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1.
Rev. bras. cir. plást ; 29(3): 438-441, jul.-sep. 2014. tab, ilus
Article in English, Portuguese | LILACS | ID: biblio-741

ABSTRACT

INTRODUÇÃO: Tradicionalmente, a fissura palatina é corrigida em duas camadas - uma camada mucosa nasal e camada muco-periosteal oral. Este estudo avaliou os resultados do fechamento em camada única de fissura palatina comparado ao fechamento tradicional em camada dupla. MÉTODOS: Trata se de revisão de prontuários de 101 casos de correção de fissura palatina realizados entre 1981 e 2012 em uma clínica assistencial/hospital terciário localizado no centro de Wisconsin. Os casos utilizaram fechamento em camada única e foram acompanhados em Clínica de Lábio Leporino por 12 meses. Foram incluídas fissura labial e palatina também como fissura palatina isolada. RESULTADOS: Todos os casos apresentaram cicatrização satisfatória exceto dois casos que necessitaram de correção posterior de pequena fistula. CONCLUSÃO: O fechamento em camada única de fissura palatina é tão efetivo quanto o fechamento tradicional em camada dupla, além disso apresenta mínimas complicações.


INTRODUCTION: Traditionally, cleft of the hard palate is repaired in two layers, with a nasal mucosal layer and an oral mucoperiosteal layer. The aim of this study was to evaluate the results of one layer closure of hard palate cleft compared to the traditional two layers closure. METHODS: The charts of 101 consecutive cases of repair of hard palate cleft performed by the authors from 1981 to 2012 at a tertiary care clinic/hospital in central Wisconsin were reviewed. The cases utilized the single layer closure and were followed in the Cleft Palate Clinic on a yearly basis. Cases included unilateral and bilateral cleft lip and palate as well as isolated cleft palate. RESULTS: All cases healed satisfactorily except for two cases that later required small fistulae repair. CONCLUSION: Single layer closure of the hard palate cleft is as effective as traditional two-layer closure, with minimal complications.


Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , History, 21st Century , Surgery, Plastic , Comparative Study , Cleft Lip , Cleft Palate , Review , Oral Surgical Procedures , Evaluation Study , Palate, Hard , Mouth , Nasal Cavity , Surgery, Plastic/methods , Cleft Lip/surgery , Cleft Lip/pathology , Cleft Palate/surgery , Oral Surgical Procedures/methods , Palate, Hard/surgery , Mouth/surgery , Mouth/pathology , Nasal Cavity/surgery , Nasal Cavity/pathology
2.
AAPS PharmSciTech ; 10(3): 906-16, 2009.
Article in English | MEDLINE | ID: mdl-19609837

ABSTRACT

Limited aqueous solubility of exemestane leads to high variability in absorption after oral administration. To improve the solubility and bioavailability of exemestane, the self-microemulsifying drug delivery system (SMEDDS) was developed. SMEDDS comprises of isotropic mixture of natural or synthetic oil, surfactant, and cosurfactant, which, upon dilution with aqueous media, spontaneously form fine o/w microemulsion with less than 100 nm in droplet size. Solubility of exemestane were determined in various vehicles. Ternary phase diagrams were plotted to identify the efficient self-emulsification region. Dilution studies, droplet size, and zeta potential of the formulations were investigated. The release of exemestane from SMEDDS capsules was studied using USP dissolution apparatus in different dissolution media and compared the release of exemestane from a conventional tablet. Oral pharmacokinetic study was performed in female Wistar rats (n = 8) at the dose of 30 mg kg(-1). The absorption of exemestane from SMEDDS form resulted in about 2.9-fold increase in bioavailability compared with the suspension. Our studies illustrated the potential use of SMEDDS for the delivery of hydrophobic compounds, such as exemestane by the oral route.


