Effect of two different combinations of antiretrovirals (AZT+ddI and AZT+3TC) on cytokine production and apoptosis in asymptomatic HIV infection.

Nineteen HIV-seropositive antiretroviral therapy-naive and asymptomatic individuals (200-500 CD4/microl) were enrolled in a prospective study aimed at analyzing the immunologic and virologic effects of two different combinations of nucleoside reverse transcriptase inhibitors (AZT+ddI and AZT+3TC), and randomly assigned to one of the treatment group. Immunologic (CD4 and CD8 counts, mitogen-stimulated cytokine production, unstimulated and mitogen-stimulated apoptosis) and virologic (HIV viral load) determinations were performed pre-therapy and 15, 30, 90, 200 and 360 days after initiation of therapy. Results showed that the two combinations had comparable effects on increasing CD4 counts and the CD4/CD8 ratio and in reducing HIV viral load. In contrast, AZT+3TC was more efficient in improving interleukin-2 (IL-2) and interferon gamma (IFNgamma) production as well as the type 1/type 2 cytokine ratio and in down modulating the susceptibility of peripheral blood mononuclear cells to in vitro mitogen-stimulated apoptotic cell death. These data suggest that the combination of AZT+3TC has a stronger effect on potentially beneficial immune parameters (IL-2 production; reduction of apoptosis) than the one between AZT+ddI. The combination of AZT+3TC could be more advantageous in the therapy of HIV infection even when used in association with a protease inhibitor.

Estimating the value of a generic quality-of-life measure.

In this paper, data from a clinical trial of a new antiviral agent for treating patients with zoster are used to answer the following question: Does the Nottingham Health Profile (NHP) add to the information obtained from the clinical measures? Three ways in which the NHP could add information are measured. First, Cox's regression analysis is used to determine whether health-related quality-of-life scores obtained at diagnosis give information about disease prognosis. Second, changes in mean NHP scores in different dimensions are computed after pain resolution to determine whether NHP scores provide more sensitive indicators of disease resolution. Third, linear regression is used to determine whether the impacts of disease on quality of life are measured adequately by the clinical parameters. These analyses show that use of the physical mobility and energy dimensions of the NHP increases understanding of disease prognosis; demonstrates the continuing impact of zoster on patients' sleep patterns and energy levels, disease symptoms not included as clinical measures, that persist after the cessation of zoster-associated pain; and gives a measure of the impact of zoster on the patient, which includes unmeasured and measured levels of severity.

Increased gentamicin nephrotoxicity in normal and diseased dogs administered identical serum drug concentration profiles: increased sensitivity in subclinical renal dysfunction.

Attempts to avoid gentamicin-induced nephrotoxicity in the presence of renal dysfunction assume that the nephrotoxicity threshold is unchanged from that of the normal patient. The purpose of the present study was to compare the response of the subclinically diseased kidney to the normal kidney when exposed to identical serum concentrations of gentamicin. This study used exponentially declining infusions based on preinfusion pharmacokinetics to achieve identical serum gentamicin concentration profiles in intact (intact-gentamicin) and subtotally nephrectomized (nephrectomized-gentamicin) beagle dogs. After 10 daily 12-hr infusions, relative nephrotoxicity was compared using serum chemistries and histopathologic analysis in intact- and nephrectomized-control (untreated) dogs. For intact-gentamicin and nephrectomized-gentamicin dogs, respectively, infusion steady-state serum concentrations were 5.3 +/- 0.3 vs. 5.5 +/- 0.5 (microgram/ml) and elimination rates were 0.19 +/- 0.02 vs. 0.20 +/- 0.01(hr-1) (mean +/- S.E.M.). Postinfusion histopath scoring of renal lesions (0-30, with 30 being most severe) were 11 +/- 5 (nephrectomized-gentamicin), 4 +/- 2 (nephrectomized-control), 2 +/- 2 (intact-gentamicin) and 0 +/- 0 (intact-control). Gentamicin-induced renal dysfunction in nephrectomized dogs was characterized further by administering nonindividualized multiple dosage regimens. Toxicity in the subclinical disease state was marked by oliguria and acute renal failure in contrast to the mild polyuria seen in intact animals. These findings support increased sensitivity to gentamicin nephrotoxicity in dogs with mild renal dysfunction secondary to subtotal surgical nephrectomy.

