Biomedical subjects

F M Balis

Publications and source records attributed to F M Balis.

At least 91 records · Page 5Linked to original sources

PubMed1994

Clinical and pharmacokinetic evaluation of long-term therapy with didanosine in children with HIV infection.

BACKGROUND: Didanosine has demonstrated promising antiviral activity and a tolerable toxicity profile in short term studies. We describe a cohort of HIV-infected children who were treated for a prolonged period of time with didanosine. METHODS: Children (6 months to 18 years of age) with symptomatic HIV infection or an absolute CD4 count < 0.5 x 10(9) cells/L, received oral didanosine at doses between 20 mg/m2 to 180 mg/m2 every 8 hours. Clinical, immunological, and virological parameters were assessed at least every 2 months. The pharmacokinetics of didanosine were evaluated in 85 patients. RESULTS: Previously untreated children (n = 51) and children who had received prior antiretroviral therapy (n = 52) were enrolled in the study (median time on study 22.6 months; range 2 to 48). The long-term administration of didanosine was well tolerated and no new toxicities were observed. The absolute CD4 count increased by > or = .05 x 10(9) cells/L in 28 of 87 (32%) of patients after 6 months of therapy. Responses were also sustained in 41% of these children after 3 years of therapy. Children entering the study with a CD4 count > 0.1 x 10(9) cells/L (n = 51) had a marked survival advantage (P = .00002) with an estimated survival probability after 3 years of 80% compared to 39% for children with lower CD4 counts. Although the area under the curve of didanosine increased proportionally with the dose, there was considerable interpatient variability at each dose level. There was no apparent relationship between surrogate markers of clinical outcome and plasma drug concentration. CONCLUSIONS: Didanosine was well tolerated with chronic administration, and toxicities were uncommon and usually reversible. In 41% of patients, the CD4 count increased and was maintained at the higher level even after years of treatment.

Adolescent↗

PubMed1994

Cerebral subarachnoid sampling of cerebrospinal fluid in the rhesus monkey.

A previously described rhesus monkey model with two intraventricular catheter systems was expanded to provide a means of studying drug concentrations of chemotherapeutic agents such as methotrexate (MTX) in the cerebral subarachnoid cerebrospinal fluid (CSF) following intrathecal drug injection. A continuous intraventricular infusion of MTX was started through the lateral ventricular catheter 44 h before surgical placement of the cerebral subarachnoid catheter to allow for steady-state concentrations to be attained throughout the subarachnoid space. Monkeys were anesthetized intramuscularly with ketamine hydrochloride (7 mg/kg) and xylazine (6 mg/kg) to allow placement of a temporary lumbar catheter for sampling of lumbar CSF Sodium thiopental (2.5%) was given intravenously if needed for intubation and anesthesia was maintained with isoflurane (0.5 to 1.5%) and oxygen during the surgical placement and sampling of the cerebral subarachnoid catheter. A midline incision was made over the frontal bone and a 3/8-inch trephine was used to expose the dura adjacent to the lateral midline. Following puncture of the dura with an 18-gauge spinal needle, the cerebral subarachnoid catheter (0.025-inch [i.d.] x 0.047-inch [o.d.] Silastic tube) was passed into the subarachnoid space for approximately 10 to 17 mm. The CSF from the cerebral subarachnoid catheter was collected by gravity flow Ventricular, lumbar subarachnoid, and cerebral subarachnoid CSF were collected concurrently at 44, 46, and 48 h after the start of MTX infusion. Mean ventricular, lumbar subarachnoid, and cerebral subarachnoid CSF methotrexate concentrations at steady state were 5.8, 1.0, and 1.5 mumol/L, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Desulfuration of 6-mercaptopurine. The basis for the paradoxical cytotoxicity of thiopurines in cultured human leukemic cells.

