Mushir M Ali

Publications (10)19.25 Total impact

• Article: Reduced bioavailability of tamoxifen and its metabolite 4-hydroxytamoxifen after oral administration with biochanin A (an isoflavone) in rats.

  Sheelendra Pratap Singh, Wahajuddin, K S R Raju, Mushir M Ali, Kanchan Kohli, Girish Kumar Jain
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  ABSTRACT: The aim of this study was to investigate the effect of biochanin A (BCA) on the pharmacokinetics of tamoxifen, a substrate of P-glycoprotein (P-gp) and cytochrome 3A (CYP3A), in female rats. The tamoxifen was administered orally (10 mg/kg) without or with oral BCA (100 mg/kg) in female rats. As BCA is an inhibitor of CYP 3A and P-gp it was expected to increase the bioavailability of tamoxifen, a known substrate of CYP3A4/Pgp. Surprisingly, compared with the control group (treated with tamoxifen alone), BCA pretreated animals showed significantly (p < 0.05) decreased area under the plasma concentration-time curve from time zero to time infinity (AUC(0-∞)) and peak tamoxifen concentrations (C(max)). Consequently, the relative bioavailability (RB%) of tamoxifen co-administered with BCA was remarkably decreased compared with the control group. The AUC(0-∞) and C(max) of 4-hydroxytamoxifen in BCA pretreated rats were also significantly (p < 0.05) lower than those from the control group. However, there were no apparent changes in the metabolite ratio (MR; AUC(0-∞) of 4-hydroxytamoxifen to tamoxifen) by co-administration of BCA. If the results of this study are further confirmed by clinical trials, tamoxifen dosages should be adjusted to avoid potential drug interaction when tamoxifen is used clinically in combination with BCA and BCA-containing dietary supplements.
  Phytotherapy Research 12/2011; 26(2):303-7. · 2.09 Impact Factor
• Article: Liquid chromatography-mass spectrometry method for the quantification of tamoxifen and its metabolite 4-hydroxytamoxifen in rat plasma: application to interaction study with biochanin A (an isoflavone).

  Sheelendra Pratap Singh, Wahajuddin, Mushir M Ali, Kanchan Kohli, Girish Kumar Jain
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  ABSTRACT: Tamoxifen is the agent of choice for the treatment of estrogen receptor-positive breast cancer. Tamoxifen is a substrate of P-glycoprotein (P-gp) and microsomal cytochrome P450 (CYP) 3A, and biochanin A (BCA) is an inhibitor of P-gp and CYP3A. Hence, it could be expected that BCA would affect the pharmacokinetics of tamoxifen. In the present study we have developed and validated a simple, sensitive and specific LC-ESI-MS/MS method for the simultaneous quantification of tamoxifen and its metabolite 4-hydroxytamoxifen with 100 μL rat plasma using centchroman as an internal standard (IS). Tamoxifen, 4-hydroxytamoxifen and IS were separated on a Supelco Discovery C18 (4.6 mm × 50 mm, 5.0 μm) column under isocratic condition using 0.0 1M ammonium acetate (pH 4.5):acetonitrile (10:90, v/v) as a mobile phase. The mobile phase was delivered at a flow rate of 0.8 mL/min. The method was proved to be accurate and precise at linearity range of 0.78-200 ng/mL with a correlation coefficient (r) of ≥ 0.996. The intra- and inter-day assay precision ranged from 1.89 to 8.54% and 3.97 to 10.26%, respectively; and intra- and inter-day assay accuracy was between 87.63 and 109.06% and 96 and 103.89%, respectively for both the analytes. The method was successfully applied to study the effect of oral co-administration of BCA (an isoflavone) on the pharmacokinetics of tamoxifen and 4-hydroxytamoxifen in female rats. The coadministration of BCA caused no significant changes in the pharmacokinetics of tamoxifen and 4-hydroxytamoxifen. However, the peak plasma concentration (C(max)) of 4-hydroxytamoxifen in BCA pretreated rats was significantly (P<0.05) lower than those from control group.
  Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 08/2011; 879(27):2845-51. · 2.78 Impact Factor
• Article: High-throughput quantification of isoflavones, biochanin A and genistein, and their conjugates in female rat plasma using LC-ESI-MS/MS: Application in pharmacokinetic study.

