Recurrent posterior reversible encephalopathy syndrome in mitochondrial disorder.

OBJECTIVES: Recurrent posterior reversible encephalopathy syndrome (PRES) has not been reported in association with multi-system mitochondrial disorder (MID). CASE REPORT: In a 60-year-old HIV-negative, Caucasian female with short stature, double vision, struma, memory impairment, chronic renal failure requiring hemodialysis, seizures, intermittent atrial fibrillation, arterial hypertension, hyperlipidemia, anemia, hypacusis, tinnitus, and a daughter with multiple sclerosis, short stature and hypothyroidism; another daughter with schizophrenia, and a son who died from encephalopathy at age 3 months, an MID was suspected. At age 53 years, she experienced sudden, transient blindness for 2 days bilaterally during an episode of high blood pressure with complete recovery within 2 weeks. At age 60 years, a similar episode occurred. Four weeks later, she experienced a third PRES episode with high blood pressure, seizures, impaired consciousness and reversible blindness for 2 days. MRI at the second episode was indicative of a PRES, and MRI at the third episode additionally revealed occipital bleedings, acute embolic stroke and features indicating PRES. CONCLUSIONS: This case indicates that MID may be associated with recurrent PRES, triggered by recurrent episodes of high blood pressure. Whether high blood pressure was a manifestation of the MID or related to other causes remains speculative. PRES does not seem to be a primary but is rather a secondary manifestation of an MID.

In vivo disposition of irinotecan (CPT-11) and its metabolites in combination with the monoclonal antibody cetuximab.

BACKGROUND: The present study was designed to investigate whether a combination of irinotecan and the monoclonal antibody cetuximab shows potential to modulate the pharmacokinetics of irinotecan and its metabolites. PATIENTS AND METHODS: All patients, suffering from advanced colorectal cancer, received irinotecan (350 mg/m2) every third week and cetuximab as a loading dose (400 mg/m2) on day 2, followed by a weekly maintenance dose (250 mg/m2). Plasma samples were analysed after the first (MONO) and second (CMAB) irinotecan infusions. RESULTS: No significant alterations in the plasma concentrations and pharmacokinetics of irinotecan and its metabolites were observed after combination with cetuximab. Only differentiation of irinotecan into lactone and carboxylate plasma concentrations resulted in a distinctly lower cmax of the active lactone in the CMAB and a significantly higherAUClast in the MONO schedule (p<0.02). CONCLUSION: The results of this study indicated that cetuximab has no clinically relevant impact on the pharmacokinetics of irinotecan, its activation into SN-38, or its detoxification by beta-D-glucuronidation.

Pharmacokinetics and metabolism of irinotecan combined with capecitabine in patients with advanced colorectal cancer.

BACKGROUND: Irinotecan (CPT-11) in combination with 5-fluorouracil/folinic acid is used successfully for first-line treatment of metastatic colorectal cancer. Capecitabine (CCB) represents a very convenient alternative to 5-fluorouracil, either as single agent or in a combination of regimens acting synergistically and with the potential to further improve efficacy. Both CPT-11 and CCB need to be activated by human carboxyl esterases, therefore a probable pharmacokinetic drug interaction was checked. PATIENTS AND METHODS: Ten patients suffering from advanced colorectal cancer were enrolled in this trial. CPT-11 was administered as a 30-min i.v.-infusion (70 mg/m2) weekly. CCB was given p.o. twice daily for two weeks (2,000 mg/m2 daily) starting the day after the first CPT-11 infusion. Plasma samples were analysed during/after the first (MONO) and third (CAPIRI) CPT-11 infusion. RESULTS: CCB did not alter CPT-11 plasma disposition, and no significant changes in c(max), AUC(last), Vdss and Cl(tot) during CAPIRI treatment could be observed. However, co-administration of CCB appeared to decrease SN-38 (the cytotoxic CPT-11 metabolite) plasma concentrations during the first three hours after initiation of CPT-11 infusion, with strongly time-dependent plasma percentage differences between control and CAPIRI treatment (p < 0.005, R = 0.981). Co-administration of CCB also had a similar impact on the initial plasma disposition of SN-38gluc, but not on that of the APC metabolite. CONCLUSION: Overall, our findings indicate that, while the administration of CCB resulted in reversible lower formation rates of SN-38 and SN-38gluc, it did not have a significant impact on CPT-11 pharmacokinetics.

Pharmacokinetics of gemcitabine combined with trastuzumab in patients with advanced breast cancer.

BACKGROUND: Combining the monoclonal antibody trastuzumab (TMAB) with chemotherapy is a new strategy in treatment of advanced breast cancer in HER+++ overexpressing patients. PATIENTS AND METHODS: The disposition of gemcitabine has been investigated in 8 breast cancer patients (prospective cross-over design). Gemcitabine was administered as a 30-min i.v. infusion (1,000 mg/m(2) in 250 ml) on day 1 weekly for 3 weeks. On day 2 TMAB was infused with a loading dose of 4 mg/kg (90-min infusion) followed by a weekly maintenance dose of 2 mg/kg (30-min infusion). Pharmacokinetic analysis was performed after the first (= MONO) and after the third gemcitabine infusion (= TMAB). RESULTS: Cmax was 22.2 microg/ml (t(max) = 24 min) in the MONO and 24.6 microg/ml (t(max) = 23 min) in the TMAB schedule. Gemcitabine distributed rapidly from plasma within a few minutes and was eliminated with a t1/2el of about 80 min in both arms of the study. The metabolite difluorodeoxyuridine (dFdU) appeared in plasma with t1/2appin = 12.8 min (MONO) or t1/2appin = 10.2 min (TMAB) reaching a mean peak concentration of 35.9 microg/ml (MONO) or 30.4 microg/ml (TMAB), respectively. CONCLUSION: The results gave evidence that TMAB does not affect the disposition of gemcitabine.