Reconstruction of wave front and object for inline holography from a set of detection planes.

We illustrate the errors inherent in the conventional empty beam correction of full field X-ray propagation imaging, i.e. the division of intensities in the detection plane measured with an object in the beam by the intensity pattern measured without the object, i.e. the empty beam intensity pattern. The error of this conventional approximation is controlled by the ratio of the source size to the smallest feature in the object, as is shown by numerical simulation. In a second step, we investigate how to overcome the flawed empty beam division by simultaneous reconstruction of the probing wavefront (probe) and of the object, based on measurements in several detection planes (multi-projection approach). The algorithmic scheme is demonstrated numerically and experimentally, using the defocus wavefront of the hard X-ray nanoprobe setup at the European Synchrotron Radiation Facility (ESRF).

Treatment of complicated intra-abdominal infections: comparison of the tolerability and safety of intravenous/oral trovafloxacin versus intravenous imipenem/cilastatin switching to oral amoxycillin/clavulanic acid.

Three- to four-times-daily intravenous (i.v.) imipenem/cilastatin switching to oral amoxycillin/clavulanic acid is often used to manage complicated intra-abdominal infections. Trovafloxacin, a clinically and bacteriologically proven new-generation fluoroquinolone antibiotic, given as single-agent, once-daily i.v./oral therapy, can provide equivalent clinical and bacteriological efficacy. Tolerability and safety of up to 14 days treatment with 300 mg i.v. alatrofloxacin (the prodrug of trovafloxacin) switching to 200 mg oral trovafloxacin were compared with those of 1 g i.v. imipenem/cilastatin switching to 625 mg oral amoxycillin/clavulanic acid. Comparable incidences of adverse events, mainly mild or moderate in intensity, were experienced in each treatment group. For both therapies, gastrointestinal events were most common, but diarrhoea was reported by proportionately more comparator group patients. In conclusion, once-daily i.v.-to-oral trovafloxacin has a comparable safety profile to i.v. imipenem/cilastatin followed by oral amoxycillin/clavulanic acid. Cost saving may be achieved with trovafloxacin due to the lack of any need to monitor creatinine levels and the once-daily dosing regimen that allows a switch to the same orally administered drug.

Role of neutrophils and macrophages in experimental nephrosis of the rat.

The single dose administration of the aminonucleoside of puromycin (PAN) induces a nephrotic syndrome in rats characterized by massive proteinuria and progressive histologic changes. This model of acute parenchymal nephritis is thought to be mediated by the renal recruitment of monocytes and macrophages. To investigate the role of leukocytes in the experimental nephrotic syndrome model, the effects of two methylxanthines, pentoxifylline (45 mg/kg i.p. twice daily) and torbafylline (5 mg/kg i.p. twice daily) were compared with controls over a 2-week period. Pentoxifylline treatment was associated with 3- and 6-fold reductions in urinary protein excretion at 7 and 14 days, respectively, compared with PAN-treated control animals (p < .01). Similarly, 14-day dosing of torbafylline resulted in a 3-fold decrease in urinary protein excretion. Glomerular filtration and electrolyte excretion rates were similar between all treatment groups. There were significant reductions in glomerular neutrophil and macro-phage counts, but not T-cells (OX19+) or suppressor/cytotoxic T-cells (0X8+), in kidneys of rats given either treatment compared with PAN con-trol rats. In summary, both pentoxifylline and torbafylline attenuated the proteinuria and glomerular macrophage and neutrophil infiltration associated with PAN administration. These data support the role of macrophages and neutrophils in the pathogenesis of acute parenchymal injury and the potential role of pentoxifylline or related analogues in the attenuation of the ensuing renal deficit associated with minimal lesion disease.

Double-blind comparison of single-dose alatrofloxacin and cefotetan as prophylaxis of infection following elective colorectal surgery. Trovafloxacin Surgical Group.