Subject(s)
Androstadienes/administration & dosage , Androstadienes/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Aromatase Inhibitors/administration & dosage , Aromatase Inhibitors/pharmacokinetics , Animals , Area Under Curve , Biological Availability , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Drug Delivery Systems , Electrochemistry , Emulsions , Excipients , Female , Hydrogen-Ion Concentration , Mass Spectrometry , Microscopy, Electron, Transmission , Particle Size , Rats , Rats, Wistar , Surface-Active Agents/chemistry , Thermodynamics
3.
Talanta ; 78(4-5): 1310-4, 2009 Jun 15.
Article in English | MEDLINE | ID: mdl-19362193

ABSTRACT

Bicalutamide is a non-steroidal antiandrogen and is an oral medication that is used for treating prostate cancer. To evaluate the bioavailability of bicalutamide from bicalutamide self-microemulsifying drug delivery systems (SMEDDS) and bicalutamide suspension formulations, a sensitive, specific reversed-phase high performance liquid chromatographic (HPLC) method using ultraviolet detection was developed and validated for the analysis of bicalutamide (BCT) in rat blood plasma. Letrozole (LZ) was used as the internal standard. The chromatographic separation was achieved on C18 column at 35 degrees C, with a mobile phase consisting of water: acetonitrile (adjusted to pH 3.0 with 20% o-phosphoric acid) (60:40), at a flow rate of 1.0 mL min(-1). Bicalutamide and letrozole were well separated with retention times of 10.9+/-0.2 and 5.7+/-0.2 min, respectively. The method was successfully used to determine pharmacokinetics of bicalutamide, following oral administration of bicalutamide suspension and bicalutamide SMEDDS to wistar rats. Significant difference was observed in main pharmacokinetic parameters of tmax, Cmax and AUC(0 --> infinity) between SMEDDS and suspension, and a two fold increase in the relative bioavailability of bicalutamide was observed with the SMEDDS compared with suspension formulation. It was concluded that the absorption of bicalutamide from SMEDDS was enhanced.


Subject(s)
Anilides/pharmacokinetics , Chromatography, High Pressure Liquid/methods , Nitriles/pharmacokinetics , Tosyl Compounds/pharmacokinetics , Androgen Antagonists/blood , Androgen Antagonists/pharmacokinetics , Anilides/blood , Animals , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Biological Availability , Dosage Forms , Emulsions , Female , Nitriles/blood , Pharmaceutical Preparations , Pharmacokinetics , Rats , Rats, Wistar , Suspensions , Tosyl Compounds/blood
4.
Anticancer Agents Med Chem ; 9(3): 246-75, 2009 Mar.
Article in English | MEDLINE | ID: mdl-19275520

ABSTRACT

In the present review, the discovery and development of quinazoline as tyrosine kinase inhibitors has been described. The synthesis of most potent quinazoline inhibitors of EGFR, VEGFR and PDGRF has been discussed. Structure activity relationship for quinazoline as tyrosine kinase inhibitors has been established. It was found that C-4, C-6 and C-7 positions in quinazoline are appropriate sites for designing new tyrosine kinase inhibitors. This review should help the medicinal chemist in designing more effective tyrosine kinase inhibitors.


Subject(s)
Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Design , Humans , Molecular Structure , Protein Kinase Inhibitors/chemistry , Quinazolines/chemistry , Stereoisomerism , Structure-Activity Relationship
5.
Eur J Med Chem ; 44(3): 1355-62, 2009 Mar.
Article in English | MEDLINE | ID: mdl-18316139

ABSTRACT

A small library of 2-indolinone derivatives with the 2,6-dichlorophenyl ring at the N(1) position and with varying substitutions including aryl groups at the 3-position were synthesized, and their structures were confirmed by spectral analysis. All molecules were screened for their in vitro cytotoxic activity on SW620 colon cancer cell lines. Among the designed series compounds 4c, 4f and 4j were found to be active at concentrations of 2-15 microg/ml. Some 3D-QSAR models were also built to understand the structure-activity relationship.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Colonic Neoplasms/pathology , Indoles/chemical synthesis , Indoles/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Indoles/chemistry , Magnetic Resonance Spectroscopy , Quantitative Structure-Activity Relationship , Spectrometry, Mass, Fast Atom Bombardment , Spectrophotometry, Infrared
6.
AAPS PharmSciTech ; 9(2): 628-34, 2008.
Article in English | MEDLINE | ID: mdl-18473177

