Changes in serum hypoxanthine levels after walk loads at mild to high intensity in healthy humans.

Effect of mild intensity exercise on the serum levels of hypoxanthine was studied. Eighteen healthy subjects performed 2 to 4 bouts of 5 minutes walk load at different intensities. At the beginning, thirteen of them walked at intensity more than 80% of the maximum. The serum levels of hypoxanthine increased to the levels of more than 6 times of resting values showing a peak at 10 to 20 minutes after the completion of the walk load. In 62 bouts of the walk load by 18 subjects, statistically significant relationship was demonstrated between intensity of the walk load and increase in serum concentration of hypoxanthine at 10 minutes after the completion of the walk load with correlation coefficient of 0.556. The serum hypoxanthine levels were significantly increased by the walk load even at mild intensity between 41 and 60%. Increment in the serum hypoxanthine concentration also showed positive and statistically significant correlation with physiological cost index. These results suggest that the serum levels of hypoxanthine increase following mild as well as moderate to submaximal intensity of exercise, and its increment may be used as an indicator of energy balance in the muscle during exercise at mild to high intensity.     

Estimation of energy intake in clinical practice: a comparison between a food record protocol and a precoded food record book

The aim of this study was to compare energy intake estimated from a clinical food record protocol (CFRP) with that from a precoded food record book (PFRB) as reference method. Food and fluid consumption were recorded in 10 older patients using a CFRP in parallel with a PFRB during a 6-day period. The results showed that there were no significant differences in mean energy intake estimated from the CFRP as compared with that estimated from the PFRB. The correlation coefficient between the calculated daily energy intake from the CFRP and PFRB was 0.96. The differences in energy intake (kcal/day) between the CFRP and PFRB, plotted against their mean value for 10 patients, showed that results were within the limits of agreement (mean +/- 2SD) for nine patients. The differences in each day's energy intake between the two methods plotted against their mean value showed that 97% of the estimated daily energy intake was within the limits of agreement. The weighted kappa between the two methods was 0.76. The CFRP would seem to be acceptable for the estimation of mean energy intake in the hospital setting.     

Relation between changes in serum hypoxanthine levels by exercise and daily physical activity in the elderly.

Effect of exercise at mild intensity on the serum levels of hypoxanthine was studied in eleven healthy elderly subjects. They were divided into the active and sedentary groups according to their daily physical activity. They performed exercise testing to walk for 5 minutes keeping heart rate at approximately 70% of the maximum heart rate. Mean intensity of exercise estimated according to Karvonen's formula in the active or sedentary group was 41.8 +/- 9.6% or 34.1 +/- 6.1%, respectively. In the sedentary group, the serum hypoxanthine levels at 10 minutes after completion of walk load was significantly higher than that before exercise. Changes in the serum hypoxanthine levels in the active and sedentary groups were -0.97 +/- 1.36 and 0.80 +/- 0.57 micromol/liter, respectively (p < 0.05). This result suggests that mild intensity exercise increases the serum hypoxanthine concentration in the elderly leading inactive daily life, and physical activity suppresses an increase in the serum hypoxanthine levels by mild exercise.     

Reduction in extrathyroidal triiodothyronine production by propylthiouracil in man.

To determine if propylthiouracil (PTU) inhibited extrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion in man, PTU was administered to T4-treated hypothyroid patients and serial measurements of T4, T3, and thyrotropin (TSH) carried out. All patients had proven thyroidal hypothyroidism and had been receiving 0.1 or 0.2 mg T4 daily for at least 2 mo before study. Hormone measurements were made for 5 consecutive days before and daily during a 7-day treatment period with PTU, 1,000 mg/day. In eight patients receiving 0.1 mg T4 daily, administration of PTU resulted in a prompt fall in mean serum T3 concentrations from 78 plus or minus 6 ng/100 ml (SEM) to 61 plus or minus 3 ng/100 ml after 1 day. The mean serum T3 concentrations ranged from 55 to 60 ng/100 ml during the remainder of the PTU treatment period (P less than 0.01). The mean control serum TSH concentration was 29.6 muU/ml and it increased to a peak of 40 muU/ml on the 5th and 6th days. In five patients receiving 0.2 mg T4 daily, the mean control serum T3 concentration was 84 plus or minus 7 NG/100ML. It fell to 70 plus or minus 5 ng/100 ml after 1 day and 63 plus or minus 7 ng/100 ml after 2 days of PTU administration and thereafter ranged from 6) to 69 ng/100 ml (P LESS THAN 0.01). Serum TSH concentrations did not increase. No changes in serum T4 concentrations were found in either group. In five patients who received 100 mg methimazole (MMI) daily for 7 days there were no changes in serum T4, T3, or TSH concentrations. These results indicate that PTU, but not MMI, produces a prompt and sustained, albeit modest, reduction in serum T3 concentrations in patients whose sole or major source of T3 is ingested T4. These findings most likely result from inhibition of extrathyroidal formation of T3 from T4.     

