ml), AUC_0–24 of 22.5 (14.75 to 34.59 μg/ml · h), and half-life of 3.93 h (3.18 to 4.73 h); for pyrazinamide, C_max of 34.21 μg/ml (30.00 to 41.60 μg/ml), AUC_0–24 of 386.6 μg/ml · h (320.0 to 463.7 μg/ml · h), and half-life of 6.821 h (5.71 to 8.042 h); and for ethambutol, C_max of 2.278 μg/ml (1.694 to 3.098 μg/ml), AUC_0–24 of 20.41 μg/ml · h (16.18 to 26.27 μg/ml · h), and half-life of 7.507 (6.517 to 8.696 h). The isoniazid PK data analysis suggested that around two-thirds of the participants were slow acetylators. Dose, weight, and weight-adjusted dose were not significant predictors of PK exposure, probably due to weight-banded dosing. In this first pharmacokinetic study of antituberculosis drugs in Malawian adults, measures of pharmacokinetic exposure were comparable with those of other studies for all first-line drugs except for rifampin, for which the C_max and AUC_0–24 values were notably lower. Contrary to some earlier observations, HIV status did not significantly affect the AUC of any of the drugs. Increasing the dose of rifampin might be beneficial in African adults, irrespective of HIV status. Current co-trimoxazole prophylaxis was associated with an increase in the half-life of isoniazid of 41% (P = 0.022). Possible competitive interactions between isoniazid and sulfamethoxazole mediated by the N-acetyltransferase pathway should therefore be explored further.     

Pharmacology of a New 1-Oxa-β-lactam (LY127935) in Normal Volunteers

The pharmacokinetics of 1-oxa-β-lactam (LY127935), a new semisynthetic β-lactam antibiotic, was studied in four healthy adult volunteers (mean age of 27 years, mean body surface area ± standard error [SE] of 1.87 ± 0.08 m², and mean creatinine clearance ± SE of 116 ± 12 ml/min per 1.73 m²). Immediately after completion of a 1-g, 20-min intravenous (i.v.) infusion, the mean serum level ± SE was 70.7 ± 8.5 μg/ml. After a 1-g intramuscular (i.m.) injection, peak serum levels occurred from 30 min to 1 h, and the mean peak serum level ± SE was 52.3 ± 1.6 μg/ml. Beginning at 1 h, the serum concentrations after i.m. administration were higher than those after i.v. administration. At 8 h, the mean serum level ± SE was 3.8 ± 0.6 μg/ml after completion of the i.v. infusion and 4.8 ± 0.7 μg/ml after the i.m. injection. The mean serum half-lives for the β phase i.v. and i.m. administration were similar (2.3 ± 0.7 h and 2.4 ± 0.2 h, respectively). The mean apparent volume of distribution ± SE was 16.6 ± 1.9 liters per 1.73 m². The mean serum clearance ± SE of LY127935 was 85.4 ± 12.7 ml/min per 1.73 m², and the mean renal clearance ± SE was 54.5 ± 4.4 ml/min per 1.73 m.² Urine concentrations of LY127935 were at least 140 μg/ml in each volunteer during the first 12 h after i.m. or i.v. administration. The mean percentages of the dose recovered in the urine ± SE within 2 h after i.v. or i.m. administration were similar (30 ± 4 and 34 ± 11, respectively). Only 67 ± 3% and 75 ± 13% were recovered in the urine within 24 h after i.v. and i.m. administration, respectively.     

Direct and Synergistic Interactions of 3,5,3′-Triiodothyronine and the Adrenergic System in Stimulating Sugar Transport by Rat Thymocytes

