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B Monsarrat

Publications and source records attributed to B Monsarrat.

At least 37 records · Page 2Linked to original sources
PubMed1994

Clinical pharmacology and metabolism of Taxol (paclitaxel): update 1993.

Paclitaxel may be one of the most important anticancer agents to be developed over the past 2 decades. With its unique mechanism of action as an inducer of tubulin assembly, paclitaxel has demonstrated impressive antitumor activity in patients with breast, lung (both non-small cell and small cell), head and neck, and advanced and platinum-refractory ovarian carcinomas. Unfortunately, there has been a relative lack of pharmacologic data available for paclitaxel, compared with other agents in similar phases of development. This scarcity of data is due, in part, to the aqueous insolubility of paclitaxel and to difficulties in developing sensitive analytic assays to measure the full range of drug concentrations achieved in small animals, both of which have limited preclinical pharmacologic studies. This report reviews the pharmacology of paclitaxel as ascertained during early clinical trials. Although most early studies used prolonged intravenous administration schedules of the agent as both monotherapy and in chemotherapy combinations, more recent studies have evaluated shorter administration schedules. In addition, available information pertaining to the pharmacodynamic and metabolic profiles of paclitaxel are discussed. Such information may be useful in designing rational treatment regimens of paclitaxel as a single agent and in chemotherapy combinations, potentially resulting in the optimal utilization of this important agent in cancer chemotherapeutics.

Animals↗
PubMed1993

Hepatic metabolism and biliary excretion of Taxol in rats and humans.

To date there have been limited studies of the metabolism and disposition of Taxol in animals and humans. Renal disposition of unmetabolized Taxol has been documented to account for a maximum of 5% to 10% of an administered dose of Taxol in humans, but the principal processes involved in drug disposition, particularly the roles of biliary excretion and drug metabolism, have not been evaluated. Therefore, the biliary excretion of Taxol has been studied in rats and in a human patient receiving Taxol in a phase I trial. Of the total doses administered to rats and the patient, 40% and 20%, respectively, were excreted in the bile in the forms of unmetabolized Taxol and Taxol metabolites until 24 hours posttreatment. Although the biliary excretion of unmetabolized Taxol accounted for 10% and 3% of total drug disposition in the rats and in the patient, respectively, the remaining portion consisted of several metabolites. Nine metabolites were detected in rat bile, and five metabolites were detected in human bile. The chemical structures of four of the rat metabolites and three of the human metabolites have been identified thus far. With the exception of baccatin III, a minor metabolite found only in rat bile that lacks the side chain at C-13 position of the taxane ring, the other metabolites were monohydroxylated or dihydroxylated and had intact taxane rings and side chains at taxane ring positions C-2 and C-13. The taxane ring and both the C-2 and C-13 side chains were susceptible to hydroxylation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Transforming growth factor beta 1 (TGF-beta 1) inhibits growth of a human ovarian carcinoma cell line (OVCCR1) and is expressed in human ovarian tumors.

The effects of EGF and TGF-beta 1 on the proliferation of 2 ovarian carcinoma cell lines (IGROV1 and OVCCR1) were evaluated. The cell lines were adapted to grow in a restricted serum (0.5%) medium. EGF was required for proliferation of both ovarian cell lines. Low doses of TGF-beta 1 inhibited clonogenic capacity and attenuated the EGF-mediated stimulation of DNA synthesis in OVCCR1 cells. TGF-beta 1 inhibited OVCCR1 cell proliferation by blocking the cell cycle at the G1/S transition. TGF-beta 1 did not affect either clonal or monolayer growth of IGROV1 cells. Both cell lines express type-I and type-III TGF-beta receptors, suggesting that the unresponsiveness of IGROV1 cells to TGF-beta 1 occurs at a post-receptor level. TGF-beta 1 mRNA was detected in OVCCR1 cells and in 8 out of 11 of the ovarian tumor specimens examined.

Cell Division↗
PubMed1992

Further evidence that morphine-6 beta-glucuronide is a more potent opioid agonist than morphine.

