Search

Background/Purpose: Treatment of Type 2 diabetes (T2D) remains an unmet need, particularly a medication with low toxicity. BTI320 (SugarDown®) is fractionated galactomannan with inhibitory activity on carbohydratehydrolyzing enzymes. The primary objective of this study was to investigate the efficacy and safety of BTI320 on glycemic control in T2D. Subjects/Methods: This was a double-blind, placebo-controlled, multi-center study in 60 T2D adults. Subjects ingested 4 g BTI320 or placebo 10 minutes before meals 3 times daily for 12 weeks. The primary endpoint was the change from Baseline to Week 12 in 2-hr post-prandial glucose (PPG) AUC between groups. Results/Conclusion: A consistent trend was observed in favor of BTI320 vs. placebo in change from Baseline at Week 12 in 2-hr PPG AUC (-795.00 vs. -228.75 mg/dL*min), HbA1c (-0.7% vs. +1.1%), lipids, weight/BMI, and blood pressure. At Week 12, BTI320 had more subjects with stable glucose levels (84.6% vs. 79.2%). According to CGM, the BTI320 group had more subjects with stable glucose levels (84.6 vs. 79.2%) and BTI320 subjects experienced relative hypoglycemia for shorter duration than placebo consistently across all visits. No differences were observed in AE profiles between groups. BTI320 was proven to be efficacious and safe in T2D. This study is registered at ClinicalTrials.gov (NCT03655535).

BTI320 is a proprietary fractionated mannan polysaccharide being studied for attenuation of postprandial glucose excursion. The apparent blood glucose‐lowering effect of this compound is effective in lowering postprandial hyperinsulinemia, participating in the metabolic regulation of other lipid molecules; the consequence of this activity is yet to be validated with BTI320 with respect to the risk of cardiovascular disease. The primary objective of the study was to determine the postprandial glucose and insulin responses to 3 test meals containing rice alone or consumed with BTI320 (study A) or 3 test meals (SpriteTM) alone or consumed with BTI320 (study B). Twenty overweight but otherwise healthy volunteers, 4 female and 6 male (mean age 29 years, BMI 27–28 kg/m2) in study A and 6 female and 4 male (mean age 32 years, BMI 25‐32 kg/m2) in study B participated in the BTI320 evaluations. Standardized postprandial response methodology was utilized. In study A the addition of 6‐ and 12‐g BTI320 tablets reduced postprandial glucose responses to white rice by 19% and 32% and reduced postprandial insulin responses by 16% and 24%, respectively (P ≤ .05). In study B 2.6 and 5.2 g BTI320 reduced the glycemic index by 10% and 14%, respectively, and led to 14% and 18% decreases in the insulinemic index of the soft drink (P ≤ .05). These 2 studies demonstrated that the consumption of BTI320 before carbohydrate food or sugary beverage significantly reduced postprandial glucose levels and insulin responses to that meal or beverage in a dose‐dependent manner.

Delafloxacin, a fluoroquinolone, has activity against Gram‐positive organisms including methicillin‐resistant S aureus and fluoroquinolone‐susceptible and ‐resistant Gram‐negative organisms. The intravenous formulation of delafloxacin contains the excipient sulfobutylether‐β‐cyclodextrin (SBECD), which is eliminated by renal filtration. This study examined the pharmacokinetics and safety of SBECD after single intravenous (IV) infusions in subjects with renal impairment. The study was an open‐label, parallel‐group, crossover study in subjects with normal renal function or mild, moderate, or severe renal impairment, and those with end‐stage renal disease undergoing hemodialysis. Subjects received 300 mg delafloxacin IV or placebo IV, containing 2400 mg SBECD, in 2 periods separated by ≥14‐day washouts. SBECD total clearance decreased with decreasing renal function, with a corresponding increase in area under the concentration‐time curve (AUC0‐∞). After IV delafloxacin 300 mg administration, SBECD mean total clearance was 6.28 and 1.24 L/h, mean AUC0‐∞ was 387 and 2130 h·μg/mL, and mean renal clearance was 5.36 and 1.14 L/h in normal and severe renal subjects, respectively. Similar values were obtained after IV placebo administration. In subjects with end‐stage renal disease, delafloxacin 300 mg IV produced mean SBECD AUC0‐48 values of 2715 and 7861 h·μg/mL when dosed before and after hemodialysis, respectively. Total SBECD clearance exhibited linear relationships to estimated glomerular filtration rate and creatinine clearance. Single doses of IV delafloxacin 300 mg and IV placebo were well tolerated in all groups. In conclusion, decreasing renal function causes reduced SBECD clearance and increased exposures, but SBECD continues to exhibit a good safety and tolerability profile in IV formulations.

Delafloxacin is a novel anionic fluoroquinolone with robust activity against Gram-positive, Gram-negative, atypical, and anaerobic bacteria, including methicillin-resistant S aureus. Delafloxacin is currently being studied for the treatment of acute bacterial skin and skin structure infections and community-acquired pneumonia. This was a phase 1, open-label pharmacokinetic and safety study of a single intravenous dose of 300 mg delafloxacin in subjects with mild, moderate, and severe hepatic impairment (Child-Pugh class A, B, and C, respectively) compared with matched healthy controls. The effects of hepatic impairment were assessed by ANOVA of log-transformed values for AUC0-∞ , Cmax , and systemic clearance, with hepatic group as a fixed effect. Mean AUC0-∞ and Cmax in each impairment group were not significantly different from those of the pooled healthy subjects (P > 0.05). The 90% confidence interval (CI) of the percentage ratios of least-squares means of AUC0-∞ did not indicate significant differences between the impairment groups and pooled healthy controls: Child-Pugh class A (mild) 114.4 (CI: 95.6, 137.0), Child-Pugh class B (moderate) 114.8 (CI: 95.9, 137.4), and Child-Pugh class C (severe) 115.1 (CI: 96.1, 137.8). A single IV infusion of delafloxacin was generally well tolerated in all treatment groups. The exposure and clearance of delafloxacin in subjects with mild, moderate, or severe hepatic impairment did not significantly differ from those of pooled, matched healthy subjects. Based on these pharmacokinetic data, dose adjustment of delafloxacin in the presence of hepatic impairment is not needed.