  Sheelendra Pratap Singh, Mushir M Ali, Girish Kumar Jain
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  ABSTRACT: Isoflavones containing foods and dietary supplements are widely consumed for putative health benefits (e.g. cancer chemoprevention, beneficial effects on serum lipids associated with cardiovascular health, reduction of osteoporosis, relief of menopausal symptoms). This paper describes the development and validation of a sensitive high throughput LC-ESI-MS/MS method for quantifying biochanin A (BCA) and genistein (GEN), and their conjugates in rat plasma. The analytes were separated on a Supelco Discovery C18 (4.6×50 mm, 5.0 μm) column under isocratic condition using acetonitrile/methanol (50:50, v/v) and 0.1% acetic acid in the ratio of 90:10 v/v as a mobile phase. The intra- and inter-day assay precision ranged from 2.66 to 8.34% and 4.40 to 8.10% (RSD %), respectively, and intra- and inter-day assay accuracy was between 90.67-109.25% and 95.86-106.32%, respectively, for both the analytes. The lowest quantitation limit for BCA and GEN was 0.5 ng/mL in 0.1 mL of rat plasma. The method was successfully applied to the estimation of BCA, GEN and their conjugates in rat plasma following oral administration of BCA. Circulating conjugates (glucuronides/sulfates) of BCA and GEN were quantified using enzymatic hydrolysis of plasma samples. The levels of isoflavones glucuronides/sulfates were found to be much greater than the corresponding aglycones.
  Journal of Separation Science 11/2010; 33(21):3326-34. · 2.73 Impact Factor
• Article: Transdermal delivery of valsartan: I. Effect of various terpenes.

  Mohammad Rizwan, Mohammed Aqil, Abdul Ahad, Yasmin Sultana, Mushir M Ali
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  ABSTRACT: The objective of the present study was to investigate the effect of various terpenes, including a diterpene, forskolin (FSK; a putative penetration enhancer), on skin permeation of valsartan. Permeation studies were carried out with Automated Transdermal Diffusion Cells Sampling System (SFDC 6, LOGAN Instruments Corp., NJ, USA) through rat skin and human cadaver skin (HCS) using ethanol: IPB (pH 7.4) (40:60) as vehicle. The efficacy of the study terpenes for permeation of valsartan across rat skin and human cadaver skin was found in the order of cineole > d-limonene > l-menthol > linalool > FSK and cineole > d-limonene > linalool > l-menthol > FSK, respectively. No apparent skin irritation (erythema, edema) was observed on treatment of skin with terpenes including FSK. FT-IR, DSC, and histopathological studies revealed that FSK enhanced the skin permeation of the active drug by disruption and extraction of lipid bilayers of SC in consonance with other terpenes.
  Drug Development and Industrial Pharmacy 07/2008; 34(6):618-26. · 1.49 Impact Factor
• Article: Purification, refolding, and characterization of recombinant LHRH-T multimer.

  Komal Raina, Amulya K Panda, Mushir M Ali, G P Talwar
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  ABSTRACT: To make the native LHRH immunogenic, a multimer of LHRH interspersed with T non-B peptides (r-LHRH-d2) was expressed as recombinant protein in Escherichia coli. The expression level of the recombinant protein was around 15% of the total cellular protein and it aggregated as inclusion bodies. Inclusion bodies from the bacterial cells were isolated and purified to homogeneity. Instead of high concentrations of chaotropic agents, r-LHRH- d2 was solubilized in 50 mM citrate buffer at pH 3 containing 2 M urea. The protein was refolded by 5-fold dilution (pulsatile) with cold 10 mM citrate buffer at pH 6 in presence of 0.3 M L-arginine. Purification of r-LHRH-d2 was carried out by successive passages on CM-Sepharose column at pH 6.0 which retained extraneous proteins and pH 4.8 at which r-LHRH-d2 bound to the resin. The elution was carried out by using linear salt gradient (0.1-1 M NaCl). The overall yield of the purified r-LHRH-d2 was 40% of the initial inclusion body proteins. The purity and homogeneity were confirmed by a single homogeneous peak on analytical HPLC eluting out at 29.51 min and by single band on SDS-PAGE reactive with polyvalent anti-LHRH antibodies. Mass spectroscopic analysis indicated the protein to be of 16.6 kDa which equals the theoretically expected mass. The N-terminal amino acid analysis of r-LHRH-d2 showed the sequence which corresponded to the designed protein. The CD spectrum of the refolded r-LHRH-d2 showed that the multimer has considerable beta sheet structure like the monomeric LHRH protein.
  Protein Expression and Purification 10/2004; 37(1):8-17. · 1.59 Impact Factor
• Article: A recombinant luteinising-hormone-releasing-hormone immunogen bioeffective in causing prostatic atrophy.