The antinociceptive properties of morphine-6 beta-glucuronide (M6G) and morphine (oral, i.c.v. and s.c.) were examined in two tests involving different nociceptive stimuli [i.e., cutaneous-thermal (tail-flick) and chemical-visceral (acetic acid-writhing)] in both naive and chronically treated mice. Twenty min after i.c.v. injection, M6G was 47 and 360 times more potent than morphine in the writhing and tail-flick tests, respectively. This difference was not due to differences in affinity because M6G displayed lower apparent affinities (Ki) for mu and kappa binding sites in vitro. After systemic injection, the two opiates were equieffective, although M6G produced a 10-fold longer antinociceptive effect. These differences with route of administration partially result from the hydrophilic nature of M6G because its inflow into the brain compartment was at least 10-fold lower than that of morphine, whereas the rate of elimination of the parent molecule was 3 times greater. After chronic treatment, mice readily develop tolerance and marked physical dependence to the antinociceptive effects of M6G. In vivo binding studies showed that M6G exerts its antinociceptive effect at low (less than 1%) fractional occupancy of [3H]diprenorphine-specific binding sites. In contrast, morphine needs to occupy 9.5 (writhing) to 47 (tail-flick) times more opioid binding sites to produce the same antinociceptive activity. M6G thus appears to have greater pharmacological potency than morphine, which in comparison possesses a low intrinsic efficacy.

Administration, Oral↗
PubMed1991

CSF baclofen levels after intrathecal administration in severe spasticity.

The pharmacokinetic parameters in the CSF of baclofen given to 4 patients as an intrathecal bolus are reported. Considerable inter-individual variability in the parameters was observed. The elimination half-life ranged from 0.9 to 5 h and the clearance from 0.013 to 0.08 l.h-1. In order to optimize treatment, it is suggested that CSF baclofen levels be matched to changes in Hoffman's monosynaptic reflex (H reflex).

Adult↗
PubMed1990

Transforming growth factor beta (TGF-beta) reverses phorbol diester resistance of a breast adenocarcinoma (MCF-7) subline.

We investigated the effects of TGF-beta on a MCF-7 subline (MCF-7:RPh-4) which is resistant to phorbol diesters with respect to growth inhibition and estrogen receptor content modulation. This biological unresponsiveness of MCF-7:RPh-4 cells to phorbol esters seems to be unrelated to activation of protein kinase C. In the presence of 80 nM PMA (12-O-tetradecanoylphorbol-13-acetate), TGF-beta induced a dose-dependent inhibition of MCF-7:RPh-4 cell proliferation. MCF-7:RPh-4 cells grown in PMA-free medium for at least 28 days remained insensitive to PMA but lost sensitivity to TGF-beta. Under these conditions, addition of 80 nM PMA restored sensitivity to TGF-beta. In the presence of a fixed concentration of TGF-beta, the dose-dependent inhibition of proliferation and the decrease in estrogen receptor content induced by PMA were comparable to those observed in PMA-treated parental MCF-7 cells. These observations indicate that TGF-beta reverses PMA resistance in MCF-7:RPh-4 cells. In addition, TGF-beta does not modify the basal or PMA-stimulated phosphorylation of Mr 28,000 endogenous protein. These results suggest that TGF-beta interferes with the protein kinase C pathway independently of enzyme activation.

Adenocarcinoma↗
PubMed1990

Morphine metabolism in the naturally morphine-tolerant afghan pika: a preliminary study.

The afghan pika (Ochotona rufescens), a lagomorph which is naturally tolerant to the analgesic action of morphine, metabolizes morphine into morphine 3-glucuronide apparently faster than does the rabbit, another lagomorph which is however normally responsive to morphine. In the two species, following morphine administration, another unidentified component appears very soon (5 min) in pika blood plasma and much later (60 min) in rabbit blood plasma. This unknown component which appears not to be morphine derived might be involved in the natural resistance of the Afghan pika to morphine.

Animals↗
PubMed1989

Translesion synthesis is the main component of SOS repair in bacteriophage lambda DNA.

Agents that interfere with DNA replication in Escherichia coli induce physiological adaptations that increase the probability of survival after DNA damage and the frequency of mutants among the survivors (the SOS response). Such agents also increase the survival rate and mutation frequency of irradiated bacteriophage after infection of treated bacteria, a phenomenon known as Weigle reactivation. In UV-irradiated single-stranded DNA phage, Weigle reactivation is thought to occur via induced, error-prone replication through template lesions (translesion synthesis [P. Caillet-Fauquet, M: Defais, and M. Radman, J. Mol. Biol. 117:95-112, 1977]). Weigle reactivation occurs with higher efficiency in double-stranded DNA phages such as lambda, and we therefore asked if another process, recombination between partially replicated daughter molecules, plays a major role in this case. To distinguish between translesion synthesis and recombinational repair, we studied the early replication of UV-irradiated bacteriophage lambda in SOS-induced and uninduced bacteria. To avoid complications arising from excision of UV lesions, we used bacterial uvrA mutants, in which such excision does not occur. Our evidence suggests that translesion synthesis is the primary component of Weigle reactivation of lambda phage in the absence of excision repair. The greater efficiency in Weigle reactivation of double-stranded DNA phage could thus be attributed to some inducible excision repair unable to occur on single-stranded DNA. In addition, after irradiation, lambda phage replication seems to switch prematurely from the theta mode to the rolling circle mode.