The thiopurines have a wide array of effects on purine metabolism, but the primary mechanism of cytotoxicity for both 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) appears to be incorporation of drug into DNA following conversion to the thioguanylate form. In murine leukemic cell lines exposed to a range of thiopurine concentrations in vitro, cell survival curves have displayed a phenomenon termed paradoxical cytotoxicity, defined as a decrease in cytotoxicity with increasing drug concentration. The paradoxical cytotoxicity of thiopurines has usually been attributed to concentration-dependent perturbations in the cell cycle. The present study assessed whether the paradoxical cytotoxicity of 6-MP occurred in cultured human leukemic cells, and investigated the biochemical and cell-cycle alterations occurring in these lines at thiopurine concentrations associated with the reverse of cytotoxicity. Paradoxical cytotoxicity was observed in the two human leukemic cell lines examined, but only when 6-MP concentrations exceeded 100 microM. The extent of incorporation of 6-MP metabolites into DNA as thiol-versus non-thiol-containing metabolites was analyzed by performing parallel experiments with 14C- and 35S-radiolabeled drug. With 5 microM 6-MP, approximately 50% of drug was incorporated into DNA as a thionucleotide; however, with increasing drug concentrations, the degree of thionucleotide incorporation remained unchanged or decreased, and the amount incorporated as the desulfurated metabolite (presumably adenylate or guanylate) increased. With 500 microM 6-MP, less than 10% of the drug was incorporated as the thionucleotide. Perturbations in cell cycle reflected the relative amounts of thiol- and non-thiol-containing nucleotide formed at various concentrations of 6-MP. These results suggest that thiopurines may be vulnerable to a unique mechanism of detoxification, in which a human cell can metabolize a cytotoxic drug to a comparatively potent "self-rescue" agent.

Carbon Radioisotopes↗

PubMed1993

A phase II evaluation of thiotepa in pediatric central nervous system malignancies.

BACKGROUND: Both thiotepa and its active metabolite, tepa, efficiently cross the blood-brain barrier. After intravenous administration, the cerebrospinal fluid concentrations achieved are nearly identical to those in plasma. This provides a strong rationale for testing this agent against brain tumors. METHODS: Sixty pediatric patients with recurrent primary brain tumors were treated on a multiinstitutional Phase II study of intravenous thiotepa at a dose of 65 mg/m2 administered every 3 weeks. This dose is the result of a prior pediatric Phase I trial and is significantly higher than those previously recommended. RESULTS: Three of 13 assessable patients with medulloblastoma had partial responses lasting 22, 25, and 54 weeks. Although no objective responses were observed in 16 assessable patients with malignant gliomas and 14 with brain stem gliomas, 5 of 16 and 4 of 14 patients in these respective strata had prolonged periods of stable disease (SD) lasting from 12 to more than 33 weeks. Nine assessable patients with ependymoma had no objective response, but two had SD, both for more than 33 weeks. Myelosuppression was the principle toxic effect encountered and appeared to be more severe in patients who had received prior craniospinal radiation therapy or nitrosourea therapy. CONCLUSIONS: By conventional Phase II criteria, thiotepa appears to have activity in medulloblastoma. Based on several patients with prolonged SD, it also may possess some limited activity in brain stem and malignant gliomas. The steep in vitro dose-response curve of thiotepa and the long durations of response or SD observed with the dose reported here suggest that moderate-dose to high-dose thiotepa with cytokine support or autologous bone marrow rescue may be associated with an improved response rate to this agent.

Adolescent↗

PubMed1993

Variability in the oral bioavailability of all-trans-retinoic acid.

BACKGROUND: Orally administered all-trans-retinoic acid (all-trans-RA) can induce complete remission in a high proportion of patients with acute promyelocytic leukemia. A previous pharmacokinetic study in patients with acute promyelocytic leukemia raised the possibility that the absorption of orally administered all-trans-RA is a saturable process that would have significant clinical impact on dosing strategies. PURPOSE: This study was specifically designed to examine the saturability of all-trans-RA absorption by measuring the effect of doubling the oral dose of all-trans-RA on plasma drug concentration in patients receiving long-term oral therapy. METHODS: Six patients with solid tumors received oral doses of 10-mg gelatin capsules of all-trans-RA. Patients were studied on 2 consecutive days after they received 28 days of all-trans-RA administered as two daily 78-mg/m2 doses. The study assigned the patients to two groups. Three patients took a 156-mg/m2 dose on day 28 and a 78-mg/m2 dose on day 29; the other three patients took the lower dose on day 28 and the double dose on day 29. Blood samples for the determination of all-trans-RA plasma concentration were obtained at 30-minute intervals starting just prior to drug administration and continuing for a total of 7 hours. The plasma concentration of all-trans-RA was measured by high-performance liquid chromatography. RESULTS: Plasma concentrations following an oral dose of all-trans-RA were highly variable, with peak concentrations ranging from 0.07 to 1.2 microM for the 78-mg/m2 dose level. Doubling the dose from 78 to 156 mg/m2 increased plasma concentration in all six patients, but the increase was unpredictable and not related to dose, ranging from less than a 1.2-fold to more than a 10-fold increase. CONCLUSION: The current study does not support the hypothesis that the gastrointestinal absorption of all-trans-RA involves a saturable process but instead suggests that absorption is highly variable among patients. This wide interpatient variability suggests that pharmacokinetic drug monitoring may have an important role in the management of patients receiving all-trans-RA.

