Disposition and metabolism of [¹4C]PTZ601 in healthy volunteers.

1. Six healthy male subjects were given a single dose of 500 mg of [14C]PTZ601 (mean radioactivity 79.2 µCi) by intravenous (IV) infusion over 1 h, and observed for 5 days post-dose during which pharmacokinetic (PK) samples were collected. Plasma PTZ601 concentrations and metabolite identification were determined using LC-MS/MS; PK parameters were estimated by non-compartmental analysis. Excretion and mass balance were determined with liquid scintillation analysis and metabolites profiling was characterized by HPLC online radiochemical detection. 2. The disposition of PTZ601 was best described by a fast absorption, followed by a biphasic elimination phase. Peak PTZ601 plasma concentrations were reached within 0.5-1 h. The mean elimination half-life was 1.6 h and clearance was 13 L/h. 3. Recovery of the radioactivity dose was complete (mean 92%). The main route of excretion (parent and metabolites) was the renal route, as urine accounted for 69-77%, while feces only 13-22%, of the total radioactivity. 4. The majority of the drug was excreted in urine as multiple open ring metabolites: M17.3 (oxidative ring-opened product) and M22.2 (di-cysteine conjugate of 17.3); unchanged PTZ601 in urine contributed to 15% of radioactivity. The major metabolites detected in plasma were M17.3, M12.8 (acetylated M17.3), M22.2, and M41.4 (methylated M17.3). 5. PTZ601 was well tolerated.

Evaluating Native Bee Communities and Nutrition in Managed Grasslands.

Native pollinators are important for providing vital services in agroecosystems; however, their numbers are declining globally. Bees are the most efficient and diverse members of the pollinator community; therefore, it is imperative that management strategies be implemented that positively affect bee community composition and health. Here, we test responses of the bee and flowering plant communities to land management treatments in the context of grasslands in the upper Midwestern United States, a critical area with respect to bee declines. Twelve sites were selected to examine floral resources and wild bee communities based on three different types of grasslands: tallgrass prairie remnants, ungrazed restorations, and grazed restorations. Total bee abundance was significantly higher in ungrazed restorations than remnants, but there were no significant differences among grasslands in community composition or Shannon diversity. Across the three grassland types we also examined mass and lipid stores as nutritional health indicators in three sweat bees (Halictidae), Augochlora pura, Agapostemon virescens, and Halictus ligatus. Although there were no differences in lipid content, total average bee mass was significantly higher in Ag. virescens collected from ungrazed restorations as compared to remnants. Floral abundance of native and non-native species combined was significantly higher in grazed restorations compared to remnants and ungrazed restorations. However, ungrazed restorations had higher abundance and richness of native flowering ramets. These data suggest that bee abundance and nutrition are driven by high abundance of native flowering plant species, rather than total flowering plants.

Establishment of dorsal-ventral and terminal pattern in the Drosophila embryo.

Dorsal-ventral and terminal pattern formation in the Drosophila embryo is mediated via inductive signals originating during oogenesis from the somatic follicle cells that ensheath the developing oocyte. This somatically expressed spatial information controls dorsal-ventral development by defining the polarity of a signal transduction pathway that results in the graded nuclear concentration of the dorsal gene product, a transcription factor.

Hepatomegaly with severe steatosis in HIV-seropositive patients.

OBJECTIVE: To describe death attributed to severe hepatomegaly and macrovesicular steatosis without inflammation or necrosis in HIV-seropositive patients without AIDS. PATIENTS: Patients from the AIDS Clinical Trials Group (ACTG) Adverse Reactions and the Food and Drug Administration's (FDA) Spontaneous Report databases. RESULTS: Six fatal and two non-fatal cases in which no known cause of hepatic steatosis could be found were identified. With one possible exception, none of the six fatal cases had a diagnosis of AIDS and all were in reasonable nutritional status (as indicated by weight and/or serum albumin); the majority were mildly to moderately overweight. All had received at least 6 months of antiretroviral therapy, and all had gastrointestinal complaints without other non-hepatic abdominal pathology. At least three out of the six had no history of progressively abnormal liver function tests until a few weeks prior to the onset of symptoms and subsequent death. Further investigation of the FDA and ACTG databases identified two similar but non-fatal cases in which abnormalities resolved after cessation of antiretroviral therapy. CONCLUSIONS: The cases described represent a degree of hepatic abnormalities that has not been reported previously in HIV-seropositive patients, and are probably an underestimate of actual incidence, since patients with possible etiologies of liver disease were excluded from the clinical history, laboratory, microbiologic, or histologic examination. The etiology of hepatic disease may be associated with antiretroviral therapy, HIV, or an unidentifiable infection, and requires further investigation.