Bacteriophage lambda↗
PubMed1988

Identification of partially methylated methyl glycosides by gas chromatography-mass spectrometry of trimethylsilyl derivatives. Application to mycobacterial glycolipid antigen analysis.

Partially methylated glycosides play an important role in the stereospecificity of glycolipid antigen-antibody binding reactions. A method for the structural determination of partially methylated methyl glycosides is described. The proposed method, which is an alternative to that using alditol acetates, consists in the analysis of trimethylsilyl glycoside derivatives by gas chromatography-mass spectrometry in the electron impact (EI) mode. Seven partially methylated methyl rhamnopyranosides were synthesized, then purified by high-performance liquid chromatography. After trimethylsilylation, their EI mass spectra showed characteristic fragmentation patterns allowing the determination of the position and the number of methoxy groups in the sugar ring. This method was successfully applied to the structural elucidation of partially methylated sugars contained by a quantitatively minor phenolic glycolipid antigen isolated from Mycobacterium kansasii. Moreover, the carbons involved in the glycosidic linkages of the glycolipid tetrasaccharide moiety were also identified by this method after permethylation, methanolysis and trimethylsilylation.

Antigens, Bacterial↗
PubMed1988

CSF morphine levels after lumbar intrathecal administration of isobaric and hyperbaric solutions for cancer pain.

The objectives of this study were to compare the pharmacokinetic properties and the duration of analgesia following intrathecal administration (L5-S1) of 2 mg morphine in 2 forms: (1) an isobaric (NaCl 0.9%) and (2) a hyperbaric solution (7% dextrose). The study was carried out on 5 cancer patients with severe, intractable pain in the lower half of the body. Samples of CSF were collected at the level of the 10th thoracic vertebra at regular intervals for 15 h after administration. Morphine concentrations were determined by HPLC. The pharmacokinetic properties of the solutions (I and II) were quite different. Peak levels (I) were reached in 5-15 min (30 and 60 micrograms/ml); they then fell rapidly during the 1st hour (7 and 11 micrograms/ml) with an elimination half-life of 10 and 15 min, followed by a change in slope (elimination half-life of 108 and 140 min). Peak levels (II) were reached in 4-5 h (0.8-3.3 micrograms/ml); they then fell progressively according to a single exponential function (elimination half-life: 144-246 min). The duration of analgesia for a dose of 2 mg was 30 h for solution 2 and 24 h for solution 1. The hyperbaric solution, which produced the same degree of analgesia as the isobaric solution, limited the cephalad diffusion of morphine and reduced or abolished the central depressant effects of the drug.

Chromatography, High Pressure Liquid↗
PubMed1988

The stability of morphine in isobaric and hyperbaric solutions in a drug delivery system.

Intrathecal preparations of morphine for use in intractable pain must contain no preservatives. They are generally formulated in saline (isobaric) or dextrose (hyperbaric) which raises questions of stability. The behaviour of morphine in hyperbaric and isobaric solutions stored in a reservoir for implantation has been examined and the effect of temperature and the time of contact of morphine with the different components of the reservoir as well as the sterilization procedure have been investigated. The best stability was observed with a hyperbaric solution in which there was 15 to 20 times less pseudomorphine than in the isobaric solution, which was found to contain 1% pseudomorphine after 1 month of storage at 37 degrees C in the reservoir. Similar solutions stored in ampoules did not degrade.

Atmospheric Pressure↗
PubMed1987

Oxidative biotransformation of the antitumour agent elliptinium acetate: Structural characterization of its human and rat urinary metabolites.

The electrophilic properties of the antitumour drug N(2)-methyl-9-hydroxyellipticinium acetate (Celiptium) are revealed by the detection of thiol-conjugate metabolites in man and rat urine. Besides the unchanged drug and its glucuronide, the cysteinyl- (in man) and the N-acetylcysteinyl- (in man and rat) conjugates have been unambiguously characterized using NMR, UV and mass spectral data. The urinary excretion profile exhibits total excreted products of 21% (in man) and 9% (in rat) with respect to the administered dose. The unchanged drug is found to be the major excreted compound from urine in both species (17% in man, 6.3% in rat); whereas the glucuronide (2.6% in man, 1.5% in rat), cysteinyl- (1.3% in man) and N-acetylcysteinyl- (0.2% in man, 1.2% in rat) conjugates represent the minor excreted compounds. The presence of the latter thio-conjugates provides an indirect proof of the in vivo generation of an oxidized intermediate form of the administered drug.

