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Biomedical subjects

A Rahman

Publications and source records attributed to A Rahman.

At least 199 records · Page 11Linked to original sources
PubMed1994

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.

Biotransformation↗
PubMed1994

A new procedure for the preparation of liposomal doxorubicin: biological activity in multidrug-resistant tumor cells.

We describe a new procedure for the preparation of liposomal doxorubicin. Doxorubicin can be efficiently complexed to preformed or lyophilized cardiolipin-containing liposomes. Complex formation was performed by vigorous vortexing. As much as 96.8% of the initial drug quantity may be bound to those liposomes under optimal incubation conditions (4 h at 37 degrees C). The binding study showed the presence of two levels of specific binding (dissociation constants, 28 +/- 8 microM and 1.0 +/- 0.3 mM). The drug is firmly integrated in the liposome-membrane lipid bilayer rather than binding at the surface. Cytotoxicity studies using tumor cells revealed efficient drug delivery using liposome-complexed doxorubicin. This new liposomal doxorubicin preparation reverses multidrug resistance in MCF-7/ADR and CH LZ cells at levels equivalent to that obtained with a previously described liposome-encapsulated doxorubicin preparation, showing that the drug is integrated as well in the liposome carrier and is transported as well into cells. Increased concentration of liposomes at the subcytotoxic level in liposome-complexed doxorubicin enhances drug cytotoxicity in multidrug-resistant CH LZ cells as compared with liposome-encapsulated drug. This new preparation for liposomal doxorubicin may be carried out immediately prior to clinical administration, offering advantages in terms of cost and stability.

Breast Neoplasms↗
PubMed1994

Up-regulation of the connexin43+ gap junction network in haemopoietic tissue before the growth of stem cells.

The early developmental stages of haemopoiesis are thought to be regulated by paracrine growth factors and by the haemopoietic environment. Are gap junctions involved here? Gap junctions are structures in cell membranes allowing the direct transfer of ions and small molecules between adjacent cells and are known to be involved in development. We have found that although connexin43 gap junctions are rare (0.00016 +/- 0.0002/microns2 tissue) in normal adult mouse marrow their expression is 80-fold higher (0.0292 +/- 0.0147/microns2) in neonatal marrow. One difference between neonatal and adult haemopoietic tissue is that in the latter more haemopoietic cells are dividing. To test if more gap junctions were due to increased division we altered adult blood-formation by mobilizing or destroying end cells--granulocytes and red cells--or by forcing stem cells to divide by making them regenerate an ablated blood-forming system. Mobilizing end cells had no effect on the number or distribution of gap junctions in marrow but forced stem cell division caused a 100-fold increase in gap junction expression and did so before any recognizable haemopoietic cells formed. There were greater than normal numbers of gap junctions in radio-protected adult mouse marrow. The cells coupled by gap junctions are TE-7+ mesodermally derived fibroblasts, STRO-1+ stromal cells, and CD45+ and CD34+ haemopoietic cells. We propose that there is a latent network of Cx43+ gap junctions in normal quiescent marrow. In response to events that call for active division of stem cells this network is amplified and coupled to haemopoietic stem cells, perhaps enabling them to divide.

Animals↗
PubMed1994

Amino Acid analysis of intellan, a herbal product used in enhancing brain function.

Analysis of the drug "INTELLAN" and two reputed plants i.e. Centella asiatica and Herpestis monniera used in the preparation of the drug reveals that glutamic and aspartic acids are present in high concentration in the drug and are also required by brain in high concentration to keep itself in higher gears. Both these amino acids are used as neurotransmitters and also in stabilizing and stimulating the activities of brain, thus resulting in better performance.

Journal Article↗
PubMed1994

Role of diet on the enterohepatic recycling of estrogen in women taking contraceptive pills.