  G P Talwar, Komal Raina, Jagdish C Gupta, Ruma Ray, S Wadhwa, Mushir M Ali
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  ABSTRACT: Previous studies with a semi-synthetic vaccine indicated the utility of immunization against luteinising-hormone-releasing-hormone (LHRH) in prostate cancers. To overcome the limitations of the previous vaccine, which caused carrier induced suppression of antibody response on repeated immunizations and was costly to synthesize, two recombinant vaccines were designed, in which diptheria or tetanus toxoid used as carriers were replaced by 4-5 T non B peptides. The paper reports the immunogenecity, efficacy and safety of these multimer vaccines in rats, a homologous experimental animal. All animals generated anti-LHRH antibodies, which caused the decline of testosterone to castration levels at and above 0.15 OD units of antibody titres. The prostate was significantly atrophied in all animals immunized with these vaccines.
  Vaccine 10/2004; 22(27-28):3713-21. · 3.77 Impact Factor
• Article: Improved immune response from biodegradable polymer particles entrapping tetanus toxoid by use of different immunization protocol and adjuvants.

  Rajeev S Raghuvanshi, Yogesh K Katare, Komal Lalwani, Mushir M Ali, Om Singh, Amulya K Panda
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  ABSTRACT: Poly lactide-co-glycolide (PLGA) and polylactide (PLA) particles entrapping immunoreactive tetanus toxoid (TT) were prepared using the solvent evaporation method. The effect of different formulation parameters such as polymer hydrophobicity, particle size and use of additional adjuvants on the generation of immune responses in experimental animals was evaluated. Immune responses from hydrophobic polymer particles were better than those from hydrophilic polymer. Immunization with physical mixtures of different size particles resulted in further improvement in anti-TT antibody titers in Wistar rats. Physical mixture of nano and microparticles resulted in early as well as high antibody titers in experimental animals. Immunization with polymer particles encapsulating stabilized TT elicited anti-TT antibody titers, which persisted for more than 5 months and were higher than those obtained with saline TT. However, antibody responses generated by single point immunization of either particles or physical mixture of particles were lower than the conventional two doses of alum-adsorbed TT. Immunization with nanoparticles along with alum resulted in very high and early immune response: high anti-TT antibody titers were detected as early as 15 days post-immunization. Use of a squalene emulsion along with the particles during immunization enhanced the level of anti-TT antibody titers considerably. Single point immunization with admixtures of PLA microparticles and alum resulted in antibody response very close to that achieved by two injections of alum-adsorbed TT; the antibody titers were more than 50 microg/ml over a period of 6 months. These results indicated that the judicious choice of polymer and particles size, protecting the immunoreactivity of the entrapped antigen and the appropriate design of immunization protocol along with suitable adjuvant can lead to the generation of long lasting immune response from single dose vaccine formulation using polymer particles.
  International Journal of Pharmaceutics 11/2002; 245(1-2):109-21. · 3.35 Impact Factor
• Article: Potentiation of immune response from polymer-entrapped antigen: toward development of single dose tetanus toxoid vaccine.

