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Biomedical subjects

D L Cutler

Publications and source records attributed to D L Cutler.

At least 19 recordsLinked to original sources
PubMed2003

Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules.

Temozolomide, an oral DNA methylator that inactivates the DNA repair enzyme O(6)-alkylguanine-DNA alkyltransferase (AGAT), has demonstrated anticancer activity on protracted schedules. Protracted schedules may lead to an 'autoenhancement' of temozolomide's inherent cytotoxic potential by cumulative reduction of the cell's capacity for AGAT-mediated DNA repair and resistance. This study was undertaken to characterise AGAT inactivation and regeneration in the peripheral blood mononuclear cells (PBMCs) of patients treated on two protracted temozolomide schedules. O(6)-alkyl guanine-DNA alkyltransferase activity was measured in the PBMCs of patients treated on two phase I protracted temozolomide studies. Patients were treated daily for either 7 days every 2 weeks (Schedule A) or 21 days every 4 weeks (Schedule B). The effects of various temozolomide doses (75-175 mg m(-2)), treatment duration (7-21 days), and temozolomide plasma levels on AGAT inactivation and regeneration, as well as the relation between AGAT inactivation and toxicity, were studied. O(6)-alkyl guanine-DNA alkyltransferase activity in PBMCs was measured serially in 52 patients. Marked inactivation of AGAT occurred following 7 days of temozolomide treatment, with mean AGAT activity decreasing by 72% (P<0.0001). Similarly, mean AGAT activity decreased by 63 and 73% after 14 and 21 days of treatment, respectively (P<0.001 for both comparisons). O(6)-alkyl guanine-DNA alkyltransferase inactivation was greater after 7 days of treatment with higher doses of temozolomide than lower doses and remained markedly reduced 7 days post-treatment. However, AGAT inactivation following temozolomide treatment for 14 and 21 days was similar at all doses. On the continuous 21-day schedule, AGAT inactivation was significantly greater in patients who experienced severe thrombocytopenia than those who did not (90.3+/-5.5 vs 72.5+/-16.1%, P<0.045). In conclusion, protracted administration of temozolomide, even at relatively low daily doses, leads to significant and prolonged depletion of AGAT activity, which may enhance the antitumour activity of the agent.

Antineoplastic Agents, Alkylating↗
PubMed2002

Phase I and pharmacological study of the oral farnesyltransferase inhibitor SCH 66336 given once daily to patients with advanced solid tumours.

A single-agent dose-escalating phase I study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile and recommended dose for phase II studies. Plasma pharmacokinetics were determined as well as the SCH 66336-induced inhibition of farnesyl protein transferase in vivo. SCH 66336 was given orally once daily (OD) without interruption to patients with histologically-confirmed solid tumours. Routine antiemetics were not prescribed. 12 patients were enrolled into the study. Dose levels studied were 300 mg (6 patients) and 400 mg (6 patients) OD. Pharmacokinetic sampling was performed on days 1 and 15. Although at 400 mg OD only 1 patient had a grade 3 diarrhoea, 3 out of 6 patients interrupted treatment early due to a combination of various grade 1-3 toxicities (diarrhoea, uremiacreatinine, asthenia, vomiting, weight loss) indicating that this dose was not tolerable for a prolonged period of time. At 300 mg OD, the same pattern of toxicities was observed, but all were grade 1-2. Therefore, this dose can be recommended for phase II studies. Pharmacokinetic analysis showed that peak plasma concentrations as well as the AUCs were dose-related, with increased parameters at day 15 compared with day 1, indicating some accumulation upon multiple dosing. Plasma half-life ranged from 5 to 9 h and appeared to increase with increasing dose. Steady state plasma concentrations were attained by day 14. A large volume of distribution at steady state suggested extensive distribution outside the plasma compartment. There is evidence of inhibition of protein prenylation in some patients after OD oral administration of SCH 66336. SCH 66336 can be safely administered using a continuous oral OD dosing regimen. The recommended dose for phase II studies using this regimen is 300 mg OD.

Administration, Oral↗
PubMed2001

Phase I and pharmacokinetic study of the oral farnesyl transferase inhibitor SCH 66336 given twice daily to patients with advanced solid tumors.