We report novel polymyxin analogues with improved antibacterial in vitro potency against polymyxin resistant recent clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa . In addition, a human renal cell in vitro assay (hRPTEC) was used to inform structure-toxicity relationships and further differentiate analogues. Replacement of the Dab-3 residue with a Dap-3 in combination with a relatively polar 6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl side chain as a fatty acyl replacement yielded analogue 5x, which demonstrated an improved in vitro antimicrobial and renal cytotoxicity profiles relative to polymyxin B (PMB). However, in vivo PK/PD comparison of 5x and PMB in a murine neutropenic thigh model against P. aeruginosa strains with matched MICs showed that 5x was inferior to PMB in vivo, suggesting a lack of improved therapeutic index in spite of apparent in vitro advantages.

Objective The aim of the study was to compare all-cause adverse events (AEs) and those caused by intravenous (IV) catheter-site complications (IVCSCs) using data from a previously published study of the use of linezolid or vancomycin for treatment of complicated skin and skin structure infections (cSSSI) suspected or proven to be caused by methicillin-resistant Staphylococcus aureus. Methods To examine the incidence of AEs caused by the 2 antibiotic treatments, we conducted a post hoc analysis of data from a prospective, open-label, randomized, multicenter phase 4 study. Patients were randomized to treatment with either oral (PO) or IV linezolid 600 mg every 12 hours or with IV vancomycin 15 mg/kg every 12 hours with dose adjustment as needed. Study treatment was administered for 7 to 14 days. We excluded patients with baseline bacteremia (n = 11) and those who started on PO linezolid (n = 215). We analyzed data only from patients who received at least 1 dose of IV study medication. Results Patient demographics and types of cSSSI were comparable among patients receiving linezolid (n = 315) and vancomycin (n = 511). Mean durations of IV therapy for patients receiving linezolid and vancomycin were 4.5 days and 7.6 days (1,418 and 3,884 patient-days, respectively). All-cause AEs were reported in 50% and 51% of patients in the linezolid and vancomycin groups, respectively; all-cause IVCSCs were reported in 2% and 7%, respectively. Treatment-related IVCSCs were reported in 1 patient in the linezolid group and 16 patients in the vancomycin group. Conclusions The overall rate of AEs was similar among patients receiving linezolid and vancomycin, but AEs caused by IVCSCs were more frequent among patients receiving vancomycin and rare episodes of bacteremia and sepsis were more common in the linezolid group.

BACKGROUND When hospital-acquired or ventilator-associated bacterial pneumonia (HABP/VABP) is caused by gram-positive and gram-negative pathogens or both (mixed infections), the adequacy of gram-negative coverage (GNC) can confound the assessment of a gram-positive agent under study. This analysis examines the influence of gram-negative infections and the adequacy of GNC on clinical efficacy and all-cause mortality in the telavancin HABP/VABP phase 3 ATTAIN trials (Assessment of Telavancin for Treatment of Hospital-Acquired Pneumonia). METHODS This post hoc analysis evaluated 3 patient groups from ATTAIN: (1) gram-positive-only infections, (2) gram-positive-only and mixed infections-adequate GNC, and (3) gram-negative-only infections and mixed infections with inadequate GNC. For each, clinical efficacy at test of cure and all-cause mortality at day 28 were compared for telavancin and vancomycin. RESULTS/CONCLUSIONS In the ATTAIN safety population there were 16 more deaths in the telavancin arms than in the vancomycin arms. Of these, 13 were in patients with gram-negative-only infections (n = 9) or with mixed infections and inadequate GNC (n = 4) and all had estimated baseline creatinine clearances of

Two studies were conducted in HIV-infected subjects to assess the potential for azithromycin to interact with zidovudine and dideoxyinosine. Both studies used 12 subjects. The zidovudine study dosed subjects with 1200 mg/day of azithromycin (n = 7) (later changed to 600 mg/day [n = 5]) for Days 8 to 21 of a 21-day course of 100 mg, five times/day of zidovudine. Subjects treated with 200 mg of dideoxyinosine twice daily for 21 days received 1200 mg of azithromycin or an equivalent amount of placebo/day for Days 8 to 21. Antiretroviral plasma and urine sampling were conducted on Days 1, 7, and 21 for zidovudine and on Days 7 and 21 for dideoxyinosine. Peripheral mononuclear cells were also collected for quantitation of phosphorylated zidovudine. Azithromycin had no significant impact on the C max and A UC of zidovudine, although it significantly decreased the zidovudine t max by 44% and increased the intracellular exposure to phosphorylated zidovudine by 110%. Azithromycin had no significant effect on dideoxyinosine pharmacokinetics. Based on the results of these studies, it is concluded that azithromycin may be safely coadministered with both zidovudine and dideoxyinosine.

Background: Trovafloxacin is a new fourth-generation fluoroquinolone whose pharmacokinetics and in vitro activity suggest that it is well suited for antibiotic prophylaxis in elective hysterectomy. Methods: In a randomized, double-blind, multicenter study, parallel groups of women 18 years of age or older received either 200 mg trovafloxacin by mouth and intravenous (IV) placebo or 2 g cefoxitin by IV infusion and placebo by mouth before elective vaginal or abdominal hysterectomy for nonmalignant disease. Results: In the 103 and 97 patients in the trovafloxacin and cefoxitin groups, respectively, who were evaluable for efficacy, the prophylactic success rates at hospital discharge (96% in both groups) and 30 ± 6 days after hysterectomy (88% and 91% in the trovafloxacin and cefoxitin groups, respectively) were statistically equivalent. Both antibiotics were well tolerated. Conclusion: A single oral 200 mg dose of trovafloxacin is as effective and safe as a standard cefoxitin parenteral regimen in the prevention of primary bacterial infection after elective vaginal or abdominal hysterectomy for nonmalignant disease.

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.

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.

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.