Clinical Pharmacology of Ticarcillin (α-Carboxyl-3-Thienylmethyl Penicillin, BRL-2288)

Clinical pharmacological studies of ticarcillin (alpha-carboxyl-3-thienylmethyl penicillin, BRL-2288) were conducted in patients with metastatic cancer and leukemia.After administration of 0.5 g intramuscularly, 1 g intramuscularly, and 1 g intravenously, the mean peak concentrations in serum were 18, 35, and 106 mug/ml, respectively. Greater than 80% of ticarcillin was excreted in the urine during the subsequent 6-h period. The mean concentrations in the serum of patients 15 min after they received an intravenous injection of 4 g of ticarcillin with and without probenecid were 508 and 519 mug/ml, respectively. Serum levels were determined in patients who received ticarcillin for therapy of infection in doses of 5 g every 6 h. The mean drug concentration in serum 15 min after the rapid administration of the first dose was 433 mug/ml. Subsequent doses were given during a 2-h infusion and the study was repeated 2 days later. The average initial serum level (4 h after the completion of the preceding dose) was 19 mug/ml, and the mean serum level at 15 min was 213 mug/ml. Drug concentrations in the serum of patients receiving ticarcillin by infusion in doses of 3.5 g every 4 h were also determined. In patients with normal renal function, the average initial serum level (2 h after completion of the preceding dose) was 49 mug/ml and the mean level at 15 min was 210 mug/ml. Drug concentrations in the serum of patients with impaired renal function were considerably higher. No detectable levels of ticarcillin were found in the cerebrospinal fluid.     

Effect of the exercise of seven consecutive days hill-walking on fluid homeostasis.

1. The effect of 7 consecutive days of strenuous exercise, hill-walking, on water balance and distribution was studied in five subjects. The exercise was preceded and followed by 3 control days. The diet was fixed throughout but water was allowed ad libitum. 2. Packed cell volume was measured daily. Serum electrolytes and arginine vasopressin were measured twice daily. Daily water, sodium and potassium balances were calculated. 3. During exercise there was a fall in packed cell volume, reaching a maximum of 11% by day 5 and a retention of sodium reaching a cumulative maximum of 358 mmol by day 6. During and immediately after exercise there was a retention of potassium, reaching a total of 120 mmol by day 3 after stopping exercise. 4. There was a loss of 650 ml of water on day 1 of exercise, followed by a modest retention reaching a cumulative maximum of 650 ml on day 5 of exercise. 5. Neither arginine vasopressin nor serum electrolyte concentrations were affected by exercise. 6. From the packed cell volume, sodium and water balances it was calculated that by day 5 of exercise there was an increase in plasma volume of .068 litre (22%), an increase in interstitial fluid volume of 2.0 litres (17%) and a decrease in intracellular fluid volume of 1.8 litres (8%). 7. These changes, together with the clinical observation of facial and ankle oedema during the experiemnt, suggest that continuous exercise may cause oedema and thus may be a factor in the aetiology of high-altitude oedema.     

Effect of physical exercise on the digoxin concentrations in skeletal muscle and serum in man

Summary. Seven healthy men performed an exercise on a bicycle ergometer during one hour after 2 weeks intake of digoxin and with the last dose taken 24 hours before the exercise. Blood samples and skeletal muscle biopsies (m. quadriceps femoris, vastus lateralis) were taken before and after the exercise for analysis of serum and skeletal muscle digoxin concentrations. A percutaneous needle biopsy technique was used for muscle sampling and digoxin was analysed by radioimmunoassay. One minute after completion of the exercise a significantly higher digoxin concentration was found in the thigh muscle than before exercise, indicating an increased digoxin binding in this muscle. Serum digoxin concentration decreased significantly during exercise. After exercise serum digoxin concentration increased again but was still, 30 min after exercise, significantly lower than before exercise.     

Multiple-dose pharmacokinetics of cefprozil and its impact on intestinal flora of volunteers.

