PAC fixed dose: pharmacokinetics of a 1-hour paclitaxel infusion and comparison to BSA-normalized drug dosing

BACKGROUND: The aim of this study was to determine the pharmacokinetics (PKs) of a 175-mg fixed dose of paclitaxel (PAC) after a 1-h infusion in cancer patients and to compare them with the PK parameters from a study with a dose normalized to the body surface area (BSA) (100 mg/m2). PATIENTS AND METHODS: PAC PKs were studied during the first course of therapy in 13 patients. A fixed dose of 175 mg PAC was administered weekly by a 1-h infusion to patients with advanced cancer. Total PAC in serum was quantified by high-performance liquid chromatography (HPLC). PK parameters were calculated by non-compartmental and model-dependent methods. RESULTS: The mean BSA of 12 patients (1 patient excluded from all analyses because of prolonged infusion duration) was 1.79 m2 (coefficient of variation (CV) 7.8%), the mean dose referred to the individual BSAs was 98.3 mg/m2 (CV 8.3%). The mean area under the curve (AUC) was 6,193 ng/ml x h (CV 46%), the mean plasma clearance (Clp) was 19.7 l/h/m2 (CV 45%), and the volume of distribution at steady state (Vss) was 121.6 l/m2 (CV 52%). The mean residence time (MRT) was 7.6 h (CV 46%), the mean distribution half-life (t1/2 alpha) of PAC(tot) was 0.4 h (CV 62%), and the elimination half-life (t1/2 beta) 10.0 h (CV 42%). Maximum plasma concentration Cmax was 3,161 ng/ml (CV 36%). The mean time above 0.05 microM (42.7 ng/ml) was 19.7 h, and the mean time above 0.1 microM (85.4 ng/ml) was 10.6 h. CONCLUSIONS: In this study, a fixed dose of PAC of 175 mg corresponds to a mean BSA-normalized dose of 98.3 mg/m2 (range 88.8-117.4 mg/m2). A higher variability of PK parameters was observed compared to previously published results of a PK study with BSA-normalized dosing of 100 mg/m2. However, the AUC and the time above threshold concentrations did not depend on the dose. Therefore, a fixed dose of 175 mg weekly could be an option for palliative treatment with PAC and may offer a simple but effective schedule for PAC treatment.     

Differential in vitro neurotoxicity of the flame retardant PBDE-99 and of the PCB Aroclor 1254 in human astrocytoma cells

Polybrominated diphenyl ethers (PBDEs) are an important class of flame retardants. Because of their presence in maternal milk and their structural similarity to polychlorinated biphenyls (PCBs), concern has been raised on their possible developmental neurotoxicity. Aim of the present study was to investigate the in vitro effects of PBDE-99 (2,2', 4,4', 5-pentabromodiphenyl ether) on astroglial cells (human 132-1N1 astrocytoma cells) and comparing it with those of the PCB mixture Aroclor 1254. Both PBDE-99 and Aroclor 1254 caused a concentration-dependent inhibition of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) reduction, however, only the latter increased lactate dehydrogenase (LDH) release or cell death, assessed by the trypan blue assay. PBDE-99 caused translocation of the three protein kinase C (PKC) isozymes (alpha, epsilon, zeta) present in 132-1N1 astrocytoma cells, while Aroclor 1254 affected only PKCalpha and epsilon translocation. However, pre-incubation with the PKC inhibitor GF109203X or PKC down-regulation by the phorbol ester PMA, had minimal or no effect on PBDE-99 or Aroclor 1254-induced cytotoxicity. Similarly, the calcium chelator BAPTA-AM, the tyrosine kinase inhibitor genistein, and the MEK (mitogen activated protein kinase kinase) inhibitor PD98059 had no effect on PBDE-99 and Aroclor 1254 cytoxicity. On the other hand, the phosphatidylinositol 3 kinase (PI-3K) inhibitor LY290042 enhanced PBDE-99 toxicity, but did not affect Aroclor 1254. Because of the involvement of PI-3K in apoptotic cell death, the ability of PBDE-99 and Aroclor 1254 to induce apoptosis in astrocytoma cells was investigated. PBDE-99, but not Aroclor 1254, caused apoptotic cell death in astrocytoma cells, assessed by the TUNEL method and by Hoechst 33258 staining, via a p53 dependent mechanism. These results suggest that PBDE-99 and Aroclor 1254 exert differential cytotoxic effects on human astroglial cells.     