Adenocarcinoma↗

PubMed1993

Pharmacokinetics of piroxantrone in a phase I trial of piroxantrone and granulocyte-colony stimulating factor.

Piroxantrone is an anthrapyrazole derivative with broad antitumor activity in vitro. In previous phase I trials, the dose-limiting toxicity of this agent was myelosuppression. Therefore, a phase I and pharmacokinetic study of a 1-h infusion of piroxantrone in combination with granulocyte-colony stimulating factor was conducted. In this article, we report the results of the pharmacokinetic analysis. Thirty-seven patients were studied over a dosage range of 150 to 555 mg/m2. The plasma elimination of piroxantrone was biexponential with a mean (+/- SD) t1/2 alpha of 3.2 +/- 2.7 min and a mean (+/- SD) t1/2 beta of 82 +/- 92 min. Clearance was 840 +/- 230 ml/min/m2. A limited sampling strategy was developed to allow the estimation of total drug exposure (area under the plasma concentration-time curve) from the plasma piroxantrone concentrations at 30, 60, and 120 min after the start of the infusion. The pharmacokinetic behavior of a presumed piroxantrone metabolite not previously described in plasma was also characterized. Based on in vitro cytotoxicity studies with partially purified extract of this compound, we do not believe that it contributes to the antitumor effects of piroxantrone at the concentrations observed in plasma. Finally, piroxantrone elimination was linear over the nearly 4-fold dose range studied, indicating that when dose adjustments are made, systemic drug exposure will remain predictable.

Adult↗

PubMed1993

Mechanism of resistance to cyclopentenyl cytosine (CPE-C) in Molt-4 lymphoblasts.

Cyclopentenyl cytosine (CPE-C), a carbocyclic analogue of cytidine, has preclinical antineoplastic activity against ara-C resistant murine leukemias and a broad spectrum of human tumor xenografts. CPE-C is a prodrug and requires intracellular phosphorylation to cyclopentenyl cytosine triphosphate (CPE-CTP) which depletes endogenous CTP pools. The initial step in this activation process is catalyzed by uridine/cytidine kinase. We studied the mechanism of resistance to CPE-C in a Molt-4 T-cell leukemia line made resistant to CPE-C (Molt-4R) by culturing it in the continuous presence of increasing concentrations of CPE-C. Using a tetrazolium based colorimetric assay to assess cytotoxicity, the IC90 for the parent Molt-4 cells (Molt-4WT) was 0.5 microM after a 24 hr drug exposure. In contrast, cytotoxicity was not observed at concentrations as high as 1 mM in the Molt-4R cells. Following a brief exposure to 1 microM CPE-C, parent drug could be detected intracellularly in the resistant and sensitive cell lines. However, CPE-CTP formation was reduced markedly in the resistant cell line. Measurement of the activity of anabolic and catabolic enzymes in the Molt-4WT and Molt-4R cells revealed equivalent activities of alkaline and acid phosphatases as well as cytidine and dCMP deaminase but there was a significant reduction in uridine/cytidine kinase activity in Molt-4R cells. Endogenous ribonucleotide pools and CPE-CTP pools were measured in the absence and presence of CPE-C. CTP pools were reduced markedly in Molt-4WT cells following exposure to CPE-C. However, CTP pools in Molt-4R cells exposed to 100 microM CPE-C were two times greater than in the untreated Molt-4WT cells. At high concentrations of CPE-C (10 and 100 microM), Molt-4R cells were able to generate amounts of CPE-CTP equivalent to that seen in Molt-4WT cells exposed to 1 microM CPE-C (a cytotoxic concentration of drug in Molt-4WT cells), but no cytotoxic effect was seen in Molt-4R cells. Therefore, in addition to decreased uridine/cytidine kinase activity, a second mechanism of resistance that is the result of alterations in CTP synthetase activity also appears to be operative. Elucidation of the mechanism of resistance in vitro may provide insight into the mechanism of action of the drug and potential mechanisms of resistance in vivo.

