One-hour Intravenous Infusion Research Articles

Improving drug retention in liposomes by aging with the aid of glucose

This paper describes a novel method to improve drug retention in liposomes for the poorly water-soluble (lipophilic) model drug asulacrine (ASL). ASL was loaded in the aqueous phase of liposomes and the effects of aging conditions and drug loading levels on drug retention were investigated using an in vitro bio-relevant drug release test established in this study. The status of intra-liposomal drug was investigated using differential scanning calorimetry (DSC) and cryo-transmission electron microscopy (cryo-TEM). Pharmacokinetics and venous tolerance of the formulations were simultaneously studied in rabbits following one-hour intravenous infusion via the ear vein. The presence of glucose during aging was found to be crucial to accelerate drug precipitation and to stabilize the liposomal membrane with high drug loading (8.9% over 4.5% w/w) as a prerequisite. Although no drug crystals were detected, DSC showed a lower phase-transition peak in the glucose-assisted aged ASL-liposomes, indicating interaction of phospholipids with the sugar. Cryo-TEM revealed more ‘coffee bean’ like drug precipitate in the ASL-liposomes aged in the glucose solution. In rabbits, these liposomes gave rise to a 1.9 times longer half-life than the fresh liposomes, with no venous irritation observed. Inducing and stabilizing drug precipitation in the liposome cores by aging in the presence of sugar provided an easy approach to improve drug retention in liposomes. The study also highlighted the importance of bio-relevance of in vitro release methods to predict in vivo drug release.

First-in-human phase I study of EZN-4176, a locked nucleic acid antisense oligonucleotide (LNA-ASO) to androgen receptor (AR) mRNA in patients with castration-resistant prostate cancer (CRPC).

5052 Background: EZN-4176 is a third generationLNA-ASO that binds the ligand binding domain of AR mRNA resulting in full length AR mRNA degradation and decreased AR protein expression. Methods: Patients (pts) (performance status ECOG≤1) with progressing CRPC were eligible; prior abiraterone and enzalutamide treatment were allowed. EZN-4176 was administered as a weekly (QW) one-hour intravenous infusion. The starting dose was 0.5 mg/Kg with a 4-week dose-limiting toxicity (DLT) period. After determination of the DLT and the maximum tolerated dose (MTD) for weekly administration, a fortnightly schedule (Q2W) was initiated; a 3+3 modified Fibonacci dose escalation design was pursued. PD studies evaluated AR expression in tissue utilizing antibodies to the amino and carboxy-termini of the AR. Results: 22 pts were enrolled (median age 70.6 years, range 59 – 84 years). One pt was treated with the Q2W schedule. Two DLTs (G3/G4 ALT/AST elevation) occurred at 10 mg/Kg, which was therefore identified as the MTD for the weekly schedule. Multiple pts treated at 6.5 and 10 mg/Kg (5/9 pts, 55%) developed ≥G2 ALT and/or AST elevation after the first cycle requiring dose reduction and treatment delay. The most frequent adverse events (AEs) all-grades were fatigue (21/22 pts, 95.4%), nausea (10/22 pts, 45.4%), constipation (8/22 pts, 36.3%), AST (8/22 pts, 36.3%) and ALT (10/22 pts, 45.4%) elevation. The most frequent G3/4 AEs were AST (4/22 pts, 18.1%) and ALT (5/22 pts, 22.7%) elevation. Maximum PSA and circulating tumor cells (CTCs) declines are summarized below. There were no objective soft tissue responses. PD studies did not document any knockdown of AR expression Conclusions: EZN-4176 has limited antitumour activity in CRPC at its MTD for weekly administration. Safety, PK, PD and efficacy data will be presented. Clinical trial information: NCT01337518. [Table: see text]

PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours

BackgroundThe purpose of this phase Ib clinical trial was to determine the maximum tolerated dose (MTD) of PR-104 a bioreductive pre-prodrug given in combination with gemcitabine or docetaxel in patients with advanced solid tumours.MethodsPR-104 was administered as a one-hour intravenous infusion combined with docetaxel 60 to 75 mg/m2 on day one given with or without granulocyte colony stimulating factor (G-CSF) on day two or administrated with gemcitabine 800 mg/m2 on days one and eight, of a 21-day treatment cycle. Patients were assigned to one of ten PR-104 dose-levels ranging from 140 to 1100 mg/m2 and to one of four combination groups. Pharmacokinetic studies were scheduled for cycle one day one and 18F fluoromisonidazole (FMISO) positron emission tomography hypoxia imaging at baseline and after two treatment cycles.ResultsForty two patients (23 females and 19 males) were enrolled with ages ranging from 27 to 85 years and a wide range of advanced solid tumours. The MTD of PR-104 was 140 mg/m2 when combined with gemcitabine, 200 mg/m2 when combined with docetaxel 60 mg/m2, 770 mg/m2 when combined with docetaxel 60 mg/m2 plus G-CSF and ≥770 mg/m2 when combined with docetaxel 75 mg/m2 plus G-CSF. Dose-limiting toxicity (DLT) across all four combination settings included thrombocytopenia, neutropenic fever and fatigue. Other common grade three or four toxicities included neutropenia, anaemia and leukopenia. Four patients had partial tumour response. Eleven of 17 patients undergoing FMISO scans showed tumour hypoxia at baseline. Plasma pharmacokinetics of PR-104, its metabolites (alcohol PR-104A, glucuronide PR-104G, hydroxylamine PR-104H, amine PR-104M and semi-mustard PR-104S1), docetaxel and gemcitabine were similar to that of their single agents.ConclusionsCombination of PR-104 with docetaxel or gemcitabine caused dose-limiting and severe myelotoxicity, but prophylactic G-CSF allowed PR-104 dose escalation with docetaxel. Dose-limiting thrombocytopenia prohibited further evaluation of the PR104-gemcitabine combination. A recommended dose was identified for phase II trials of PR-104 of 770 mg/m2 combined with docetaxel 60 to 75 mg/m2 both given on day one of a 21-day treatment cycle supported by prophylactic G-CSF (NCT00459836).