Mireya Wessolossky,1 Verna L Welch,2 Ajanta Sen,1 Tara M Babu,1 David R Luke21Division of Infectious Diseases, University of Massachusetts Medical School, Worcester, MA, USA; 2Medical Affairs, Pfizer Inc, Collegeville, PA, USABackground: Although invasive pulmonary aspergillosis (IPA) is more prevalent in immunocompromised patients, critical care clinicians need to be aware of the occurrence of IPA in the nontraditional host, such as a patient with chronic lung disease. The purpose of this study was to describe the IPA patient with chronic lung disease and compare the data with that of immunocompromised patients.Methods: The records of 351 patients with Aspergillus were evaluated in this single-center, retrospective study for evidence and outcomes of IPA. The outcomes of 57 patients with chronic lung disease and 56 immunocompromised patients were compared. Patients with chronic lung disease were defined by one of the following descriptive terms: emphysema, asthma, idiopathic lung disease, bronchitis, bronchiectasis, sarcoid, or pulmonary leukostasis.Results: Baseline demographics were similar between the two groups. Patients with chronic lung disease were primarily defined by emphysema (61%) and asthma (18%), and immunocompromised patients primarily had malignancies (27%) and bone marrow transplants (14%). A higher proportion of patients with chronic lung disease had a diagnosis of IPA by bronchoalveolar lavage versus the immunocompromised group (P < 0.03). The major risk factors for IPA were found to be steroid use in the chronic lung disease group and neutropenia and prior surgical procedures in the immunocompromised group. Overall, 53% and 69% of chronic lung disease and immunocompromised patients were cured (P = 0.14); 55% of chronic lung patients and 47% of immunocompromised patients survived one month (P = 0.75).Conclusion: Nontraditional patients with IPA, such as those with chronic lung disease, have outcomes and mortality similar to that in the more traditional immunocompromised population.Keywords: Aspergillus, moulds, intensive care units, chronic lung disease, antifungals

Background Incorporation of the solubilizing excipient, sulfobutylether-β-cyclodextrin (SBECD), in the intravenous (IV) formulation of voriconazole has resulted in the recommendation that this formulation be used with caution in patients with creatinine clearances (Clcr) Methods A total of 128 patients aged 11–93 years who had a baseline Clcr cr) and Clcr levels while on therapy were compared with baseline values and between groups. Results The groups had similar characteristics apart from the larger proportion of females that received fluconazole. Baseline Scr was higher in those receiving caspofungin, but maximal increases of Scr and decreases in Clcr were greatest for the fluconazole group. Acute kidney injury (AKI), assessed by RIFLE criteria, was more frequent in the fluconazole vs. the caspofungin group (p Conclusions Treatment of fungal infections in patients with compromised renal function with an SBECD-containing antifungal agent was not associated with AKI in clinical practice. Since the infecting organism was associated with AKI, decision on which antifungal to use should be determined by susceptibilities to the organism and not the incorporation of SBECD in the IV formulation.

Background. The disposition of sulfobutylether-bcyclodextrin (SBECD), the solubilizing excipient in intravenous (IV) voriconazole, was assessed in seven male subjects with end-stage renal disease on hemodialysis and six subjects with normal renal function. Methods. All subjects received twice-daily IV voriconazole at the standard voriconazole dose [6 mg/kg (96 mg/kg SBECD) every 12 h (Q12h) on Day 1 followed by 3 mg/kg (48 mg/kg SBECD) Q12h on Days 2–4, with a single IV dose on the morning of Day 5]. Subjects were sampled at selected pre-dose trough times, at selected times after infusions and intensively on Day 3 (non-dialysis) and Day 4 (dialysis with high-flux membranes). Compartmental analyses were performed by NONMEM. Results. SBECD disposition was characterized by a twocompartment model. In renal failure, mean central (V1) and peripheral compartment volumes (V2) were 9.9 and 6.5 L, respectively. In normal subjects, V1 and V2 were 9.6 and 5.2 L, respectively; SBECD clearance (CL) was 130 mL/min. CL in renal failure off-dialysis was 2.6 and 48 mL/min during dialysis; mean half-life decreased from 79 to 5 h during dialysis (normal subjects: 2.1 h). Conclusion. Hemodialysis can significantly reduce levels of SBECD in subjects with end-stage renal disease.

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.

Despite its use in commercially available drugs such as intravenous voriconazole, there is little known in the medical literature about the clinical pharmacology of the solubilizing agent, sulfobutylether-beta-cyclodextrin (SBECD). This paper summarizes all known data on SBECD pharmacokinetics and safety. In animals, volume of distribution approximates extracellular water volume and clearance is determined by the glomerular filtration rate. SBECD does not have any apparent effects on cardiovascular or respiratory systems, nor on autonomic and somatic functions in animals. In 1- and 6-month studies in rats and dogs, the most noteworthy findings were renal tubular vacuolation and foamy macrophages in the liver and lungs. Mild toxicity in the kidney and liver as a consequence of vacuolation occurred in rats at the maximum dose of 3000 mg/kg, which is approximately 50-fold greater than the SBECD dose typically administered in man. Doses up to 1500 mg/kg produced no histopathological evidence of toxicity in dog kidneys. SBECD has also been studied in healthy volunteers and subjects with renal dysfunction. Whereas plasma SBECD levels accumulate in those with renal compromise, there were no deleterious effects on renal function. Nonetheless, serum creatinine levels should be monitored in subjects with renal compromise receiving multiple doses of SBECD.

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.

Dose-limiting nephrotoxicity has hampered the clinical usefulness of amphotericin-B (AmpB). Recently, vascular decongestants, such as pentoxifylline, have shown benefit in reducing drug-associated renal damage of AmpB in rats. The present study investigated a dose-dependent protection of a structurally similar methylxanthine, HWA-448, in the candidiasis rat model given a single dose of AmpB. Forty-eight hours after inoculation with Candida albicans, each rat was treated with 0.8 mg/kg of AmpB or sterile water; animals were further randomized to receive 0.5, 1, 5, or 10 mg/kg i.v. of HWA-448 or saline given every 12 h for 3 doses. Kidney fungal counts, morphology, and renal function were compared between treatment groups upon completion of the study. Rats administered AmpB with HWA-448 had markedly improved renal function compared with those given AmpB alone; these effects were independent of the administered dose of HWA-448. The antifungal effect of AmpB was not impaired with concomitant HWA-448. Marked accumulation of granulomas and organisms was found in all rat groups. In summary, coadministration of low doses of HWA-448 attenuated the dose-limiting nephrotoxicity without impairing the antifungal effect of AmpB.

