Utility of 18F-fluoroestradiol (18F-FES) PET/CT imaging as a pharmacodynamic marker in patients with refractory estrogen receptor-positive solid tumors receiving Z-endoxifen therapy.

BACKGROUND: Z-endoxifen is the most potent of the metabolites of tamoxifen, and has the potential to be more effective than tamoxifen because it bypasses potential drug resistance mechanisms attributable to patient variability in the expression of the hepatic microsomal enzyme CYP2D6. 18F-FES is a positron emission tomography (PET) imaging agent which selectively binds to estrogen receptor alpha (ER-α) and has been used for non-invasive in vivo assessment of ER activity in tumors. This study utilizes 18F-FES PET imaging as a pharmacodynamic biomarker in patients with ER+ tumors treated with Z-endoxifen. METHODS: Fifteen patients were recruited from a parent therapeutic trial of Z-endoxifen and underwent imaging with 18F-FES PET at baseline. Eight had positive lesions on the baseline scan and underwent follow-up imaging with 18F-FES 1-5 days post administration of Z-endoxifen. RESULTS: Statistically significant changes (p = 0.0078) in standard uptake value (SUV)-Max were observed between the baseline and follow-up scans as early as 1 day post drug administration. CONCLUSION: F-FES PET imaging could serve as a pharmacodynamic biomarker for patients treated with ER-directed therapy.

Behavioral, metabolic, and lipidomic characterization of the 5xFADxTg30 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is associated with both extracellular amyloid-ß (Aß) plaques and intracellular tau-containing neurofibrillary tangles (NFT). We characterized the behavioral, metabolic and lipidomic phenotype of the 5xFADxTg30 mouse model which contains overexpression of both Aß and tau. Our results independently reproduce several phenotypic traits described previously for this model, while providing additional characterization. This model develops many aspects associated with AD including frailty, decreased survival, initiation of aspects of cognitive decline and alterations to specific lipid classes and molecular lipid species in the plasma and brain. Notably, some sex-specific differences exist in this model and motor impairment with aging in this model does compromise the utility of the model for some movement-based behavioral assessments of cognitive function. These findings provide a reference for individuals interested in using this model to understand the pathology associated with elevated Aß and tau or for testing potential therapeutics for the treatment of AD.

Clinical outcomes among patients with tuberculous meningitis receiving intensified treatment regimens.

SETTING: National Center for Tuberculosis and Lung Diseases (NCTLD), Tbilisi, Georgia.OBJECTIVE: To determine clinical outcomes of patients with tuberculous meningitis (TBM) treated with an intensified regimen including a fluoroquinolone (FQ) and an injectable agent.DESIGN: Prospective cohort of patients aged ≥16 years initiating treatment for TBM at the NCTLD from January 2018 to December 2019. Treatment outcomes and neurologic disability at 1, 6 and 12 months after treatment initiation were assessed.RESULTS: Among 77 patients with median follow-up time of 363 days (IQR 269-374), 97% received a FQ, 62% an injectable agent, 44% linezolid and 39% a carbapenem. Fifty-seven patients (74%) successfully completed treatment, 2 (2.6%) had treatment failure, 6 (7.8%) died, and the remainder (12%) were lost to follow up. Among 11 patients treated for multidrug-resistant TBM, the median follow-up time was 467 days and one patient (8%) died. Regarding neurologic outcomes, 14/76 (18%) patients had Modified Rankin Scores of 0 at baseline, improving to 85% (56/66) and 94% (47/50) at 6 and 12 months, respectively.CONCLUSION: Intensified multidrug treatment regimens including a FQ and an injectable agent in all patients and newly implemented drugs in patients with multidrug-resistant TBM resulted in low mortality and favorable neurologic outcomes.

Differentiation of promyelocytic (HL-60) cells into mature granulocytes: mitochondrial-specific rhodamine 123 fluorescence.