ABSTRACT

The purpose of this research work was to formulate and characterize self-micro emulsifying drug delivery system containing exemestane. The solubility of exemestane was determined in various vehicles. Pseudo ternary phase diagram was used to evaluate the micro-emulsification existence area. SMEDDS formulations were tested for micro-emulsifying properties, and the resultant formulations loaded with exemestane (ME1, ME2, ME3, ME4 and ME5) were investigated for clarity, phase separation, globule size and shape, zeta potential, effect of various diluents and dilutions, thermodynamic and thermal stability. From the results it is concluded that increase in droplet size is proportional to the concentration of oil in SMEDDS formulation. Minor difference in the droplet size and zeta potential was observed by varying the diluents (deionized water and 0.1 N HCl) and dilutions (1:10, 1:50 and 1:100). Formulations, which were found to be thermodynamically stable (ME1, ME2, ME3 and ME4), were subjected to stability studies as per International Conference on Harmonization (ICH) guidelines. No significant variations were observed in the formulations over a period of 3 months at accelerated and long-term conditions. TEM photographs of microemulsions formulations further conformed the spherical shape of globules. Among the various SMEDDS formulations, ME4 offer the advantages of good clarity systems at high oil content and thus offer good solubilization of exemestane. Thus this study indicates that the SMEDDS can be used as a potential drug carrier for dissolution enhancement of exemestane and other lipophilic drug(s).


Subject(s)
Androstadienes/chemistry , Aromatase Inhibitors/chemistry , Drug Carriers , Oils/chemistry , Surface-Active Agents/chemistry , Chemistry, Pharmaceutical , Drug Compounding , Drug Stability , Emulsions , Microscopy, Electron, Transmission , Particle Size , Solubility , Surface Properties , Technology, Pharmaceutical/methods , Temperature , Thermodynamics
7.
J Ethnopharmacol ; 117(1): 123-9, 2008 Apr 17.
Article in English | MEDLINE | ID: mdl-18346858

ABSTRACT

Terminalia arjuna has been marked as a potential cardioprotective agent since vedic period. The present study was aimed to investigate the effects of butanolic fraction of Terminalia arjuna bark (TA-05) on Doxorubicin (Dox)-induced cardiotoxicity. Male wistar rats were used as in vivo model for the study. TA-05 was administered orally to Wistar rats at different doses (0.42 mg/kg, 0.85 mg/kg, 1.7 mg/kg, 3.4 mg/kg and 6.8 mg/kg) for 6 days/week for 4 weeks. Thereafter, all the animals except saline and TA-05-treated controls were administered 20 mg/kg Dox intraperitonially. There was a significant decrease in myocardial superoxide dismutase (38.94%) and reduced glutathione (23.84%) in animals treated with Dox. Concurrently marked increase in serum creatine kinase-MB (CKMB) activity (48.11%) as well as increase in extent of lipid peroxidation (2.55-fold) was reported. Co-treatment of TA-05 and Dox resulted in an increase in the cardiac antioxidant enzymes, decrease in serum CKMB levels and reduction in lipid peroxidation as compared to Dox-treated animals. Electron microscopic studies in Dox-treated animals revealed mitochondrial swelling, Z-band disarray, focal dilatation of smooth endoplasmic reticulum (SER) and lipid inclusions, whereas the concurrent administration of TA-05 led to a lesser degree of Dox-induced histological alterations. These findings suggest that butanolic fraction of Terminalia arjuna bark has protective effects against Dox-induced cardiotoxicity and may have potential as a cardioprotective agent.


Subject(s)
Doxorubicin/toxicity , Heart/drug effects , Plant Extracts/pharmacology , Terminalia , Animals , Catalase/metabolism , Creatine Kinase, MB Form/blood , Free Radical Scavengers/pharmacology , Glutathione/metabolism , Lipid Peroxidation/drug effects , Male , Myocardium/metabolism , Myocardium/ultrastructure , Rats , Rats, Wistar , Superoxide Dismutase/metabolism , Terminalia/chemistry
8.
Invest New Drugs ; 26(6): 505-16, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18322652