PURPOSE: A single-agent dose-escalating phase I and pharmacokinetic study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile, maximum-tolerated dose, and recommended dose for phase II studies. Plasma and urine pharmacokinetics were determined. PATIENTS AND METHODS: SCH 66336 was given orally bid without interruption to patients with histologically or cytologically confirmed solid tumors. Routine antiemetics were not prescribed. RESULTS: Twenty-four patients were enrolled onto the study. Dose levels studied were 25, 50, 100, 200, 400, and 300 mg bid. Pharmacokinetic sampling was performed on days 1 and 15. At 400 mg bid, the dose-limiting toxicity (DLT) consisted of grade 4 vomiting, grade 4 neutropenia and thrombocytopenia, and the combination of grade 3 anorexia and diarrhea with reversible grade 3 plasma creatinine elevation. After dose reduction, at 300 mg bid, the DLTs consisted of grade 4 neutropenia, grade 3 neurocortical toxicity, and the combination of grade 3 fatigue with grade 2 nausea and diarrhea. The recommended dose for phase II studies is 200 mg bid, which was found feasible for prolonged periods of time. Pharmacokinetic analysis showed a greater than dose-proportional increase in drug exposure and peak plasma concentrations, with increased parameters at day 15 compared with day 1, indicating some accumulation on multiple dosing. Plasma half-life ranged from 4 to 11 hours and seemed to increase with increasing doses. Steady-state plasma concentrations were attained at days 7 through 14. A large volume of distribution at steady-state indicated extensive distribution outside the plasma compartment. CONCLUSION: SCH 66336 can be administered safely using a continuous oral bid dosing regimen. The recommended dose for phase II studies using this regimen is 200 mg bid.

Administration, Oral↗
PubMed2000

A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity.

Farnesyl protein transferase (FT), an enzyme that catalyzes the first step in the posttranslational modification of ras and a number of other polypeptides, has emerged as an important target for the development of anticancer agents. SCH66336 is one of the first FT inhibitors to undergo clinical testing. We report a Phase I trial to assess the maximum tolerated dose, toxicities, and biological effectiveness of SCH66336 in inhibiting FT in vivo. Twenty patients with solid tumors received 92 courses of escalating SCH66336 doses given orally twice a day (b.i.d.) for 7 days out of every 3 weeks. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and fatigue were dose-limiting at 400 mg of SCH66336 b.i.d. Moderate reversible renal insufficiency, secondary to dehydration from gastrointestinal toxicity, was also seen. Inhibition of prelamin A farnesylation in buccal mucosa cells of patients treated with SCH66336 was demonstrated, confirming that SCH66336 inhibits protein farnesylation in vivo. One partial response was observed in a patient with previously treated metastatic non-small cell lung cancer, who remained on study for 14 months. This study not only establishes the dose for future testing on this schedule (350 mg b.i.d.) but also provides the first evidence of successful inhibition of FT in the clinical setting and the first hint of clinical activity for this class of agents.

Adult↗
PubMed2000

Psychiatric hospitalizations, arrests, emergency room visits, and homelessness of clients with serious and persistent mental illness: findings from a randomized trial of two ACT programs vs. usual care.

OBJECTIVE: This investigation examined several adverse outcomes in clients with serious mental illness in a randomized trial of Assertive Community Treatment (ACT) versus usual care. METHOD: 163 subjects were randomized to one of two ACT experimental conditions (staffed by consumers or non-consumers) or usual community care. Conditions were compared on psychiatric hospitalization, emergency room visit, arrest, and homelessness, within the two-year study period. Demographic, program, and client variables were examined for significant associations with outcomes. RESULTS: Significant differences were found between ACT and usual care in time to first arrest, but not hospitalization, homelessness or ER visits. Shorter time to first hospitalization was associated with male gender, diagnoses other than schizophrenia, high psychiatric symptomatology and lower provider case load. ER visits were associated with increased client symptomatology. Shorter times to homelessness were predicted by poorer therapeutic alliance between case manager and clients. Shorter time to first arrest was predicted by client minority status and enrollment in usual care. CONCLUSIONS: The paucity of significant main effects may have been due to a prolonged "start-up" phase of the ACT programs, poor ACT implementation, restricted availability of psychiatric hospital beds, or changes in usual care services delivered over the study period.