Abstract 753: Pharmacokinetic profile of the base-excision repair inhibitor methoxyamine-HCl (TRC102; MX) given as an one-hour intravenous infusion with temozolomide (TMZ) in the first in human phase 1 clinical trial

Abstract Background: MX is the first base excision repair (BER) inhibitor evaluated in humans. MX blocks the BER pathway by covalently binding to apurinic/pymidinic (AP) sites in DNA. In several preclinical studies, improved therapeutic efficacy has been demonstrated with various chemotherapeutic agents including alkylating agents, such as TMZ. Initial results and correlative studies of the first in humans administration of MX have been presented (AACR Annual Meeting 2009, abstract#5433). Initial PK analyses on patient samples receiving MX as a five-day continuous infusion revealed a distinct PK profile, 10-fold greater than previously estimated in dogs, where half-life of MX was estimated to be 4.5 hours. As a result, the protocol has been amended with MX administration adjusted from a five-day continuous infusion to a one-hour intravenous infusion. PK results of the one-hour intravenous infusion regimen are now presented. Methods: This ongoing phase I dose-escalation trial investigates the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile of MX given as an one-hour intravenous infusion in combination with TMZ. PD markers, including analysis of AP sites measured on DNA extracted from patients’ mononuclear cells (PBMCs) as well as DNA strand break determined by comet assay at multiple time points, are included. Results: 23 patients have enrolled, in two cohorts. In cohort A (patients with no-CNS disease), patients have enrolled in dose-levels 1 and 2 (TMZ 150 mg/m2/day, days 1-5 and MX 15 mg/m2 and 30 mg/m2 respectively). In cohort B (patients with CNS involvement) enrollment started at a DL lower (in DL1, TMZ 100 mg/m2/day, days 1-5 and MX 15 mg/m2; for DL2 TMZ increased to 150 mg/m2/day, days 1-5 and MX remained 15 mg/m2). Demographic, toxicity and efficacy data will be presented separately. The average half-life of MX administered as an one-hour continuous infusion was 55.04 hours (range: 12.2 - 100.3 hours, n = 20), statistically not different from half-life of MX administered as a five-day continuous infusion which was 45.1 hours (range: 32.1 - 68.8 hours, n = 6). PD results, performed on 22 patients, showed that administration of the combination of TMZ and MX resulted in 10-40% reduction in detectable AP sites. Comet assay results, performed on 20 patients revealed that the combination of TMZ and MX induced a 2 to 3-fold higher levels of DNA strand breaks compared to TMZ alone. Conclusions: MX has a distinct PK profile in humans, corresponding to a 10-fold increase in estimated half-life when compared to the half-life observed in dogs, which has allowed us to move to a convenient one-hour infusion regimen for further development. PD demonstration of MX's biologic activity on patients’ mononuclear cells has been demonstrated even at the lowest DL. Accrual to the trial is ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 753. doi:1538-7445.AM2012-753

Abstract 1743: Phase 1 clinical trial of the base-excision repair inhibitor Methoxyamine-HCl (TRC102; MX) in combination with Temozolomide (TMZ) in patients with solid tumors