Isolated rat thymocytes were preincubated with various catecholamines, alone and together with 3,5,3′-triiodothyronine (T₃), and the accumulation of the glucose analogues, 2-deoxy-d-glucose (2-DG) and 3-O-methylglucose (3-O-MG), was then measured. Epinephrine induced a time- and dose-dependent increase in the 15-min accumulation of 2-DG; at a concentration of 100 μM epinephrine, the effect was evident after a preincubation period of only 5 min. The lowest concentration of epinephrine at which a significant effect was evident was 1 μM. Epinephrine also produced a dose-dependent increase in the accumulation of 3-O-MG, and the lowest concentration at which a significant effect was evident was again 1 μM. Isoproterenol, a β-adrenergic agonist, like epinephrine, increased the accumulation of 2-DG, whereas the α-agonist, phenylephrine, had no effect. The response to epinephrine was inhibited by the β-antagonist, alprenolol, but the α-antagonist, phentolamine, had no effect. As previously demonstrated, T₃ increased 2-DG accumulation, and like epinephrine, its effect was blocked by alprenolol. Neither T₃ (0.1 nM) nor epinephrine (0.1 μM) had any effect when acting alone, but when added together at these concentrations, they significantly increased the accumulation of both 2-DG and 3-O-MG. Neither T₃ with isoproterenol nor T₃ with phenylephrine produced a comparable synergistic effect. But T₃ (0.1 nM) acting with isoproterenol (0.1 μM) and phenylephrine (0.1 μM) together, synergistically increased 2-DG accumulation. In addition, the α-antagonist, phentolamine, which alone had no effect, inhibited the synergistic effect induced by T₃ and epinephrine. The effects of epinephrine and T₃ alone, as well as their combined synergistic effect on 2-DG accumulation, were not blocked by the inhibitor of protein synthesis, puromycin.     

Reversal of Secondary Hyperparathyroidism by Cimetidine in Chronically Uremic Dogs

Chronic cimetidine therapy has been shown to suppress circulating concentrations of immunoreactive parathyroid hormone (iPTH) in hemodialysis patients. To evaluate the long-term metabolic effects of cimetidine treatment, we studied seven chronically uremic dogs for 20 wk. The dogs were studied under metabolic conditions before, during, and after cimetidine therapy. iPTH fell progressively in the five treated dogs from 536±70 μleq/ml (mean±SE) (nl < 100 μleq/ml) before treatment to 291±25 μleq/ml at 12 wk (P < 0.001) and 157±32 μleq/ml at 20 wk (P < 0.001). The control dogs showed no consistent change in iPTH. The fall in iPTH was not associated with a change in serum ionized calcium. However, serum phosphorus decreased from 5.7±0.9 mg/dl to 3.4±0.2 mg/dl by the 20th wk (P < 0.05). By contrast, the serum concentration of 1,25-dihydroxycholecalciferol increased in all treated dogs from 33.4±4.3 pg/ml to 51.8±2.4 pg/ml during treatment (P < 0.01). Calcium balance was negative in all seven dogs before cimetidine (−347±84 mg/72 h) and remained so in the control dogs; it became positive in the five treated dogs after 12 wk (1,141±409 mg/72 h) (P < 0.05). Phosphorus balance, 24-h fractional phosphate excretion, and creatinine clearance remained unchanged. Pooled samples of serum obtained during the control and 20th wk of therapy were fractionated by gel filtration and the eluates assayed for immunoreactivity. The decrease in iPTH was associated with a decrease in all the immunoreactive species, indicating suppression of parathyroid gland secretion.     

Pharmacokinetics of Hydroxymethylnitrofurazone,a Promising New Prodrug for Chagas' Disease Treatment

Hydroxymethylnitrofurazone (NFOH) is a trypanocidal prodrug of nitrofurazone (NF), devoid of mutagenic toxicity. The purpose of this work was to study the chemical conversion of NFOH into NF in sodium acetate buffer (pH 1.2 and 7.4) and in human plasma and to determine preclinical pharmacokinetic parameters in rats. At pH 1.2, the NFOH was totally transformed into NF, the parent drug, after 48 h, while at pH 7.4, after the same period, the hydrolysis rate was 20%. In human plasma, 50% of NFOH was hydrolyzed after 24 h. In the investigation of kinetic disposition, the concentration of drug in serum versus time curve was used to calculate the pharmacokinetic parameters after a single-dose regimen. NFOH showed a time to maximum concentration of drug in serum (T_max) as 1 h, suggesting faster absorption than NF (4 h). The most important results observed were the volume of distribution (V) of NFOH through the tissues, which showed a rate that is 20-fold higher (337.5 liters/kg of body weight) than that of NF (17.64 liters/kg), and the concentration of NF obtained by in vivo metabolism of NFOH, which was about four times lower (maximum concentration of drug in serum [C_max] = 0.83 μg/ml; area under the concentration-time curve from 0 to 12 h [AUC_0–12] = 5.683 μg/ml · h) than observed for administered NF (C_max = 2.78 μg/ml; AUC_0–12 = 54.49 μg/ml · h). These findings can explain the superior activity and lower toxicity of the prodrug NFOH in relation to its parent drug and confirm NFOH as a promising anti-Chagas'' disease drug candidate.     