Correlates of zidovudine phosphorylation with markers of HIV disease progression and drug toxicity.

OBJECTIVE: To determine the relationships between in vivo zidovudine (ZDV) phosphorylation in cells from HIV-infected patients and markers associated with disease progression and drug toxicity. DESIGN: A pharmacokinetic study of ZDV metabolism sponsored by the AIDS Clinical Trials Group (protocol 161). Plasma and intracellular pharmacokinetics following a 100 mg oral dose of ZDV were determined at weeks 4 and 24 of initial therapy in adult patients. Plasma concentrations and phosphorylated ZDV were determined by radioimmunoassay, and area under the concentration-time curves (AUC) were compared with clinical data collected during the pharmacokinetic study. SETTING: An outpatient setting at the University of Cincinnati AIDS Treatment Center, Cincinnati, Ohio, USA. PATIENTS: HIV-infected adults with CD4+ lymphocyte counts 200-500 x 10(6) cells/l with no prior history of anti-HIV therapy and no active infections requiring systemic therapy. Of 30 patients enrolled, 21 were evaluable. INTERVENTIONS: None. MAIN OUTCOME MEASURES: AUC of plasma ZDV and intracellular total phosphorylated ZDV were compared with change from baseline of the following surrogate markers: CD4+ lymphocyte count, %CD4+ lymphocytes, CD4+/CD8+ cell ratio, serum beta 2-microglobulin, serum neopterin, neutrophils, red cell count, and hemoglobin. RESULTS: No correlations between plasma AUC and markers of therapeutic response were observed. However, significant positive correlations were observed between the AUC of total phosphorylated ZDV and changes in the %CD4+ lymphocytes and CD4+/CD8+ lymphocyte ratio; a negative correlation was observed with change in hemoglobin. Patients who responded to ZDV therapy, as measured by these variables, demonstrated significantly higher intracellular AUC (> 3 pmol x h/10(6) cells) than those who did not (approximately 2 pmol x h/10(6) cells). CONCLUSIONS: The ability of HIV-infected patients to phosphorylate ZDV correlates with changes in markers associated with drug effect and toxicity. Potential individualization of therapy through monitoring of total phosphorylated ZDV in patients therefore warrants further exploration.

Pharmacokinetics and safety of amprenavir and ritonavir following multiple-dose, co-administration to healthy volunteers.

OBJECTIVE: To evaluate the safety and pharmacokinetic interaction between amprenavir (APV) and ritonavir (RTV). METHODS: Three open-label, randomized, two-sequence, multiple-dose studies having the same design (7 days of APV or RTV alone followed by 7 days of both drugs together) used 450 or 900 mg APV with 100 or 300 mg RTV every 12 h with pharmacokinetic assessments on days 7 and 14. Safety was monitored as clinical adverse events (AEs) and laboratory abnormalities. RESULTS: Relative to APV alone, RTV co-administration resulted in a 3.3- to 4-fold and 10.84 to 14.25-fold increase in the geometric least-square (GLS) mean area under the plasma concentration--time curve (AUC(tau,ss)) and minimum concentration (C(min,ss)), respectively. APV 900 mg with RTV 100 mg resulted in a 2.09-fold and 6.85-fold increase in the GLS mean AUC(tau,ss) and C(min,ss), respectively. On day 14, the geometric mean (95% confidence interval) for 450 mg APV AUC(tau,ss) (micro x h/mL) was 23.49 (19.32--28.57) with 300 mg RTV and 35.42 (30.46--44.42) with 100 microg RTV, and for the 900 mg APV with 100 mg RTV 47.11 (39.47--61.24). The 450 mg APV C(min,ss) (microg/ml) were 1.32 (1.05--1.67) and 2.01 (1.70--2.61), and 2.47 (2.08--3.32) for 900 mg APV. The most common AEs were mild and included diarrhea, nausea/vomiting, oral parasthesias, and rash. The triglyceride and cholesterol increased significantly from RTV exposure. CONCLUSION: Adding RTV to APV resulted in clinically and statistically significant increases in APV AUC and C(min) with variable effects on maximum concentration. The two RTV doses had similar effects on APV but AEs were more frequent with 300 mg RTV.