Abstract Background: MX is the first base excision repair (BER) inhibitor evaluated in humans. MX blocks the BER pathway by covalently binding to apurinic/pymidinic (AP) sites in DNA. In several preclinical studies, improved therapeutic efficacy has been demonstrated with various chemotherapeutic agents. Final results of the phase I clinical trial of pemetrexed and oral MX have been published (GJ Weiss et al). Initial results and correlative studies of the alkylating agent TMZ and MX were previously presented (AACR Annual Meeting 2009, abstract#5433). As initial PK analyses on patient samples revealed a distinct and prolonged half life in humans, 10-fold greater than estimated in dogs, this report reflects the protocol amendment from MX administration as a 5-day intravenous continuous infusion to a 1-hour intravenous infusion. Methods: This phase I dose-escalation trial investigates the safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile of MX given as an one-hour intravenous infusion in combination with daily times 5 TMZ. PD markers, including analysis of abasic sites measured on DNA extracted from patients’ mononuclear cells (PBMCs) as well as DNA strand breaks determined by comet assay at multiple time points over 5-days. Results: 23 patients have enrolled, at dose-levels (DL) 1 and 2 (TMZ 150 mg/m2/day, days 1-5 and MX 15 mg/m2 and 30 mg/m2 respectively) in two cohorts. In cohort A (patients with no-CNS disease, n =13 at DL1 and n=4 at DL2) primary tumors include lung, breast, pancreatic, colon, esophageal, ovarian, oropharyngeal, salivary gland, skin adnexal tumors. In cohort B (patients with CNS tumors, n =3 at DL1 and n=3 at DL2) primary tumors include brain, pancreatic, head and neck.The combination of MX and TMZ has been well-tolerated. For the non-CNS involvement cohort, one DLT was observed at DL1; grade 3 psychosis in a patient with progressive disease on increasing doses of opioids. A grade 3 allergic reaction classified as an idiosyncratic event resulted in further expansion to 10 evaluable patients with no additional DLTs observed. To date no DLTs have been observed at DL2 and in the CNS-involved cohort. Three patients had stable disease (lung, ovarian, head and neck) with extended dosing periods of 7, 10 and 11 months. The PK results will be presented separately. In all patients evaluated, abasic sites were blocked by MX resulting in an increase in DNA strand breaks. No significant anemia (the DLT observed in the MX and pemetrexed trial) has been observed at DL1 and 2 to date; possibly because of lower MX dose administered.Conclusions: MX has a distinct PK profile in humans, which has allowed us to move to a convenient one-hour infusion regimen. Ongoing data in this phase I clinical trial demonstrate that the combination of MX with TMZ is well tolerated and hits its target, interrupting base excision repair in all patients. Trial remains open to accrual. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1743. doi:1538-7445.AM2012-1743

Pharmacokinetic profile of the base-excision repair inhibitor methoxyamine-HCl (TRC102; MX) given as an one-hour intravenous infusion with temozolomide (TMZ) in the first-in-human phase I clinical trial.

e13662 Background: MX, the first base excision repair (BER) inhibitor evaluated in humans, blocks the BER pathway by covalently binding to apurinic/pymidinic (AP) sites in DNA. Initial results of the administration of MX have been presented (AACR Annual Meeting 2009, abstract #5433). Pharmacokinetic (PK) analyses revealed a distinct PK profile different from that observed in mice and dogs, where half- life of MX was 19 minutes and 4.5 hours (h) respectively. In humans, MX half life is estimated to be 45.3 h (range: 32 − 68.8 h). As a result, the MX administration was adjusted from a 5-day intravenous (iv) continuous infusion (CI) to a 1-hour iv infusion. Methods: This ongoing phase I dose-escalation trial investigates the safety, PK, and pharmacodynamic (PD) profile of MX given as an one-hour iv infusion in combination with TMZ. PD markers, including analysis of AP sites measured on DNA extracted from patients' mononuclear cells (PBMCs) as well as DNA strand break determined by comet assay at multiple time points, are included. Results: 4 patients enrolled, at dose-level 1 (TMZ 100 mg/m2/day po, days 1-5 and MX 15 mg/m2 IV on day 1). Various primary tumors (lung, breast, pancreatic, skin adnexal) included. The average half-life of MX was 46.8 h (range: 20.4–62.7 h, based on 8 treatment cycles from 3 patients), not statistically different from the 5-day CI regimen. Treatment has been well tolerated. One grade 3 toxicity possibly treatment related (hallucinations in one patient with progressive disease and on opioids). PD results showed that administration of the combination of TMZ and MX resulted in 30–60% reduction in detectable AP sites. Comet assay results revealed that the combination of TMZ and MX induced a 2 to 3-fold higher levels of DNA strand breaks compared to TMZ alone. Conclusions: Initial data demonstrate that MX in combination with TMZ is well tolerated. MX has a distinct PK profile in humans, which has allowed us to move to a convenient one-hour infusion regimen. PD demonstration of MX's biologic activity on patients' mononuclear cells has been demonstrated even at the first dose level. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration TRACON TRACON

A phase I dose escalation safety and pharmacokinetic (PK) study of SSR244738 administered as a one-hour intravenous (IV) infusion twice-weekly during a 3-week cycle in patients (pts) with refractory solid tumors