The pharmacokinetics of cefprozil were determined with 12 volunteers (8 received cefprozil and 4 received a placebo) after oral administration of 500 mg every 12 h over an 8-day period in a randomized, double-blind, placebo-controlled design. Concentrations in serum and urine were measured by high-pressure liquid chromatography and bioassay. The pharmacokinetic parameters were calculated on the basis of an open one-compartment model. The mean maximum concentration in serum on day 1 was 11.5 +/- 2.6 mg/liter, and the time to reach maximum concentration was 122.3 +/- 30 min after administration. Bioavailability parameters (area under the concentration-time curve from zero to infinity, maximum concentration of the drug in serum, and urinary recovery) indicated an excellent absorption. No accumulation over the 8-day period was registered. Cefprozil had a short biological elimination half-life of 58 +/- 10 min and a renal clearance of 210 +/- 51 ml/min, indicating high rates of renal excretion and tubular secretion. Analysis of the fecal flora showed an ecological impact of cefprozil on the intestinal microflora, such as a moderate decrease in enterobacteria and a slight increase in enterococci, staphylococci, and bacteroides during the study. The number of all bacterial species was already normalized 4 days after the administration period. The tolerance of cefprozil proved to be excellent; only a slight and reversible increase of liver enzymes (in two volunteers), mild cephalalgia, tiredness, and soft stool were registered during the 8-day period. Cefprozil had excellent absorption, no accumulation over an 8-day period, and only a limited impact on the intestinal microflora.     

Continuous infusion versus intermittent administration of ceftazidime in critically ill patients with suspected gram-negative infections.

The pharmacodynamics and pharmacokinetics of ceftazidime administered by continuous infusion and intermittent bolus over a 4-day period were compared. We conducted a prospective, randomized, crossover study of 12 critically ill patients with suspected gram-negative infections. The patients were randomized to receive ceftazidime either as a 2-g intravenous (i.v.) loading dose followed by a 3-g continuous infusion (CI) over 24 h or as 2 g i.v. every 8 h (q8h), each for 2 days. After 2 days, the patients were crossed over and received the opposite regimen. Each regimen also included tobramycin (4 to 7 mg/kg of body weight, given i.v. q24h). Eighteen blood samples were drawn on study days 2 and 4 to evaluate the pharmacokinetics of ceftazidime and its pharmacodynamics against a clinical isolate of Pseudomonas aeruginosa (R288). The patient demographics (means +/- standard deviations) were as follows: age, 57 +/- 12 years; sex, nine males and three females; APACHE II score, 15 +/- 3; diagnosis, 9 of 12 patients with pneumonia. The mean pharmacokinetic parameters for ceftazidime given as an intermittent bolus (IB) (means +/- standard deviations) were as follows: maximum concentration of drug in serum, 124.4 +/- 52.6 micrograms/ml; minimum concentration in serum, 25.0 +/- 17.5 micrograms/ml; elimination constant, 0.268 +/- 0.205 h-1; half-life, 3.48 +/- 1.61 h; and volume of distribution, 18.9 +/- 9.0 liters. The steady-state ceftazidime concentration for CI was 29.7 +/- 17.4 micrograms/ml, which was not significantly different from the targeted concentrations. The range of mean steady-state ceftazidime concentrations for the 12 patients was 10.6 to 62.4 micrograms/ml. Tobramycin peak concentrations ranged between 7 and 20 micrograms/ml. As expected, the area under the curve for the 2-g q8h regimen was larger than that for CI (P = 0.003). For IB and CI, the times that the serum drug concentration was greater than the MIC were 92 and 100%, respectively, for each regimen against the P. aeruginosa clinical isolate. The 24-h bactericidal titers in serum, at which the tobramycin concentrations were < 1.0 microgram/ml in all patients, were the same for CI and IB (1:4). In the presence of tobramycin, the area under the bactericidal titer-time curve (AUBC) was significantly greater for IB than CI (P = 0.001). After tobramycin was removed from the serum, no significant difference existed between the AUBCs for CI and IB. We conclude that CI of ceftazidime utilizing one-half the IB daily dose was equivalent to the IB treatment as judged by pharmacodynamic analysis of critically ill patients with suspected gram-negative infections. No evaluation comparing the clinical efficacies of these two dosage regimens was performed.     