BACKGROUND: Alatrofloxacin, the prodrug of trovafloxacin, is a novel fluoroquinolone antimicrobial agent with a broad spectrum, including activity against gram-positive and gram-negative aerobes and anaerobes. Its pharmacokinetic properties (long half-life, excellent tissue distribution, and good safety profile) suggest a role in surgical prophylaxis. This prospective, multicenter, double-blind trial compared alatrofloxacin with cefotetan, an approved drug for surgical prophylaxis, in reducing postoperative infections. METHODS: The efficacy and safety of a single 200-mg intravenous dose of alatrofloxacin were compared to a single 2-g intravenous dose of cefotetan in 492 patients undergoing elective colorectal surgery. The efficacy of alatrofloxacin as a prophylaxis for wound, intra-abdominal, or remote-site postoperative infectious complications was compared with cefotetan in 317 clinically evaluable patients; 161 received alatrofloxacin and 156 received cefotetan. The patients were monitored for infections and safety for 30 days postoperatively. RESULTS: No statistically significant between-treatment difference was detected in successful clinical response rates at the end of the study (72% for each group). The incidence of primary wound infections at the time of hospital discharge was also similar: 21% in patients treated with alatrofloxacin and 18% in those treated with cefotetan. Safety, established by the incidence of adverse events, did not differ statistically between the groups. CONCLUSIONS: A single intravenous dose of alatrofloxacin given within 4 hours prior to surgery was as effective as an intravenous dose of cefotetan in the prevention of postoperative infectious complications in patients undergoing elective colorectal surgery. The safety profiles of the two medications were similar.

Treatment of acute gynecologic infections with trovafloxacin. Trovafloxacin Surgical Group.

BACKGROUND: Trovafloxacin, a broad-spectrum fourth-generation quinolone with gram-positive and gram-negative aerobic and anaerobic bacterial activity, is available in oral and intravenous formulations. The objective of this prospective, multicenter, double-blind, randomized study was to compare the efficacy of trovafloxacin with that of cefoxitin, an approved drug for treatment of acute gynecologic infections, together with amoxicillin/clavulanic acid as oral follow-on treatment. METHODS: Patients with a clinical diagnosis of acute pelvic infection received either intravenous alatrofloxacin with oral trovafloxacin follow-on (trovafloxacin) or a combined regimen of cefoxitin followed by amoxicillin/clavulanic acid for a maximum of 14 days. The primary endpoint was clinical response to therapy on follow-up at day 30. RESULTS: Clinical success rates were comparable between the trovafloxacin (n = 107) and comparative (n = 119) groups at study end (90% vs. 86%, respectively; 95% confidence interval, -4.5, 12.5). Among clinically evaluable patients, clinical success rates for infections involving Enterococcus species were higher with trovafloxacin than with the comparative regimen at the end of treatment (96% and 85%) and at study end (96% and 86%). CONCLUSION: Intravenous alatrofloxacin followed by oral trovafloxacin for a maximum of 14 days of total therapy was efficacious in the treatment of acute pelvic infections.

Trovafloxacin in the treatment of intra-abdominal infections: results of a double-blind, multicenter comparison with imipenem/cilastatin. Trovafloxacin Surgical Group.

BACKGROUND: Trovafloxacin, a new broad-spectrum fourth-generation quinolone, has in vitro activity against most gram-negative and gram-positive anaerobes and aerobes. Trovafloxacin is available as both an intravenous formulation, alatrofloxacin, and a single daily oral tablet. Excellent tissue pharmacokinetics and oral bioavailability suggest usefulness in the treatment of complicated intra-abdominal infections. Thus, the efficacy of alatrofloxacin followed by oral trovafloxacin was compared with the standard regimen of intravenous imipenem/cilastatin followed by oral amoxicillin/clavulanic acid in this prospective, multicenter, double-blind trial. METHODS: Patients were randomized to receive either 300 mg alatrofloxacin daily followed by 200 mg oral trovafloxacin daily or 1 g imipenem/cilastatin intravenously thrice daily followed by 500 mg oral amoxicillin/clavulanic acid thrice daily for up to 14 days following surgical intervention of a documented intra-abdominal infection. Efficacy was assessed at the end of therapy and at follow-up (day 30). RESULTS: At the end of the study, cure or improvement occurred in 83% (129/156) and 84% (127/152) of clinically evaluable patients in the trovafloxacin and comparative groups, respectively. Pathogen eradication rates, adverse-event profiles, and significant laboratory abnormalities were comparable between groups. CONCLUSION: Intravenous alatrofloxacin with or without oral trovafloxacin was as effective as intravenous imipenem/cilastatin followed by oral amoxicillin/clavulanic acid in complicated intra-abdominal infections.

