Publications by authors named "Ketul Patel"

17 Publications

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A prospective longitudinal study to evaluate bone health, implication of FRAX tool and impact on quality of life (FACT-P) in advanced prostate cancer patients.

Am J Clin Exp Urol 2021 15;9(3):211-220. Epub 2021 Jun 15.

King George's Medical University Lucknow, India.

Background: Androgen-deprivation therapy (ADT) as a treatment modality in advanced prostate cancer has deleterious effect on bone mineral density (BMD) and quality of life (QOL). Using FRAX (Fracture Risk Assessment) model, candidates at high risk of fractures can be predicted and appropriate treatment can be initiated at early step to prevent skeletal-related events. Objectives of the present study were to evaluate bone health, implication of FRAX tool in advanced prostate cancer and to see the impact of ADT and Bone-directed therapy (BDT) on FRAX and FACT-P QOL scores.

Material & Method: We conducted a prospective longitudinal study of 83 localized and metastatic prostate cancer patients from March 2017 to Dec 2020. FRAX tool using BMD femoral neck (GE-Lunar) was used to compute the probability of 10-year Major osteoporotic fracture (MOF) and hip fracture risk %. Patients who received monthly Zolendronic acid with or without Vitamin-D/calcium supplementation were classified as BDT group. FRAX and FACT-P were measured at baseline and 12 months follow-up and compared between different therapeutic modalities to see the impact on clinical outcomes.

Results: Majority of patients had skeletal metastasis (78.3%) and high-grade disease at presentation. Secondary osteoporosis was the most commonly (82.05%) observed clinical risk factor (CRF) followed by smoking (19.23%). Hip fracture risk ≥3% accounted for larger proportion of patients than did MOF risk ≥20% (21.2% and 2.5%, respectively). Statistically significant reduction was observed in both MOF and hip fracture risk in BDT group, while worsening on ADT. ADT duration correlated positively with both MOF and hip fracture risk (R=0.148, P<0.001 and R=0.164, P<0.001, respectively). FRAX score accurately predict future fracture events in majority (80%) of high-risk patients. Statistically and clinically significant worsening in PWB, EWB, PCS, FACT-P Total, FACT-P TOI and FAPSI scores were observed in patients on ADT. Statistically and clinically significant improvement was noted in physical well-being in BDT group. However, other QOL domains and FACT-P total scores remained stable.

Conclusions: ADT caused duration depended worsening of FRAX and FACT-P score in these patients while improvements of FRAX were seen on BDT. FRAX tool is advantageous in identifying the patients who require early intervention or therapy to decrease skeletal-related events.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303024PMC
June 2021

Possible competitive modes of decarboxylation in the annulation reactions of ortho-substituted anilines and arylglyoxylates.

Org Biomol Chem 2021 01 6;19(4):845-853. Epub 2021 Jan 6.

Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education and Research, S. A. S. Nagar, Punjab 160062, India.

Annulation reactions of ortho-substituted anilines and arylglyoxylates in the presence of KSO at 80 °C under metal-free neutral conditions have been investigated, which extended a platform for the tandem synthesis of nitrogen heterocycles. While arylglyoxylic acids are known to undergo decarboxylation to form an acyl radical in the presence of KSO and used in the Minisci acylation of electron-deficient (hetero)aromatics, their reactions with electron-rich ortho-substituted anilines to form nitrogen heterocycles have recently been studied. Depending upon the experimental conditions used in the reactions, the mechanism of the formation of heterocycles involving reactions of an acyl radical or aryl iminocarboxylic acids has been postulated. Given the subtle understanding of the mechanisms of annulation reactions of 2-substituted anilines and arylglyoxylates in the presence of KSO, an extensive mechanistic investigation was undertaken. In the current study, the various mechanistic pathways including the generation of acyl, imidoyl, aminal, and N,O-hemiketal radicals have been postulated based on different possible decarboxylation modes. Some of the proposed intermediates are supported based on the available analytical data. The protocol uses a single, inexpensive reagent KSO, which offers not only transition-metal-free conditions but also serves as the reagent for the key decarboxylation step. Taken together, this study complements the current development of the annulation reactions of 2-substituted anilines and arylglyoxylates in terms of synthesis and mechanistic understanding.
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http://dx.doi.org/10.1039/d0ob00360cDOI Listing
January 2021

Identification and structure-activity relationship studies of small molecule inhibitors of the human cathepsin D.

Bioorg Med Chem 2021 01 21;29:115879. Epub 2020 Nov 21.