Adult↗
PubMed2000

Population pharmacokinetics of temozolomide in cancer patients.

PURPOSE: To evaluate covariate effects on the pharmacokinetics of temozolomide in cancer patients, and to explore the dose-pharmacokinetics-toxicity relationship of temozolomide. METHODS: Non-linear mixed-effects modeling approach was used to analyze the data from 445 patients enrolled in eleven Phase I and Phase II clinical trials. All patients in the phase I trials had advanced cancer. Patients in the phase II trials had anaplastic astrocytoma (AA), glioblastoma multiforme (GBM) or malignant melanoma (MM). A sparse sampling scheme was prospectively developed using Phase I data and was successfully implemented in Phase II trials. Population factors included age, gender, height (HT), weight (WT), body surface area (BSA), serum creatinine (Sr.Cr.), estimated creatinine clearance, serum chemistry data as indices of hepatic function and disease, smoking status, and selected concomitant medications. Descriptive statistics were used to summarize the toxicity and temozolomide dose and exposure relationship. RESULTS: The pharmacokinetics of temozolomide follows a one-compartment model with first order absorption and elimination. Temozolomide clearance (CL) increased with BSA for both genders. The population mean clearance for GBM or AA patients was 11.2 L/hr for male with BSA equal to 2.0 m2, and 8.8 L/hr for female with BSA equal to 1.7 m2. The mean clearance for MM patients was slightly higher. The inter-subject variability in clearance was 15%, and the residual variability was 26%. Other factors investigated in this analysis had little effect on clearance. The overall incidence of neutropenia and thrombocytopenia were 5-8%. Temozolomide dose and AUC did not predict nadir neutrophil and platelet counts due to large variability in counts. CONCLUSIONS: The current dose regimen is administered according to BSA which is the most important factor influencing temozolomide clearance. No further dose adjustment is required.

Adult↗
PubMed2000

In vivo effects of interleukin-10 on human cytochrome P450 activity.

BACKGROUND: Injection of lipopolysaccharide into human volunteers leads to an increase in serum interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha and a significant decrease in cytochrome P450 (CYP)-mediated drug metabolism. The in vivo effects of the noninflammatory cytokine interleukin-10 (IL-10) on CYP-mediated drug metabolism was examined. METHODS: IL-10 (8 microg/kg) and placebo were administered for 6 days to 12 healthy volunteers in a double-blind crossover study. Tolbutamide (CYP2C9), caffeine (CYP1A2), dextromethorphan (CYP2D6 and CYP3A), and midazolam (CYP3A) were administered on days 4 and 5 to determine individual CYP activities. RESULTS: Few clinically apparent side effects were observed after administration of IL-10; however, blood chemistries reflected an acute-phase response. A significant drop in serum albumin (mean percentage change +/- SD between groups; 4.7% +/- 6.0%, P < or = .02), a significant increase in serum ferritin (736% +/- 717%, P < or = .001), and a significant reduction in platelet count (49% +/- 12%, P < or = .0001) was observed after administration of IL-10. IL-10 significantly (P < or = .02) decreased CYP3A activity 12% +/- 17%, as reflected by midazolam clearance. CYP2C9 activity was significantly (P < or = .005) increased by 38% +/- 35%, as reflected by the tolbutamide urinary metabolic ratio and oral clearance. However, administration of IL-10 resulted in a 40% increase in the fraction unbound of tolbutamide. Therefore no difference in the unbound clearance of tolbutamide was observed between placebo (23.3 +/- 9.7 L/h) or IL-10 (23.5 +/- 11.4 L/h) administration. No significant changes in either CYP1A2 or CYP2D6 activities were observed between placebo and treatment arms of the study. CONCLUSION: IL-10 administration resulted in an acute-phase response. Administration of IL-10 did not alter CYP1A2, CYP2C9, and CYP2D6 activities. CYP3A-mediated biotransformation was reduced by administration of IL-10.