The effect of diet on the enterohepatic recycling of estrogen after oral administration of 1 mg non-radioactive estriol (E3) was studied in six women using contraceptive pills. The women were followed for two consecutive menstrual cycles, firstly on a high fibre diet (HFD) and then changing on to low fibre diet (LFD) during the next cycle, hence each subject acted as its own control. The extent of enterohepatic recycling of estriol (E3) during the early follicular phase of menstrual cycle was assessed by monitoring during 48 hours, the urinary excretion of its two major metabolites, i.e., estriol-3-qlucuronide (E3-3-G) and estriol 16 alpha-glucuronide (E3-16 alpha-G). An increase in values of the variables including E3-3-G/E3-16 alpha-G output ratio, E3-3-G output as % of total (E3-3-G+E3-16 alpha-G) excretion and total E3 (E3-3-G+E3-16 alpha-G) output as % dose was noted as a result of change from high to low fibre diet. The urinary excretion of E3 in the form of its metabolites was also delayed as a result of dietary change. These findings reveal that extent of enterohepatic recycling of estrogen containing contraceptives could be higher in women on LFD as compared to those who are on HFD.

Adult↗
PubMed1994

Peripheral blood granulocytes and mononuclear cell responses in monkeys with experimental shigellosis.

Changes in neutrophil response to N-formyl-methionyl-leucyl-phenylalanine (FMLP) and the phenotype of peripheral blood mononuclear cells were studied in monkeys after oral challenge with Shigellae. Monkeys were first challenged with S. dysenteriae 1 which caused shigellosis in some of the monkeys. After recovery, the monkeys were rechallenged with S. flexneri 2a. No difference in sensitivity was observed in the monkeys during shigellosis caused by either S. dysenteriae 1 or S. flexneri 2a. The optimal dose of FMLP for neutrophil polarization, a measure of early cell activation, in normal healthy monkeys was 10(-7) M when 67% of the neutrophils were polarized. Neutrophils from monkeys ill with shigellosis required higher doses of FMLP (10(-6) and 5 x 10(-7) M) for maximum polarization. As the monkeys recovered, a gradual decrease in the doses of FMLP for optimal neutrophil polarization was also observed. The percentage of CD2-positive T lymphocytes, the earliest marker for T lymphocytes in the peripheral blood, decreased when the monkeys developed shigellosis and returned to normal levels as the monkeys improved. However, there was no change in the percentage of CD20-positive peripheral blood B lymphocytes.

Animals↗
PubMed1993

Locus of the interaction among 5-fluorouracil, leucovorin, and interferon-alpha 2a in colon carcinoma cells.

Prior studies from these laboratories demonstrated 3.2-fold potentiation of 5-fluorouracil (FUra) cytotoxicity by recombinant human interferon-alpha 2a (rIFN-alpha 2a) in GC3/cl colon adenocarcinoma cells that was significantly enhanced to 14-fold when FUra was combined with rIFN-alpha 2a + a mixture of the diasteroisomers of the biologically active (6S) and inactive (6R) leucovorin or 5-formyl-H4PteGlu (LV), events that were reversible by thymidine (dThd). In GC3/clTS-c3/c3 cells, deficient in thymidylate synthase, rIFN-alpha 2a cytotoxicity was not influenced by the concentration of dThd, indicating no direct effect at the level of dThd-less stress. Direct assays of thymidylate synthase indicated no significant difference between FUra-induced accumulation of total thymidylate synthase or free or unbound thymidylate synthase in cells receiving FUra + modulators. In addition, the cytotoxic activity of CB3717, a specific quinazoline-based inhibitor of thymidylate synthase, was not potentiated by rIFN-alpha 2a. These studies suggested that thymidylate synthase was not the primary target site for rIFN-alpha 2a activity. Since data indicated that a 5-fluoropyrimidine was required in the interaction among FUra, LV, and rIFN-alpha 2a, attention was focused at the level of DNA. Both DNA single-strand breaks (SSBs) and DNA double-strand breaks (DSBs) induced by FUra were significantly elevated by rIFN-alpha 2a and LV administered as single modulators and were influenced by the concentrations of both FUra and rIFN-alpha 2a. However; when FUra was combined with LV, rIFN-alpha 2a further potentiated the frequency of DNA SSBs, and data correlated with the relative cytotoxic activity of FUra-LV-rIFN-alpha 2a combinations. No effect on CB3717-induced DNA SSBs or DSBs by rIFN-alpha 2a was demonstrated. Drug exposure for 48 h was required to detect measurable differences in DNA SSB frequency among FUra-LV-rIFN-alpha 2a treatment groups and correlated with decreased clonogenic survival under these conditions. Continuous exposure to FUra (72 h) allowed shorter exposures to LV and/or rIFN-alpha 2a (48 h) to maintain maximal cytotoxicity. Shorter exposure times for FUra during continuous exposure to the modulators were less cytotoxic. Data suggest that the primary locus of the interaction among FUra, LV, and rIFN-alpha 2a lies at the level of DNA. rIFN-alpha 2a may exert its effects via enhancement of FUra base excision or incorporation into DNA, events that subsequently become influenced by thymidylate synthase inhibition and dThd-less stress and are further potentiated by LV.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗
PubMed1993