Aten Porus Lifesciences, Bangalore 560068, India; Avaliv Therapeutics, Naples, FL, USA. Electronic address:

Cathepsin D, an aspartyl protease, is an attractive therapeutic target for various diseases, primarily cancer and osteoarthritis. However, despite several small molecule cathepsin D inhibitors being developed, that are highly potent, most of them show poor microsomal stability, which in turn limits their clinical translation. Herein, we describe the design, optimization and evaluation of a series of novel non-peptidic acylguanidine based small molecule inhibitors of cathepsin D. Optimization of our hit compound 1a (IC = 29 nM) led to the highly potent mono sulphonamide analogue 4b (IC = 4 nM), however with poor microsomal stability (HLM: 177 and MLM: 177 μl/min/mg). To further improve the microsomal stability while retaining the potency, we carried out an extensive structure-activity relationship screen which led to the identification of our optimised lead 24e (IC = 45 nM), with an improved microsomal stability (HLM: 59.1 and MLM: 86.8 μl/min/mg). Our efforts reveal that 24e could be a good starting point or potential candidate for further preclinical studies against diseases where Cathepsin D plays an important role.
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http://dx.doi.org/10.1016/j.bmc.2020.115879DOI Listing
January 2021

Palladium-Catalyzed Serendipitous Synthesis of Arylglyoxylic Amides from Arylglyoxylates and ,-Dialkylamides in the Presence of Halopyridines.

ACS Omega 2018 Aug 8;3(8):8787-8793. Epub 2018 Aug 8.

Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education and Research, S. A. S. Nagar, Mohali, Punjab 160062, India.

A palladium-catalyzed synthesis of arylglyoxylic amides by the reaction of arylglyoxylates and ,-dialkylamides in the presence of a 2,3-dihalopyridine has been realized for the first time. An anticipated 2,3-diaroylpyridine did not form in this reaction. The current study unveils an unprecedented role of 2,3-dihalopyridine toward this amidation. Our mechanistic study reveals that the arylglyoxylate could react with halopyridine to form a traceless activated pyridyl ester of arylglyoxylic acid, which upon subsequent reaction with amino surrogate, ,-dialkylamides could form the arylglyoxylic amides.
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http://dx.doi.org/10.1021/acsomega.8b00894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6645305PMC
August 2018

Homoarginine Supplementation Prevents Left Ventricular Dilatation and Preserves Systolic Function in a Model of Coronary Artery Disease.

J Am Heart Assoc 2019 07 15;8(14):e012486. Epub 2019 Jul 15.

2 Department of Biomedical Sciences New York Institute of Technology College of Osteopathic Medicine Old Westbury NY.

Background Homoarginine ( hA rg) has been shown to be cardioprotective in a model of ischemic heart failure; however, the mechanism remains unknown. hA rg can inhibit tissue-nonspecific alkaline phosphatase ( TNAP ), an enzyme that promotes vascular calcification. We hypothesized that hA rg will exert beneficial effects by reducing calcification in a mouse model of coronary artery disease associated with TNAP overexpression and hypercholesterolemia. Methods and Results TNAP was overexpressed in the endothelium in mice homozygous for a low-density lipoprotein receptor mutation (wicked high cholesterol [ WHC ] allele). WHC and WHC -endothelial TNAP mice received placebo or hA rg supplementation (14 mg/L in drinking water) starting at 6 weeks of age simultaneously with an atherogenic diet. Outcomes were compared between the groups after 4 to 5 weeks on treatment. Experiments were performed in males, which presented a study limitation. As expected, WHC -endothelial TNAP mice on the placebo had increased mortality (median survival 27 days, P<0.0001), increased coronary calcium and lipids ( P<0.01), increased left ventricular end-diastolic diameter ( P<0.0001), reduced ejection fraction ( P<0.05), and increased myocardial fibrosis ( P<0.0001) compared with WHC mice. Contrary to our hypothesis, hA rg neither inhibited TNAP activity in vivo nor reduced coronary artery calcification and atherosclerosis in WHC -endothelial TNAP mice; however, compared with the placebo, hA rg prevented left ventricular dilatation ( P<0.01), preserved ejection fraction ( P<0.05), and reduced myocardial fibrosis ( P<0.001). Conclusions The beneficial effect of hA rg supplementation in the setting of calcified coronary artery disease is likely due to its direct protective actions on the myocardial response to the ischemic injury and not to the inhibition of TNAP activity and calcification.
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http://dx.doi.org/10.1161/JAHA.119.012486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662144PMC
July 2019

Palladium-Catalyzed Decarboxylative Ortho-Acylation of Tertiary Benzamides with Arylglyoxylic Acids.