The post insult administration of vascular decongestants has resulted in attenuation of experimental acute renal failure (ARF) following the introduction of various nephrotoxins including drugs, heavy metals, and endotoxin. In the present study, the dose-dependent effects of a novel methylxanthine, HWA-138, were studied in the glycerol-induced murine model of ARF. Renal function, assessed by serial inulin clearances at 24 and 48 h after glycerol injection, urinary electrolyte excretion rates, and renal morphology, was compared between controls and those given glycerol and single i.v. doses of 0.1, 0.5, 1.0, 5.0, and 10.0 mg/kg of HWA-138, or physiologic saline. Whereas significant renal dysfunction was found in all animal groups given glycerol, the mean inulin clearance values of animals given HWA-138 1 mg/kg closely approximated values found in control rats. There were no changes in renal electrolyte excretion rates in animals given HWA-138 compared with relative natriuresis found in untreated glycerol ARF rat. Although a modest decrease in medullary congestion was associated with rats given 1 mg/kg of HWA-138, there was no obvious structural improvement found with HWA-138. The present data provide further evidence of the potential of methylxanthines in the glycerol-ARF murine model.

In clinical practice, estimations of renal function are commonly used to calculate the appropriate dose for drugs that are renally cleared. Continuous-infusion inulin clearance (CLIN), 4-hour creatinine clearance (CLCR,m), and 24-hour creatinine clearance (CLCR,a) were measured in 109 subjects (86 men and 23 women) with varying degrees of stable renal function (CLIN, 6 to 209 ml/min) and compared with CLCR values as predicted by five equations on the basis of plasma creatinine concentrations, age, weight, and/ or height. The CLCR,m was positively correlated with CLIN (r = 0.92; p < 0.0001) but exceeded CLIN by 15% between the range of 30 and 209 ml/min (CLIN). Similarly, CLCR,a correlated well with both CLCR,m (r = 0.84; p < 0.0005) and CLIN (r = 0.84; p < 0.0001). The relative role of tubular secretion in the overall clearance of creatinine increased with declining CLIN and exceeded 40% when CLIN was below 30 ml/min. CLCR estimated by the Cockcroft-Gault and Mawer methods did not significantly differ from either CLCR,m or CLCR,a, whereas the other equations generally underestimated CLCR. Among the numerous mathematical equations, CLCR as estimated by the method proposed either by Mawer or Cockcroft and Gault was the best predictor of CLIN (CLIN = 1.05CLCR −18.38 or CLIN = 1.12CLCR −20.60, respectively; r = 0.81; p < 0.0001). The present data support the use of estimator equations proposed by Cockcroft and Gault or Mawer for rapid estimation of renal function in the clinical setting. Clinical Pharmacology and Therapeutics (1990) 48, 503–508; doi:10.1038/clpt.1990.186

The mechanism of amphotericin B (AmB) nephrotoxicity may be related to changes in vascular flow within the kidney, resulting in significant decreases in glomerular filtration rate and tubular integrity. The toxic and antifungal effects of AmB with and without the vascular decongestants pentoxifylline (PTX) and a methylxanthine analog, HWA-138, were compared in the murine model of candidiasis. At 48 h after inoculation with Candida albicans, half of the rats received a single intravenous 0.8 mg/kg dose of AmB whereas the others were administered sterile water. After 1 h, rats were randomized to receive three doses of 45 mg/kg PTX intraperitoneally, 5 mg/kg HWA-138 intravenously, or saline every 12 h. Renal function and Candida cell counts were estimated 24 h after AmB administration. Mean inulin clearances were significantly greater in rats coadministered AmB and PTX or HWA-138 than in AmB controls. Candida counts in kidneys of rats administered HWA-138 were similar independent of AmB therapy and markedly reduced compared with other groups. Whereas both vascular decongestants prevented drug-associated renal toxicity, the coadministration of AmB with HWA-138 resulted in a profound antifungal effect.

The combined use of lovastatin, a hypolipidemic agent effective in the reduction of cholesterol levels, and the lipophilic immunosuppressant, cyclosporine, was studied in the obese rat model. Pharmacokinetics, immunosuppressive activity, lipid levels, and creatinine clearances were compared between groups administered drug-free vehicle, lovastatin or cyclosporine alone, or concomitant cyclosporine and lovastatin. All groups were pre-treated with either oral lovastatin 2.5 mg kg-1 day-1 or propylene glycol vehicle for 1 week. Although no differences in renal function were observed in rat groups administered cyclosporine or lovastatin alone, there was a significant reduction in baseline creatinine clearance following combination therapy compared to placebo controls (70 +/- 18 vs 121 +/- 16 per cent of baseline; p less than 0.05). No differences in trough cyclosporine concentrations were observed between groups. Similarly, mean areas under the whole blood concentration-time profiles were not significantly different with or without concomitant lovastatin (61823 +/- 27295 vs 41470 +/- 10312 ng h ml-1; p = 0.13). No differences in systemic clearance or volume of distribution of parent cyclosporine were observed with combination therapy. Furthermore, lipid levels and T-lymphocyte activity were unchanged with the addition of lovastatin. Per cent increases in creatine kinase were significantly correlated with percentage drop in baseline renal function, suggesting the development of rhabdomyolysis. The present data support the interaction between cyclosporine and lovastatin observed clinically, resulting in acute renal dysfunction. Caution should be exercised in their combined use.