Adult↗
PubMed1999

Effect of gastric pH on the relative oral bioavailability and pharmacokinetics of temozolomide.

PURPOSE: Temozolomide is an imidazotetrazine alkylating agent which undergoes chemical conversion at physiological pH to the active species 5-(3-methyltriazene-1-yl)imidazole-4-carboxamide (MTIC) but is stable at acid pH. This study evaluated the effect of an increase in gastric pH, through the use of ranitidine, on the oral bioavailability and plasma pharmacokinetics of temozolomide and MTIC. METHODS: Fifteen patients with advanced cancer were enrolled of which 12 were evaluable, all of whom had pharmacokinetic blood sampling. Each patient received temozolomide 150 mg m(-2) day(-1) for 5 days in cycle 1 and also received ranitidine 150 mg every 12 h either on days 1 and 2 or days 4 and 5. Gastric pH was monitored by the use of the Heidelberg capsule system. RESULTS: Following the administration of ranitidine there was a rise in gastric pH by 1-2 pH units over the duration of the study period (pH range 2.2-5.2 without ranitidine and 3.5-6.0 with ranitidine). There was no difference in the pharmacokinetic parameters of temozolomide or MTIC with or without the concomitant administration of ranitidine. There was however, a lower C(max) for temozolomide and MTIC for patients receiving ranitidine on day 1 and 2 versus day 4 and 5. Temozolomide was rapidly absorbed [time to maximum plasma concentration (t(max)) 1.8 h] and eliminated [elimination half-life (t(1/2)) 1.8 h] and MTIC followed a similar pattern with a t(max) of 1.9 h and a t(1/2) of 1.9 h. Overall, the AUC of the MTIC represented about 2-4% of the AUC for temozolomide.

Administration, Oral↗
PubMed1999

Pharmacoimmunodynamic interactions of interleukin-10 and prednisone in healthy volunteers.

OBJECTIVE: The pharmacoimmunodynamic interactions of recombinant human interleukin-10 and prednisolone were examined in 12 normal male volunteers. METHODS: Single doses of interleukin-10 (8 microg/kg subcutaneous injection), interleukin-10 with prednisone (15 mg by mouth), placebo with prednisone, or placebo were administered. Drug concentrations yielded pharmacokinetic parameters. Response measurements included whole blood lipopolysaccharide-stimulated cytokine (tumor necrosis factor-alpha, interleukin-1beta) production, phytohemagglutinin-stimulated whole blood lymphocyte proliferation, and differential white blood cell counts (including monocytes, lymphocytes, and neutrophils). Extended indirect-response models were used to deal with diverse drug interactions in assessing single and joint effects of interleukin-10 and prednisolone. RESULTS: No pharmacokinetic alterations in interleukin-10 or prednisolone were found. Dosing with interleukin-10 produced strong inhibition of ex vivo cytokine production for the 24-hour postdosing period, whereas prednisolone, the active form of prednisone, was partly inhibitory for only 3 hours. Prednisolone significantly inhibited (P < .05) ex vivo lymphocyte proliferation for 6 hours, whereas interleukin-10 failed to alter this measure. Their joint effects on these responses were inhibitory consonant with the stronger agent. Marked changes in various leukocyte kinetics occurred. The steroid caused monocytopenia, lymphocytopenia, and neutrophilia, with IC50 or SC50 values of 10 to 20 ng/mL. Interleukin-10 elevated monocytes and neutrophils and lowered lymphocyte counts, with IC50 or SC50 values of 0.7 to 1.3 ng/mL. Dynamic modeling showed loss of prednisolone effects on monocytes and additive steroid/interleukin-10 effects on lymphocytes and neutrophils, with neutrophils exhibiting greater changes in net response. CONCLUSION: Interleukin-10 and prednisolone interacted favorably for the measured pharmacoimmunodynamic indices with no kinetic alterations but net responses that were similar to or greater than effects produced by the more strongly acting agent.

Adult↗
PubMed1999

Effects of single intravenous doses of recombinant human interleukin-10 on subsets of circulating leukocytes in humans.