ACS Omega 2017 Jul 21;2(7):3806-3815. Epub 2017 Jul 21.

Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab 160062, India.

A palladium-catalyzed ortho-acylation of tertiary benzamides using arylglyoxylic acids has been described. Unlike the palladium insertion reported to occur in the distorted N-C(O) amide bond of tertiary benzamides, the current study unveils ortho C-H palladation in acylic or cyclic ,-dialkylbenzamides affording ortho-acylated tertiary benzamides in good to excellent yields. Our experimental study on the mechanism provides information on the tendency of the amide nitrogen toward weak coordination with palladium as opposed to oxygen. However, density functional theory calculations suggest coordination of amide oxygen to palladium, which makes the mechanism especially interesting. A Pd(II)/Pd(III) catalytic cycle and nucleophilic attack by the acyl radical rather than arylglyoxylate anion are supported by mechanistic studies.
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http://dx.doi.org/10.1021/acsomega.7b00717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6641690PMC
July 2017

EUS-guided fine-needle core liver biopsy sampling using a novel 19-gauge needle with modified 1-pass, 1 actuation wet suction technique.

Gastrointest Endosc 2018 02 24;87(2):469-475. Epub 2017 May 24.

Department of Surgery, University of California at Los Angeles, Los Angeles, California, USA; Department of Medicine, University of California at Los Angeles, Los Angeles, California, USA.

Background And Aims: EUS-guided fine-needle core biopsy sampling is a safe and effective technique for diagnosis of focal liver lesions. However, data are limited in its role in parenchymal disease. We evaluated the utility of EUS-guided parenchymal liver biopsy sampling with a modified 1-pass wet suction technique (EUS-modified liver biopsy sampling [EUS-MLB]) in patients with unexplained increase in liver-associated tests.

Methods: We retrospectively evaluated the safety and efficacy of EUS-MLB in patients referred for EUS to evaluate for biliary obstruction and pancreatic disorders but with associated unexplained liver tests. EUS-MLB was performed during the same session after biliary obstruction was excluded.

Results: One hundred sixty-five consecutive patients underwent EUS-MLB. The median age was 52 years (interquartile range [IQR], 42-65). Sixty-eight patients (41%) were men. The median of the maximum intact core tissue length was 2.4 cm (IQR, 1.8-3.5). The median total specimen length (TSL) was 6 cm (IQR, 4.3-8). The median number of complete portal tracts (CPTs) per TSL was 18 (IQR, 13- 24). The mean number of CPTs per sample length was 7.5 cm. Adverse events were uncommon (1.8%) and included abdominal pain and self-limited hematoma.

Conclusions: EUS-guided fine-needle biopsy sampling using a novel 19-gauge core needle with a modified 1-pass 1 actuation wet suction technique (EUS-MLB) is a safe and effective way to evaluate patients with unexplained liver tests abnormalities who are undergoing EUS for exclusion of biliary obstruction.
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http://dx.doi.org/10.1016/j.gie.2017.05.013DOI Listing
February 2018

Endoscopic Ultrasound Liver Biopsies Accurately Predict the Presence of Fibrosis in Patients With Fatty liver.

Clin Gastroenterol Hepatol 2017 09 15;15(9):1477-1478. Epub 2017 Apr 15.

Department of Medicine, University of California at Los Angeles, Los Angeles, California; Baptist Medical Center, Jacksonville, Florida.

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http://dx.doi.org/10.1016/j.cgh.2017.04.017DOI Listing
September 2017

Intramolecular Minisci acylation under silver-free neutral conditions for the synthesis of azafluorenones and fluorenones.

Org Biomol Chem 2017 Mar;15(10):2199-2210

Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education and Research, S. A. S. Nagar, Punjab 160062, India.

Despite its synthetic potential, intramolecular acylation by the Minisci reaction remains unexplored. The development of a new intramolecular Minisci acylation under silver-free neutral conditions providing access to azafluorenones and fluorenones is described. Distinct from the current literature known approaches for Minisci acylation, the report described herein features a method that: (a) avoids the use of silver that is invariably used in Minisci acylation, (b) does not require any acidic conditions for the activation of pyridines, and
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http://dx.doi.org/10.1039/c7ob00077dDOI Listing
March 2017

Intramolecular Acylation of Unactivated Pyridines or Arenes via Multiple C-H Functionalizations: Synthesis of All Four Azafluorenones and Fluorenones.