Rhodamine 123, a fluorescent dye which binds as a result of the transmembrane potential, was used to stain the mitochondria of HL-60 cells, a cell line established from human promelocytic leukemia cells. The DMSO-induced differentiation of promyelocytic cells into mature granulocytes caused a fourfold decrease in fluorescence intensity that paralleled the disappearance of S-phase and G2M cells. This suggests that upon myeloid differentiation whereby the cells enter an irreversible quiescent state, the mitochondrial mass of the cells has decreased. This suggestion is corroborated by electron microscopy, which shows a decrease in the number of mitochondria, and by decreases in total mitochondrial protein and cytochrome oxidase activity. The respiratory rate of isolated mitochondria did not change, suggesting that the transmembrane potential remained the same. Undifferentiated cells in exponential phase of growth exhibit an intracellular heterogeneity of fluorescence intensity. This heterogeneity appears to have a cell age basis, as late S/G2M cells, obtained by centrifugal elutriation, yielded twice the fluorescence intensity of early G1 cells.

Highly Variable Expression of ESR1 Splice Variants in Human Liver: Implication in the Liver Gene Expression Regulation and Inter-Person Variability in Drug Metabolism and Liver Related Diseases.

Estrogen receptor alpha (ESR1) plays an important role in many tissues including the liver. Numerous alternative splice variants of ESR1 exist that encode ESR1 proteins with varying functions. We aim to study ESR1 genomic organization and its mRNA expression profile in human liver by incorporating information from literature and genomic databases (Ensembl, NCBI and GTEx), and employing a quantitative method to measure all known ESR1 mRNA splice variants in 36 human livers. We re-constructed ESR1 genomic organization map that contains 29 exons. ESR1 mRNA splice variants with varying 5' untranslated region (5'UTR) and/or missing each of eight coding exons are readily detectable in liver and other tissues. Moreover, we found extensive inter-individual variability in splice variant pattern of ESR1 transcripts. Specifically, ESR1 transcripts lacking first coding exon are the main transcripts in liver, which encode ESR1 proteins missing N-terminal 173 amino acids (for example, ERα46), reported previously to have either constitutive activity or dominant negative effects depending on cellular context. Moreover, some livers predominantly express ESR1 transcripts missing exon 10 or 16, encoding C-terminal truncated ESR1 proteins with varying ESR1 activities. Inter-person variability in ESR1 expression profile may contribute to inter-person variability in drug metabolism and susceptibility to liver related diseases.

Prevalence of pulmonary tuberculosis among students in three eastern Ethiopian universities.

SETTINGS: Three universities located in eastern Ethiopia: Haramaya University, Haramaya; Dire-Dawa University, Dire-Dawa; and Jigjiga University, Jigjiga. OBJECTIVE: To determine the burden of pulmonary tuberculosis (PTB) among university students and to identify risk factors for the development of TB disease. DESIGN: All full-time university students were screened for symptoms of PTB and sputum was collected for acid-fast bacilli (AFB) examination and culture for Mycobacterium tuberculosis. RESULTS: Of 35 344 students screened, we identified 153 PTB cases that occurred over the 1-year study period, or 433/100 000 students. Of these, 117 (76%) PTB cases were found through passive case finding at student health centres, while 36 (24%) previously undiagnosed patients were identified through active case finding. Sixteen cases detected using active case finding (44%) were smear-positive. Living in a dormitory with 5 students and attending university for 2 years were both significantly associated with PTB (adjusted OR 2.49 and 3.79, respectively, P < 0.001). In persons who underwent drug susceptibility testing, 11 (30.5%) had resistance to at least one first-line anti-tuberculosis drug. CONCLUSION: We found a high burden of TB among university students in eastern Ethiopia. Screening for PTB upon university admission and at regular intervals should be considered to minimise TB transmission on university campuses.

The interdisciplinary management of hypodontia patients in the UK: a national service evaluation.