Pharmacokinetics of azithromycin after single- and multiple-doses in children.

STUDY OBJECTIVE: To characterize the disposition and tolerance of azithromycin after single and multiple oral doses of 12 mg/kg in children with and without cancer. DESIGN: Open-label, nonrandomized pharmacokinetic study. SETTING: Two pediatric hospitals. PATIENTS: Twelve children with cancer admitted to the inpatient unit for empiric antibiotic treatment of febrile neutropenia, and 16 hospitalized patients receiving antibiotic therapy INTERVENTIONS: Patients received azithromycin suspension either as a single dose or daily dose every morning for 5 consecutive days. Serial blood samples were collected up to 120 hours after a single dose or during and after multiple doses to characterize the pharmacokinetic parameters estimated for a two-compartment absorption model. MEASUREMENTS AND MAIN RESULTS: All 28 patients were evaluable for safety. Azithromycin was well tolerated except in one patient with cancer who experienced abdominal cramps and withdrew from the study. Pharmacokinetic results were not determined in five patients because of insufficient concentration-time data. The mean +/- SD estimates of oral clearance, terminal half-life, maximum concentration in serum (Cmax), and time to achieve Cmax in the 23 evaluable patients were 4.83 +/- 3.59 L/hour/kg, 54.5 +/- 36.4 hours, 318.2 +/- 174.5 microg/L, and 2.4 +/- 1.1 hours, respectively. These estimates did not differ between single-dose (14 patients) and multiple-dose (9 patients) groups. Pharmacokinetic parameters were not different between the 11 children with cancer and the 12 without cancer. CONCLUSION: Azithromycin 12 mg/kg results in proportionately higher serum concentrations than previously published results for lower doses (5 mg/kg). Variability in concentration profiles among patients is substantial, and age or other yet unidentified clinical factors may explain some of the differences observed.

Toleration of intravenous azithromycin.

OBJECTIVE: To study the toleration of various infusate concentrations of single intravenous doses of azithromycin. DESIGN: Randomized, double-blind, two-treatment, two-period, crossover. SETTING: Clinical pharmacology unit. PARTICIPANTS: Twenty-four healthy men aged 19-41 years. STUDY DESIGN: All subjects were initially randomized to receive single 1-hour intravenous infusions of azithromycin 1 g at infusate concentrations of 1, 2, or 5 mg/mL (n = 6 each) compared with placebo (n = 6). Subjects who were randomized to receive 1 mg/mL concentrations were subsequently administered 5 mg/mL concentrations at least 2 weeks later, those given 2 mg/mL were crossed over to 4 mg/mL, and those in the 5-mg/mL group were crossed over to 1 mg/mL concentrations. MAIN OUTCOME MEASURES: Subjects recorded intravenous infusion toleration using visual analog scales ranging from 0 (no signs or symptoms) to 10 (poor toleration) for erythema, pain, swelling, and tenderness. Vascular Doppler recordings were obtained during and after infusion cephalad to the infusion site. RESULTS: Infusion site reactions increased in incidence and severity with infusion concentrations of 4 and 5 mg/mL; the most frequent reactions were tenderness and erythema. There were no apparent trends in Doppler readings. CONCLUSIONS: Single doses of azithromycin 1 g at infusate concentrations up to 2 mg/mL were well tolerated when administered over 1 hour to healthy men.

Disposition of oral azithromycin in humans.