2539 Background: SSR244738 is a new cytotoxic agent (G2-cell cycle inhibitor). In this first in man study the original schedule of administration was an IV infusion once every 3 weeks (Q3W); and due to the high clearance variability, 1300 mg/m2 was considered the maximum administered dose (MAD). The study was amended to test the twice weekly schedule (D1-D4-D8-D11-D15, every 3 weeks). Methods: Standard escalation was used in cohorts of 3–6 pts. PK profiles (up to T48h or T96h) were obtained in each pt after the 1st and the 5th administration (D1 and D15) of Cycle 1. In the Q3W, there was a trend to lower clearance (CL) in CYP2C9 *3/*3 and *1/*3 genotype pts therefore genotype samples were analyzed at baseline to identify poor metabolizers (PM) and adjust-dosing accordingly. Results: 22 heavily pretreated patients received SSR244738 at doses of 200 (3 pts), 280 (4 pts), 400 (3 pts), 560 (3 pts), 780 (3 pt), 1000 (6 pts; one pt was a PM and received 500 mg/m2). 15 females, 7 males, median age: 60 years (29–82), ECOG: (0:12, 1:9, Unk:1). Main tumor types: ovary, lung, breast, colon and prostate. Nb cycles/pts: > 2 cycles/21 (95%), > 4 cycles/9 (41%), > 6 cycles/6 (27%), > 8 cycles/2 (9%). The most common reason for treatment discontinuation was disease progression. DLT was seen in 2 pts at 1000 mg/m2 dose level: one patient had febrile neutropenia associated with Grade 3 mucositis and the second patient had Grade 3 neutropenia, which caused a treatment delay. Both pts showed high SSR244738 plasma exposures on D15. SD was reported in 11 patients. No CRs or PRs were observed. SSR244738 exhibited an overall low plasma CL (mean [range]: 0.9 [0.3–2.1] L/h). CL slightly decreased with repeated administration. The distribution volume was low [Vss mean (CV%): 11.6 L (30%)] and the terminal half life was long [mean (CV%): 15.6 h (58%)]. No deviation from dose proportionality could be observed, despite the moderate-to-high inter-individual variability (CV<64%) in exposure. Conclusions: SSR244738 is well tolerated with PK profile similar to the Q3W schedule; by changing the schedule of administration we were able to reach the MAD dose (5000 mg/m2/cycle). [Table: see text]

Estramustine plus docetaxel as second-line therapy in patients with hormone-refractory prostate cancer resistant to docetaxel alone

Objective Although docetaxel (DOC) plus prednisone is currently the treatment of choice for hormone-refractory prostate cancer (HRPC), no standard therapy is available for those patients who progress during DOC treatment. The aim of this study was to evaluate whether the addition of estramustine (E) can overcome DOC resistance. Methods Patients who had not responded to DOC in a previous randomised phase II trial received a one-hour intravenous infusion of DOC 70 mg/m 2 on day 2 in combination with oral E 840 mg/day divided into three daily administrations on days 1–5. The primary endpoint was a >50% decrease in PSA; the secondary endpoints were biochemical progression-free survival, overall survival, the objective response rate, and toxicity. Results A biochemical response was observed in 52% of the 25 patients evaluable for response. The only grade 4 event was a cerebral stroke that occurred a few days after the administration of the first treatment course. Treatment discontinuation due to worsened compliance was observed in the patients who received a higher cumulative number of courses. Conclusions Our findings suggest that the addition of E may be useful in selected HRPC patients resistant to DOC alone.

A phase I dose escalation safety and pharmacokinetic (PK) study of SSR244738 administered as a one-hour intravenous (IV) infusion every 3 weeks in patients (pt) with refractory solid tumors

2518 Background: This phase I study of SSR244738, a G2-cell cycle inhibitor cytotoxic agent, was aimed to establish the dose limiting toxicities (DLT), the maximum administered dose (MAD) and to characterize the PK profile of the proposed schedule. Methods: SSR244738 was administered as one-hour IV infusion every 3 weeks in pts (selected according common phase I criteria) starting with a modified accelerated dose escalation scheme. PK profiles (up to day 8) were obtained in each pt after the 1st administration. CYP2C9 and CYP3A5 genotypes were analyzed to identify pts’ metabolizer status. Results: 2 centers enrolled 14 heavily pretreated pts: 5 females, 9 males, median age: 52 years (32–67), ECOG PS: 0 (93% pts); main tumor types: head and neck, lung, melanoma, and breast. 40 cycles (median = 2, range: 1–11) were administered in 6 dose levels (DL) ranging from 165 to 1,300 mg/m2. Accelerated dose escalation was stopped at 660 mg/m2 for non-proportionally increase of PK parameters respect to the dose administered . SSR244738 was well tolerated up to 1,300 mg/m2: one DLT (abnormal liver function tests ALFT) was reported in one breast cancer pt with liver metastases. Only one pt (hepatocarcinoma) was withdrawn from the study due to toxicity (ALFT) after 3 cycles at 1,000 mg/m2. 2 stable diseases were reported. PK data: mean T1/2 of 23h (range: 9.20–127), mean Vss: 11.1 L (6.43–15.8) and mean Clearance (CL): 0.71 L/h (0.041–1.43). This large variability of the CL (CV% =63%) could in part be explained by CYP2C9 genotype: so far CL is <0.4 in 2 poor metabolizers (PM) and >0.6 in extensive metabolizers. Conclusion: Due to the high CL variability, 1300 mg/m2 is considered as the MAD. 3 pts will be accrued at 1,300mg/m2 to complete the DL (a reduced dose will be given to CYP2C9 PM). Weekly and twice-weekly schedules will be tested. No significant financial relationships to disclose.