Objective To examine the distribution of interdisciplinary clinics for hypodontia patients in the UK and to assess the provision of orthodontic-restorative care for hypodontia patients in units where this service is and is not available.Design Prospective, online-questionnaire.Setting Hospital orthodontic departments in the UK.Participants In total, consultants from 92 orthodontic departments completed the questionnaire.Methods Orthodontic consultants were asked to complete a questionnaire regarding the provision of orthodontic-restorative care for hypodontia patients in their units.Results Overall, 100% of teaching hospitals and 51% of district general hospitals (DGHs) that responded have an interdisciplinary clinic for hypodontia patients. In 51% of units, the majority of patients assessed on the interdisciplinary clinic undergo their restorative care at the same secondary care unit. In 59% of units where an interdisciplinary clinic is not available most of the restorative care for hypodontia patients is provided by the GDP, whilst in 38% of units a specialist restorative dentist in another secondary care unit provides most of the restorative care.Conclusions The provision of an interdisciplinary clinic for hypodontia patients varies amongst hospital units throughout the UK. The provision of orthodontic-restorative care for hypodontia patients also varies between these units.

Pharmacologically guided phase I clinical trials based upon preclinical drug development.

Since our original proposal 4 years ago, considerable support has evolved for the concept of pharmacologically guided dose escalation in phase I clinical trials with new anticancer drugs. The original focus has been broadened to develop additional links between preclinical testing and phase I clinical trials. Recent experiences with very lengthy phase I trials for at least eight drugs have provided particular impetus for this project. The original pharmacodynamic hypothesis for the proposal was equal toxicity at equal plasma levels. Specifically, two facets of the concept were that (a) dose-limiting toxicity correlates with, and in turn is predicted by, drug concentrations in plasma and (b) that the quantitative relationship between toxicity and drug exposure, as measured by plasma drug concentration times time (C x T), holds across species. If true, this hypothesis would suggest that dose escalations in humans could be safely based on measurement of drug levels in plasma, rather than on empirical escalation schemes. In addition to the collection of a larger retrospective data base to validate this hypothesis, practical results have already been achieved. In two studies sponsored by the National Cancer Institute (NCI), the escalation pattern was prospectively modified on the basis of measurements of drug levels in plasma. In addition, for three NCI-sponsored drugs, more careful matching of schedules between clinical and preclinical testing produced entry doses that were up to 25 times higher than doses used in standard procedures. Consequently, the phase I trials for each drug were completed with a savings of 12-24 months. As a result of work in both the United States and Europe, a substantial collection of data now demonstrates that coordination with preclinical pharmacology and toxicology studies can save both time and resources in early clinical trials without a loss of safety.

Pharmacology and clinical toxicity of 4'-iodo-4'-deoxydoxorubicin: an example of successful application of pharmacokinetics to dose escalation in phase I trials.

In a prospective phase I trial involving 35 patients with metastatic carcinoma, we tested a pharmacokinetic strategy for guiding dose escalation of the anthracycline 4'-iodo-4'-deoxydoxorubicin (I-DOX), a new analogue reported to be more potent and less toxic than doxorubicin. This strategy is potentially a safe and more rapid way of determining the maximum tolerated dose (MTD) of anticancer agents. Retrospective studies have shown that the total plasma drug exposure after a dose lethal to 10% of mice (LD10) is approximately equivalent to the total exposure produced in humans by the MTD. Thus, we intended to aim dose escalation in humans to achieve the area under the curve for I-DOX plasma concentration x time (AUC) equivalent to that produced in mice by an LD10. However, differences in I-DOX pharmacokinetics and metabolism in BDF1 mice and humans at the initial dose prevented immediate application of this strategy. Therefore, we escalated the dose by the modified Fibonacci scheme while investigating the pharmacology of I-DOX and its major plasma metabolite 4'-iodo-4'-deoxy-13-dihydrodoxorubicin (I-DOXOL). Plasma pharmacokinetics was characterized by rapid elimination and extensive metabolism of I-DOX to I-DOXOL. The ratio of I-DOXOL to I-DOX plasma AUC was 12.8 +/- 7.3 SD. The plasma pharmacokinetics of I-DOX and I-DOXOL were linear in the range of tested doses (2-90 mg/m2). The LD10 in mice was 6.8 mg/kg for I-DOXOL and 6 mg/kg for I-DOX, and the concentration of drug that inhibited by 50% (IC50) the growth of human granulocyte-macrophage colony-forming units (CFU-GM) was 80 nM for I-DOXOL and 50 nM for I-DOX. From these findings, we concluded that the toxic effects of I-DOX and I-DOXOL are equivalent and reset the pharmacokinetic target of escalation to the sum of I-DOX and I-DOXOL AUCs at I-DOX LD10. Then we safely applied pharmacokinetically guided escalation to determine the MTD (80 mg/m2). The plasma AUC of I-DOX and I-DOXOL at the human MTD is 71% of the AUC at mouse LD10. The only dose-limiting toxic effect was severe granulocytopenia.