Recombinant human interleukin-10 (rhIL-10) is a potent and specific immunomodulatory agent which inhibits endotoxin-stimulated pro-inflammatory cytokine production by monocytes, blocks T-lymphocyte activation by antigen presenting cells, and modulates T(H)1/T(H)2 balance in immune responses. In previous clinical trials, rhIL-10 administered to healthy volunteers induced rapid and transient elevations of neutrophil and monocyte counts and reductions of lymphocyte counts in addition to suppression of endotoxin-stimulated whole blood cytokine synthesis. We sought to better characterize the effects of rhIL-10 on immunophenotypically defined subsets of circulating leukocytes that could be relevant to its immunomodulatory effects. Healthy volunteers were given single doses of 10 microg/kg rhIL-10 (n = 8) or equivalent placebo (n = 4) by intravenous injection. Significant changes of circulating leukocytes included transiently increased neutrophils and monocytes with parallel increases of CD33+ and CD14+ cells. Total lymphocytes as well as total CD3+, CD3+/CD4+ and CD3+/CD8+ cells transiently decreased. Mean fluorescence intensity of CD11a (integrin alpha-chain subunit of lymphocyte function antigen-1, LFA-1) on lymphocytes transiently but significantly decreased, suggesting a mechanism for transient alteration of lymphocyte trafficking. In addition, mean fluorescence intensity of HLA-DR (major histocompatibility class II) on CD14+ cells (predominantly monocytes) transiently but significantly decreased, implying a possible alteration of antigen presenting function. Further study will be required to elucidate the immunomodulatory roles and potential clinical significance of these hematologic changes in therapeutic trials of rhIL-10 in patients with chronic inflammatory and autoimmune diseases.

Adult↗
PubMed1999

Pharmacokinetics of flutamide in patients with renal insufficiency.

AIMS: The aim of this study was to determine the pharmacokinetic parameters of flutamide, a nonsteroidal antiandrogenic compound, and its pharmacologically active metabolite, hydroxyflutamide, in renal insufficiency. Haemodialysis (HD) clearance of flutamide and hydroxyflutamide was also determined. METHODS: Pharmacokinetic parameters were assessed for flutamide and hydroxyflutamide in 26 male subjects with normal renal function (creatinine clearance by 24 h urine collection, CLcr, greater than 80 ml min(-1) 1.73 m(-2); n=6) or reduced renal function; CLcr=50-80 (n=7), 30-49 (n=3), 5-29 (n=4), and <5 ml min(-1) 1.73 m(-2)-HD (n=6), following a single, oral 250 mg flutamide dose. Subjects undergoing HD received a second 250 mg dose of flutamide 4 h prior to HD; blood and dialysate were collected during HD to determine dialysability of flutamide and hydroxyflutamide. RESULTS: Cmax, tmax, AUC, t1/2, and renal clearance of flutamide and hydroxyflutamide did not differ between groups. Less than 1% of the dose appeared in dialysate as hydroxyflutamide. No serious adverse events were observed. CONCLUSIONS: Renal function did not affect flutamide nor hydroxyflutamide disposition. HD did not alter hydroxyflutamide pharmacokinetics. Dosing adjustments for renal impairment or HD are not indicated for flutamide.

Androgen Antagonists↗
PubMed1999

Pharmacokinetic and adrenal interactions of IL-10 and prednisone in healthy volunteers.

The pharmacokinetic and adrenal interactions of recombinant human interleukin-10 and prednisolone were examined in this open-label, randomized, four-way crossover study in 12 healthy adult male volunteers. Single doses of IL-10 (8 micrograms/kg s.c.), IL-10 with prednisone (15 mg p.o.), placebo with prednisone, or placebo were administered on four separate occasions with at least 3-week interceding washout periods. Measurements included plasma prednisone, prednisolone and cortisol, unbound prednisolone, and serum IL-10 concentrations. Pharmacokinetic parameters were determined using noncompartmental and model-fitting analysis, while area analysis and an indirect response model were used to assess cortisol dynamics. IL-10 exhibited prolonged serum concentrations owing to dual-absorption processes that were largely unaffected by prednisone. The Cmax values were about 3 ng/mL, while the tmax occurred at 7 to 9 hours. Prednisolone exhibited rapid systemic kinetics with a Cmax of 235 ng/mL, tmax at 1.11 hours, and t1/2 of 2.54 hours with no significant alterations owing to IL-10. Both prednisolone and prednisolone/IL-10 caused marked suppression of cortisol concentrations with similar magnitude and IC50 values; however, IL-10 alone significantly increased the 24-hour AUC of cortisol by 20%. Thus, IL-10 and prednisolone do not interact in disposition or adrenal suppression to a clinically significant degree.