Influence of fluid resuscitation on renal microvascular PO2 in a normotensive rat model of endotoxemia

IntroductionSeptic renal failure is often seen in the intensive care unit but its pathogenesis is only partly understood. This study, performed in a normotensive rat model of endotoxemia, tests the hypotheses that endotoxemia impairs renal microvascular PO2 (μPO2) and oxygen consumption (VO2,ren), that endotoxemia is associated with a diminished kidney function, that fluid resuscitation can restore μPO2, VO2,ren and kidney function, and that colloids are more effective than crystalloids.MethodsMale Wistar rats received a one-hour intravenous infusion of lipopolysaccharide, followed by resuscitation with HES130/0.4 (Voluven®), HES200/0.5 (HES-STERIL® ® 6%) or Ringer's lactate. The renal μPO2 in the cortex and medulla and the renal venous PO2 were measured by a recently published phosphorescence lifetime technique.ResultsEndotoxemia induced a reduction in renal blood flow and anuria, while the renal μPO2 and VO2,ren remained relatively unchanged. Resuscitation restored renal blood flow, renal oxygen delivery and kidney function to baseline values, and was associated with oxygen redistribution showing different patterns for the different compounds used. HES200/0.5 and Ringer's lactate increased the VO2,ren, in contrast to HES130/0.4.ConclusionThe loss of kidney function during endotoxemia could not be explained by an oxygen deficiency. Renal oxygen redistribution could for the first time be demonstrated during fluid resuscitation. HES130/0.4 had no influence on the VO2,ren and restored renal function with the least increase in the amount of renal work.

Pharmacogenetics of Cyclophosphamide in Patients with Beta Thalassemia Major Undergoing Bone Marrow Transplantation.

Cyclophosphamide (Cy) is commonly used in conditioning therapy for bone marrow transplantation (BMT). The conversion of Cy to its first active metabolite 4-hydroxy cyclophosphamide (4-HCy) is mediated by several enzymes of the cytochrome P450 (CYP450) family [CYP2B6, 2C9, 2C19 and 3A4]. Since the pharmacokinetics (PK) of 4-HCy is formation rate limited, the AUC ratio of 4-HCy/Cy reflects better the degree of systemic exposure to 4-HCy. The PK of Cy and HCy exhibits up to 20 fold inter-individual variation in patients during conditioning. To understand the mechanisms underlying the variation in Cy metabolism, we analyzed the PK of Cy and 4-HCy in 40 consecutive patients with beta thalassemia major undergoing BMT and correlated them with the common polymorphisms of CYP450 2B6, 2C9 and 2C19 genes and the pre transplant hepatic status (Lucarelli class) of the patient. All patients received Cy at a dose of 50mg/kg as one-hour intravenous infusion for 4 days (day -5 to -2) after 4 days of busulfan (day-9 to -6). Levels of Cy and 4-HCy were measured using high performance liquid chromatography. Genotyping for CYP2B6 G516T, CYP2C9 *2, *3 and CYP2C19*2 and *3 were done using PCR-RFLP methods. There was a 4–20 fold inter-patient variation in the PK of Cy and 4-HCy. Mean AUC of Cy was 2288±1169 mg* h/ml, (range: 674–5126), while that of AUC of 4-HCy was 5.67±2.52 mg* h/ml (range: 0.817–11.17). Patients with wild type CYP2B6 G/G genotype had significantly higher Cy 4-hydroxylation than those with the homozygous mutant genotype (T/T).CYP4502B6, 2C9, 2C19 genotypes and ratio of AUC 4HCy/AUC CyCYP2B6G/G (n=15)G/T (n=8)T/T (n=16)t-test p value0.0033±0.00140.003±0.00130.0023±0.00110.03 (G/G vs. T/T)CYP2C9*1/*1 (n=25)*1/*2 (n=3)*1/*3 (n=9)*2/*3 (n=2)*3/*3 (n=1)0.003±0.00160.0037±0.00090.0023±0.00110.0014, 0.00150.00730.076 (*1/*2 vs. *1/*3)CYP2C19*1/*1 (n=26)*1/*2 (n=10)*2/*2 (n=3)0.0026±0.0010.0036±0.00120.0029±0.00130.016 (1/1 vs. 1/2)One patient with homozygous mutant genotype CYP 2C9 3/3 showed 2.6 fold higher Cy 4-hydroxylation (0.0073 vs. 0.0026), while two patients with CYP2C9 2/3 genotype had 2 fold lower than the mean of the ratio for all 2C9 genotypes. Patients with CYP2C19 1/2 genotype showed significantly higher ratio than those with CYP2C19 1/1 genotype. No association was found between patients' pre- transplant liver status (Lucarelli class) and Cy 4-hydroxylation. We conclude that 4-hydroxylation of Cy is significantly influenced by CYP2B6, 2C9 and 2C19 genotypes. This could explain the wide inter individual variation in Cy PK which should be correlated with toxicity and outcome of BMT.