The pharmacokinetics, tissue distribution, and toxicity of free amphotericin B (free AmB) or amphotericin B encapsulated in liposomes (L-AmB) were characterized in experimental diabetic rats and compared with data obtained from nondiabetic rats. After 7 days of insulin-controlled diabetes or saline, each rat was administered a single intravenous bolus dose of free AmB or L-AmB (0.8 mg/kg body weight). Blood samples were obtained before administration and serially thereafter for the assessment of serum pharmacokinetics, nephrotoxicity, and biochemical parameters. Before drug treatment, diabetic rats demonstrated marked increases in serum cholesterol and triglyceride levels compared with levels in nondiabetic rats. A significant increase in serum creatinine levels was observed in nondiabetic rats given free AmB but not in other groups. Whereas AmB pharmacokinetics were significantly altered in diabetic rats administered free AmB, no kinetic differences were found between groups given L-AmB. Renal AmB levels were markedly increased in nondiabetic rats given free AmB compared with those in all other groups. Furthermore, significantly greater concentrations of free AmB were found in lung tissue of rats administered L-AmB independent of disease state. Hepatic levels of AmB were reduced in diabetic rats administered free AmB. The disposition and nephrotoxicity of L-AmB were independent of vascular lipid composition.

The 3-day course of azithromycin (AZM) 500 mg/d was introduced to the US market in June 2002.The objective of this study was to evaluate changes in health-related quality of life (HRQOL) as measured by the St. George's Respiratory Questionnaire (SGRQ) over a 1-month period in patients receiving a 3-day course of AZM for bacterial acute exacerbation of chronic bronchitis (AECB).This was a prospective, multicenter, observational study evaluating outpatient adults with AECB who received either 3 days of AZM 500 mg/d or 5- to 14-day courses of other antibiotics (usual care [UC]) as directed by the clinician. Patients completed 2 HRQOL instruments-the SGRQ and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36)-at baseline, day 14, and end of study (EOS) at days 24 to 28. In addition, patients kept a diary for the first 14 days after initiating antibiotic therapy.One hundred twenty-eight patients (57 AZM, 71 UC) were clinically evaluable. There were no significant differences between treatment groups in clinical presentation or baseline demographics, with the exception of a higher percentage of patients with diabetes mellitus in the UC group compared with the AZM group (16.9% vs 3.5%; P = 0.02). Both groups reported similar improvements in signs and symptoms, absenteeism, concomitant respiratory medication use, resource utilization, compliance, and treatment satisfaction as reported in the patient diary. The AZM group reported statistically significant improvement (simple contrasts for end of study vs baseline) in SGRQ measures (total score, P0.001; symptoms, P = 0.031; activity, P0.001; impacts, P0.001) and the SF-36 mental and physical summary components, compared with baseline (both, P0.001). Similarly, the UC group reported significant improvement in all SGRQ measures and in the SF-36 physical component score (P0.01), but not in the SF-36 mental component score, compared with baseline. At EOS, 80.0% of AZM patients and 59.0% of UC patients had aor =4-point improvement on the SGRQ total score; however, this difference was not statistically significant in the multivariate analysis. In addition, 89.5% of AZM patients and 89.9% of UC patients were satisfied or very satisfied with their treatment (P = NS). Resource utilization was similar between the groups.In this observational study, patients with AECB treated with a 3-day course of AZM experienced significant improvements in HRQOL as measured by a change ofor =4 points on the SGRQ and SF-36 physical and mental component scores versus baseline.

HWA-138, a pentoxifylline analog, has been shown to increase yeast urinary clearance and to reduce yeast counts in the kidneys of rats infected with Candida albicans. Furthermore, HWA-138 has also been shown to prevent amphotericin B-induced acute renal failure in rats. We report here on the effects of HWA-138 alone and in combination with amphotericin B in the treatment of systemic candidiasis in mice. When single doses of HWA-138 were administered intravenously (10, 25, or 50 mg/kg of body weight) into infected mice, no significant improvement in survival was observed. In infected mice treated intravenously with multiple doses of HWA-138 (10, 25, or 50 mg/kg once daily for 5 consecutive days), a significant increase in survival time was seen only in animals also receiving 25 mg of HWA-138 per kg (14 +/- 3 days test versus 9 +/- 1 days control; P less than 0.05). The coadministration of subtherapeutic doses of amphotericin B and HWA-138 resulted in increased survival time. Combination therapy with amphotericin B (0.1-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) resulted in a significant increase in survival time over controls (19 +/- 4, 19 +/- 5, and 21 +/- 9 days, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P less than 0.05). Combination therapy with amphotericin B (0.2-mg/kg single dose) and HWA-138 (10-, 25-, or 50-mg/kg multiple doses) also resulted in a significant increase in survival time over controls (24 +/- 6, 24 +/- 6, and 24 +/- 6, respectively, versus 9 +/- 3 days; P < 0.05). Variance analysis of these findings indicate synergistic activity between amphotericin B and HWA-138 in the treatment of experimental candidiasis in mice.

We describe a modification of the commercially available cyclosporine (CAS) 3H-RIA kit, allowing detection of drug in lipoprotein fractions obtained by ultracentrifugation. Sodium bromide solutions containing the lipoprotein fractions were dried and reconstituted with drug-free plasma. Methanolic extractions were centrifuged, and 250 microL of the supernate was dried and reconstituted with 50 microL of methanol. Buffer, radioactive tracer, and monoclonal antibody were then added and incubated for 2 h at 4 degrees C. Samples were subjected to charcoal de-activation and then centrifuged, and the radioactivity in the supernate was counted. The limit of detection of CSA was 2.5 micrograms/L; analytical recovery was between 97.5% and 101.3%. Within- and between-day CVs were less than 9%. We conclude that the present method may be beneficial for therapeutic drug monitoring of CSA in lipoprotein fractions.

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.

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.

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 a 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 μg/ml. Mean values for area under the serum concentration versus time curve were 1.27 ± 0.65 and 7.14 ± 1.34 μg · 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) of 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. Clinical Pharmacology & Therapeutics (1997) 61, 641–648; doi

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.

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.

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.