Antineoplastic Agents↗

PubMed1993

Prolongation of drug exposure in cerebrospinal fluid by encapsulation into DepoFoam.

Prolonged maintenance of a therapeutic drug concentration in the cerebrospinal fluid is required for optimal treatment of leptomeningeal leukemia or carcinomatosis with cell cycle-specific antimetabolites. The pharmacokinetics of 1-beta-D-arabinofuranosylcytosine (ara-C) encapsulated into DepoFoam (Depo/Ara-C) was studied in six rhesus monkeys after intrathecal injection into the lumbar sac. Following a single 2-mg dose, the Depo/Ara-C concentration decreased biexponentially with initial and terminal half-lives of 14.6 and 156 h, respectively. The free drug concentration remained above the reported minimal cytotoxic level of 0.1 micrograms/ml (0.4 microM) for more than 672 h (28 days). In contrast, the half-life of ara-C following an intralumbar bolus dose of unencapsulated drug in a single animal was 0.74 h. A single intrathecal injection of Depo/Ara-C can maintain a therapeutic drug concentration in the cerebrospinal fluid for a very prolonged period.

Animals↗

PubMed1993

Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion.

Topotecan, a water-soluble semisynthetic analogue of camptothecin, is the first topoisomerase I inhibitor to undergo evaluation in pediatric patients with refractory malignancies. A phase I and pharmacokinetic study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities, the incidence and severity of other toxicities, and the pharmacokinetics of topotecan in children. Twenty-nine patients received 42 courses of i.v. topotecan administered as a 24-h continuous infusion every 21 days at doses ranging from 2.0 to 7.5 mg/m2. Dose-related hematological toxicity was the dose-limiting toxicity. Leukopenia, neutropenia, and thrombocytopenia occurred sporadically at the 3.0- to 5.5-mg/m2 dose levels, but at 7.5 mg/m2 4 of 5 patients experienced dose-limiting thrombocytopenia (grade 4) and 2 of 5 had dose-limiting neutropenia (grade 4). No other dose-limiting toxicities were observed. Nausea and vomiting were mild and occurred in < 20 and 10% of patients, respectively. Grade 2 hematuria occurred in one patient. No objective responses were observed. Pharmacokinetic studies revealed a linear relationship between the steady-state topotecan concentration and dose. The mean steady-state concentration at the MTD was 18.2 +/- 3.7 nmol/liter and the total body clearance was 28.3 +/- 6.5 liters/h/m2. Elimination was biexponential with a t1/2 alpha of 14.4 +/- 1.8 min and a t1/2 beta of 2.9 +/- 1.1 h. The recommended starting dose for phase II pediatric trials is 5.5 mg/m2. Although this dose exceeds the MTD identified in heavily pretreated adult patients receiving topotecan on the same schedule, it is less than the MTD for minimally pretreated adult patients. Therefore, dose escalation to 7.5 mg/m2 in phase II pediatric trials should be considered for patients who tolerate treatment well at the 5.5-mg/m2 dose.

Adolescent↗

PubMed1993

Plasma and cerebrospinal fluid pharmacokinetic study of topotecan in nonhuman primates.