  Y K Katare, Amulya K Panda, Komal Lalwani, Irshad Ul Haque, Mushir M Ali
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  ABSTRACT: Poly(lactide) (PLA) polymer particles entrapping immunoreactive tetanus toxoid (TT) were used for generation of immune response using single point immunization. Immunization with different sizes of polymer particles encapsulating immunoreactive TT elicited anti-TT antibody titers that persisted for more than 5 months. However, antibody response generated by single point immunization of either nanoparticles or microparticles were lower than the conventional two doses of alum adsorbed TT. To overcome this limitation, alum was used with particles that improved anti-TT antibody response. Immunization with nanoparticles along with alum resulted in very high and early immune response: high anti-TT antibody titers were detected as early as 15 days postimmunization. However anti-TT antibody titers declined rapidly with time. Immunization with admixture of microparticles and alum elicited higher antibody titers than the particles alone and the antibody titers were high particularly during the later part of the postimmunization period. Single point immunization with admixture of PLA microparticles and alum resulted in an antibody response very close to that achieved by two injection of alum-adsorbed TT. Physical mixture of both a nano- and microparticles along with alum resulted in sustained anti-TT antibody response from very early days of postimmunization until 150 days. The antibody titers were maintained around 50 microg/ml for more than 5 months. These results indicated that immune response from polymer particles can be further improved by use of additional adjuvant. Furthermore, using various size particles or physical mixture of different size particles along with alum, it is possible to modulate the kinetics of immune response using polymer particles based immunization.
  Drug Delivery 10(4):231-8. · 1.46 Impact Factor
• Article: A recombinant luteinising-hormone-releasing-hormone immunogen bioeffective in causing prostatic atrophy

  G.P Talwar, Komal Raina, Jagdish C Gupta, Ruma Ray, S Wadhwa, Mushir M Ali
  [show abstract] [hide abstract]
  ABSTRACT: Previous studies with a semi-synthetic vaccine indicated the utility of immunization against luteinising-hormone-releasing-hormone (LHRH) in prostate cancers. To overcome the limitations of the previous vaccine, which caused carrier induced suppression of antibody reponse on repeated immunizations and was costly to synthesize, two recombinant vaccines were designed, in which diptheria or tetanus toxoid used as carriers were replaced by 4–5 T non B peptides. The paper reports the immunogenecity, efficacy and safety of these multimer vaccines in rats, a homologous experimental animal. All animals generated anti-LHRH antibodies, which caused the decline of testosterone to castration levels at and above 0.15 OD units of antibody titres. The prostate was significantly atrophied in all animals immunized with these vaccines.
  Vaccine.
• Article: Purification, refolding, and characterization of recombinant LHRH-T multimer

  Komal Raina, Amulya K Panda, Mushir M Ali, G.P Talwar
  [show abstract] [hide abstract]
  ABSTRACT: To make the native LHRH immunogenic, a multimer of LHRH interspersed with T non-B peptides (r-LHRH-d2) was expressed as recombinant protein in Escherichia coli. The expression level of the recombinant protein was around 15% of the total cellular protein and it aggregated as inclusion bodies. Inclusion bodies from the bacterial cells were isolated and purified to homogeneity. Instead of high concentrations of chaotropic agents, r-LHRH- d2 was solubilized in 50 mM citrate buffer at pH 3 containing 2 M urea. The protein was refolded by 5-fold dilution (pulsatile) with cold 10 mM citrate buffer at pH 6 in presence of 0.3 M l-arginine. Purification of r-LHRH-d2 was carried out by successive passages on CM–Sepharose column at pH 6.0 which retained extraneous proteins and pH 4.8 at which r-LHRH-d2 bound to the resin. The elution was carried out by using linear salt gradient (0.1–1 M NaCl). The overall yield of the purified r-LHRH-d2 was 40% of the initial inclusion body proteins. The purity and homogeneity were confirmed by a single homogeneous peak on analytical HPLC eluting out at 29.51 min and by single band on SDS–PAGE reactive with polyvalent anti-LHRH antibodies. Mass spectroscopic analysis indicated the protein to be of 16.6 kDa which equals the theoretically expected mass. The N-terminal amino acid analysis of r-LHRH-d2 showed the sequence which corresponded to the designed protein. The CD spectrum of the refolded r-LHRH-d2 showed that the multimer has considerable β sheet structure like the monomeric LHRH protein.
  Protein Expression and Purification.