BACKGROUND: The oral bioavailability of azithromycin is approximately 37% in healthy subjects; little is known about the disposition of the remaining 63% of the dose. This study attempted to describe the fate of azithromycin before absorption. METHODS: Twelve subjects with ileostomies in place for > 1 month were studied in this open-label, randomized, three-center, two-period, two-treatment crossover study. Subjects randomly received single 500 mg intravenous infusion (over 1 hour) or two 250 mg oral capsules after a fast for > 12 hours. Blood and ileostomy samples were collected serially after each administration and analyzed for azithromycin and two metabolites (descladinose and 9a-N-desmethyl metabolites) by HPLC with electrochemical detection. RESULTS: Mean +/- SD peak concentration values after oral and intravenous administration were 0.21 +/- 0.08 and 3.40 +/- 1.12 microgram/ml. Mean values for area under the serum concentration versus time curve were 1.27 +/- 0.65 and 7.14 +/- 1.34 micrograms x hr/ml, respectively. The absolute bioavailability of 16.2% was approximately one-half the value observed previously in healthy subjects. Recovery in ileostomy fluid (percent of dose in 24 hours) or azithromycin, descladinose, and 9a-N-desmethyl metabolites were 13%, 0.5%, and 1% (total, 15%) after intravenous dosing and 47%, 13%, and 2% (total, 62%) after oral dosing. Total and ileal clearances were 776 +/- 126 and 158 +/- 63 ml/min after intravenous dosing. CONCLUSION: Because more descladinose metabolite was detected after oral dosing, acid degradation of azithromycin before absorption contributed to some loss in oral bioavailability. Further, ileal clearance (biliary plus intestinal excretion clearance) in this population represented 21% of total clearance. Taken together, these data suggest that the cause of low oral bioavailability of azithromycin is the result of incomplete absorption rather than acid degradation or extensive first-pass metabolism.

Safety, toleration, and pharmacokinetics of intravenous azithromycin.

To date, the clinical pharmacology of large intravenous doses of azithromycin has not been described. In the present study, single 2-h intravenous infusions of 1, 2, and 4 g of azithromycin were administered to three parallel groups (in each group, six received active drug and two received placebo) of healthy male subjects. Toleration (assessed by scores of subject-administered visual analog scale tests spanning 0 [good] to 10 [poor]), safety, pharmacokinetics, and serum motilin levels were monitored for up to 240 h after the start of each intravenous infusion. Mean nausea scores of 0.0, 0.0, 1.0, and 0.5 and abdominal cramping scores of 0.0, 0.0, 0.4, and 0.4 for 12-h periods after doses of 0, 1, 2, and 4 g of azithromycin, respectively, suggested that azithromycin was well tolerated. Because of the standardized 1-mg/ml infusates, all subjects in the 4-g dosing group complained of an urgent need to urinate. There were no consistent trends in endogenous motilin levels throughout the study. The maximum concentration of azithromycin in serum (10 micrograms/ml after a 4-g dose) and the area under the concentration-time curve (82 micrograms.h/ml after a 4-g dose) were dose related. The mean pharmacokinetic parameters were an elimination half-life of 69 h, total systemic clearance of 10 ml/min/kg, and a volume of distribution at steady state of 33.3 liters/kg. The pharmacokinetic results suggest that the long half-life of azithromycin is due to extensive uptake and slow release of the drug from tissues rather than an inability to clear the drug. Single intravenous doses of up to 4 g of azithromycin in healthy subjects are generally well tolerated, and quantifiable concentrations may persist in serum for 10 days or more.

The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension.

Present product labelling indicates that azithromycin capsules should not be taken with food. However, three recent studies demonstrated that food does not significantly decrease the bioavilabilities of three new formulations of azithromycin (250 mg tablets, 1000 mg sachet, 500 mg paediatric suspension). With a 500 mg dosage, the mean relative bioavailability of azithromycin following ingestion of a standard high-fat breakfast was 96% when administered as two 250 mg tablets and 113% when administered as a suspension. The mean relative bioavailability of a 1000 mg sachet was 112%. The absolute bioavailability of the sachet formulation, relative to a 1 h iv infusion of 1000 mg, was 44%. Thus, azithromycin tablets, suspension and sachet may be given without regard to meals, further enhancing the convenience of once-daily, short-duration dosing regimens.