Although suprofen has been associated with the development of acute renal failure in greater than 100 subjects, the mechanism of damage remains unclear. The direct nephrotoxic effects of a single dose of 15 mg of suprofen were compared in the recirculating isolated rat kidney perfused with cell-free buffer with or without the addition of 5 mg/dL of uric acid. There were no significant differences in renal sodium excretion, oxygen consumption, or urinary flow rates in kidneys perfused with suprofen compared with the drug-free control groups. In contrast, a significant decline in glomerular filtration rate was found after the introduction of suprofen to the kidney perfused with uric acid; no changes were found with suprofen in the absence of uric acid. A significant decrease in the baseline excretion rate of uric acid was found in rats given suprofen, compared with drug-free controls. However, the fractional excretion of uric acid was unchanged between the groups over the experimental period. In summary, suprofen causes acute declines in renal function, most likely by directly altering the intrarenal distribution of uric acid.

The influence of food and water intake on renal function was assessed by comparisons between the hyperphagic Zucker obese rat and its lean littermate, which demonstrates nocturnal dominance in activity. Serum creatinine and cortisol levels, creatine kinase activities, creatinine and urine clearances, and sodium and potassium excretion rates were measured over a 24-hour period in both lean and obese rats (n = 24 each). Six rats in each group were studied every 8 h to permit characterization over a 12-hour light/dark cycle at 2-hour intervals. Urine and creatinine clearances were increased in lean rats during the dark phase coincident with onset of eating. Similarly, renal sodium and potassium excretion rates were markedly increased during the dark cycle, despite relatively constant serum potassium and sodium levels over the 24-hour period. In contrast, no circadian patterns in urine and creatinine clearances were found in the obese rat, which exhibits continuous feeding habits throughout the 24-hour period. Moreover, renal electrolyte excretion in the obese rat was modestly increased during the dark cycle, unlike the significant differences over time observed in lean rats. Serum creatinine levels were increased during the dark cycle in both rat groups. Creatine kinase activity, a measure of ambulatory activity, was constant in lean rats during the study period. Although creatine kinase activity was increased in obese rats during the dark cycle, no correlations with renal functional parameters were found. These results indicate that differences in food and water intake are significant determinants in diurnal cyclic changes in renal function.

Although a significant interaction between cyclosporine and amphotericin-B (AmpB) has been observed clinically, these findings have not been duplicated in animal studies. A total of 64 male albino rats were used in single- and multiple-dose experiments with AmpB and CsA in the absence or presence of systemic Candida infection. No significant differences in glomerular filtration rate were found in rats given single i.v. doses of AmpB 1 mg/kg compared with AmpB and CsA. Furthermore, rats given i.p. AmpB 1 mg/kg and CsA 10 mg/kg daily for 10 days showed no significant differences in GFR compared with animals given CsA alone. Morphology and CsA whole-blood pharmacokinetics were not different between groups administered single-dose CsA, AmpB, or the combination; similarities also existed with multiple-dose studies. In an attempt to mimic the clinical setting, 2 groups of rats were administered i.p. CsA 10 mg/kg/day for 10 days followed by inoculation of Candida albicans. After 48 hr, a single i.v. dose of AmpB 1.0 mg/kg was associated with a 33% decline in GFR compared with those given sterile water (P less than 0.05). Systemic clearance of CsA was markedly reduced in candidiasis rats administered AmpB compared with controls given sterile water. A significant reduction in renal Candida colony-forming units was found in rats given CsA and AmpB compared with those administered CsA alone. These data suggest that the presence of systemic Candida highlights the interaction of CsA and AmpB in the rat model.

The effects of pentoxifylline, a new methylxanthine with marked hemorrheologic properties, were studied following brief renal artery occlusion in the isolated rat kidney model perfused with cell-free Krebs-Henseleit buffer. Anuria was observed in 3 of 6 control kidneys within 5 min after reperfusion; urine flow was maintained in all rat kidneys perfused with pentoxifylline (2500 ng/ml). Glomerular filtration rate was significantly greater in kidneys administered pentoxifylline compared with controls following 40 min of postocclusion reperfusion (460 +/- 100 vs. 100 +/- 110 microliters/min/gKW; P less than 0.01). Pretreatment of kidneys with indomethacin, a nonspecific cyclooxygenase inhibitor, blocked the protective effects of pentoxifylline in this setting. These data suggest that the addition of pentoxifylline may prevent hypoxia-related changes in renal function of transplanted kidneys. Stimulation of renal prostaglandin synthesis, as well as an interaction at the level of the adenosine receptors, were most likely responsible for the observed beneficial effects of pentoxifylline.

The mechanism of acute nephrotoxicity following the administration of amphotericin B (AmpB) remains unclear despite a number of studies describing hypermagnesuria, hyperkaluria, and hemodynamic changes. The present experiments attempted to elucidate the mechanism by using a novel hemorheologic probe, pentoxifylline (PTX). Acute studies were performed with rats given single intravenous doses of AmpB (1 mg/kg of body weight) with or without intraperitoneal PTX (45 mg/kg). Renal function, assessed by inulin clearance (CLIN) and electrolyte handling, and morphology were compared with those of controls given sterile water and PTX. A significant decrease in CLIN not observed in rats given AmpB and PTX or in the controls was found in rats given AmpB. Electrolyte handling was not different among groups. Whereas pronounced (3 and 4+ on a scale of mild to significant [1+ to 4+]) vascular congestion was found in rats given AmpB, rats coadministered PTX had mild (1 and 2+) medullary and glomerular vascular congestion. In chronic studies, intravenous AmpB (1 mg/kg per day) or sterile water was coadministered with intraperitoneal PTX (45 mg/kg every 12 h) or saline for 10 days. Mean CLIN of rats coadministered AmpB and PTX was not significantly different from that of PTX control rats (1.61 +/- 0.19 versus 1.31 +/- 0.29 ml/min per g of kidney weight). A 46% decline in CLIN was found in rats treated with AmpB and saline (P less than 0.05). Renal sodium and potassium excretions were increased in both AmpB-treated groups compared with controls. Coupled with histologic evidence of the acute studies, these data suggest that the benefit of PTX in the prevention of AmpB-induced nephrotoxicity is, in part, due to vascular decongestion.