Enhancement of fluorinated pyrimidine-induced cytotoxicity by leucovorin in human colorectal carcinoma cell lines.

Reduced folates have been shown to increase the cytotoxicity of 5-fluorouracil (5-FU) by stabilizing the 5-fluoro-2'-deoxyuridine-5'-monophosphate-thymidylate synthase complex, thus increasing the block in the DNA synthetic pathway. Using an in vitro colorimetric [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] cytotoxicity assay, we tested the effects of 5-FU and 5-fluoro-2'-deoxyuridine (FdUrd) with and without leucovorin (LV) on a panel of 11 human colorectal carcinoma cell lines. The effect of LV on 5-FU and FdUrd was quantitatively similar. A clinically achievable level of LV (20 microM) increased the cytotoxicity in all three replicate experiments in 10 of the 11 cell lines (P less than .05, binomial test). LV alone at a concentration of 20 microM had no effect on cell survival. In three cell lines, 50% inhibition of growth occurred at a clinically achievable area under the curve of 5-FU alone. With the addition of LV, one additional cell line showed 50% growth inhibition at a clinically achievable level of 5-FU. Hence large clinical trials may be necessary to detect a significant improvement in survival as a result of adding LV to the fluorinated pyrimidines.

Neocarzinostatin-induced DNA strand scission and subsequent cell cycle traverse in HeLa S3 cells.

HeLa cells were synchronized at the G1-S boundary by double thymidine block and treated for 1 hr with varying concentrations of the antibiotic anticancer protein neocarzinostatin (NCS). Cells were then released from the block and allowed to resume their cycle. Aliquots were removed at various times in order to monitor cell cycle progression and to assess repair of DNA strand breaks. Dose-dependent DNA strand breakage occurred at all concentrations of NCS tested down to 0.05 microgram/ml. Flow cytometry revealed that NCS-treated cells were delayed in entering S phase and that once in S phase their rate of progression through it was retarded significantly. At all concentrations of NCS tested, the majority of cells did not enter G2 by 12 hr. Untreated cells, on the other hand, completed mitosis by this time. NCS-treated cells had little ability to repair DNA breaks. There appeared to be a correlation between the initial number of NCS-induced DNA breaks and the delayed entry into the S phase but little correlation between the lack of strand scission repair and the retarded progress through S phase.

Effects of leucovorin on idoxuridine cytotoxicity and DNA incorporation.

Leucovorin (LV) increased the growth inhibition produced by iododeoxyuridine (IdUrd), a halogenated analogue of thymidine, in a murine tumor cell line (L1210) and three human tumor cell lines (HL-60, HT-29, and MCF-7). This increased growth inhibition was associated with increased incorporation of IdUrd into DNA. Consistent with previous reports, IdUrd (as iododeoxyuridine monophosphate) inhibited thymidylate synthase (TS) and was dehalogenated intracellularly by TS to generate thymidine nucleotides. In all four cell lines, LV decreased the dehalogenation of IdUrd, producing a 3-fold increase in the labeled iododeoxyuridine triphosphate/dTTP ratios in cytoplasm and labeled IdUrd/thymidine in DNA derived from tritiated IdUrd. In intact L1210 cells, apparent TS activity was inhibited 50% by 3 microM IdUrd alone and 75% by the combination of 3 microM IdUrd and 20 microM LV. Apparent TS activity was unchanged with 20 microM LV alone. In all cell lines except HL-60, the ratios of labeled iododeoxyuridine triphosphate/dTTP derived from tritiated IdUrd were 3-fold lower than the labeled IdUrd/thymidine ratios in DNA. This observation suggests that replicative DNA polymerases preferentially incorporate iododeoxyuridine triphosphate into DNA compared to the endogenous substrate dTTP. This preferential incorporation was independent of the effect of LV. These novel findings suggested that a potential mechanism for the effects of LV on IdUrd was increased inhibition of TS analogous to the interaction between fluoropyrimidines and LV. Enzyme inhibition studies using L1210 cell extracts showed that iododeoxyuridine monophosphate was a weak inhibitor of TS (Ki greater than 10 microM) when compared to 5-fluorodeoxyuridine monophosphate (Ki less than 10 nM). Despite the major differences in potency of these two halogenated pyrimidines, LV appears to modulate the activity of IdUrd as well as 5-fluorodeoxyuridine. LV may provide a clinically useful approach to improve the radiosensitizing and/or cytotoxic properties of IdUrd.