Pharmacokinetics of azithromycin in pediatric patients with acute otitis media.

The objective of our study was to characterize the pharmacokinetics of azithromycin after the oral administration of multiple doses in suspension to children with acute otitis media. Thirteen children (ranging in age from 7.5 months to 5 years) received a single oral dose of 10 mg of azithromycin per kg of body weight on day 1 followed by single daily doses of 5 mg/kg on days 2 to 5. Each child fasted overnight before receiving the final dose on day 5. Multiple blood samples were collected after the last dose. Concentrations of azithromycin in serum were measured by a specific high-performance liquid chromatography-mass spectrometry method. The means and standard deviations for the maximum concentration of azithromycin in serum, the time to maximum concentration of azithromycin in serum, the area under the concentration-time curve (from 0 to 24 h), and the elimination half-life were 224 +/- 120 ng/ml, 1.8 +/- 0.4 h, 1,841 +/- 651 ng.h/ml, and 31.6 +/- 6.6 h, respectively. Concentrations in serum (means +/- standard deviations) at 0 h (predose) and at 24, 48, and 72 h after the final dose were 51 +/- 26, 47 +/- 21, 27 +/- 17, and 17 +/- 13 ng/ml, respectively. Thus, the once-daily administration of azithromycin resulted in sustained systemic exposure to the drug. The drug dosage regimen used in this study should lead to tissue drug concentrations exceeding the MICs for common pathogens.

Influence of human serum albumin content in formulations on the bioequivalency of interferon alfa-2a given by subcutaneous injection in healthy male volunteers.

To determine the influence of human serum albumin (HSA) content in formulations on the bioequivalency of recombinant interferon alfa-2a, a double-blind, randomized, two-way crossover study was conducted in 24 healthy male volunteers. Subjects received a single subcutaneous injection of 18 million IU of Roferon-A reconstituted with either the diluent containing 10 mg of HSA or the HSA-free diluent; final HSA contents in the 2 formulations were 15 mg and 5 mg, respectively. Administration of the 2 formulations resulted in similar 48-hour Roferon-A serum concentration-time profiles and comparable frequency and intensity of adverse events. The statistical analysis using the two one-sided tests procedure showed that both formulations were bioequivalent for pharmacokinetic parameters such as Cmax, tmax, AUC48, and AUC. We conclude that a threefold change in HSA content in formulations does not alter the bioequivalency of Roferon-A.

Phase I/II study of pentoxifylline with zidovudine on HIV-1 growth in AIDS patients.

Tumor necrosis factor-alpha (TNF alpha), a potential regulator of HIV-1 replication, is involved in the progression of AIDS and associated disorders such as muscle wasting, fever and gastrointestinal problems. HIV-seropositive patients were assigned to receive zidovudine (ZDV; 100 mg 4-5 times/d) alone (n = 14), pentoxifylline (PTX; 400 mg every 8 h), a drug known to block TNF alpha release (n = 7), or PTX and ZDV (n = 11) for 12 weeks in a prospective, open-label study. Weekly compliance checks and biweekly blood and 24-h urine samples were obtained for immunological assessments. Baseline TNF alpha levels were elevated in all study patients, independent of disease stage. There were no appreciable differences in immunologic variables (CD4 counts, total and unbound p24 antigen, TNF alpha, beta 2-microglobulin, and urinary neopterin levels) between groups. The mean HIV-1 viral load, as measured by a quantitative polymerase chain reaction technique, was 1.9-fold above baseline values after 12 weeks of ZDV and PTX compared with 8- to 9-fold greater levels in patients given either agent alone (p < 0.05). TNF alpha levels correlated with viral load (r = 0.67; p < 0.0001) in patients given the combined drug regimen. Virological evidence of lack of progression in AIDS patients suggests the beneficial use of ZDV and PTX in delaying progressive HIV-1 disease compared with each drug alone.