Exercise‐associated hyponatraemia on the Kokoda Trail

Objective: The objective of the present study was to determine the prevalence of exercise‐associated hyponatraemia in hikers/trekkers along the Kokoda Trail. Methods: This was a cross‐sectional study of 191 trekkers on the Kokoda Trail, Papua New Guinea. Blood was taken and analysed immediately using point‐of‐care technology 2 days walk from each end of the Trail. Results: The main outcome measure was hyponatraemia defined as serum sodium level less than 135 mmol/L. Three participants (1.6%, 95% CI 0.5–4.5%) were found to have mild hyponatraemia. The hyponatraemic group had a median estimated fluid intake on the day of testing that was almost double that of the normal sodium group (6 L vs 3.3 L). Conclusion: Exercise‐associated hyponatraemia occurs in trekkers on the Kokoda Trail. Strategies for prevention of exercise‐associated hyponatraemia should be delivered to trekkers via the trekking companies, chiefly focussing on only drinking in response to thirst.     

Multiple-dose pharmacokinetics of ceftazidime and its influence on fecal flora.

Eight healthy volunteers each received 2.0 g of ceftazidime by constant intravenous infusion over 20 min twice daily every 12 h for 8 days. Concentrations of ceftazidime in serum and urine were measured by a microbiological assay and by high-pressure liquid chromatography. Qualitative and quantitative studies on aerobic and anaerobic fecal flora were carried out before, during, and 2 weeks after the end of treatment. The mean (+/- standard deviation) maximum drug concentration in serum at the end of the 20-min infusion (day 1) was 185.5 +/- 28.5 micrograms/ml, decreasing to 0.8 +/- 0.4 microgram/ml after 12 h. The mean recovery of drug in urine at 12 h was 71.5 +/- 12.2%. Pharmacokinetic parameters calculated on the basis of a two-compartment model were as follows: elimination half-life, 110.5 +/- 15.2 min; volume of distribution at steady state, 21.2 +/- 2.6 liters/100 kg; volume of distribution by the area method, 26.2 +/- 4.0 liters/100 kg; area under the serum concentration-time curve, 293.3 +/- 47.8 micrograms X h/ml; total body clearance, 116.4 +/- 20.3 ml/min per 70 kg; renal clearance, 82.2 +/- 15.1 ml/min per 70 kg. The agar diffusion test and high-pressure liquid chromatographic analysis showed a good correlation of results. Metabolites of ceftazidime could not be detected by high-pressure liquid chromatography in serum or urine. No accumulation of ceftazidime could be observed during the 8-day study period. Mean maximum drug levels in serum were 185.5 to 214.5 micrograms/ml, and mean trough levels were 0.8 to 1.1 micrograms/ml (days 1 to 8). No severe side effects were noted. During ceftazidime treatment, anaerobes were left intact, whereas members of the family Enterobacteriaceae could be isolated from stool in only three of eight subjects. Two weeks after discontinuation of the drug, all stool specimens contained ampicillin- and cefazolin-resistant gram-negative rods.     

Micropuncture studies of proximal tubule albumin concentrations in normal and nephrotic rats

The concentration of serum albumin in proximal tubule fluid of normal rats and animals with aminonucleoside nephrosis was studied using renal micropuncture techniques. Albumin was quantitated by an ultramicrodisc electrophoresis method capable of measuring 3 chi 10(-11) g of albumin, in 10 nl volumes. With this sensitivity, only small samples of tubule fluid were required for analysis. Collection times could be kept short, therefore decreasing the opportunity for sample contamination with extraneous serum albumin. The measured mean concentration of albumin in proximal tubule fluid (1 mg/100 ml in females and 0.7 mg/100 ml in males) was somewhat lower than values reported by others, but even these values are apt to have been artifactually high as a result of animal preparation and trace contamination of samples during micropuncture. Rats injected with aminonucleoside of puromycin 4 days earlier, showed a significant increase in tubule-fluid albumin concentration coincident with a fall in serum albumin concentration and a 43-fold increase in urine albumin concentration. Tubular absorption of albumin was small relative to that of water. Although albumin filtration was significantly increased over that in normal animals, the glomerular basement membrane still served as a highly efficient barrier to albumin transfer.     

Intrapulmonary pharmacokinetics of azithromycin in healthy volunteers given five oral doses.