ABSTRACT

We have reported earlier a novel combination of four structurally designed synthetic neuropeptide analogs of vasoactive intestinal peptide (VIP), bombesin, substance P and somatostatin, code-named DRF 7295 which have anti-tumor efficacy for adenocarcinomas in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). The discovery, synthesis, in vitro and in vivo efficacy was reported (Jaggi et al., Invest New Drugs, 2008). Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to most sensitive to DRF7295 in vitro and in vivo (Jaggi et al., Invest New Drugs, 2008). We have further investigated and report here the modulation of cellular signaling in gastrointestinal carcinomas by DRF 7295, which may be mediating its observed anticancer activity in these cancer types. DRF 7295 inhibits the binding of specific neuropeptides initiating a cascade of cellular signaling events leading to programmed cell death. It down regulates the second messenger cAMP, epidermal growth factor (EGF) dependent proliferation and the phosphorylated MAP Kinase pERK1/2 in gastrointestinal carcinomas, thus depriving the tumour cells of critical pro-proliferative cellular signals. It triggers bcl2 and Caspase 3 dependent apoptotic cell death and induces p53 tumor suppressor protein in the treated carcinoma cells in vitro. It has significant anti-angiogenic potential as reflected in the inhibition of tube like formation in the endothelial cells and down regulation of VEGF levels. Tumour xenograft studies confirmed the in vivo efficacy of DRF 7295 for gastrointestinal carcinomas (Jaggi et al., Invest New Drugs, 2008). The Phase I clinical trials have shown DRF 7295 to be well tolerated and devoid of systemic toxicities of the conventional cytotoxics (Mukherjee et al., Phase I dose escalating study of DRF7295: a new class of peptide based drugs. "Abstract" ASCO ID:948, 2003). The drug may have a promising role in disease stabilization in colorectal and other cancers. Thus DRF 7295 is a novel targeted drug in the class of signal transduction modulators, with potential for treatment of gastrointestinal carcinomas.


Subject(s)
Antineoplastic Agents/pharmacology , Gastrointestinal Neoplasms/drug therapy , Peptides/pharmacology , Signal Transduction/drug effects , Apoptosis/drug effects , Caspase 3/drug effects , Caspase 3/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclic AMP/metabolism , Down-Regulation/drug effects , Drug Combinations , Drug Screening Assays, Antitumor/methods , Epidermal Growth Factor/drug effects , Epidermal Growth Factor/metabolism , Gastrointestinal Neoplasms/physiopathology , Humans , Mitogen-Activated Protein Kinase 1/drug effects , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/drug effects , Mitogen-Activated Protein Kinase 3/metabolism , Phosphorylation/drug effects , Proto-Oncogene Proteins c-bcl-2/drug effects , Proto-Oncogene Proteins c-bcl-2/metabolism , Tumor Suppressor Protein p53/drug effects , Tumor Suppressor Protein p53/metabolism
9.
Invest New Drugs ; 26(6): 489-504, 2008 Dec.
Article in English | MEDLINE | ID: mdl-18217205

ABSTRACT

A novel peptide combination consisting of four synthetic neuropeptide analogs of Vasoactive Intestinal Peptide (VIP), Bombesin, Substance P and Somatostatin has been found to have potent anticancer activity in vitro and in vivo. The receptors of these four neuropeptides are known to be over expressed in various cancers. We have found the presence of native neuropeptides in the culture supernatant of the primary tumor cells of human colon adenocarcinomas. It was further demonstrated by receptor-ligand assays that not only do these tumor cells synthesize and secrete four peptide hormones but also possess specific high affinity receptors on their surface. Screening a large panel of analogs to the four peptide hormones on tumor cell proliferation led to the identification of four cytotoxic analogs, the combination of which was code-named DRF7295. The design and synthesis of the peptide analogs have been described in this paper. In vitro anticancer activity of DRF7295 was studied in a large panel of human tumor cells. Gastrointestinal tumor cells of the colon, pancreas and duodenum were found to be most sensitive to DRF7295 with moderate activity seen in glioblastoma, prostate, leukemia and those of oral cancer cells. Efficacy studies in xenograft models of colon and duodenum resulted in T/C% of less than 40%, which is indicative of strong tumor regressing potential of DRF7295 in gastrointestinal cancers. Acute and long-term toxicity studies as well as safety pharmacology studies conducted indicate the safety of the drug upon systemic administration with no significant adverse pharmacological effects.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Delivery Systems , Gastrointestinal Neoplasms/drug therapy , Peptides/pharmacology , Animals , Antineoplastic Agents/adverse effects , Bombesin/analogs & derivatives , Cell Line, Tumor , Drug Combinations , Female , Gastrointestinal Neoplasms/physiopathology , Humans , Male , Mice , Mice, Nude , Peptides/adverse effects , Rats , Rats, Wistar , Receptors, Bombesin/drug effects , Receptors, Bombesin/metabolism , Receptors, Neurokinin-1/drug effects , Receptors, Neurokinin-1/metabolism , Receptors, Somatostatin/drug effects , Receptors, Somatostatin/metabolism , Receptors, Vasoactive Intestinal Peptide/drug effects , Receptors, Vasoactive Intestinal Peptide/metabolism , Somatostatin/analogs & derivatives , Substance P/analogs & derivatives , Toxicity Tests , Vasoactive Intestinal Peptide/analogs & derivatives , Xenograft Model Antitumor Assays
10.
Indian J Biochem Biophys ; 45(2): 91-7, 2008 Apr.
Article in English | MEDLINE | ID: mdl-21086721