Influence of pentoxifylline on renal function in HIV-seropositive patients.

Pentoxifylline (PTX) has potential usefulness in HIV-seropositive patients due to its beneficial effects on renal function, its inhibitory effects on tumor necrosis factor alpha, and its vascular effects on microcirculatory disturbances. The present study prospectively evaluated the effects of multiple oral doses of PTX (400 mg three times daily for 12 weeks) on renal function in 11 HIV-seropositive patients compared with 14 control patients. Four of these patients had HIV-associated nephropathy, manifested by high urinary microalbumin outputs (72 +/- 56 micrograms/min; mean +/- SD). Ambulatory 24-h urine collections were analyzed for creatinine, electrolytes, and immunological markers at weekly intervals for 12 weeks. Urine flow rates diminished to one-half baseline values by week 12; changes were related to both time and treatment sequences. There were significant decreases in creatinine clearances and electrolyte excretion rates over the study period that were not associated with treatment regimens. No differences were found in fractional electrolyte, uric acid, microalbumin, and neopterin excretion rates either between or within groups. One subject with high microalbumin excretion rates had a significant drop over the 12 weeks (133 to 4 micrograms/min); the other 3 subjects had similar or elevated microalbumin outputs by the end of the study. Although well tolerated, therapeutic doses of PTX did not significantly affect renal function in HIV-seropositive patients.

Immunosuppressive effect of cyclosporine in the hyperlipidemic rat model.

The immunosuppressive effects of 2.5 (n = 6) and 5 mg kg-1 day-1 (n = 7) of cyclosporine (CSA) given intravenously for 9 days to the immunized, hyperlipidemic Zucker rat model were compared with drug-free animals (n = 6) and lean litter-mates given 0 (n = 6), 5 (n = 6), and 10 mg kg-1 day-1 (n = 8) of CSA. Thus, based on body weights, both obese rats and lean litter-mates received total doses of 0, 1, and 2 mg of CSA. No significant differences in percent change in baseline body weight were found; in contrast, spleen weights were markedly greater in treated animals compared with controls. Serum cholesterol, triglycerides, and lipoprotein levels of obese rats were significantly greater than values found in lean litter-mates. CSA concentrations in whole blood, serum, and the lipoprotein fractions obtained 4 h after the final dose were greater in obese rats compared with lean litter-mates. Immunosuppressive activity, as assessed by ex vivo T-lymphocyte proliferation assay, was equivocal between all rats given CSA, independent of dose and obesity, and significantly greater than control animals. Whereas serum CSA levels were correlated to cholesterol levels (r = 0.95, p < 0.0001), there were no significant correlations with immunosuppressive activity. The present data suggest that increased binding of CSA to lipoproteins in the vascular compartment does not significantly impact on its immunosuppressive activity.

Failure of predicted creatinine clearance equations in HIV-seropositive patients.

The Cockcroft and Gault (CG) [1976] method of predicted creatinine clearances (CCR) accurately predicts measured 24-hour CCR values in healthy volunteers. The present study compared the relationship between measured and predicted CCR through 5 methods: CG, J1 [Jelliffe 1971], J2 [Jelliffe 1973], M [Mawer et al. 1972], and H [Hull et al. 1981], in 42 HIV-seropositive patients: 21 ARC/21 AIDS, 35M/7F, 26 homosexual/16 intravenous drug users, age: 37 +/- 7 years, actual body weight: 74 +/- 14 kg, CD4: 0.286 +/- 0.185 x 10(9) cells per liter (mean +/- SD). Measured CCR values poorly correlated with serum creatinine levels (r = -0.35; p < 0.01). The average measured CCR was 106 +/- 29 ml/min compared with 94 +/- 21 (CG; r = 0.49), 78 +/- 13 (J1; r = 0.41), 77 +/- 14 (J2; r = 0.44), 97 +/- 21 (M; r = 0.51) and 95 +/- 17 ml/min (H; r = 0.32). Standardization to body surface area or lean body weight or stratification by patient factors (gender, disease stage, risk factors, drug treatment) did not improve correlations. However, patients with normal microalbumin excretion rates had more predictable CCR values compared with those who had excess excretion, suggesting the influence of HIV-associated nephropathy on CCR estimation. Since all predicted CCR equations consistently underestimated actual values, these equations should be used with caution in estimating measured CCR in HIV-seropositive patients.