The intrapulmonary pharmacokinetics of oral azithromycin were studied in 25 healthy volunteers, each of whom received an initial dose of 500 mg and then 250 mg once daily for four additional doses. Bronchoscopy, bronchoalveolar lavage, and venipuncture were performed 4, 28, 76, 124, 172, 244, 340, and 508 h after the first dose was administered. Azithromycin concentrations in epithelial lining fluid (ELF), alveolar macrophages, peripheral blood monocytes, and serum were measured by high-performance liquid chromatography. Azithromycin was extensively concentrated in cells and ELF. Drug concentrations in AMs (peak mean +/- standard deviation, 464 +/- 65 micrograms/ml) exceeded 80 micrograms/ml up to 508 h (21 days) following the first dose, while concentrations in PBMs (peak, 124 +/- 28 micrograms/ml) exceeded 20 micrograms/ml up to 340 h (14 days). Azithromycin concentrations in ELF peaked at 124 h (3.12 +/- 0.93 micrograms/ml) and were detectable up to 172 h (7 days), when they were 20 times the concurrent serum concentrations. Although the clinical significance of antibiotic concentrations in these compartments is nuclear, the sustained lung tissue penetration and extensive phagocytic accumulation demonstrated in this study support the proven efficacy of azithromycin administered on a 5-day dosage schedule in the treatment of extracellular or intracellular pulmonary infections.     

A quantitative assessment of phencyclidine dependence produced by oral self-administration in rhesus monkeys

Three rhesus monkeys were trained to self-administer orally delivered phencyclidine (PCP) and water under concurrent fixed-ratio schedules. Liquid deliveries were contingent upon lip-contact responses on solenoid-operated drinking spouts. PCP deliveries exceeded water deliveries throughout the experiment, indicating that the drug was functioning as a positive reinforcer. The monkeys were also trained to lever press under a fixed-ratio 64 or fixed-ratio 80 schedule of food delivery. Food was available during three 1 hr periods each day, with 6.5 hr of liquid availability between each food component. After behavior stabilized for at least 10 days under these conditions, water was substituted for PCP for 2, 4, 8 or 24 days. Food-maintained responding was severely disrupted for the first 2 days of water substitution, with a steady recovery over the following 6 days. The monkeys were noticeably irritable during water substitution, but there were no other physical signs of PCP withdrawal. Disruptions in food-maintained responding were immediately reversed when PCP was reinstated. Subsequently, the PCP concentration was varied (0.062, 0.125, 0.25, 0.5 and 1 mg/ml), and PCP intake (milligrams per kilogram), as well as the magnitude of disruptions in pellet deliveries (upon termination of PCP access), also varied directly with PCP intake. The amount of PCP intake was also altered by limiting PCP (0.25 mg/ml) access to every 2nd or 4th day, with water available on intervening days. Pellet deliveries were substantially disrupted during water substitution, and food-maintained responding immediately returned to control levels when PCP became available.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of ceftazidime and cefamandole pharmacokinetics and blister fluid concentrations.

Eight healthy male volunteers received 1 g of either ceftazidime or cefamandole as an intravenous infection. Serial blood samples were taken over the next 8 h. Urine samples were collected over 24 h. Levels of these antibiotics were measured in the fluid of blisters resulting from application of cantharides. The concentration of ceftazidime in serum at 0.25 h after intravenous injection was 83.3 micrograms/ml. The serum half-lives for the respective drugs were 1.8 and 0.8 h. The mean apparent volume of distribution of ceftazidime (13.6 liters) was greater than that of cefamandole (9.8 liters). Plasma clearance was 111 ml/min for ceftazidime and 216 ml/min for cefamandole. The maximum blister fluid concentration of ceftazidime was 45.9 micrograms/ml, and that of cefamandole was 22.1 micrograms/ml. The relative availability of each drug in blister fluid compared with serum was similar.     

Amino acid administration in acute, compensated renal failure in the post-traumatic phase

Three patient groups compensated acute renal failure and previous surgery were evaluated, who had been nourished isocaloric (1700 kcal) and practically isonitrogen (33-35 g amino acid), but of various mixtures of amino acids. Besides the uniform daily energy intake of 750 ml of 40% invert sugar and 250 ml of 20% Lipofundin, the daily amino acid infusion of group I (n = 13) was only 500 ml EAS pfrimmer (34.5 g), of group II (n = 10) 250 ml EAS pfrimmer and 250 ml of 7.5% Intrafusin, and of group III (n = 16) 250 ml EAS pfrimmer and 350 ml Aminofusin Hepar (33.1 g). During evaluation of the aminograms, low initial values under the bottom reference region of glycine, serine, arginine and histidine in serum were recorded at the start of the trial in all 3 patient groups. During the course of the 4-day infusion therapy, the serum values of patients in groups II and III appeared to improve more than those in group I. Contrarily, the serum levels of phenylalanine, methionine and 3-methyl histidine were 2-3 times higher than the reference region at the start of the trial. With regard to a decrease in the high serum levels, patient group II appeared to be superior to groups I and III. No significant differences were observed during the clinical course.     