ABSTRACT

Interleukin-2 (IL-2), a potent cytokine has been used in anti-cancer therapy for over a decade now. IL-2, originally identified as a growth factor for T lymphocytes is a 15 kDa hydrophobic glycoprotein that induces the activation, clonal proliferation and differentiation of T and B-lymphocytes and enhances the cytotoxicity of monocytes and natural killer (NK) cells. Here, we report a simple method for the cloning, high-level expression and purification of IL-2 protein, which can be easily extended to other bioactive therapeutic proteins. The IL-2 gene was amplified from human spleen cDNA and cloned in a prokaryotic (E. coli) expression system. An optimal expression of the IL-2 protein was determined by varying the expression conditions like temperature, inducer concentration and duration of induction. The protein was expressed as inclusion bodies and a panel of reagents including detergents, urea and guanidine hydrochloride were used to solubilize it. After solubilization, the protein was renatured and subjected to a single step gel-filtration chromatography to yield immunobioactive IL-2 protein with > 99% purity.


Subject(s)
Escherichia coli/genetics , Interleukin-2/genetics , Chromatography, Gel , Electrophoresis, Polyacrylamide Gel , Enzyme-Linked Immunosorbent Assay , Humans , Interleukin-2/isolation & purification , Recombinant Proteins/genetics , Recombinant Proteins/isolation & purification
11.
Invest New Drugs ; 26(1): 25-34, 2008 Feb.
Article in English | MEDLINE | ID: mdl-17851638

ABSTRACT

In vitro and in vivo pharmacological screening of Betulinic acid (BA) and five dihydro-BA derivatives modified at C-3 position [4-nitrobenzyl-oximino (1), 2-4-difluoro-benzoyloxy (2), 2-4-difluoro-benzylidene-amino (3), benzoyl-hydrazono (4), and 4-fluorophenyl-hydrazono (5)], having potent in vitro anti-cancer activity was carried out using ADME, animal PK and tumor studies. We found that BA and the derivatives had poor aqueous solubility (<0.1 microg/ml), low to moderate permeability (log Pe<-5.0) and high plasma protein binding (>70%). Although BA and 5 were metabolized by human liver microsomes, derivatives 1, 2, 3 and 4 possessed good in vitro metabolic stability. Except 3 which inhibited CYP1A2 isoform by more than 50% none of the other compounds inhibited key cytochrome P450 enzyme isoforms (CYP1A2, CYP2C9, CYP2D6 and CYP3A4) at 10 microM. Based on in vitro results one derivative 1 was tested in rodent PK and tumor studies. We found that 1 exhibited favorable pharmacokinetic characteristics of a systemically administered drug and showed better in vivo anti-tumor efficacy as compared to BA in a human colon cancer xenograft model. Our results show that BA derivatives are potential anti-cancer compounds which need to be explored in detail.


Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms, Experimental/prevention & control , Triterpenes/pharmacology , Xenograft Model Antitumor Assays/methods , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Blood Proteins/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Cytochrome P-450 Enzyme System/metabolism , Dose-Response Relationship, Drug , HT29 Cells , Humans , Ketoconazole/pharmacology , Male , Mice , Mice, Nude , Molecular Structure , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Pentacyclic Triterpenes , Protein Binding , Quinidine/pharmacology , Rats , Rats, Wistar , Sulfaphenazole/pharmacology , Triterpenes/metabolism , Triterpenes/pharmacokinetics , Tumor Burden/drug effects , U937 Cells , Betulinic Acid
12.
Anticancer Agents Med Chem ; 7(6): 685-709, 2007 Nov.
Article in English | MEDLINE | ID: mdl-18045063