The two Staphylococcal bi-component toxins, leukocidin and gamma-hemolysin, share one component in common.

Staphylococcal bi-component toxins, leukocidin and gamma-hemolysin, consist of two protein components, i.e. F and S for leukocidin and H gamma I and H gamma II for gamma-hemolysin. In this study we purified H gamma I and H gamma II to homogeneity from the culture medium of Staphylococcus aureus RIMD 310925 and compared their properties with those of F and S purified from the same source. The N-terminal 59- and C-terminal 2-residue amino acid sequences, apparent molecular mass, and isoelectric point of purified H gamma I were the same as those of F. In an Ouchterlony double diffusion test a fused line without spur was formed between F and H gamma I using either anti-F or anti-H gamma I antibodies. A synergistic action of F and H gamma II caused hemolysis of human red blood cells, and H gamma I acted synergistically with S to exhibit leukocidin activity. We conclude that the two toxins share one protein component (F = H gamma I) in common and leukocidin- and gamma-hemolysin-specific activities are determined by S and H gamma II, respectively. It is also reported that the N-terminal 58-residue sequence of H gamma II is 72% similar to the corresponding sequence of S.

Amino Acid Sequence↗
PubMed1993

Modulation of doxorubicin resistance in multidrug-resistant cells by liposomes.

In this study, we have confirmed the ability of liposome-encapsulated doxorubicin to modulate drug resistance, as previously observed in CH LZ cells (Thierry et al., Cancer Commun. 1, 311-316, 1989), in two human multidrug-resistant (MDR) cell lines, the breast cancer MCF-7/ADR cell line, and the ovarian carcinoma SKVLB cell line. This effect was specific to MDR cells, as liposomally encapsulated doxorubicin did not enhance cell sensitivity to the drug in the parental cell lines. Cytotoxicity assays demonstrated that empty liposomes in the presence of free doxorubicin (Dox) reversed resistance to the drug at a level that may be higher than that observed when liposome-encapsulated Dox is used. This effect seems to be due to the high affinity of Dox for cardiolipin, one of the liposome components, which leads to the association of the drug and the cardiolipin-containing liposomes in the culture medium before entry into the cells. Neither pretreatment of empty liposomes before drug treatment nor combined incubation of vincristine and empty liposomes alter MDR in CH LZ cells, suggesting that the drug must be encapsulated or complexed to the liposomes to overcome MDR. Because MDR in CH LZ cells does not seem to be related to GSH level, MDR modulation by liposome-encapsulated Dox apparently may not be effected by altering the GSH function. These results suggest that the enhancement of sensitivity of MDR cells using Dox encapsulated in liposomes or complexed with liposomes may be explained by an increase in cell drug incorporation and by an intracellular drug redistribution. Fluorescence confocal microscopy study indicated that Dox is transported and distributed mainly in intracytoplasmic vesicles in SKVLB and MCF-7/ADR cells, whereas in parental cells the drug is located mainly in the nucleus. In addition, presentation of Dox in liposomes modifies the drug distribution pattern in MDR cells by partially shifting the drug to nuclear compartments. Thus, liposome-associated Dox may bypass the vesicular drug transport in MDR cells, resulting in the enhancement of the drug biological activity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Overcoming multidrug resistance in human tumor cells using free and liposomally encapsulated antisense oligodeoxynucleotides.