Pharmacokinetics of cefoperazone in patients with neoplastic disease.

The pharmacokinetics of cefoperazone, a new semisynthetic cephalosporin, were studied in 34 patients with neoplastic disease. This compound was administered in a variety of doses and schedules without observable toxicity in any patient. The mean peak serum concentration after a 15-min intravenous infusion of 2 g was 264 microgram/ml after the first dose; the serum half-life was 2.1 h. There was no significant change in half-life or serum concentrations after 4 or 7 days of therapy. The mean peak serum concentration after infusion of 1 g over 15 min was 133 microgram/ml, with a mean of 10.7 microgram/ml at 6 h. The serum half-life was 2 h. The mean peak serum concentration after infusion of 1 g over 0.5 h was 101 microgram/ml. When 8 g was subsequently administered daily by a continuous infusion schedule, levels were maintained at 80 microgram/ml. When the dose was increased to 16 g daily, serum concentrations were maintained at an average of 153 microgram/ml. Only 37% of cefoperazone was recovered in the urine in a 12-h period after the initial dose, suggesting the importance of other mechanisms of excretion; however, serum concentrations in one patient with renal insufficiency were significantly higher than serum concentrations in patients with normal renal function.     

Pharmacokinetics of once-daily darunavir-ritonavir and atazanavir-ritonavir over 72 hours following drug cessation

The object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavir-ritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavir-ritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0- to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0- to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC(50)] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the protein-binding-corrected IC(50) for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations.     

Bioequivalence assessment of zidovudine (Retrovir) syrup, solution, and capsule formulations in patients infected with human immunodeficiency virus.

The objectives of this open-labeled, multiple-dose, three-way-crossover trial were to evaluate the safety and tolerance of zidovudine (Retrovir) oral syrup and to assess the bioequivalence of this formulation relative to zidovudine solution and capsule formulations in human immunodeficiency virus-infected patients. Over the 7-day study, 12 adult male subjects received 12 administrations each of the capsule, solution, and syrup formulations every 4 h (six times daily) in a randomized sequence. Frequent blood samples were collected over the 4-h period after dose 12 was administered. Zidovudine concentrations in plasma were determined by a specific and sensitive radioimmunoassay. Results from statistical analyses indicated that all three formulations were bioequivalent with respect to systemic availability (area under the time-concentration curve) and that the syrup was also equivalent to the solution with respect to the maximum peak concentration in serum. The lower relative maximum peak concentration in serum (approximately 81%) and small delays in time to peak concentration (less than 30 min) of the capsule formulation as compared with the liquid formulations are thought to be due to the additional processes of disintegration and dissolution associated with capsule administration. All three preparations were well tolerated during the 7-day study.     

Control of Thyroid Hormone Secretion in Normal Subjects Receiving Iodides

The administration of exogenous iodides (saturated solution of potassium iodide, SSKI) to normal male volunteers resulted in a significant decrease in the serum concentration of thyroxine (T₄) and triiodothyronine (T₃) and a significant increase in serum concentration of thyrotropin (TSH). During the control period (phase I), serum concentrations of T₄ averaged 6.9±1.8 μg/100 ml (mean ±SD), T₃ 106±15 ng/100 ml, and TSH 3.7±1.3 μU/ml. During the administration of 1 drop of SSKI twice daily for 11 days (phase II), there was a small but significant decrease in the serum concentration of T₄ and T₃ (5.8±1.6 μg/100 ml and 91±19 ng/100 ml, respectively) and a small but significant increase in the serum concentration of TSH (6.0±3.5 μU/ml). During the administration of 5 drops of SSKI twice daily (phase III) over the following 12-19 days, these changes persisted, except for a small increase in the serum concentration of T₃ (97±20 ng/100 ml), which was statistically significant when compared to values obtained during phase II. Values returned to control levels 14 days after withdrawal of SSKI. Almost all these observed changes took place within the limits of the normal range. It is postulated that, in euthyroid individuals, iodides specifically inhibit release of T₄ and probably of T₃. The resulting slight decrease in values for serum T₄ and T₃ elicits a small increase in TSH secretion which, it is postulated, antagonizes the inhibition of hormone release induced by iodides. As a result, a new equilibrium is reached which maintains the euthyroid state.