A Phase II study of docetaxel in patients with liver metastases from breast cancer

BackgroundPrevious phase II studies of docetaxel have indicated that hepatic metastases from breast cancer respond well to first-line treatment with docetaxel. The objective of this prospective, open label phase II study therefore was specifically to evaluate the activity and safety of docetaxel in this indication. Patients and methodsThe study recruited 47 women (mean age 50 years, range 33–66 years) with hepatic metastases from breast cancer who fulfilled the eligibility criteria. After pre-medication with steroids, patients received a one-hour intravenous infusion of docetaxel 100 mg/m2 at three-weekly intervals for up to eight cycles. Response to treatment during medication was assessed after three, six and where appropriate, eight cycles and every three month follow-up thereafter, until disease progression or death. ResultsThe best overall response rate (ORR) for evaluable patients was 64.3% (95% CI: 48.0%–78.5%). In terms of the primary efficacy parameters, the ORR at the sixth cycle of treatment was 62% (95% CI: 45%–80%) with 17% complete responses. The median duration of response was 139 days (95% CI: 111–216 days) and the median survival duration calculated on an intent-to-treat basis was 335 days (227–568 days, 95% CI). One (2%) toxic death was reported. ConclusionsDocetaxel is a highly effective cytotoxic agent in the treatment of patients with liver metastases from breast cancer.

A phase I study of docetaxel and 5-fluorouraciI in patients with advanced solid malignancies

This study was undertaken to evaluate the feasibility of administering docetaxel (Taxotere; Rhône-Poulenc-Rorer) as a one-hour intravenous (i.v.) infusion on day 1 combined with 5-fluorouracil (5-FU) as a bolus i.v. injection for five (days 1-5) or three (days 1-3) consecutive days every four weeks. Thirty-seven patients with advanced solid malignancies were treated with 115 total courses involving seven dose levels of the two regimens of docetaxel and 5-FU (docetaxel/5-FU [mg/m2]/mg/m2/d]). In an effort to reduce fluid retention and hypersensitivity phenomena related to docetaxel, patients received premedication with dexamethasone 8 mg orally twice daily for three consecutive days beginning 24 hours before treatment. Severe (grade 4) neutropenia lasting longer than seven days with or without fever and/or severe mucositis, precluded further dose escalation above docetaxel 60 mg/m2 on day 1 and 5-FU 300 mg/m2/day administered on days 1-5 every four weeks. The rates of these toxic effects were also unacceptably high above docetaxel 60 mg/m2 on day 1 and 5-FU 300 mg/m2/day administered on days 1-3 every four weeks. Nine patients experienced various manifestations of fluid-retention that were potentially related to study drugs. However, neither treatment delay nor discontinuation of treatment was required. Nausea, vomiting, diarrhea, and fatigue, were mild to modest in severity and occurred infrequently (< 10% of courses). Two patients with metastatic breast cancer experienced complete responses and a partial response occurred in a patient with metastatic non-small-cell lung cancer. Based on the results of this study, the regimen of docetaxel 60 mg/m2 on day 1 followed by 5-FU 300 mg/m2/d i.v. for three or five days every four weeks is well tolerated and these doses are recommended for further evaluations. The feasibility of administering docetaxel 60 mg/m2 followed by 5-FU 300 mg/m2 for three or five days every four weeks and the preliminary antitumor activity noted indicate that further disease-directed studies of docetaxel and 5-FU are warranted in patients with relevant solid malignancies.

Multicenter, Randomized, Comparative Study of Recombinant vs. Natural Streptokinases in Acute Myocardial Infarct (TERIMA)

To compare the effects on hemostasis and coronary patency of recombinant (rSK) and natural (nSK) streptokinases in patients with acute myocardial infarct (AMI). Patients from 7 hospitals, <70 years old, less than 12 h after the onset of AMI symptoms, with ST segment elevation or bundle branch block, without contraindications for thrombolytic therapy, were randomized to receive 1.5 million units of nSK or rSK in a one-hour intravenous infusion. Fibrinogen, fibrinogen degradation products (FDP) and thrombin time were monitored. A coronary angiography was performed after 5-10 days in those patients who gave their consent and did not refer allergy to iodine contrasts. Images were blindly evaluated by an independent committee. 224 patients were randomized (113 nSK and 111 rSK). Groups were equivalent in all baseline and demographic variables except that rSK patients were 5.4 years significantly older. They were also comparable in all the clinical characteristics. Both treatments produced the same changes in hemostasis. Fibrinogen levels decreased, FDP and thrombin time increased immediately after thrombolysis and returned to baseline 2 days afterwards, but fibrinogen values continued to increase up to day 10. Coronary patency (TIMI 2-3) rates at 7.8+/-2.7 and 8.0+/-2.7 days after fibrinolysis were 70.7% and 67.1% for nSK and rSK groups, respectively (non-significant difference). Hypotension and arrhythmias were the most frequent adverse events in both groups, which did not differ in this respect either. Five patients from each group died, one of them (nSK) due to gastroduodenal bleeding probably related to treatment. rSK behaved similarly to nSK regarding coronary patency at 8 days after thrombolysis and the changes induced on fibrinogen, FDP and thrombin time. These results suggest that the same benefit/risk profile reported for AMI patients treated with nSK can be expected for rSK.