Adrenal Glands↗
PubMed1999

Disposition of recombinant human interleukin-10 in subjects with various degrees of renal function.

The pharmacokinetics of intravenously administered recombinant human interleukin-10 (rHuIL-10) were evaluated in 18 subjects with creatinine clearances (Clcr) between 2.7 and 116.7 mL/min/1.73 m2. Serum samples for rHuIL-10 were obtained over a 48-hour period after a single 25 micrograms/kg i.v. bolus infusion. AUC, total body clearance (Clp), and steady-state volume of distribution (Vdss) were derived by compartmental methods. Analysis of serum concentrations showed statistically significant group differences for log-transformed AUC and original scale Clp (p < 0.01). The AUC and effective half-life increased, while the mean Clp of rHuIL-10 decreased as renal function declined. A linear relationship between AUC and Clcr as well as Clp and Clcr demonstrates that the disposition of rHuIL-10 is altered in subjects with renal insufficiency. No serious adverse events were noted.

Adult↗
PubMed1998

Pharmacokinetics and leukocyte responses of recombinant human interleukin-10.

PURPOSE: To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHuIL-10) following single s.c. and i.v. dosing. METHODS: A randomized two-way cross-over study was undertaken in 17 healthy volunteers in which rHuIL-10 was administered as 25 microg/kg s.c. and i.v. doses. Blood samples were collected for 48 hr after dosing to determine serum IL-10 concentrations. Inhibitory activity of IL-10 on ex vivo production of inflammatory cytokines (TNF-alpha and IL-1beta) by LPS-treated peripheral blood cells were measured over 96 hr. RESULTS: A physiologically-relevant modeling approach was developed to determine the pharmacokinetics for two routes of administration (s.c. and i.v.). The i.v. dose showed polyexponential disposition with CL of 65 mL/kg/hr, Vss of 70 mL/kg, and t1/2 of 1.94 hr. Absolute bioavailability averaged 42% for s.c. dosing which produced lower but sustained concentrations. Substantial and prolonged suppression of TNF-alpha and IL-1beta production was achieved during IL-10 treatment. The Hill Function was used to account for the joint concentration-dependent immunosuppressive action of rHuIL-10 after both i.v. and s.c. doses. The IC50 values were about 0.03 ng/ml and Imax values were about 0.85 for both TNF-alpha and IL-1beta suppression. The degree of change as well as the duration of leukocyte response was greater after s.c. administration than after i.v. administration. CONCLUSION: rHuIL-10 shows favorable PKPD characteristics especially by the s.c. route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.

Cross-Over Studies↗
PubMed1998

Mental health in the Oregon Health Plan: fragmentation or integration?

The Oregon Health Plan was implemented in 1994 with a 50% expansion of Medicaid enrollment to include some of the working poor. Over 75% of Oregon Medicaid clients are now enrolled in health maintenance organizations (HMOs). Outpatient chemical dependency services have been capitated since May 1995. Capitated mental health services have been provided for the 25% of eligibles who live in demonstration counties since January 1995. Expansion and capitation appear to have been achieved without major trauma. More challenging has been the attempted integration of public sector behavioral health services with private sector health plans. Stakeholders interviewed for this study were especially concerned about the long-term impact on Medicaid clients with chronic mental illness. Strong leadership and clear policies regarding the mixture of public, private nonprofit, and private for profit entities are necessary if the state is to achieve its aim of integration without fragmenting a system of care for people with severe mental illness.

Attitude to Health↗