Topotecan, a water soluble semisynthetic analogue of camptothecin, is a topoisomerase I inhibitor that has recently entered phase II clinical trials. Topotecan has shown significant preclinical activity in refractory murine tumors and in human tumor xenograft models. In addition, objective antineoplastic activity has been observed in recent adult phase I clinical trials. Topotecan is unstable in solution and is rapidly and spontaneously converted to a less active open ring form which predominates at physiological pH. This study was undertaken to better define the pharmacokinetic behavior of this highly unstable compound in both plasma and cerebrospinal fluid (CSF) and to measure the degree of CSF penetration of this novel antineoplastic agent. Three nonhuman primates with indwelling Ommaya reservoirs received 10 mg/m2 i.v. topotecan administered as a 10-min infusion. Frequent plasma and CSF samples were obtained and immediately extracted and assayed with a reverse phase high performance liquid chromatography assay to quantitate the concentration of topotecan (lactone). Samples were then acidified and reinjected to quantitate total drug (lactone ring plus open ring). Peak plasma concentrations of topotecan ranged from 0.27 to 0.45 microM. Plasma disappearance of the lactone ring was biexponential with a distribution half-life (t1/2 alpha) of 22 +/- 5 min and an elimination half-life (t1/2 beta) of 1.3 +/- 0.1 h. Total body clearance of topotecan was 72.1 +/- 15.8 liters/h/m2. The volume of distribution at steady state was 88.6 +/- 33.2 liters/m2. Peak CSF concentrations of topotecan occurred at 30 min following drug administration and ranged from 0.044 to 0.074 microM. CSF disappearance paralleled that in plasma. The mean ratio of the area under the CSF concentration-time curve to that in plasma was 0.32 (range, 0.29 to 0.37). The mean CSF penetration of topotecan exceeds 30%, which is significantly greater than the penetration of most structurally similar chemotherapeutic agents. The impact of chemotherapy on the survival of patients with primary or metastatic central nervous system malignancies is very limited. Therefore, this novel antineoplastic agent is an excellent candidate for further study in patients with high risk or refractory central nervous system tumors.

Animals↗

PubMed1993

Time course of induction of metabolism of all-trans-retinoic acid and the up-regulation of cellular retinoic acid-binding protein.

A study of chronic i.v. dosing of all-trans-retinoic acid (all-trans-RA) was performed to determine whether induction of the capacity-limited elimination process for all-trans-RA occurred with long-term drug administration. Because up-regulation of the cellular retinoic acid-binding proteins (CRABP) may act to bind all-trans-RA intracellularly, the amount of CRABP in skin biopsy samples obtained during and following the course of all-trans-RA administration was also determined. Four adult rhesus monkeys received 50 mg/m2 of all-trans-RA by bolus i.v. injection daily for 8 consecutive days and again for one additional dose following a 7-day period without drug. The plasma disappearance curve of all-trans-RA was characterized by a plateau phase, the duration of which decreased during the period of chronic drug administration, followed by a terminal exponential decay phase, which is consistent with a capacity-limited (saturable) elimination process. The Vmax of this process increased from 0.06 mumol/min on the first day to 0.17 mumol/min by the eighth day of all-trans-RA administration, consistent with induction of an enzymatic process. The amount of CRABP measured in skin biopsy specimens was rapidly induced, increasing to approximately 3-fold baseline levels by day 3 of all-trans-RA administration. It remained at this level throughout the period of chronic drug administration but diminished following the 7-day period without drug. These findings suggest that an intermittent schedule of administration for all-trans-RA has potential advantages over a continuous administration schedule. A period of time without drug administration would allow for return of plasma drug clearance toward baseline levels and down-regulation of CRABP, which could result in higher plasma drug concentrations and possibly less cytoplasmic binding of drug.

Animals↗

PubMed1993

Pharmacokinetics of PEG-L-asparaginase and plasma and cerebrospinal fluid L-asparagine concentrations in the rhesus monkey.

The pharmacokinetics of the polyethylene glycol-conjugated form of the enzyme L-asparaginase and the depletion of L-asparagine from the plasma and cerebrospinal fluid (CSF) following an i.m. dose of 2500 IU/m2 PEG-L-asparaginase was studied in rhesus monkeys. PEG-L-asparaginase activity in plasma was detectable by 1 h after injection and maintained a plateau of approximately 4 IU/ml for more than 5 days. Subsequent elimination from plasma was monoexponential with a half-life of 6 +/- 1 days. Plasma L-asparagine concentrations fell from pretreatment levels of 14-47 microM to < 2 microM by 24 h after injection in all animals and remained undetectable for the duration of the 25-day observation period in four of six animals. In two animals, plasma L-asparagine became detectable when the PEG-L-asparaginase plasma concentration dropped below 0.1 IU/ml. Pretreatment CSF L-asparagine levels ranged from 4.7 to 13.6 microM and fell to < 0.25 microM by 48 h in five of six animals. CSF L-asparagine concentrations remained below 0.25 microM for 10-14 days in four animals. One animal had detectable CSF L-asparagine concentrations within 24 h and another had detectable concentrations within 1 week of drug administration despite a plasma PEG-L-asparaginase activity profile that did not differ from that of the other animals. These observations may be useful in the design of clinical trials with PEG-L-asparaginase in which correlations among PEG-L-asparaginase pharmacokinetics, depletion of L-asparagine, and clinical outcome should be sought.