Journal Article↗
PubMed1985

Evidence for electrophilic properties of N2-methyl-9-hydroxy ellipticinium acetate (Celiptium) from human biliary metabolites.

The human biliary metabolism of the antitumor agent N2-methyl-9-hydroxyellipticinium acetate is described. Three major compounds have been identified by high-performance liquid chromatography and comparison with synthetic reference derivatives: the unchanged drug, the O-glucuronide conjugate and the cysteinyl-ellipticinium adduct. The latter one is the expected detoxification compound of an intermediate electrophilic quinone-imine derivative generated in vivo. This result provides a further evidence that hydroxylated forms of ellipticine derivatives might be activated by a biooxidation route.

Adult↗
PubMed1985

Synthesis and cytotoxic activity of hydroxylated derivatives of olivacine in relation with their biotransformation.

The chemical synthesis of 9-hydroxyolivacine and 7-hydroxyolivacine based on a biomimetic approach is described. These two hydroxylated derivatives have been found as main in vitro metabolites of olivacine after incubation with rat hepatic microsomes. The pretreatment of animals with benzo[a]pyrene caused a large increase in both microsomal hydroxylations, whereas the pretreatment with phenobarbital caused a weak increase, with a preservation of 9-hydroxylation/7-hydroxylation ratio greater than 1 in both cases. The two hydroxyolivacines have been also found as principal in vivo metabolites of olivacine in rat bile as glucuronide and sulfate conjugates. The pretreatment of animals with benzo[a]pyrene reverses the 9-hydroxyolivacine/7-hydroxyolivacine ratio excretion in bile to a value that is less than 1. In both in vitro and in vivo experiments, the free metabolites were identified by HPLC and UV-visible, MS, and 1H NMR spectra. Hydroxylation at position 9 increases the in vitro cytotoxicity against leukemia L1210 cells (ID50 = 0.06 microM compared to 2.03 microM for olivacine) and an opposite effect is observed for hydroxylation at position 7 (ID50 = 12.8 microM). On the other hand, hydroxylation at position 9 has no effect on the in vivo antitumor activity against L1210. This might be related to the oxidative and conjugative metabolic pathways that play an important role in antitumor activity and deactivation of olivacine and its hydroxy metabolites.

Animals↗
PubMed1983

Conversion of sterols and triterpenes by mycobacteria. I Formation of progesterone and 1-dehydroprogesterone from Mycobacterium aurum, strain A+.

Side-chain degradation of sterols by bacteria is known to proceed via oxidation of a terminal methyl group followed by a succession of beta-oxidative steps. By this pathway, the pregnane backbone is not produced. However, examination of cholesterol degradation products using a strain of Mycobacterium aurum shows that progesterone and 1-dehydroprogesterone are present at low levels. These pregnane derivatives were identified by gas-liquid chromatography combined with mass spectrometry. This indicates that an alternative pathway for sterol side-chain degradation occurs in bacteria, which could be of great interest for the biological production of corticosteroid precursors.

Cholesterol↗
PubMed1983

Metabolism of the anti-tumour drugs N2-methyl-9-hydroxyellipticinium acetate (NSC 264137) and N2-methyl-9-hydroxyolivacinium acetate in the rat: preliminary identification of biliary 9-(O)-glucuronide and 10-(S)-glutathione conjugates.

The metabolites of the two anti-tumour drugs, N2-methyl-9-hydroxyellipticinium acetate (9-OH-NME, NSC 264137) and N2-methyl-9-hydroxyolivacinium acetate (9-OH-NMO), in bile of i.v.-treated rats have been studied. Three products have been identified in the bile: the unmetabolized drug (17% excreted products for ellipticinium, 3% for olivacinium derivative); a major metabolite, the corresponding 9-(O)-glucuronide (80 and 96%, respectively) and a minor metabolite, a possible 10-(S)-glutathione conjugate (3 and 1%). The elimination yield of these three products excreted over a period of 12 h represents 36% (ellipticinium) and 74% (olivacinium) of the administered dose. The detection of glucuronide and glutathione conjugates of these pyridinium derivatives was possible by direct injection of bile on to h.p.l.c. without prior extraction with organic solvents, in which these polar metabolites are poorly soluble. Metabolites were tentatively identified by the comparison of h.p.l.c. behaviour (retention times and u.v. absorption ratios) with those of reference samples. Reference conjugates have been prepared by chemical synthesis for the 9-(O)-glucuronides and by biosynthesis for the 10(S)-glutathione derivatives. The detection of the GSH conjugates in bile can be considered as the first experimental evidence of the involvement of oxidative activation in vivo of these ellipticine and olivacine derivatives.

Alkaloids↗