The pharmacokinetics and renal toxicity of two liposomal intravenous preparations of cyclosporine (CSA) (A, dimyristoylphosphatidylcholine (DMPC): stearylamine molar ratio 7:1; and B, DMPC: dimyristoylphosphatidylglycerol molar ratio 4:1) were assessed in the murine model and compared to the commercially available intravenous formulation of CSA (IV) and drug-free controls. No significant differences in steady-state area beneath the whole blood concentration-time curves were found between formulations and IV following 10 mg/kg per day CSA for 10 days. However, the apparent volume of distribution was significantly greater in A compared to B or IV formulations (13.82 ± 2.9 vs. 7.23 ± 3.98 and 7.67 ± 3.01 l/kg, p < 0.05), most likely due to the significantly prolonged biologic half-life of this formulation. Although the glomerular filtration rate was not significantly different between A and saline controls (1056 ± 536 and 1130 ± 550 μl/min per g KW, respectively), dosing with B or IV resulted in significant impairment (522 ± 429 and 572 ± 353 μl/min per g kidney weight (KW), respectively; p < 0.05). Triglyceride levels remained unchanged in all groups. However, cholesterol concentrations were significantly increased compared to baseline in rats administered formulation A (98 ± 31 vs. 70 ± 19 mg/dl; p < 0.05). In summary, dosing of liposomal formulation A resulted in equivalent concentrations of CSA as the IV formulation without the dose-limiting nephrotoxicity. These data offer a nontoxic delivery system for intravenous CSA.

The disposition of labetalol was assessed in 16 patients on dialysis after intravenous dosing with 0.7 to 1.0 mg/kg during an interdialytic period and just before hemodialysis (n = 8) and during continuous ambulatory peritoneal dialysis (CAPD) (n = 8). The plasma concentration time data exhibited triexponential decay in all patients. The terminal t 1/2 of labetalol was 12.90 +/- 4.68 hours, the total body clearance was 1198.2 +/- 249.4 ml/min, and the AUC was 921.4 +/- 175.2 ng hr/ml during the interdialytic period. No significant changes were observed in these parameters after dosing with labetalol just before dialysis. The hemodialysis clearance of labetalol was 30.67 +/- 5.49 ml/min, and only 0.189 +/- 0.042 mg of labetalol was removed by hemodialysis. The terminal t 1/2 averaged 13.05 +/- 6.32 hours during CAPD. Steady-state volume of distribution, total body clearance (Clp), and CAPD clearance were 10.39 +/- 2.77 L/kg, 1397.2 +/- 372.3 ml/min, and 1.94 +/- 0.65 ml/min, respectively. The fraction of the dose recovered in the CAPD dialysate during the 72-hour study period was 0.14% +/- 0.09%. The decay of the antihypertensive effect of labetalol was gradual and paralleled the decline in the log plasma concentration. There was a significant correlation between labetalol plasma concentration and the fall in supine diastolic and mean blood pressure after the interdialytic dose and during CAPD. Although labetalol is removed by dialysis, dialysis does not significantly enhance Clp.

Although the circadian pattern of cyclosporine (CSA) pharmacokinetics and toxicity has been described previously in both animal and clinical studies, the mechanism of this action is unknown. The present study compared the pharmacokinetics and experimental nephrotoxicity of chronic CSA in both the genetically-hyperlipidemic rat model and the lean litter-mate. Once daily dosing (25 mg/kg via gavage) was either at the start of the active (1900) or inactive (0700) cycle (Nov 1987 to Jan 1988). Serial serum samples following the final dose were assayed by both polyclonal (nonspecific) and monoclonal (specific for parent CSA) RIA. Renal toxicity was assessed by 24-hr creatinine clearances, fractional clearances of sodium and potassium, and inulin clearances (CIN). Despite a greater than 2-fold increase in serum CSA concentrations, there were no changes in renal function in obese rats dosed at the start of the active period compared to the inactive period. Furthermore, mean CIN of the lean group administered drug at the start of the active period was not significantly different from time-matched placebo-treated lean rats. However, there was an 80% drop in CIN in rats treated with CSA at the start of the inactive period compared to control group. There were no differences in electrolyte handling. Insulin concentrations, independent of time of dosing, were markedly elevated in obese rats dosed CSA compared to placebo-treated obese or both lean groups. Serum triglyceride levels were significantly correlated with pharmacokinetic parameters of total but not parent CSA. In summary, significant differences in toxicity were observed due to time of dosing and lipid profiles. Although the mechanism of this action remains unclear, it appears that increased non-fasting serum triglyceride levels following the active period most likely reduced CSA distribution into kidney tissue preventing the dose-limiting nephrotoxicity.

Although cyclosporine (CSA) is established in the prevention of allograft rejection, its use has been associated with dose-limiting toxicities, most notably to the kidney and liver. To date, the pathogenesis of the acute form of nephrotoxicity is unclear but may be related to inhibition of vasodilatory prostaglandins resulting in vasoconstriction and ischemia. The present study investigated the coadministration of CSA with a unique hemorheologic agent, pentoxifylline (PTX), in the murine model. A total of 48 rats were orally dosed with CSA 25 mg/kg for 10 days with either PTX 45 mg/kg i.p. or saline every 12 hr. Posttreatment renal function, assessed by creatinine (CCR) and inulin (CIN) clearances and renal electrolyte handling, was compared with baseline data and between groups. In an attempt to assess prostaglandin-mediated changes in enteral absorption, oral CSA pharmacokinetics with and without PTX were compared to the pharmacokinetics of similar groups (N = 8) administered i.v. CSA. Mean CIN of rats coadministered CSA and PTX (942 +/- 214 microliters/min/g KW) was similar to control rats 884 +/- 185 microliters/min/g KW); both were significantly greater than CSA alone (537 +/- 211 microliters/min/g KW; p less than .01). Likewise, percent of baseline CCR was significantly reduced in rats treated CSA (61 +/- 24%) compared to controls 113 +/- 41%) and rats coadministered PTX (117 +/- 75%; p less than .05). No differences in percent change from baseline electrolyte handling were observed among groups. Further, no differences in CSA pharmacokinetics with or without PTX were found.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of pentoxifylline in experimental acute renal failure. The beneficial effects of post-insult administration of pentoxifylline, a novel hemorheologic agent experimentally studied in various ischemic diseases, were evaluated in two models of acute renal failure (ARF): direct nephrotoxicity (mercuric chloride 4 mg/kg via femoral vein) and hemoglobinuria (glycerol 10 ml/kg i.m.). Glomerular filtration rate (GFR) was estimated at baseline and following drug administration by creatinine clearances; tubular function was assessed by renal fractional and absolute electrolyte excretions. The incidence of mortality was decreased with a single dose of pentoxifylline 45 mg/kg (21.4%) compared to control rats (71.4%) 48 hours following induction of ARF with mercuric chloride. Although GFR and renal electrolyte excretion were significantly greater in rats given pentoxifylline compared to saline, the magnitude of difference was minimal. A return to baseline GFR was observed in the glycerol group administered a single i.p. dose of pentoxifylline 45 mg/kg (100.8 ± 54.8%) compared to saline controls (45.6 ± 22.7%; P < 0.05). No differences in renal electrolyte excretion or mortality were observed in this model. Taken together, these data suggest that pentoxifylline, administered shortly after the initiation of ARF, exerts an ameliorative effect on the course and mortality of experimental ARF. The mechanism of amelioration most likely involves the stimulation of renal vasodilator prostaglandins as well as prevention of vascular congestion.