ABSTRACT

The disease of cancer has been ranked second after cardiovascular diseases and plant-derived molecules have played an important role for the treatment of cancer. Nine cytotoxic plant-derived molecules such as vinblastine, vincristine, navelbine, etoposide, teniposide, taxol, taxotere, topotecan and irinotecan have been approved as anticancer drugs. Recently, epothilones are being emerging as future potential anti-tumor agents. However, targeted cancer therapy has now been rapidly expanding and small organic molecules are being exploited for this purpose. Amongst target specific small organic molecules, quinazoline was found as one of the most successful chemical class in cancer chemotherapy as three drugs namely Gefitinib, Erlotinib and Canertinib belong to this series. Now, quinazoline related chemical classes such as quinolines and naphthyridines are being exploited in cancer chemotherapy and a number of molecules such as compounds EKB-569 (52), HKI-272 (78) and SNS-595 (127a) are in different phases of clinical trials. This review presents the synthesis of quinolines and naphthyridines derivatives, screened for anticancer activity since year 2000. The synthesis of most potent derivatives in each prototype has been delineated. A brief structure activity relationship for each prototype has also been discussed. It has been observed that aniline group at C-4, aminoacrylamide substituents at C-6, cyano group at C-3 and alkoxy groups at C-7 in the quinoline ring play an important role for optimal activity. While aminopyrrolidine functionality at C-7, 2'-thiazolyl at N-1 and carboxy group at C-3 in 1,8-naphthyridine ring are essential for eliciting the cytotoxicity. This review would help the medicinal chemist to design and synthesize molecules for targeted cancer chemotherapy.


Subject(s)
Antineoplastic Agents , Naphthyridines/chemical synthesis , Quinolones/chemical synthesis , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Humans , Immunologic Factors/chemical synthesis , Immunologic Factors/chemistry , Naphthyridines/chemistry , Quinazolines/chemistry , Quinazolines/pharmacology , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolones/chemistry , Structure-Activity Relationship
13.
Article in English | MEDLINE | ID: mdl-17936093

ABSTRACT

A simple, sensitive, specific and high-resolution reversed-phase liquid chromatographic method utilizing ultraviolet detection has been developed and validated for simultaneous determination of topotecan and four intestinal permeability markers (atenolol, antipyrine, propranolol and furosemide) as suggested by US-FDA. Chromatography was carried out on C-18 column with mobile phase comprising water (pH 3.0) and acetonitrile gradient pumped at a flow rate of 1 ml min(-1). The validation parameters included specificity, accuracy, precision, sensitivity and stability studies. Topotecan, an anti-cancer drug widely used in metastatic carcinoma, is a P-glycoprotein substrate having oral bioavailability of 30% with large inter-patient variability. The present method was successfully applied for demonstrating P-gp mediated transport of topotecan and its inhibition using verapamil in Caco-2 cell monolayer. The method can be used in identification of novel P-gp inhibitors for topotecan and estimating the contribution of P-gp in affecting oral bioavailability of topotecan. The other applications of method include its use in validation of Caco-2 monolayer assay for getting biowaiver based on Biopharmaceutic Classification System and its extrapolation to in situ and/or in vivo studies.


Subject(s)
Chromatography, High Pressure Liquid/methods , Intestinal Absorption/physiology , Topotecan/analysis , ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Antipyrine/analysis , Atenolol/analysis , Caco-2 Cells , Drug Stability , Furosemide/analysis , Humans , Permeability , Propranolol/analysis , Reproducibility of Results , Sensitivity and Specificity
14.
Bioorg Med Chem Lett ; 17(23): 6660-4, 2007 Dec 01.
Article in English | MEDLINE | ID: mdl-17950602

ABSTRACT

Several 1,8-naphthyridine-3-carboxamide derivatives (8-23) were synthesized and tested for in vitro cytotoxicity against eight cancer cell lines and a normal cell line. Compound 12 exhibited high cytotoxicity (IC(50)=1.37microM) in HBL-100 (breast) cell line while compounds 17 (IC(50)=3.7microM) and 22 (IC(50)=3.0microM) have shown high cytotoxicity in KB (oral) and SW-620 (colon) cell lines, respectively. The synthesized 1,8-naphthyridine-3-carboxamides were also evaluated for anti-inflammatory and myeloprotective activities, indicated by modulation in cytokine and chemokine levels secreted by dendritic cells.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Antineoplastic Agents/chemical synthesis , Inflammation Mediators/pharmacology , Naphthyridines/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor/methods , Humans , Inflammation Mediators/antagonists & inhibitors , K562 Cells , KB Cells , Mice , NIH 3T3 Cells , Naphthyridines/pharmacology
15.
J Pept Sci ; 13(8): 544-8, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17617800