Incidence of microalbuminuria in ambulatory patients with acquired immunodeficiency syndrome.

Nephropathies associated with human immunodeficiency syndrome (HIVAN) are characterized by gross proteinuria, lack of change in blood pressure, and various histologic lesions. The present study prospectively measured microalbuminuria in 72 HIV-seropositive patients (3 asymptomatic, 32 AIDS-related complex, 37 AIDS) screened for Phase I clinical pharmacology studies. There were 14 patients (19.4%) that had abnormal urinary levels of microalbumin; 7 of these patients (50%) had proteinuria similar to those values found in diabetic nephrotic syndrome. Microalbumin levels were not correlated with race, sex, risk factors of AIDS, disease history, or concurrent drug therapy. In contrast, urinary microalbumin levels were correlated with CD 4 T-cell and WBC counts, tumor necrosis factor alpha and beta 2-microglobulin levels, suggesting an association between AIDS progression and microalbuminuria. By monitoring urinary microalbumin levels, those patients susceptible to the development of nephrotic syndrome could be identified and prophylactic measures initiated.

Bioavailability of labetalol in patients with end-stage renal disease.

The pharmacokinetics and pharmacodynamics of labetalol were assessed after a single oral and intravenous dose in eight patients with end-stage renal disease (ESRD) maintained on chronic hemodialysis, and in eight age-and sex-matched normal volunteers. The mean area under the serum concentration-time curve, volume of distribution, clearance, and terminal elimination half-life values after a single intravenous dose of 0.5 mg/kg of labetalol were not significantly different between ESRD patients and normal volunteers. Similarly, the absolute bioavailability of an oral dose of 200 mg of labetalol was 0.33 in ESRD patients and was not significantly different from that of normal volunteers (0.26). However, a significant decrease in the area under the mean blood pressure-time curve was found after a single oral dose in ESRD patients, which was not observed in normal volunteers. The pharmacokinetics of labetalol were not associated with changes in blood pressure. Thus, when given orally to the ESRD patient, labetalol should be slowly titrated and the blood pressure closely monitored.

Pharmacokinetics of cyclosporine in bone marrow transplantation: longitudinal characterization of drug in lipoprotein fractions.

The pharmacokinetics of cyclosporine (CSA; 2 mg/kg given iv over a period of 2 h every 12 h) in whole blood, plasma, high-density lipoproteins (HDL), and low-density lipoproteins (LDL) were studied after single (n = 10) and multiple (31 days; n = 6) doses in patients receiving allogeneic bone marrow transplants. Whereas HDL-cholesterol levels decreased significantly, LDL-cholesterol levels increased from day 1 to day 31 of CSA dosing. The mean area under the concentration-time curve and half-life values of CSA in whole blood or total plasma did not differ after single or multiple doses. Greater amounts of CSA were contained in the HDL relative to the LDL fraction over the 24-h period after a single dose; the reverse was found after multiple dosing. Cyclosporine was not detectable in the very LDL fractions. The percentage of total plasma CSA contained in each lipoprotein fraction was independent of the concentration of CSA in total plasma or whole blood. The pharmacokinetics of CSA in the various biologic matrices were not associated with measurements of kidney and liver function. Taken together, the variability of CSA pharmacokinetics previously reported in whole blood or total plasma was also found in lipoprotein fractions. The relative changes in CSA content of lipoproteins may offer an explanation for differences in drug effect with multiple dosing.