The isolated perfused porcine skin flap (IPPSF). I. A novel in vitro model for percutaneous absorption and cutaneous toxicology studies.

This article describes the development of a novel in vitro alternative animal model for dermatology and cutaneous toxicology. A single-pedicle, axial-pattern, island-tubed skin flap was created in crossbred Yorkshire weanling pigs in one surgical procedure, then transferred 2 or 6 days later to a computer-controlled temperature-regulated perfusion chamber for 10-to 12-hr studies. Perfusate consisted of Krebs-Ringer bicarbonate buffer (pH 7.4) containing albumin and glucose. Viability was assessed by glucose utilization, lactate production, an absence of significant concentrations of the intracellular enzyme lactate dehydrogenase in the perfusate, and light and electron microscopy. A mean lactate to glucose ratio of 1.6 for flaps harvested 2 days after surgery and 1.8 for flaps taken 6 days after surgery suggested primarily anaerobic glycolysis. This preparation would be a humane alternative animal model for studies in cutaneous toxicology, physiology, oncology, and percutaneous drug absorption and metabolism.

Influence of thyroid function on the pharmacokinetics of gentamicin in pigs.

Hypothyroidism or hyperthyroidism was induced in 10 pigs (5 pigs/group) and each pig was administered gentamicin (6 mg/kg of body weight, IV). Low thyroxine and triiodothyronine resulted in a decrease in creatinine clearance (P = 0.04), an increase in serum creatinine concentration (P = 0.003), and a decrease in gentamicin systemic clearance (P = 0.002), compared with findings in control pigs (n = 5). These effects probably were secondary to a decreased glomerular filtration rate associated with hypothyroidism. A strong correlation among the 3 treatment groups was found between gentamicin systemic clearance and creatinine clearance (r = 0.72; P = 0.004) and between gentamicin systemic clearance and serum creatinine concentration (r = -0.77; P = 0.0007). Hyperthyroidism induced a slight but significant decrease in protein binding (P = 0.002). However, the significant changes in the hypothyroid pigs and the hyperthyroid pigs were not of a magnitude sufficient to alter gentamicin elimination half-life. Gentamicin disposition was best described, with a 4-compartment open model.

Identification of a subgroup of Sprague-Dawley rats highly sensitive to drug-induced renal toxicity.

Laboratory rats available from breeding facilities are usually assumed to be homogeneous populations within each strain; however, previous studies in our laboratory suggested that there may be a subgroup of Sprague-Dawley rats which are highly sensitive to aminoglycoside nephrotoxicity. The present study clearly identifies a subpopulation of Sprague-Dawley rats which was highly sensitive to nephrotoxicity from supratherapeutic doses (75 mg kg-1 day-1) of the aminoglycoside antibiotic gentamicin. Gentamicin was administered subcutaneously in a divided regimen, 25 mg/kg every 8 hr, for 7 days. Statistical analysis of post-treatment serum creatinine (SCR) and urea nitrogen (SUN) concentrations demonstrated two distinct populations: normally responding rats (SCR = 1.92 +/- 0.54 mg/dl, SUN = 71.5 +/- 18.4 mg/dl, N = 87) and highly sensitive rats (SCR = 4.10 +/- 0.83 mg/dl, SUN = 146.4 +/- 24.9 mg/dl, N = 12) (mean +/- SD). Comparison of predosing blood and serum chemistries between these two populations revealed statistical differences only in initial serum osmolality, oxygen tension, and total protein. Since there is a subpopulation of humans which are at risk for developing aminoglycoside nephrotoxicity due to unknown host factors, these highly sensitive Sprague-Dawley rats may provide an animal model for investigating this human clinical problem.

Prediction of pharmacokinetic profiles of ampicillin sodium, gentamicin sulfate, and combination ampicillin sodium-gentamicin sulfate in serum and synovia of healthy horses.