A 24-week open-label phase I/II evaluation of the HIV protease inhibitor MK-639 (indinavir).

OBJECTIVE: To investigate the safety, pharmacokinetics, and activity of the orally bio-available protease inhibitor MK-639. DESIGN: An open-label Phase I/II trial of medically stable subjects with screening CD4 lymphocyte counts < or = 300 x 10(6)/I and > or = 20,000 HIV RNA copies/ml. Pharmacokinetics were performed at days 1 and 15. In order to better understand the relationships between drug exposure, baseline activity markers, and their changes during the study, mathematical modeling was performed using the traditional sigmoid-Emax relationship of pharmacologic effect and first order inhomogeneous differential equations for a two compartment system. RESULTS: The five men enrolled had extensive prior nucleoside therapy (mean, 32.6 +/- 25.6 months), a low mean CD4 lymphocyte cell count (CD4 count, 66.1 +/- 61 x 10(6)/I and CD4 percentage, 4.4 +/- 3.1%), high soluble tumor necrosis factor-alpha type II (sTNFII) receptor concentration (6.23 +/- 2.76 ng/ml) and high viral load (5.13 +/- 0.46 log10 RNA copies/ ml; geometric mean, 133,941 copies/ml). The drug was well tolerated at a dose of 600 mg every 6 h. The steady state concentrations Cmax and Cmin were 4.94 +/- 2.16 microM and 0.28 +/-0.1 microM, respectively, which are approximately equal to 50 and 3 times the 95% inhibitory concentration (IC95) for clinical isolates, respectively. The mean increase in CD4 cell count was 143 x 10(6)/ (217% increase ), the mean increase in CD4 percentage was 5.2 percentage points (118%), mean decrease in HIV RNA was 1.55 log10 RNA copies/ml (a geometric mean difference of 130,120 copies/ml or 97% decrease) with a slow upward drift on continued therapy to a mean 0.64 log10 RNA copies/ml decrease by week 24 (a geometric mean difference of 103,084 copies/ml or 77% decrease), and a mean decrease in sTNFII receptors of 2.78 ng/ml (45% decrease). The mean CD4 counts per week as a function of the starting CD4 counts fit a sigmoid-Emax relationship (r2 = 0.998, P < 0.0001) with the return of CD4 cells being strongly related to the number of CD4 cells at baseline. Drug exposure as measured by either the total exposure (area under the concentration/time curve) or as the Cmin gave similar significant relationships to the fractional inhibition of HIV generation (r2 = 0.999, P < 0.0001, and r2 = 0.996, P < 0.0001, respectively). CONCLUSIONS: MK-639 appears to have significant dose-related antiviral activity and is well tolerated.

Molecular analysis of viridans and nutritionally deficient (variant) streptococci causing sequential episodes of endocarditis in a patient.

Clinical blood isolates from sequential episodes of endocarditis occurring over a six-month period of time in an addict were investigated. The pathogens were Streptococcus sanguis II, Streptococcus mitis, and a nutritionally deficient (variant) streptococcus. The authors determined the DNA relatedness of these isolates by antibiograms, plasmid profiles, chromosomal endonuclease restriction digestions, and dot blot DNA-DNA hybridization analyses. The S. sanguis II and nutritionally deficient streptococcal strain had similar antibiograms being resistant to penicillin; neither produced beta-lactamase. No plasmids were found. The restriction endonuclease chromosomal digestion patterns of these isolates were unique and epidemiologically unrelated to each other. Dot blot DNA-DNA hybridizations, using the nutritionally deficient streptococcal DNA as the probe, showed homology to the preceding clinical isolates, S. sanguis II and S. mitis, at 15.4% and 45.1% hybridization levels, respectively. The nutritionally deficient streptococcus was only 4.2% homologous to a S. mitis ATCC strain and another nutritionally deficient streptococci isolate. Therefore, this patient had endocarditis with three distinct streptococcal strains.