Disposition and Elimination of Meropenem in Cerebrospinal Fluid of Hydrocephalic Patients with External Ventriculostomy

The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 ± 23.7 μg/ml. A CSF maximum (C_maxCSF) of 0.63 ± 0.50 μg/ml (mean ± standard deviation) was observed 4.1 ± 2.6 h after the end of the infusion. C_maxCSF and the area under the curve for CSF (AUC_CSF) depended on the AUC for serum (AUC_S), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at β phase [t_1/2β] of 7.36 ± 2.89 h in CSF versus t_1/2β of 1.69 ± 0.60 h in serum). The AUC_CSF/AUC_S ratio for meropenem, as a measure of overall CSF penetration, was 0.047 ± 0.022. The AUC_CSF/AUC_S ratio for meropenem was similar to that for other β-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa.     

In Vitro Activities of a Wide Panel of Antifungal Drugs against Various Scopulariopsis and Microascus Species

The in vitro activities of 11 antifungal drugs against 68 Scopulariopsis and Microascus strains were investigated. Amphotericin B, 5-fluorocytosine, fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, voriconazole, and ciclopirox showed no or poor antifungal effect. The best activities were exhibited by terbinafine and caspofungin, where the MIC and MEC (minimal effective concentration) ranges were 0.0313 to >16 μg/ml and 0.125 to 16 μg/ml, respectively. The MIC and MEC modes were both 1 µg/ml for terbinafine and caspofungin; the MIC₅₀ and MEC₅₀ were 1 µg/ml for both drugs, whereas the MIC₉₀ and MEC₉₀ were 4 µg/ml and 16 µg/ml, respectively.     

Ceftolozane-Tazobactam Pharmacokinetics in a Critically Ill Patient on Continuous Venovenous Hemofiltration

Extended-infusion ceftolozane-tazobactam treatment at 1.5 g every 8 h was used to treat multidrug-resistant Pseudomonas aeruginosa in a critically ill patient on continuous venovenous hemofiltration. Serum drug concentrations were measured at 1, 4, 5, 6, and 8 h after the start of infusion. Prefilter levels of ceftolozane produced a maximum concentration of drug (C_max) of 38.57 μg/ml, concentration at the end of the dosing interval (C_min) of 31.63 μg/ml, time to C_max (T_max) of 4 h, area under the concentration-time curve from 0 to 8 h (AUC_0–8) of 284.38 μg · h/ml, and a half-life (t_1/2) of 30.7 h. The concentrations were eight times the susceptibility breakpoint for the entire dosing interval.     

Double-Blind Evaluation of the Safety and Pharmacokinetics of Multiple Oral Once-Daily 750-Milligram and 1-Gram Doses of Levofloxacin in Healthy Volunteers

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (n = 10) or placebo group (n = 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (C_max) values were generally attained within 2 h postdose. The mean values of C_max and area under the concentration-time curve from 0 to 24 h (AUC_0–24) following a single 750-mg dose were 7.1 μg/ml and 71.3 μg · h/ml, respectively, compared to 8.6 μg/ml and 90.7 μg · h/ml, respectively, at steady state. Following the single 1-g dose, mean C_max and AUC_0–24 values were 8.9 μg/ml and 95.4 μg · h/ml, respectively; corresponding values at steady state were 11.8 μg/ml and 118 μg · h/ml. These C_max and AUC_0–24 values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/F), apparent volume of distribution (V_ss/F), half-life (t_1/2), and renal clearance (CL_R) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/F, V_ss/F, t_1/2, and CL_R following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.     