Pharmacokinetics of intraventricular and intravenous N,N',N''-triethylenethiophosphoramide (thiotepa) in rhesus monkeys and humans.

The cerebrospinal fluid (CSF) and plasma pharmacokinetics of N,N',N"-triethylenethiophosphoramide (thiotepa), an alkylating agent used for treatment of carcinomatous meningitis, were determined in rhesus monkeys in order to assess the relative advantage of intraventricular versus systemic administration of the drug. Following an i.v. thiotepa dose of 0.9 mg/kg (11 mg/sq m), peak plasma levels of parent drug reached approximately 1 microgram/ml. Thiotepa was rapidly equilibrated with lumbar and ventricular CSF. Systemic, lumbar, and ventricular exposure to the drug, measured as area under the curve (AUC), were similar in all cases. After a 1-mg intraventricular dose of thiotepa, peak ventricular levels were greater than 100 micrograms/ml. However, peak levels in the lumbar CSF at 1 h after intraventricular administration were less than 10 micrograms/ml. The AUC for ventricular CSF was nearly 100-fold greater for the intraventricular route than for the i.v. route; however, the AUC for lumbar CSF following intraventricular delivery was only 5% of the AUC for ventricular CSF. N,N',N''-Triethylenephosphoramide, an active metabolite of thiotepa observed in all fluids, appeared to have a much slower total body clearance than thiotepa. Comparison of the data obtained from monkey experiments with data from a patient with meningeal disease supports the use of the monkey as a model for intraventricular pharmacokinetics. The data presented indicate that there is no relative advantage to intraventricular administration of thiotepa at the doses currently used in clinical trials.

Alteration of the secondary structure of newly synthesized DNA from murine bone marrow cells by 5-fluorouracil.

The present study evaluates the effects of 5-fluorouracil (FUra) on the structure of newly synthesized DNA purified from bone marrow cells. DNA synthesis was decreased by 30 and 45% of control in the presence of 19 and 100 microM FUra, respectively. Furthermore at these concentrations of FUra, the DNA strand sizes were smaller as determined by alkaline sucrose gradients. Enzymatic digestion of the DNA demonstrated that most of the FUra (greater than 90%) was localized in the internucleotide linkage and not at the chain terminus. As the concentration of FUra was varied, the percentage of FUra at the chain terminus was unchanged, suggesting that the decrease in chain size as well as inhibition of DNA synthesis was not due to chain termination. DNA that had been synthesized in the presence of FUra was shown to fragment after increasing time as demonstrated by alkaline sucrose gradient analysis. This time-dependent fragmentation was associated with an increased number of strand breaks as determined by neutral and alkaline sucrose gradient analysis. A parallel study demonstrated a time-dependent excision of FUra from DNA over this same time period. In summary, these studies demonstrate an association between the excision of FUra from DNA and the changes in secondary structure of newly synthesized DNA.

Incorporation of iododeoxyuridine into DNA of granulocytes in patients.