A double-blinded comparative evaluation of three media for chromophore testing with viridans and nutritionally variant (deficient) streptococci.

A double-blinded prospective comparison of chromophore testing among 109 clinical isolates of alpha-hemolytic gram-positive cocci and 48 strains of nutritionally variant (deficient) streptococci (NVS) for its sensitivity, specificity, and predictive value under stimulated clinical laboratory conditions was performed after growth in three different media--Todd-Hewitt broth supplemented with 10 micrograms/mL of pyridoxal (THBP), THBP with 0.8% (w/v) yeast-extract (THBP + YE), and a semisynthetic chemically defined medium with Todd-Hewitt dialyzate (CDMT). The chromophore detection rates of Streptococcus mitis were 60.7, 67.9, and 78.6% after growth in THBP, THBP + YE, and CDMT, respectively. After growth in THBP there was significantly lower chromophore detection than either THBP + YE or CDMT for NVS (P less than 0.001), with a trend toward significantly less detection for S. mitis (0.15 greater than P). For Streptococcus sanguis II the detection rates were 45.7, 57.1, and 54.3%, respectively, for each medium. There was no significant difference between the detection rates after growth in THBP + YE or CDMT. One NVS was persistently chromophore negative, the first so described. There was a similar number of presumably false positive chromophore S. sanguis I strains (3 of 12) detected after growth in THBP + YE or CDMT. The sensitivity of chromophore detection for NVS (pooling results in THBP + YE and CDMT) was 95.8% and specificity was 59.6%. For a nonvariant streptococcus, the sensitivity was 61.9% and specificity was 93.5% for an isolate to be either S. mitis or S. sanguis II.

Regeneration of cervical epithelium after laser vaporization.

The process of reepithelialization after laser vaporization of normal cervical squamous epithelium was examined using light and electron microscopy. Tissue specimens were obtained from seven patients at time intervals ranging from seven to 16 days after laser vaporization. Immature squamous epithelium appeared at the edge of the laser crater between seven and 14 days, and by 14 to 16 days, the immature epithelium covered the entire crater area. The observations made in this study concur with those of other studies of the healing process of squamous epithelium, whereby immature cells from the surrounding undamaged epithelium migrate into the damaged area, eventually differentiating into a full thickness of epithelium.

Time kill curve analysis of vancomycin and rifampin alone and in combination against nine strains of nutritionally deficient streptococci.

Endocarditis caused by nutritionally deficient streptococci has a high bacteriologic and clinical failure rate, despite appropriate antimicrobial therapy. We investigated by time kill curve methodology nine clinical endocarditis isolates of nutritionally deficient streptococci to determine the in vitro efficacies of vancomycin and rifampin alone and in combination. The combination of vancomycin and rifampin demonstrated synergy and bactericidal activity in five of the strains. In one strain, this combination inhibited growth by greater than 2 log10 CFU/ml when compared to the growth control or either antibiotic alone, but it failed to be bactericidal. Indifference, defined as less than or equal to 2 log10 CFU per milliliter increase in killing of the combination compared to the next most active single agent, was demonstrated with the remaining three isolates. Changing the antibiotic concentrations in the time kill curve studies for these latter strains failed to demonstrate synergistic activity of the antibiotic combination. The vancomycin and rifampin combination may be a promising therapeutic modality for which in vivo correlation is indicated.

Genetic heterogeneity among nutritionally deficient streptococci.