Normative data for a user-friendly paradigm for pattern electroretinogram recording

PURPOSE: To provide normative data for a user-friendly paradigm for the pattern electroretinogram (PERG) optimized for glaucoma screening (PERGLA). DESIGN: Prospective nonrandomized case series. PARTICIPANTS: Ninety-three normal subjects ranging in age between 22 and 85 years. METHODS: A circular black-white grating of 25 degrees visual angle, reversing 16.28 times per second, was presented on a television monitor placed inside a Ganzfeld bowl. The PERG was recorded simultaneously from both eyes with undilated pupils by means of skin cup electrodes taped over the lower eyelids. Reference electrodes were taped on the ipsilateral temples. Electrophysiologic signals were conventionally amplified, filtered, and digitized. Six hundred artifact-free repetitions were averaged. The response component at the reversal frequency was isolated automatically by digital Fourier transforms and was expressed as a deviation from the age-corrected average. The procedure took approximately 4 minutes. MAIN OUTCOME MEASURES: Pattern electroretinogram amplitude ( micro V) and phase (pi rad); response variability (coefficient of variation [CV] = standard deviation [SD] / mean x 100) of amplitude and phase of 2 partial averages that build up the PERG waveform; amplitude ( micro V) of background noise waveform, obtained by multiplying alternate sweeps by +1 and -1; and interocular asymmetry (CV of amplitude and phase of the PERG of the 2 eyes). RESULTS: On average, the PERG has a signal-to-noise ratio of more than 13:1. The CVs of intrasession and intersession variabilities in amplitude and phase are lower than 10% and 2%, respectively, and do not depend on the operator. The CV of interocular asymmetries in amplitude and phase are 9.8+/-8.8% and 1.5+/-1.4%, respectively. The PERG amplitude and phase decrease with age. Residuals of linear regression lines have normal distribution, with an SD of 0.1 log units for amplitude and 0.019 log units for phase. Age-corrected confidence limits (P<0.05) are defined as +/-2 SD of residuals. CONCLUSIONS: The PERGLA paradigm yields responses as reliable as the best previously reported using standard protocols. The ease of execution and interpretation of results of PERGLA indicate a potential value for objective screening and follow-up of glaucoma.     

Early detection of recurrences in the follow-up of primary breast cancer in an asymptomatic or symptomatic phase

AIMS AND BACKGROUND: Periodic follow-up after primary treatment for breast cancer is a common procedure for the early detection of recurrent disease in the asymptomatic state. Anyway, there is no clinical evidence that treatment of metastases may improve the prognosis if applied in the asymptomatic state. The aim of the present study was to investigate the modality of detection of the first relapse in the asymptomatic vs the symptomatic state. METHODS: We retrospectively analyzed 717 breast cancer patients who had been consecutively referred to the Parma Oncology Division during the period 1986 to December 1988. Recurrences were detected in the course of periodic follow-up. RESULTS: A total of 211 of the 408 patients evaluated had a first relapse with a median follow-up of 94.7 months. Local and distant recurrences were 49% and 47%, respectively. Bone recurrences represented 24% of the total first recurrences, then chest wall recurrences in 23%, local regional nodes in 13%, lung in 7%, liver in 4%, and brain in 2%. The distribution of the studied patients according to recurrence site and asymptomatic or symptomatic state was different: 69% of asymptomatic patients (110) had a local recurrence vs 31% of symptomatic patients (101). A difference in survival was recorded in favor of cases detected in the asymptomatic state (P <0.001). CONCLUSIONS: The present study suggests that an early detection of local recurrence might have a favorable impact on the prognosis of patients followed after primary treatment for breast cancer. It should be considered that any difference in survival could also be explained by several "biases" and that breast cancer follow-up is still an area of investigation open to discussion in which many questions remain to be clarified.     