ABSTRACT

Six analogs (peptides 1-6) of the potent substance P (SP) derivative known as 'Antagonist D' were synthesized by substituting constrained amino acids Aib or Acp (cycloleucine, 1-amino cyclopentane carboxylic acid) at different positions in the Antagonist D sequence: D-Arg(1)-Pro(2)-Lys(3)-Pro(4)-D-Phe(5)-Gln(6)-D-Trp(7)-Phe(8)-D-Trp(9)-Leu(10)-Leu(11)-NH(2). In the preliminary in vitro antiproliferative screening of the analogs on different human cancer cell lines by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, peptide 1 was found to be the most active. Further, peptide 1 was butanoylated (analog 5) or octanoylated (analog 6) at the N-terminus. SP analogs 1, 5, and 6 were evaluated in vivo in a xenograft model of human primary colon tumor (PTC) cell line in athymic nude mice and were found to cause tumor regression. This study investigates if the use of the constrained amino acids Aib and Acp in the designed SP analogs can retain the in vitro and in vivo anticancer activities, which could be useful in cancer therapy and drug targeting. Further, the strategy of incorporation of Aib or Acp in biologically active peptides can be exploited in determining the receptor-bound conformation and in transforming these bioactive peptides into pharmacologically useful drugs.


Subject(s)
Antineoplastic Agents/pharmacology , Colonic Neoplasms/drug therapy , Peptides/pharmacology , Substance P/pharmacology , Amino Acid Sequence , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Delivery Systems , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Peptides/chemical synthesis , Peptides/chemistry , Substance P/analogs & derivatives , Substance P/chemical synthesis , Substance P/chemistry , Xenograft Model Antitumor Assays
16.
J Pept Sci ; 13(7): 458-67, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17559067

ABSTRACT

A large 40-residue precursor peptide (propeptide 5) was synthesized by linking together four designed anticancer peptide analogs to the neuropeptides: vasoactive intestinal peptide, somatostatin, bombesin and substance P, using enzyme cleavable lysyl-lysine linkers. On incubation with the enzyme trypsin, propeptide 5 was cleaved in a sequence-specific manner at the lysyl-lysine residues in the linker to release the individual peptide fragments which were identified by LC-MS. Another precursor peptide (propeptide 5a), consisting of two of the peptide analogs linked through lysyl-lysine linker, was also preferentially cleaved at the Lys-Lys site on incubation with the enzyme trypsin. Propeptide 5 showed potent anticancer activity, both in vitro and in vivo, which was greater than that of the individual component peptides. The enhanced activity suggests that the propeptide is possibly cleaved in the biological system at the lysyl-lysine site to yield the individual peptide analogs, which together show a synergistic effect. On the basis of these experimental findings, it can be concluded that pairs of basic amino acids such as Lys-Lys can be used as facile linkers for delivering multiple biologically active peptides.


Subject(s)
Cell Proliferation/drug effects , Dipeptides/chemistry , Peptide Fragments/pharmacology , Prodrugs/pharmacology , Amino Acid Sequence , Animals , Bombesin/chemistry , Cell Line, Tumor , Chromatography, Liquid , Dose-Response Relationship, Drug , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Sequence Data , Peptide Fragments/chemical synthesis , Peptide Fragments/chemistry , Prodrugs/chemical synthesis , Prodrugs/chemistry , Somatostatin/chemistry , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Substance P/chemistry , Vasoactive Intestinal Peptide/chemistry , Xenograft Model Antitumor Assays
17.
J Med Chem ; 50(8): 1744-53, 2007 Apr 19.
Article in English | MEDLINE | ID: mdl-17373779

ABSTRACT

A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50<1 microg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.


Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis , Cyclopentanes/chemical synthesis , Stilbenes/chemical synthesis , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cyclopentanes/pharmacokinetics , Cyclopentanes/pharmacology , DNA Fragmentation , Drug Screening Assays, Antitumor , Endothelial Cells/drug effects , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Solubility , Stilbenes/pharmacokinetics , Stilbenes/pharmacology , Structure-Activity Relationship , Transplantation, Heterologous , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacokinetics , Tubulin Modulators/pharmacology
18.
Appl Radiat Isot ; 65(4): 382-6, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17194598

ABSTRACT

Vasoactive intestinal peptide (VIP) receptors are expressed abundantly on many types of tumors and, hence, radiolabeled VIP analogues are being explored for tumor imaging and therapy. Here, we report synthesis of three VIP analogues and their radiolabeling with (99m)Tc via a novel tricarbonyl synthon. The radiolabeled product could be prepared in high yields (>95%) and stability. In vitro studies showed significant uptake of (99m)Tc(CO)((3))-VP05 in human colon carcinoma cells. Biodistribution studies in animal tumor model showed 0.4-1%ID/g tumor uptake.


Subject(s)
Colonic Neoplasms/diagnostic imaging , Organotechnetium Compounds/chemical synthesis , Vasoactive Intestinal Peptide/analogs & derivatives , Amino Acid Sequence , Animals , Humans , Isotope Labeling , Mice , Organotechnetium Compounds/pharmacokinetics , Radionuclide Imaging , Vasoactive Intestinal Peptide/chemical synthesis , Vasoactive Intestinal Peptide/pharmacokinetics
19.
J Pept Sci ; 13(1): 54-62, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17031871

ABSTRACT

Six octapeptide bombesin (BN) analogs were synthesized by substituting alpha-aminoisobutyric acid (Aib), in place of Ala9 or Gly11, or both, in the [D-Phe6, desMet14]-BN (6-14) sequence: D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Leu13-NH2 (P0). Additionally, Leu13 was replaced with isoleucine in two analogs and one of the analogs was butanoylated at the N-terminus. The antiproliferative activity of the analogs was tested in vitro on human pancreatic (MiaPaCa-2) and colon cancer (SW620, HT29 and PTC) cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The analogs demonstrated anticancer activity in the above cell lines at concentrations ranging from 0.01 nM to 1 microM. One of the analogs, P6, was evaluated for in vivo tumor regression in a xenograft model of human primary colon cancer in athymic nude mice and was found to cause significant reduction in tumor volume. NMR and molecular dynamics (MD) simulation studies for this analog revealed the presence of a mixed 3(10)/alpha-helical structure. This study demonstrates that the designed BN analogs retain their anticancer activity after the incorporation of the constrained amino acid, Aib, and are potential molecules for future use in cancer therapy and drug targeting.


Subject(s)
Aminoisobutyric Acids/chemistry , Antineoplastic Agents/pharmacology , Bombesin/pharmacology , Cell Proliferation/drug effects , Amino Acid Sequence , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Bombesin/analogs & derivatives , Bombesin/chemical synthesis , Cell Line, Tumor , Dose-Response Relationship, Drug , HT29 Cells , Humans , Magnetic Resonance Spectroscopy , Mice , Mice, Inbred BALB C , Mice, Nude , Models, Molecular , Molecular Structure , Structure-Activity Relationship , Thermodynamics , Xenograft Model Antitumor Assays/methods
20.
J Pharm Biomed Anal ; 43(4): 1228-35, 2007 Mar 12.
Article in English | MEDLINE | ID: mdl-17126518

ABSTRACT

The degradation of docetaxel drug substance and its injection formulation has been investigated. The majority of impurities were observed in a base degradation study and all five degradation products were characterized. These impurities were isolated, enriched and were subjected to mass and NMR spectral studies. Based on the spectral data, these were characterized as 10-deacetyl baccatin III, 7-epi-10-deacetyl baccatin III, 7-epi-10-oxo-10-deacetyl baccatin III, 7-epi docetaxel and 7-epi-10-oxo-docetaxel, respectively. The last two impurities were also detected in the stability study of docetaxel formulation. Out of these degradation impurities two substances have been previously identified while the other three previously unreported.


Subject(s)
Antineoplastic Agents/analysis , Taxoids/analysis , Antineoplastic Agents/chemistry , Chromatography, High Pressure Liquid , Docetaxel , Drug Contamination , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Taxoids/chemistry
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