The nutritionally deficient (variant) streptococci (NDS) share the auxotrophic characteristic of requiring pyridoxal or thiol group supplementation for growth. The deoxyribonucleic acid relatedness of these organisms among themselves is unknown. Improved speciation of NDS would lead to a better knowledge of their pathogenesis and possible insight into improved clinical management. Therefore, DNA-DNA hybridization and biotyping of 23 nutritionally deficient streptococci were performed. Biochemical testing using the API Rapid Strept Identification method revealed that the organisms in this study were characterized among three broad biotype groups. Only one strain was nontypeable. DNA-DNA hybridization among the nutritionally deficient streptococci that we compared revealed genetic heterogeneity. Only four (17%) of 23 isolates were highly homologous; all were of biotypes 2 and 3. Reference viridans streptococcal strains had minimal homology to the NDS strains. The data indicate that the NDS are genetically heterogeneous.

Group G Streptococci: susceptibility patterns and the effect of the inoculum size and growth phase on the bactericidal activity of penicillin.

Twenty-seven independent group G streptococcal isolates were studied by in vitro susceptibility testing against 22 different antimicrobial agents. Penicillin with a MIC90 of 0.03 micrograms/ml and ampicillin with a MIC90 of less than or equal to 0.015 micrograms/ml remain the agents of first choice for treatment of group G streptococcal infections. Tolerance was not demonstrated using the macrobroth dilution method in four media, Todd-Hewitt, Mueller-Hinton, Mueller-Hinton (cation-supplemented), and Tryptose Phosphate broths. Multiple regression analyses of time-kill curves of group G streptococci showed that the rate of cell death with penicillin at 0.04 micrograms/ml (five times greater than each organism's MIC) for both logarithmic- and stationary-phase cells with low-inocula were the same, but were five to six times greater in rate of death compared to the high-inocula cultures. Increasing the concentration to 1 microgram/ml of penicillin (125 times greater than each organism's MIC) did not significantly affect the rate of cell death for low-inocula cultures of either phase. Therefore, the size of the inoculum was found to be more significant than the phase of bacterial growth. These findings may explain the therapeutic discrepancy of relapses or prolonged group G streptococcal infections despite the organism being susceptible to the given antibiotic.

The hemolysin/bacteriocin produced by enterococci is a marker of pathogenicity.

The hemolysin/bacteriocin produced by some strains of Enterococcus faecalis is active in the lysis of human, rabbit, and horse erythrocytes, but not those from sheep. In this study, we determined that 20% of clinical enterococcal isolates tested in the clinical microbiology laboratory produced hemolysin and that pathogenic human E. faecalis were more likely to be hemolysin-producing isolates. Among the organisms isolated from different anatomic sites, variability in the degree of hemolysin production existed. We used an isogenic pair of E. faecalis organisms to demonstrate that hemolysin production was due to a hemolysin/bacteriocin determinant transmissible by a plasmid and was not strain dependent. This determinant may be linked to antibiotic resistance genes in some instances. Also, the erythrocyte lysis occurred only when hemolysin was in the presence of E. faecalis organisms, suggesting a bacterial cell dependency for activity of the hemolysin.

Metabolic disposition and pharmacokinetics of [14C]-amprenavir, a human immunodeficiency virus type 1 (HIV-1) protease inhibitor, administered as a single oral dose to healthy male subjects.

The objective of this study was to determine the metabolic profile, routes of elimination, and total recovery of amprenavir and its metabolites after a single oral dose of [14C]-amprenavir. Six healthy male subjects each received a single oral 630 mg dose of amprenavir containing 95.76 microCi of [14C]-amprenavir in this Phase I mass balance study. The metabolic disposition of amprenavir was determined through analyses of radiocarbon in whole blood, plasma, urine, and stool samples, collected for a period of 10 to 17 days postdosing. Cerebral spinal fluid (CSF) sampling was conducted on day 1. The ratio of unchanged amprenavir AUC0-->infinity to plasma radiocarbon was 27%, suggesting that most of the radiocarbon was metabolites. The median total recovery of the administered dose of radiocarbon was 89% (range: 66%-93%), with 75% (range: 56%-80%) recovered in the feces and 14% (range: 10%-17%) in the urine. Most of the recovered radiocarbon in the feces and urine was excreted within 240 and 48 hours postdose, respectively. Of the 75% of the radiocarbon dose recovered in the feces, 62% was identified as a metabolite resulting from dioxidation of the tetrahydrofuran ring (GW549445X) and 32% as a metabolite resulting from subsequent oxidation of the p-aniline sulfonate group (GW549444X). Unchanged amprenavir was below the limit of quantitation in feces and urine. Therefore, approximately 94% of the dose excreted in the feces was accounted for by these two metabolites. Concentrations of radiocarbon in the CSF were below the limit of quantitation in 5 of 6 subjects sampled. In summary, oral amprenavir is extensively metabolized in humans, with concentrations of unchanged drug below the limits of quantitation in urine and feces. The majority (75%) of administered radiocarbon was excreted in feces.