Aminolevulinic Acid↗

PubMed1993

Pharmacokinetics, cerebrospinal fluid penetration, and metabolism of piroxantrone in the rhesus monkey.

Piroxantrone is an anthrapyrazole derivative with broad anti-tumor activity in vitro and less cardiac toxicity than the anthracyclines. The metabolic pathways and central nervous system penetration of piroxantrone have not been determined. In this study we examined the pharmacokinetic behavior of piroxantrone in plasma and cerebrospinal fluid in a non-human primate model. In addition, a urinary metabolite of piroxantrone was isolated and its cytotoxicity evaluated in vitro. The disappearance of piroxantrone from plasma after an intravenous dose of 150 mg/m2 given over 60 minutes was biexponential with mean t1/2 alpha of 1.0 minutes and a mean t1/2 beta of 180 minutes. The mean area under the curve was 220 microM.min and the clearance was 1420 ml/min/m2. Piroxantrone was not detectable in the cerebrospinal fluid. Piroxantrone and three other compounds not present in pre-treatment samples were detected in urine. The major urinary metabolite was isolated. Its cytotoxicity against MOLT-4 cells in vitro was at least one log less than that of piroxantrone. In addition, one of the other compounds detected in urine was determined to be a glucuronide conjugation product of the major metabolite. The results of this study may be useful in the interpretation of the activity and toxicity of piroxantrone in clinical trials.

Animals↗

PubMed1993

A phase I trial of trimetrexate (NSC352122) on a daily x 5 schedule in patients with refractory adult leukemia.

Seven adult patients with refractory acute leukemia were administered trimetrexate (TMTX), a non-classical folate antagonist, in a phase I trial. TMTX was administered as an intravenous bolus for five consecutive days at doses of 9-12 mg/m2 based on marrow response. The maximum tolerated dose was 12 mg/m2. Hepatotoxicity was the dose-limiting toxicity. Initial dosage reductions in patients with liver disease and/or low protein concentrations may be necessary since TMTX is significantly protein bound and cleared primarily by hepatic metabolism. The recommended phase II dose on this dosing schedule is 9 mg/m2.

Adult↗

PubMed1993

Phase I study of high-dose piroxantrone with granulocyte colony-stimulating factor.

PURPOSE: We performed a phase I trial of piroxantrone with and without granulocyte colony-stimulating factor (G-CSF) to determine whether the use of this cytokine would enable us to increase the dose-intensity of piroxantrone. PATIENTS AND METHODS: Thirty-eight patients received 121 courses of piroxantrone administered once every 21 days. Initial patient cohorts received piroxantrone alone starting at 150 mg/m2 and the dose was escalated in subsequent patients until dose-limiting toxicity (DLT) was reached. Patient cohorts then received escalating doses of piroxantrone starting at 185 mg/m2 administered with G-CSF beginning day 2. RESULTS: Dose-limiting neutropenia occurred in three of six patients treated with 185 mg/m2 piroxantrone; the maximum-tolerated dose (MTD) of piroxantrone alone was 150 mg/m2. Three of six patients treated with piroxantrone and G-CSF exhibited dose-limiting thrombocytopenia at 445 mg/m2; the MTD of piroxantrone with G-CSF was thus 355 mg/m2. Seven patients developed symptomatic congestive heart failure (CHF) at cumulative piroxantrone doses ranging from 855 to 2,475 mg/m2 and two have died of cardiotoxicity. Of these patients, six of seven had previously received doxorubicin. Other nonhematologic toxicity was mild. CONCLUSION: The use of G-CSF results in a more than twofold increase in the MTD of piroxantrone. However, symptomatic cardiotoxicity is prominent, especially in patients who have received prior treatment with anthracyclines.

Adult↗

PubMed1993

Pancreatitis in human immunodeficiency virus-infected children receiving dideoxyinosine.