Iododeoxyuridine (IdUrd) competes with thymidine for incorporation into DNA. In order to measure the incorporation of the drug in vivo, granulocytes were isolated from peripheral blood of patients at various times during and after 9- to 14-day IdUrd i.v. continuous infusions. DNA was extracted and enzymatically hydrolyzed. Both thymidine and IdUrd were separated and measured by high-performance liquid chromatography. Thymidine substitution by IdUrd was less than 1% prior to the fifth day of infusion and then increased rapidly to achieve a maximal value between 7 and 17% at the end of the infusion. In our protocol, thrombocytopenia was the most frequent dose-limiting systemic toxicity. For our group of patients, there was a clear overall relationship between the extent of substitution by IdUrd and the hematological toxicity. To our knowledge, these data provide the first direct quantitative determination of substitution by a drug into DNA in vivo without the use of radiolabeled compounds. The ability to directly monitor drug incorporation into DNA may provide the basis for monitoring and improving the selectivity of therapy.

Pharmacokinetics of the hypoxic radiosensitizers misonidazole and demethylmisonidazole after intraperitoneal administration in humans.

The hypoxic radiosensitizers misonidazole or demethylmisonidazole were administered i.p. in a 2-liter volume to 6 patients affected by advanced ovarian carcinoma, and the pharmacokinetic course of the two drugs was studied. The clearance of misonidazole and demethylmisonidazole from the peritoneal fluid was 19.1 and 12.4 ml/min, respectively. At 3 hr after drug administration, both radiosensitizers had peritoneal fluid concentrations more than 8 times larger than in the plasma. The concentration x time exposure in the peritoneal fluid was 3.2 times larger than in plasma for misonidazole and 7.6 times for demethylmisonidazole. The advantage of i.p. delivery compared with systemic delivery decreases with distance from the peritoneal surface, but the advantage may be maintained for up to 1 mm or 100 cell layers. These differences between the two routes of administration provide a rational basis for the expectation that a substantial increase of the therapeutic benefits of misonidazole and demethylmisonidazole in potentiating radiation therapy or chemotherapy can be expected in treating tumors confined to the i.p. space.

Plasma pharmacokinetics of adriamycin and adriamycinol: implications for the design of in vitro experiments and treatment protocols.

The plasma pharmacokinetics of Adriamycin and adriamycinol following a 15-min infusion of 75 mg/sq m of Adriamycin were studied in ten patients previously untreated with Adriamycin. The disappearance kinetics of Adriamycin could adequately be described by a biexponential equation with an initial half-life of 8-min and a terminal half-life of 30 hr. The major drug exposure (area under the concentration-time curve) occurs during the terminal phase where drug concentrations are generally less than 10(-7) M (0.05 micrograms/ml). An improvement in the high-performance liquid chromatography sensitivity facilitated the determination of the terminal phase. The plasma kinetics of adriamycinol, the major and only known active metabolite of Adriamycin, show a rapid initial increase in plasma concentration followed by a slow decline which parallels that of Adriamycin during the terminal phase. The relative drug exposure of adriamycinol to Adriamycin was approximately 50%. The relationship between the measured plasma drug levels and free drug available for distribution into tissues was studied by comparing the plasma binding characteristics of Adriamycin and adriamycinol. A constant 20 to 25% of the total plasma concentrations of both Adriamycin and adriamycinol was freely diffusible over the whole range of observed concentrations, 20 nM to 2 microM. Thus, the free drug exposure (area under the concentration-time curve) of tumor and host tissues in vivo can be determined from these plasma measurements, since the free drug exposures in plasma and in extracellular fluid are equivalent. These results can also serve as a guide for the design of clinically relevant in vitro studies of Adriamycin and adriamycinol. The pharmacokinetic parameters determined in this study have been used to simulate plasma concentration-time courses for a variety of Adriamycin treatment schedules. Alternatives are suggested which reduce peak plasma Adriamycin concentration while antitumor area under the concentration-time curve is maintained.

Metabolism of taxol by human hepatic microsomes and liver slices: participation of cytochrome P450 3A4 and an unknown P450 enzyme.