Dopaminergic Inhibition of Metoclopramide-induced Aldosterone Secretion in Man: DISSOCIATION OF RESPONSES TO DOPAMINE AND BROMOCRIPTINE

This study was designed to investigate the role of dopaminergic mechanisms in the control of aldosterone secretion in man. Five normal male subjects in metabolic balance at 150 meq sodium/d and 60 meq potassium/d constant intake received the specific dopamine antagonist, metoclopramide, 10 mg i.v. on 2 consecutive d. On the 1st d, the subjects received an infusion of 5% glucose solution (vehicle) from 60 min before to 60 min after metoclopramide administration; on the 2nd d, an infusion of dopamine 4 μg/kg per min was substituted for vehicle. Metoclopramide in the presence of vehicle increased plasma aldosterone concentrations from 2.4±1.1 to a maximum of 17.2±2.8 ng/100 ml (P < 0.01) and serum prolactin concentrations from 7.5±5.0 to a maximum of 82.2±8.7 ng/ml (P < 0.01). Dopamine 4 μg/kg per min did not alter basal plasma aldosterone concentrations, but blunted the aldosterone responses to metoclopramide significantly; in the presence of dopamine, plasma aldosterone concentrations increased from 3.1±0.5 to 6.2±1.4 ng/100 ml (P < 0.05) in response to metoclopramide. The incremental aldosterone responses to metoclopramide were significantly lower in the presence of dopamine than with vehicle. Dopamine 4 μg/kg per min suppressed basal prolactin to <3 ng/ml and inhibited the prolactin responses to metoclopramide; serum prolactin concentrations increased to a maximum of 8.5±2.3 ng/ml with metoclopramide in the presence of dopamine.     

In Vitro Activities of Cefminox against Anaerobic Bacteria Compared with Those of Nine Other Compounds

The agar dilution MIC method was used to test the activity of cefminox, a β-lactamase-stable cephamycin, compared with those of cefoxitin, cefotetan, moxalactam, ceftizoxime, cefotiam, cefamandole, cefoperazone, clindamycin, and metronidazole against 357 anaerobes. Overall, cefminox was the most active β-lactam, with an MIC at which 50% of isolates are inhibited (MIC₅₀) of 1.0 μg/ml and an MIC₉₀ of 16.0 μg/ml. Other β-lactams were less active, with respective MIC₅₀s and MIC₉₀s of 2.0 and 64.0 μg/ml for cefoxitin, 2.0 and 128.0 μg/ml for cefotetan, 2.0 and 64.0 μg/ml for moxalactam, 4.0 and >128.0 μg/ml for ceftizoxime, 16.0 and >128.0 μg/ml for cefotiam, 8.0 and >128.0 μg/ml for cefamandole, and 4.0 and 128.0 μg/ml for cefoperazone. The clindamycin MIC₅₀ and MIC₉₀ were 0.5 and 8.0 μg/ml, respectively, and the metronidazole MIC₅₀ and MIC₉₀ were 1.0 and 4.0 μg/ml, respectively. Cefminox was especially active against Bacteroides fragilis (MIC₉₀, 2.0 μg/ml), Bacteroides thetaiotaomicron (MIC₉₀, 4.0 μg/ml), fusobacteria (MIC₉₀, 1.0 μg/ml), peptostreptococci (MIC₉₀, 2.0 μg/ml), and clostridia, including Clostridium difficile (MIC₉₀, 2.0 μg/ml). Time-kill studies performed with six representative anaerobic species revealed that at the MIC all compounds except ceftizoxime were bactericidal (99.9% killing) against all strains after 48 h. At 24 h, only cefminox and cefoxitin at 4× the MIC and cefoperazone at 8× the MIC were bactericidal against all strains. After 12 h, at the MIC all compounds except moxalactam, ceftizoxime, cefotiam, cefamandole, clindamycin, and metronidazole gave 90% killing of all strains. After 3 h, cefminox at 2× the MIC produced the most rapid effect, with 90% killing of all strains.     

Comparative Pharmacology of Cefaclor and Cephalexin

Two cephalosporin antibiotics, cefaclor and cephalexin, were administered orally to healthy, adult male volunteers for comparison of their pharmacological properties. In doses of 250 mg orally, cefaclor produced a peak serum concentration of 6.01 ± 0.55 (standard deviation [SD]) μg/ml compared with 9.43 ± 2.36 μg/ml for cephalexin (P < 0.01). The half-lives were 0.58 ± 0.07 (SD) h and 0.80 ± 0.12 (SD) h, and elimination constants were 1.22 ± 0.15 and 0.88 ± 0.13 h⁻¹ for cefaclor and cephalexin, respectively (P < 0.001). Neither drug showed accumulation over the dosing period, and both were well tolerated.