To define predictive or contributory risk factors for pancreatitis in human immunodeficiency virus-infected children receiving dideoxyinosine (ddI), the authors evaluated 95 children, 3 months to 18 years of age, who had received ddI at 60 to 540 mg/m2 per day for a mean of 56 weeks. Pancreatitis developed in 7 patients (7%) but resolved in all upon withdrawal of ddI. Neither age, sex, nor CD4 count at study entry was predictive of pancreatitis, but pancreatitis appeared more likely to develop in hemophiliacs than in other patients (4 of 23 vs 3 of 72). Pancreatitis developed only in patients who received ddI at the highest dose levels (7 of 60 patients who received ddI at a dose > or = 360 mg/m2 per day vs 0 of 35 patients who received < or = 270 mg/m2 per day). Patients in whom pancreatitis developed had received a higher mean daily dose of ddI than patients with normal amylase and lipase levels throughout the study (348 mg/m2 vs 282 mg/m2), but no relationship with the cumulative dose or the duration of ddI therapy was observed. Although a statistically significant relationship between ddI plasma concentration (area under the curve) and pancreatitis was not conclusively demonstrated, as the number of patients in whom pancreatitis actually developed was small, such a relationship may have been obscured.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1992

Dose-dependent pharmacokinetics of all-trans-retinoic acid.

BACKGROUND: Orally administered all-trans-retinoic acid (all-trans-RA) can induce remission in a high proportion of patients with acute promyelocytic leukemia. PURPOSE: To further define the drug's pharmacokinetics, a study of intravenous all-trans-RA was performed in rhesus monkeys. METHODS: A total of nine monkeys received intravenous bolus injections of all-trans-RA. Three different doses (20, 50, and 100 mg/m2) were each tested in three monkeys. Blood samples for determination of all-trans-RA concentration were obtained prior to drug administration and at 5, 10, 15, 30, 45, 60, 75, 90, 120, 150, 180, 240, 360, and 480 minutes after drug administration. RESULTS: Plasma disappearance of all-trans-RA was characterized by three distinct phases: a brief, initial exponential decline, followed by a relative plateau in the disappearance curve (the duration of which was dose dependent), and finally a terminal exponential decay. This profile is consistent with a capacity-limited (saturable) elimination process. The first-order (terminal) half-life for all-trans-RA averaged 19 minutes, and the mean clearances were 77, 52, and 59 mL/min for the 20-, 50-, and 100-mg/m2 dose groups, respectively. The mean +/- SD Michaelis constant (Km) for the capacity-limited process was 3.2 +/- 1.9 microM. CONCLUSIONS: Peak plasma concentrations following oral administration of 45 mg/m2 all-trans-RA in humans approach the Km for the capacity-limited process; thus, the dose-dependent pharmacokinetics of all-trans-RA described here may occur within the clinically used dosage range.

Animals↗

PubMed1992

Modulation of the cytotoxic effect of cyclopentenylcytosine by its primary metabolite, cyclopentenyluridine.

Cyclopentenylcytosine (CPE-C), a synthetic cytidine analogue with significant preclinical antitumor activity against both solid tumor xenografts and 1-beta-D-arabinofuranosylcytosine resistant murine leukemia cell lines, will soon enter phase I clinical trials. Unlike 1-beta-D-arabinofuranosylcytosine which is activated by deoxycytidine kinase, the enzyme responsible for the phosphorylation of CPE-C is uridine/cytidine kinase. Preclinical pharmacokinetic studies of CPE-C in nonhuman primates revealed that the primary route of elimination in this species was deamination to cyclopentenyluridine (CPE-U), an inhibitor of uridine/cytidine kinase. Since CPE-C is likely to be deaminated in humans, we investigated the modulating effect of CPE-U on the in vitro cytotoxicity of CPE-C in Molt-4 lymphoblasts. Concurrent exposure of cells to cytotoxic concentrations of CPE-C and 50 microM CPE-U resulted in the rescue of 50% of cells and exposure to CPE-U concentrations in excess of 100 microM resulted in the rescue of greater than 90% of cells. Progressive attenuation of the rescue effect was observed with delayed administration of CPE-U and no cells were rescued when addition of CPE-C was delayed for more than 2 h. At the intracellular level it was observed that the formation of the cytotoxic metabolite, cyclopentenylcytosine triphosphate, was blocked by increasing concentrations of CPE-U presumably secondary to inhibition of uridine/cytidine kinase by CPE-U. Although CPE-U can modulate the cytotoxic effects of CPE-C in vitro, the minimum CPE-U levels that are required for modulation coupled with the available preclinical pharmacokinetic data from nonhuman primates suggests that this modulation is not likely to impact on the antitumor effects of CPE-C in humans.

Cell Survival↗