Antisense oligonucleotides offer a molecular targeting tool for overcoming cellular multidrug resistance. In order to improve the in vitro and the in vivo transport of oligodeoxynucleotides, we developed a new liposomal delivery system, using the minimal volume entrapment (MVE) technique. We have demonstrated that cellular uptake and intracellular release of oligodeoxynucleotides were facilitated by delivery in liposomes. 15 mers cap phosphorothioate oligodeoxynucleotides complementary to the 5' end of the coding region or to a loop-forming site in the mdr-1 mRNA were encapsulated in liposomes by the MVE method. P-glycoprotein synthesis and doxorubicin resistance were greatly reduced by exposure of the multidrug resistant SKVLB cells to 5 microM liposomally encapsulated oligonucleotide. A lower effect was observed when free oligodeoxynucleotides were used. Oligomers antisense to the loop-forming site appeared to be more effective and more specific in modulating multidrug resistance than oligomers with antisense sequence to the 5' end coding region.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Comparative pharmacological, toxicological and antitumoral evaluation of free and liposome-encapsulated cisplatin in rodents.

The systemic toxicity and efficacy of cisplatin (CDDP) were examined in vitro and in vivo. Procedures were performed before and after the antineoplastic agent was encapsulated into multilamellar liposomes (L-CDDP). In vitro cytotoxicity evaluation in L1210 murine leukaemia and NIH OVCAR human ovarian cancer cells showed IC50 values of 0.14 and 0.05 micrograms/ml with CDDP or L-CDDP, respectively. In vivo, mice injected intravenously with L-CDDP had plasma levels of platinum 4-fold higher than with CDDP. The t1/2 alpha was 2 h and the t1/2 beta exceeded 48 h with L-CDDP; whereas a t1/2 alpha of 15 min and t1/2 beta of 12 h was observed with CDDP. The values of platinum in liver, spleen, kidneys, lungs and heart were substantially higher in L-CDDP-treated compared to CDDP-treated mice. Cytotoxic evaluation of both agents was tested in vitro (murine L1210 leukaemia and NIH OVCAR cell line) and in vivo (male CD2F1 mice). CDDP and L-CDDP showed similar cytotoxicity in tissue culture. At the highest dose given, 12 mg/kg intraperitoneally (i.p.), L-CDDP showed higher antitumour efficacy demonstrated by an increased life span of the mice. The CDDP treatment at the highest dose was lethal to all the tumour bearing mice. The nephrotoxicity in rats (blood urea nitrogen and creatinine evaluation) of L-CDDP administered i.p. was significantly less than with CDDP. In addition, the ability of kidney slices to transport organic anions [para-aminohippurate (PAH)] and consume O2 was substantially decreased in rats treated with free CDDP compared to L-CDDP. Accordingly, the liposomal encapsulation of CDDP attenuates its nephrotoxicity, but allows maintenance of antitumour efficacy and may be a potentially effective modality in clinical settings.

Animals↗
PubMed1993

Potentiation of cytotoxicity of Kaposi's sarcoma related to immunodeficiency syndrome (AIDS) by liposome-encapsulated doxorubicin.

Kaposi's sarcoma is an independent criterion for the diagnosis of AIDS and develops in nearly 15% of all cases. Current chemotherapy regimens are associated with substantial toxicity, particularly bone marrow suppression, which limit their long-term use. In an attempt to reduce treatment-related toxicity and enhance uptake of the drug in tumor cells, free and liposome-encapsulated doxorubicin was tested in vitro. The liposomes were prepared with cardiolipin, phosphatidylcholine, and cholesterol. Kaposi's sarcoma (KS)-derived spindle cells were exposed to free doxorubicin (DOX) and liposome-encapsulated doxorubicin (LED) for various time intervals and analyzed for cellular cytotoxicity, thymidine incorporation, and cellular drug uptake. Cytotoxicity studies of KS cells with free DOX and LED showed an IC50 of 288 and 7.5 ng/ml, respectively, hence demonstrating a 38-fold higher cytotoxicity by LED. Thymidine incorporation studies in KS cells demonstrated over one log higher toxicity to LED compared to free DOX. Cellular drug uptake studies showed that free DOX concentration peaked in 1 hr in KS cells whereas LED continued to accumulate up to 4 hr. At 4 hr, anthracycline uptake through LED was fivefold higher than the uptake of free drug. Similarly LED uptake in the cells evaluated by direct fluorescent microscopy was much more intense and more frequent than the uptake of free drug. Thus AIDS-KS cells appear to be exquisitely sensitive to LED, which may provide a higher therapeutic to toxicity index in clinical use.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Analgesic use and chronic renal disease in patients with headache.