Incubation of taxol with human hepatic microsomal fractions or freshly isolated human liver slices yields three metabolite high performance liquid chromatography peaks, metabolite A, metabolite B, and 6 alpha-hydroxytaxol. These metabolites are formed in patients given taxol, with 6 alpha-hydroxytaxol formation representing the principal biotransformation pathway. Metabolite B and 6 alpha-hydroxytaxol are shown to be products of different, highly regioselective cytochrome P-450 (P450) enzymes, while metabolite A results from stepwise metabolism by each of these enzymes. Correlation of metabolite B formation with P450 3A markers was good (r2 = 0.91-0.94), but the correlation of 6 alpha-hydroxytaxol formation with markers for several P450 enzymes was poor. Chemical inhibitors that selectively inhibited metabolite B formation (troleandomycin, cyclosporine), that selectively inhibited 6 alpha-hydroxytaxol formation (naringenin, quercetin), or that nonselectively inhibited both pathways (felodipine, ketoconazole) were found. Metabolite B formation was selectively reduced by anti-P450 3A4 antibodies. Expressed human P450 3A4 preparations were efficient catalysts of metabolite B formation; no expressed P450 preparation tested showed a capacity for catalyzing taxane 6 alpha-hydroxylation reactions. The combined results of several experimental approaches show that P450 3A4 is the major catalyst of metabolite B formation and that the identity of the P450 enzyme or enzymes responsible for 6 alpha-hydroxytaxol formation cannot be assigned with certainty.

Cerebrospinal fluid pharmacokinetics of intraventricular and intravenous aziridinylbenzoquinone.

The cerebrospinal fluid (CSF) pharmacokinetics of aziridinylbenzoquinone (AZQ) was studied following i.v. and intraventricular drug administration. Initial studies were performed in six rhesus monkeys with chronic indwelling Ommaya reservoirs. Following intraventricular administration of 0.2 mg of AZQ, elimination was monoexponential with half-lives of 32 and 39 min in ventricular and lumbar CSF, respectively. AZQ clearance (0.2 ml/min) was 5-fold greater than estimated CSF bulk flow, indicating that transcapillary passage and/or metabolism may be important clearance mechanisms for this drug. In spite of its rapid clearance from ventricular CSF, a substantial peak AZQ concentration was achieved in lumbar CSF (12 microM), which was 7 times higher than the peak ventricular CSF level (1.7 microM) achieved following i.v. AZQ administration (16 mg/sq m). Moreover, the mean area under the CSF concentration-time curve in ventricular CSF was 20-fold greater following intraventricular versus i.v. AZQ dosing, despite an 80-fold-lower dose. AZQ was not detectable in plasma (less than 0.06 microM) following intraventricular administration. No animals demonstrated clinical evidence of acute neurotoxicity. Subsequently, intraventricular AZQ was administered to a patient with refractory meningeal leukemia. Intraventricular AZQ (0.5 mg) resulted in a peak ventricular (56 microM) CSF level which was 80-fold higher than ventricular CSF levels achieved following systemic AZQ administration of a dose of 24 mg/sq m in humans. Moreover, intraventricular AZQ yielded substantial CSF levels without detectable plasma concentrations. These data suggest that intraventricular administration of AZQ is feasible and may have pharmacological advantages over systemic administration for the treatment of meningeal neoplasia.

Effect of intravenous dose and schedule on cerebrospinal fluid pharmacokinetics of 5-fluorouracil in the monkey.

There is little information regarding the pharmacology of 5-fluorouracil (5-FUra) in the central nervous system (CNS), despite its role in the treatment of diseases with CNS metastases and recent reports of neurotoxicity. In this study, the plasma and cerebrospinal fluid (CSF) pharmacokinetics of 5-FUra were examined in a primate model. Following a bolus dose, the area under the concentration versus time curves for 5-FUra in CSF was 48% of the plasma area under the concentration versus time curves. For continuous infusion of 5-FUra, the area under the concentration versus time curves ratio for CSF:plasma was 20 or 11%, depending upon the infusion rate. The mechanism for variations in CSF exposure based upon the pattern of plasma delivery is consistent with local metabolism of 5-FUra in the CNS. These findings should be considered in the evaluation of delivery schedules which are intended to maximize drug delivery to the CNS and/or minimize neurotoxicity.