Vascular endothelial growth factor concentrations in the plasma-activated platelets rich (P-APR) of healthy controls and colorectal cancer patients

Vascular endothelial growth factor (VEGF) is known to play a key role in tumour angiogenesis. Our preliminary published data suggest that plasma-activated platelets rich (P-APR) rather than other plasma compartments (i.e. plasma, plasma-platelets poor) or serum is the more suitable blood fraction for measuring VEGF in a miscellaneous series of gastrointestinal cancer patients. The aim of this confirmatory study was to assess VEGF in P-APR blood compartments of 30 healthy control subjects (HCS) and a homogeneous series of 62 colorectal cancer patients (CRCP), prospectively collected, to evaluate its possible clinical-biological significance. Samples of plasma (P) in both sodium citrate (SC) and sodium citrate-theophylline-adenosine-dipyridamole (CTAD) were collected from venous blood. After the centrifugation and separation methods VEGF levels were detected by ELISA in P-APR. The best differentiation between HCS and CRCP in VEGF level was seen for P-APRCTAD (median value: 255 pg/ml versus 142 pg/ml; p=0.000 by Mann-Whitney U test). No significant correlation among the P-APR VEGF concentrations and the main clinical pathological features was found. We suggest that P-APRCTAD fraction, obtained according to well standardised conditions, could represent the suitable blood compartment for the assessment of VEGF as marker of malignant intestinal transformation.     

Oral versus intravenous vinorelbine: clinical safety profile

The availability of chemotherapeutic drugs administrable by oral route represents a step forward in the management of cancer patients. Among oral agents, vinorelbine is particularly interesting for its pharmacological characteristics and clinical efficacy. Oral vinorelbine is rapidly absorbed (1.5-3 hours) with an elimination half-life of approximately 40 hours. It shows a low level of binding to plasma proteins (13%), is highly bound to platelets (78%) and has a hepatic metabolism and an absolute bioavailability of 40% with a moderate and similar interpatient variability for the two forms. Food has no influence on the pharmacokinetic profile of oral vinorelbine even if nausea/vomiting is less frequent and less severe in the fed patients than in the fasting patients. Therefore, to ensure patient comfort, it is recommended that oral vinorelbine is administered with a snack. All the metabolites of oral vinorelbine have been identified and, among these, only deacetyl-vinorelbine presented activity demonstrating that for both oral and intravenous (i.v.) routes of administration the drug has the same metabolism pattern. Oral vinorelbine is eliminated mainly in a unconjugated form via the bile. In this process, the CYP 3A4 isoform of cytochrome P450 is mostly involved. Absorption of oral vinorelbine is not delayed in elderly patients. After oral administration, blood concentrations of vinorelbine in elderly patients are within the range of values observed in younger patients. The absolute bioavailability is close to 38% in elderly whereas it is close to 40% in younger patients. This difference is not significant. As compared to the intravenous drug, oral vinorelbine demonstrated linear pharmacokinetics as well an absolute bioavailability of approximately 40%, and a reliable dose-correspondence of 80 mg/m2 oral form --> 30 mg/m2 i.v. and 60 mg/m2 oral --> 25 mg/m2 i.v. Therefore, i.v. and oral forms show similar interindividual variability, same metabolism pattern, reproducible intra-patient blood exposure, and same pharmacokinetic-pharmacodynamic relationship. Oral vinorelbine has shown significant activity in advanced non-small cell lung cancer. Given at 60 mg/m2/week for the first 3 administrations and then increased to 80 mg/m2/week achieved the same efficacy as i.v. vinorelbine in terms of progression-free survival, overall survival, objective response. Mild-to-moderate gastrointestinal toxicity, easily manageable with standard treatment was recorded. Reproducible efficacy compared to previously reported results with vinorelbine i.v. Also, in advanced breast cancer, oral vinorelbine has shown significant activity with a good therapeutic index. Albeit no formal comparison between the oral and the intravenous formulations of vinorelbine has been made, however, the oral route seems to offer major advantages to patients who are faced with a clear decrease in the frequency of hospital admissions as compared to that needed to give intravenous chemotherapy.