エドバコマブ (E5) のグラム陰性菌敗血症に対する臨床第II相試験

The efficacy, safety and usefulness of murine anti-endotoxin monoclonal IgM antibody "E5, an intravenous dose of 2 mg/kg" were evaluated in 88 patients with suspected Gram-negative sepsis from 37 institutes in Japan. Out of these, 74 patients were evaluable for the efficacy, 85 for safety and 75 for clinical usefulness. In assessing the efficacy, the patients were divided into 3 groups based on the plasma endotoxin levels (Endospecy with new PCA treatment of plasma): H group with a level of above 9.8 pg/ml and M group with a level of 3.0-9.8 pg/ml and L group with a level of below 3.0 pg/ml. 1. The efficacy rates as assessed following administration of E5 were 73.1% in the H group, 70.4% in the M group and 38.1% in the L group being higher in the groups with significantly high plasma endotoxin levels. 2. In both the H and M groups in whom plasma endotoxin levels were significantly high, the majority of the patients showed rapid reduction of the levels after administration of E5. 3. In all groups, improvement in body temperature, pulse rate, blood TNF-alpha and blood IL-6 was observed after treatment with E5. In the H and M groups with an endotoxin level of > or = 3.0 pg/ml, improvement in platelet count as well as in CRP was noted. The H group showed also improvement in WBC. 4. Improvement in the shock score was noted in all the groups but was more outstanding in the H and M groups in the early stage of treatment. 5. Side effects were seen in 5 (5.9%) of 85 patients and all thought to be allergic in symptoms such as rash, itching, fever and flare. 6. The reaction to the prick test performed before administration of E5 was negative in all these 5 patients. For 3 of the 5 patients, anti-E5 IgE antibody was measured. In all of them, the IgE levels were higher than those of healthy controls. Also, in 47.6% of patients, an elevation of anti-E5 IgG antibody was noted two weeks after the administration. 7. Clinical laboratory abnormalities were observed in 3 (3.5%) of 85 patients. They were an elevation of S-GOT.S-GPT and lowering of BUN, increased Al-p and decreased CH50, increased neutrophilia (%) and were all slight in the degree of the changes. 8. The clinical usefulness of E5 was evaluated for 75 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Pharmacokinetic and clinical studies of cefmenoxime in neonates and premature infants

Serum concentrations and urinary recovery rates of cefmenoxime (CMX) were determined in 41 mature and premature infants (with ages 0-24 days) after one shot intravenous injection of 10, 20 (1-hour intravenous drip infusion was also carried out) or 30 mg/kg for treatment and prophylaxis of various infections. Because the number of cases included was small, a comparison study was conducted by classifying them into 3 groups; 3 days or younger, 4 to 7 days, and 8 days or older, rather than dividing them into groups of mature and premature infants. Clinical evaluation was conducted in 7 male and 1 female cases 1 to 29 days old, whose diseases comprised 1 case each with septicemia, purulent otitis media and phlegmonous cellulitis, 3 with pneumonia and 2 with urinary tract infection. 1. Changes in serum concentrations and urinary recovery rates (1) Intravenous bolus injection of 10 mg/kg: Serum concentrations of the drug in the 3 age groups peaked at 28.9, 29.5 and 29.1 micrograms/ml, respectively, all at 30 minutes after the drug administration, and thereafter gradually declined. The mean level in the 3rd group was the lowest at 1.9 micrograms/ml at 6 hours. Average serum half-lives of CMX were shorter in older subjects, 3.0, 1.9 and 1.4 hours, respectively in the 3 groups. Urinary recovery rates were relatively high, 68.9 to 84.9% in the 3 cases examined during the first 6 hours, and 15.4 to 66.2% during the first 2 hours. (2) Intravenous bolus injection of 20 mg/kg: Serum concentrations of the drug in the 3 groups peaked at 65.2, 60.5 and 65.8 micrograms/ml, respectively, all at 30 minutes after the drug administration, with no significant differences noted among the groups. The levels gradually declined thereafter in all groups, but remained rather high at 20.1, 6.5 and 9.5 micrograms/ml, respectively, at 6 hours. Average serum half-lives of CMX were 3.5, 1.7 and 1.9 hours, respectively. The inversion of values obtained between the 2nd and 3rd groups appears to be attributable to that all of the 3rd group were premature infants, and the body weight of 2 cases of them were less than 2,000 g each. Urinary recovery rates ranged widely from 37.0 to 89.4% in the 4 cases examined during the first 6 hours. (3) One-hour intravenous drip infusion of 20 mg/kg: Serum concentrations of the drug in the 3 groups peaked at 57.7, 60.2 and 72.4 micrograms/ml, respectively, all at the termination of the drug infusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Short-term somatostatin infusion affects T lymphocyte responsiveness in humans