Pharmacokinetics of ampicillin sodium (11 mg/kg), gentamicin sulfate (2.2 mg/kg), and combination ampicillin sodium-gentamicin sulfate were determined for serum and synovia of healthy horses given single-dose IV injection and were not found to be different from those from other reports; however, a prolonged terminal gamma-phase for gentamicin (8,498 +/- 1,842 minutes) in serum of horses was found to exist. Pharmacokinetic interaction between combination ampicillin sodium-gentamicin sulfate was not observed int he serum or synovia. Prediction of ampicillin sodium or gentamicin sulfate concentrations in synovia, based on serum-based pharmacokinetics, cannot be accomplished solely upon analysis of peripheral-compartment pharmacokinetics. However, once equilibrium is achieved between synovia and extracellular fluid in the peripheral compartment, the decrease in drug concentrations in synovia parallels that in serum. Therefore, after 6 hours, synovial concentrations of gentamicin sulfate can be predicted based on peripheral-compartment pharmacokinetics, using an appropriate correction factor. The significance of these findings need to be correlated with clinical conditions so that a pharmacostatistical model for the prediction of synovial concentrations of drug(s) during treatment of horses with septic arthritis can be developed.

Exponential intravenous infusions in toxicological studies: achieving identical serum drug concentration profiles in individuals with altered pharmacokinetic states.

It is common practice in the clinical setting to adjust the dosage of a drug administered to a patient with altered pharmacokinetic characteristics, e.g., renal impairment, in such a way that the steady-state level of the drug is the same as that which would be observed in normal patients. This may also be done in experimental studies of the interaction of drug toxicity and a disease state. Dosage adjustment does alter average steady-state serum concentrations but the resulting concentration-time profiles of the normal and the diseased groups will be of entirely different shapes due to differences in elimination. In a toxicological study, this would lead to a confounding of the disease state and the difference in exposure. In this paper, model-independent deconvolution analysis is applied to derive the infusion schedule needed to achieve a constant serum concentration followed by a predetermined monoexponential decline in concentration. The resulting exponential infusion is applied to attain identical serum gentamicin concentration-time profiles in five pairs of subtotally nephrectomized and normal dogs during a 12-h infusion.

Exaggerated response to gentamicin-induced nephrotoxicity in Sprague-Dawley rats: identification of a highly sensitive outlier population.

A number of factors have been shown to predispose patients treated with aminoglycosides to nephrotoxicity. In a previous study in our laboratory investigating the interaction of prior renal dysfunction with gentamicin toxicokinetics, 9.4% of rats in all treatment groups were relatively more sensitive to gentamicin-induced nephrotoxicity. To determine if these outliers had an underlying disease or physiological abnormality, serum was collected from 99 Sprague-Dawley rats prior to daily treatment with 75 mg/kg gentamicin for seven days. Urea nitrogen, creatinine, Na, K, Ca, Mg, P, total protein, albumin, aspartate transaminase, serum osmolality, total white and red blood cell count, hematocrit, hemoglobin, blood gases, and thyroxine were measured. Blood was collected one and four hours after the first dose of gentamicin for pharmacokinetic analysis. Elevations in post-treatment creatinine and nitrogen were significantly greater in the outliers (4.10 +/- 0.24 mg/dl (n = 12) vs 1.92 +/- 0.06 mg/dl (n = 87) and 146.4 +/- 7.2 mg/dl (n = 12) vs 71.5 +/- 2.0 mg/dl (n = 87); both p = 0.0001) and served as criteria for identifying this subgroup. Post-treatment creatinine and urea nitrogen were not normally distributed in the entire study population. However, when the population was divided into normal and sensitive subgroups, both subgroup values were normally distributed. The gentamicin pharmacokinetic profiles were similar in both groups. Postmortem histopathology showed significant increases in tubular casts and tubular necrosis (p = 0.01) in the sensitive rats, compared to the normally responding subgroup.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of digoxin in sheep: limitations of the use of biological half-life for interspecies extrapolation.

After of single IV digoxin injection of 50 micrograms/kg of body weight, the serum digoxin concentrations of 4 sheep were fitted to a 2-compartment open model. The mean value for the elimination half-life was 7.15 hours; for area volume of distribution, 13.8 L/kg; and for total body clearance, 1.36 L/kg/hr. A comparison of this study with previous studies in sheep and cattle revealed that serious misconceptions could arise if one chose to rely upon elimination half-life as the sole descriptor of drug disposition. A more informative characterization was determined to be total body clearance and area volume of distribution.