Comparative pharmacokinetics and renal effects of cyclosporin A and cyclosporin G in renal allograft recipients.

Cyclosporin G (CSG) has produced less nephrotoxicity than cyclosporin A (CSA) at equivalent doses in animal models. Conflicting results have been reported concerning differences in the pharmacokinetics of CSA and CSG in preclinical studies, and no data exist regarding the effect of steady-state oral administration of CSG on renal function in transplant patients or CSG-induced release of endothelin and nitric oxide (NO) in vivo. The objective of the study was to examine steady-state pharmacokinetic profiles of adult renal allograft recipients receiving CSA and CSG in relation to concentrations of endothelin-1 and NO2/NO3 in urine and plasma, creatinine clearance (Clcr), and urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) 9 months after transplantation. Concentrations of CSA and CSG were measured in whole blood over a 12-hour dose interval by both a monoclonal and polyclonal fluorescence polarization radioimmunoassay for CSA. A metabolite fraction was defined as the numerical difference between the levels obtained at each time point by both assays. Patient groups were defined as follows: group 1: initial CSA (n = 6); group 2: initial CSG (n = 7); group 3: five of the seven patients in group 2 taking CSG subsequently undergoing conversion to CSA; group 4: the same five patients in group 3 restudied 1 month after 1:1 dosage conversion to CSA; and group 5: CSA groups 1 and 4 combined (n = 11). In group 1, the metabolite fraction accounted for 32% to 54% of the total measurable drug concentration at each time point, whereas in group 2, the metabolite fraction accounted for at most 10% to 15% of the total drug levels measurable by polyclonal fluorescence polarization radioimmunoassay. Although there were no significant differences in any of the mean pharmacokinetic parameters between groups using monoclonal fluorescence polarization radioimmunoassay, the normalized area under the concentration-time curve (NAUC) value was less in four of five patients after conversion from CSG to CSA, with a more variable and delayed time to reach peak concentration (tmax) but equivalent apparent oral clearance (Clpa) values. Clcr was found to change significantly with time in groups 1 and 5 but not in group 2, with CSA producing a more profound and sustained decrease than CSG. Endothelin-1 and NO2/NO3 levels in plasma and urine remained relatively constant after administration of both CSA and CSG, and there were no significant differences between groups 3 and 4 regarding mean endothelin-1 and NO2/NO3 concentrations in plasma, urinary release of endothelin-1 and NO2/NO3, and mean AUC of endothelin-1 and AUC of NO2/NO3. However, monoclonal NAUC correlated significantly with total urinary endothelin-1 within CSA groups 1 and 5 but not within CSG group 2. Metabolite NAUC correlated significantly with total urinary NAG within CSA group 1. Although limited by the small number of patients, this study suggests that 1) CSG may produce less of a reduction in Clcr over time after oral administration at steady state than does CSA, and 2) this beneficial effect of CSG may be in part due to decreased intrarenal release of endothelin-1, as urinary excretion of endothelin-1 seemed to correlate better with CSA than with CSG exposure.

Phosphorylation of nucleoside analog antiretrovirals: a review for clinicians.