Although cyclosporine (CsA) has been shown to cause decreased renal function in humans, the mechanisms important in cyclosporine nephrotoxicity are not well understood. Investigations of cyclosporine nephrotoxicity in animal models have been complicated by systemic toxic effects not seen in humans. In the present study, the direct renal effects of cyclosporine were investigated in the isolated perfused rat kidney (IPRK) model. Cyclosporine delivered by nontoxic liposomes had no effect on IPRK resistance, perfusate flow, inulin clearance, or fractional reabsorption of sodium, despite marked tissue accumulation of CsA (55.1 +/- 7.2 micrograms/g kidney tissue). In contrast, a 63% decrease in inulin clearance was observed following the administration of intravenous cyclosporine (0.1 ml). However, similar changes in IPRK function were seen after the administration of 0.1 ml of the intravenous cyclosporine vehicle, cremophor, suggesting that the alterations in function were secondary to the vehicle. All together, these findings suggest that cyclosporine nephrotoxicity may be secondary to renal innervation, toxic metabolites, or other systemic effects of cyclosporine not present in the IPRK.

Recent clinical studies have demonstrated the potential benefit of the T-cell-specific immunosuppressant, cyclosporine, in the treatment of Type I insulin-dependent diabetes. In the present study, steady-state cyclosporine pharmacokinetics, fasting glucose and insulin levels and renal function were examined in stable insulin-dependent diabetic rats and compared to non-diabetic rats. Mean creatinine clearance 30 days following diabetes induction was not significantly different from saline controls. Cyclosporine treatment (5 mg/kg/day i.v. for 13 days) did not significantly alter creatinine clearance in either group; however, renal function of vehicle-treated diabetic rats was markedly reduced compared to other groups. Serum insulin concentrations were significantly greater in diabetic rats treated with cyclosporine compared to the control group (35.1 +/- 22.7 vs. 16.0 +/- 8.1 microU/ml; P less than 0.05). Glucose levels were proportionately reduced in diabetic rats treated with cyclosporine. Area under the concentration-time curve, half-life and volume of distribution of cyclosporine were significantly reduced in diabetic rats compared to non-diabetic controls. In summary, the pharmacokinetics and pharmacodynamics of cyclosporine were significantly different in the insulin-dependent diabetic rat model compared to normal controls. Furthermore, short-term cyclosporine therapy reduced the extent of experimental diabetic nephropathy observed in this model.

A 2 1/2-year-old child being treated with carbamazepine (CBZ) for a seizure disorder on two separate occasions experienced elevated CBZ serum concentrations (28 and 23.2 mg/L), severe liver damage (SGOT greater than 6000 IU, SGPT greater than 5000 IU), and central nervous system manifestations (coma, lethargy, seizures). During the first episode, the time course of CBZ concentrations exhibited a nonlinear decline and was accompanied by CBZ-10,11-epoxide concentrations that were elevated 4-fold compared to normal values. Cerebrospinal fluid concentrations of CBZ and CBZ-10,11-epoxide were also elevated, although their ratios to serum concentrations did not suggest enhanced permeability of the central nervous system to these substances. The concentrations of CBZ-10,11-epoxide but not CBZ were elevated for the duration of time that the patient was comatose, suggesting that this metabolite may contribute to the neurotoxic side effects observed with CBZ therapy.

Time and feeding influences on cholesterol, triglyceride, glucose and insulin levels, and serum cholinesterase activity were assessed in a genetically-hyperlipidemic hyperphagic obese rat model, and compared with its lean litter-mate. Following a 28-day acclimation to a 12-hr light/dark cycle, blood samples were obtained every 2 hr from rats via tail bleed for a 24-hr period. Synchronization with other animal studies was established by endogenous serum cortisol levels [acrophase 18-20 hr after light onset (HALO) in both groups]. Triglycerides cholesterol, insulin and glucose levels were significantly elevated in obese versus lean rats. Obese rats were observed to feed throughout the 24-hr cycle, whereas lean litter-mates ate only during the dark cycle. No circadian rhythmicity was found in glucose levels with either rat group. Insulin levels were not correlated. Although triglyceride levels peaks at 13 HALO in lean rats, no pattern was observed in obese rats. Cholesterol levels were unchanged with time in either group. Cholinesterase activity followed a circadian rhythm in the lean, but not obese, rats with an acrophase estimated at 8 HALO. In contrast to previous reports, enzyme activity was not correlated with triglyceride levels in either rat group. Circadian similarities in insulin levels between rat groups suggest changes in insulin metabolism and/or secretion which are likely to be independent of feeding or activity. Conversely, triglyceride levels remained elevated throughout the 24-hr period in obese rats, whereas significant increases were observed in lean rats during the dark active cycle. These data suggest that triglyceride levels, and not insulin and cholesterol levels, are most likely dependent on feeding patterns.