The pattern of analgesic use, abuse and incidence of analgesic-associated nephropathy in 79 patients with chronic headache was studied. Sixty-eight of these patients had migraine. Most patients had consumed a combination of analgesics (81%) while 19% had taken single analgesics for their headache. Nonsteroidal anti-inflammatory drugs were the most commonly used analgesics (96.2%) followed by paracetamol (70.9%) and aspirin, phenacetin and caffeine compounds (5.1%). Mefenamic acid was the commonest nonsteroidal anti-inflammatory drug consumed (97.4%). Analgesic abuse which was defined as a minimum total of 1 kg of analgesics such as paracetamol or aspirin, phenacetin and caffeine compounds or 400 capsules/tablets of nonsteroidal anti-inflammatory drugs was noted in 65 patients. Nonsteroidal anti-inflammatory drugs were the most commonly abused analgesics (89.2%) followed by paracetamol (38.5%). Forty-five of the 65 analgesic abusers had an intravenous urogram or ultrasound performed and renal papillary necrosis was documented in one patient. Three (4.6%) of the analgesic abusers had mildly raised serum creatinine levels. Mild proteinuria of less than 1 gm/litre was present in 27.7% of abusers. In conclusion, although analgesic use and abuse is common in patients with chronic headache, the short term incidence of analgesic-associated nephropathy (2.2%) and renal impairment (4.6%) was low. Prolonged observations will be necessary to ascertain the safety of these drugs for long term use.

Analgesics↗
PubMed1993

Comparative nephrotoxicity of tetraplatin and cisplatin in rats.

Cisplatin, a useful therapeutic agent against many forms of cancer, possesses significant nephrotoxicity, necessitating a search for agents with similar therapeutic profiles but with less potential for renal damage. Since tetraplatin, another platinum analog being evaluated in phase I clinical trials, has a favorable therapeutic profile when compared to cisplatin, we examined the comparative nephrotoxicity of tetraplatin and cisplatin in rats when both compounds were administered at equimolar doses. Based on various parameters, we found that tetraplatin was less nephrotoxic. In vivo injections of equimolar doses of tetraplatin caused a much lesser rise in serum urea nitrogen and creatinine when compared to cisplatin. In vitro, renal slice accumulation of 3H-p-aminohippurate and 14C-tetraethylammonium was significantly decreased after cisplatin but not after tetraplatin. Morphological damage in the kidneys was more severe after cisplatin compared to tetraplatin. We conclude through in vivo and in vitro methodology that tetraplatin is significantly less nephrotoxic than cisplatin at comparable therapeutic doses.

Animals↗
PubMed1993

Genetic basis for a lower prevalence of deficient CYP2D6 oxidative drug metabolism phenotypes in black Americans.

Debrisoquin hydroxylase (CYP2D6) is a cytochrome P450 enzyme that catalyzes the metabolism of > 30 commonly prescribed medications. Deficiency in CYP2D6 activity, inherited as an autosomal recessive trait, was found to be significantly less common in American blacks (1.9%) than whites (7.7%). To determine the genetic basis for this difference, inactivating CYP2D6 mutations were assessed by allele-specific PCR amplification and RFLP analyses of genomic DNA from 126 unrelated whites and 127 unrelated blacks. Blacks had a twofold lower frequency (8.5 versus 23%, P = 0.001) of the CYP2D6(B) mutation (point mutation at intron 3/exon 4 splice site), while complete deletion of the CYP2D6 gene (5.5% blacks, 2.4% whites), and the CYP2D6(A) mutation (single nucleotide deletion in exon 5; 0.24% blacks, 1.4% whites) were not different between the two groups. The prevalence of heterozygous genotypes was significantly lower in blacks (25 versus 42% of extensive metabolizers, P = 0.009), consistent with the observed prevalence of the deficient trait in blacks and whites. We conclude that the same CYP2D6 mutations lead to a loss of functional expression in blacks and whites, but American blacks have a lower prevalence of the deficient trait due to a lower frequency of the CYP2D6(B) mutation. This could explain racial differences in drug effects and disease risk.

Base Sequence↗