Nucleoside analogs (zidovudine, didanosine, zalcitabine, stavudine, abacavir, lamivudine) have been administered as antiretroviral agents for more than a decade. They undergo anabolic phosphorylation by intracellular kinases to form triphosphates, which inhibit human immunodeficiency virus replication by competitively inhibiting viral reverse transcriptase. Numerous methods are used to elucidate the intracellular metabolic pathways of these agents. Intracellular and extracellular factors affect intracellular phosphorylation. Lack of standardization and complexity of methods used to study phosphorylation in patients limit interpretation of study results and comparability of findings across studies. However, in vitro and in vivo studies give important insights into mechanisms of action, metabolic feedback mechanisms, antiviral effects, and mechanisms of toxicity, and have influenced dosing regimens of nucleoside analogs.

Abacavir: absolute bioavailability, bioequivalence of three oral formulations, and effect of food.

STUDY OBJECTIVES: Study A: to determine the absolute bioavailability of a single 300-mg abacavir hemisulfate tablet. Study B: to determine the bioequivalence of two oral abacavir formulations (300-mg hemisulfate tablet, 100-mg succinate caplet), the effect of food on the bioavailability of the 300-mg hemisulfate tablet, and the bioavailability of the hemisulfate tablet relative to the hemisulfate solution. DESIGN: Phase I, randomized, open-label, balanced two- (study A) and three- or four-period (study B), crossover studies. SETTING: Two clinical research centers. SUBJECTS: Six men infected with the human immunodeficiency virus (HIV), aged 27-39 years (study A), and 18 HIV-infected men and women, aged 21-50 years (study B). INTERVENTIONS: In study A, all subjects received a single, oral 300-mg tablet of abacavir hemisulfate or a single, intravenous infusion of abacavir hemisulfate 150 mg over 60 minutes. In study B, all subjects received each of three single-dose treatments: three 100-mg abacavir succinate caplets in a fasted state, one 300-mg abacavir hemisulfate tablet in a fasted state, and one 300-mg abacavir hemisulfate tablet with a high-fat breakfast. Twelve subjects in study B also received a fourth treatment of abacavir hemisulfate 300 mg as an oral solution in a fasted state. Plasma samples collected for 24 hours (study A) or 12 hours (study B), and urine samples collected for 12 hours (study A) were analyzed by validated high-performance liquid chromatographic methods. MEASUREMENTS AND MAIN RESULTS: Abacavir pharmacokinetic parameters were calculated using standard, noncompartmental methods. In study A, the geometric least square (GLS) mean absolute bioavailability of oral abacavir was 83% (range 65-107%). In study B, the hemisulfate tablet was bioequivalent to the succinate caplet, but its time to maximum concentration (Tmax) occurred 30 minutes earlier. Administration of the abacavir hemisulfate tablet with food had no effect on area under the curve from time zero to infinity (AUC0-infinity), decreased maximum concentration (Cmax) by 26%, and delayed Tmax by 38 minutes. The relative bioavailability (GLS mean AUC0-infinity ratio) of the 300-mg abacavir hemisulfate tablet to solution was 101%, Cmax was 11% lower, and Tmax was unchanged. The most common drug-related adverse events associated with abacavir were nausea, vomiting, abdominal pain, and headache, all of which were mild. CONCLUSION: Based on our results, abacavir is safe and well tolerated and can be administered with or without meals.

Laser vaporization in the treatment of cervical intraepithelial neoplasia.

Ablative cryotherapy and laser vaporization therapy attempt to eradicate the cervical transformation zone in order to eliminate cervical intraepithelial neoplasia and to reduce the risk of invasive cancer. We reviewed the literature on both methods and our own experience with laser therapy. Review of the records of 4,557 initial cryosurgical patients as compared to those of 1,505 initial laser patients revealed cure rates of 12% and 13.8%, respectively (no significant difference, p greater than 0.14). Multiple treatments in 533 cryosurgery and 1,775 laser patients revealed cure rates of 11% and 2.6%, respectively (p less than 0.0001). Enhanced accessibility of the new squamocolumnar junction following laser surgery may result in improved early detection of initial treatment failures and significantly improve the success rates of retreatment. If so, a reduction in the development of invasive cancer in laser-treated patients may occur.