Peripheral blood lymphocytes (PBL) function was analysed in 16 young men with duodenal ulcers after one-hour intravenous infusion of somatostatin (SMS) at a dose of 250 μg/h. Proliferative responses of PBL from SMS-treated patients were significantly diminished compared with pre-treatment values, after stimulation with PHA, PWM or Con A. Spontaneous IL-2R expression was moderately increased after SMS infusion but PHA-induced IL-2R expression was not affected by this drug. Alloantigen and autoantigen stimulation of PBL showed no significant changes in the proliferative response after SMS infusion. NK cell activity was similarly unaffected. These observations establish a link between SMS exposure and possible development of immune dysfunction.

Effect of congestive heart failure on the pharmacokinetics of cibenzoline.

Six patients with chronic congestive heart failure (CHF) (New York Heart Association functional class II or III) and five healthy subjects completed this study designed to determine if CHF alters the pharmacokinetics and absolute bioavailability of cibenzoline when compared with healthy subjects. Each subject or patient was administered a one-hour intravenous infusion of 80 mg of 15N2-cibenzoline and simultaneously received an 80-mg oral dose of cibenzoline that allowed for analytic separation of each route of administration. Resulting plasma concentration-time profiles and urinary excretion rate data were used to determine pharmacokinetic parameters for cibenzoline. There were no statistically significant differences in any pharmacokinetic parameter between patients with CHF and healthy subjects. The absolute bioavailability ranged from 74% to 97% in those with CHF. The volume of distribution following the intravenous dose ranged from 3.4 to 6.1 L/kg, and plasma clearance ranged from 245 to 642 mL/min, with an apparent elimination half-life of approximately ten hours. Approximately 60% of the dose was recovered in the urine. Overall, the pharmacokinetics of cibenzoline in patients with chronic CHF do not differ from those observed in healthy subjects.

Lack of Von Willebrand Factor, Factor VIII Related Antigen and Factor VIII Coagulant Response to Human Growth Hormone Infusion in Type 2 Diabetes Mellitus

Excessive growth hormone (GH) secretion and platelet hyperaggregation have been considered to be involved in the development of the vascular complications of diabetes mellitus (DM).Trying to find a common link between GH and platelet hyperaggregation, we measured von Willebrand or ristocetin cofactor activity (VIII R:Rcof), factor VIII-related antigen (VIII R:Ag) and factor VIII coagulant activity (VIII:C) in ten type 2 DM (NIDDM) and seven normal control (C) human subjects. These three parameters were measured before (time 0), and after a one-hour intravenous infusion of 0.1U/kg bw of GH, (times 1, 4, 6, and 24 hours). The NIDDM subjects were nonobese and without clinical evidence of diabetic vascular complications. Despite remarkably high levels of GH reached during the infusion (average 280ng/ml), there were no significant changes in the measured parameters in either NIDDM or C group. The baseline levels of factors VIII R:Rcof, VIII R:Ag and VIII:C were also not significantly different in the two groups.Changes in GH serum levels seem to have no effect on the factors VIII:C, VIII R:Ag or VIII R:Rcof levels in normals (C) or in NIDDM subjects without evidence of vascular complications. These results do not preclude the possibility that there may be a different response to GH in DM patients with advanced vascular complications and probable endothelial cell abnormalities.

Metabolic fate of radioactive acyclovir in humans

The metabolic fate and the kinetics of elimination of [8- 14C]acyclovir in plasma and blood was investigated in five cancer patients. Doses of 0.5 and 2.5 mg/kg were administered by one-hour intravenous infusion. Radioactivity was distributed nearly equally in blood and plasma. The plasma and blood concentration-time data were defined by a two-compartment open pharmacokinetic model. The overall mean acyclovir plasma half-life and total body clearance ± SD were 2.1 ± 0.5 hours and 297 ± 53 ml/min/1.73 m 2. Binding of acyclovir to plasma proteins was 15.4 ± 4.4 percent. The radioactive dose was excreted predominantly in the urine (71 to 99 percent) with less than 2 percent excretion in the feces and only trace amounts of radioactivity in the expired air. Reverse-phase high-performance liquid chromatography indicated that 9-carboxymethoxymethylguanine was the only significant urinary metabolite of acyclovir accounting for 8.5 to 14.1 percent of the dose. A minor metabolite (<0.2 percent of dose) had the retention time of 8-hydroxy-9-(2-hydroxyethoxymethyl)guanine. Unchanged urinary acyclovir ranged from 62 to 91 percent of the dose. There was no indication of acyclovir cleavage to guanine. The renal clearances of acyclovir were three times higher than the corresponding creatinine clearances.