J Org Chem 2017 01 14;82(1):76-85. Epub 2016 Dec 14.

Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education and Research Sahibzada Ajit Singh Nagar, Punjab 160062, India.

An unprecedented intramolecular acylation of unactivated pyridines via multiple C(sp/sp)-H functionalizations of a methyl, hydroxymethyl, or aldehyde group has been developed providing a general access to all four azafluorenones. The application of this protocol is further demonstrated to the synthesis of azafluorenone related fused nitrogen heterocycles and fluorenones. In addition, design and synthesis of a novel fluorene based organic emitter for potential use in organic light emitting devices (OLEDs) is also reported.
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http://dx.doi.org/10.1021/acs.joc.6b02065DOI Listing
January 2017

Formation of amides, their intramolecular reactions for the synthesis of N-heterocycles, and preparation of a marketed drug, sildenafil: a comprehensive coverage.

Chem Commun (Camb) 2016 Aug;52(67):10245-8

Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education and Research, S. A. S. Nagar, Punjab 160062, India.

A unified approach to the tandem preparation of diverse nitrogen heterocycles via decarboxylative acylation of ortho-substituted amines with α-oxocarboxylic acids and subsequent intramolecular cyclizations has been developed. The key features of this work include: the first example of transition-metal-free decarboxylative amidation of α-oxocarboxylic acids with ortho-substituted amines, realization of intramolecular cyclization of amides employing nucleophiles that have previously been unexplored, mechanistic investigation of an unprecedented K2S2O8 promoted amide formation and its subsequent intramolecular cyclizations, and application to the synthesis of a best-selling marketed drug.
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http://dx.doi.org/10.1039/c6cc04259gDOI Listing
August 2016

Palladium-catalyzed regiocontrolled domino synthesis of N-sulfonyl dihydrophenanthridines and dihydrodibenzo[c,e]azepines: control over the formation of biaryl sultams in the intramolecular direct arylation.

J Org Chem 2014 Nov 4;79(22):10899-907. Epub 2014 Nov 4.

Department of Pharmaceutical Technology (Process Chemistry), National Institute of Pharmaceutical Education and Research , S. A. S. Nagar, Punjab 160062, India.

A palladium-catalyzed domino N-benzylation/intramolecular direct arylation involving sulfonanilides and 2-bromobenzyl bromides has been developed for the first time, providing a workable access to N-sulfonyl dihydrophenanthridines in good to excellent yields. Under the optimized conditions, the formation of 5,6-dihydrophenanthridines was largely controlled over the formation of biaryl sultams containing a seven member ring. The optimized condition was found extendable to the regiocontrolled domino formation of N-sulfonyl-6,7-dihydro-5H-dibenzo[c,e]azepines over the biaryl sultam formation. Using an appropriate substrate, a biaryl sultam has been obtained exclusively.
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http://dx.doi.org/10.1021/jo501910qDOI Listing
November 2014

Metachronous bilateral segmental testicular infarction: multi-parametric ultrasound imaging with grey-scale ultrasound, Doppler ultrasound, contrast-enhanced ultrasound (CEUS) and real-time tissue elastography (RTE).

J Ultrasound 2014 Sep 31;17(3):233-8. Epub 2014 May 31.

Department of Radiology, King's College Hospital, King's College London, Denmark Hill, London, SE5 9RS UK.

Segmental testicular infarction is a rare cause of acute scrotal pain. The appearances on grey-scale sonography are often indistinguishable from that of a testicular tumour, resulting in unnecessary orchiectomy. We report a case of acute bilateral testicular infarction, of unknown etiology, which was conservatively managed to resolution following a confident diagnosis achieved with the aid of contrast-enhanced ultrasound (CEUS) and real-time tissue elastography (RTE) along with conventional grey-scale and Doppler sonography. The evolving appearances on each of the sonographic modalities are described. We discuss the importance of complementing conventional sonography with CEUS and RTE in order to make a confident diagnosis and avoid unnecessary surgical intervention.
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http://dx.doi.org/10.1007/s40477-014-0098-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4142130PMC
September 2014

Transient auditory dysfunction: a description and study of prevalence.

Ear Nose Throat J 2013 Aug;92(8):352-6

Department of Otolaryngology, University Hospital Coventry and Warwickshire, Clifford Bridge Rd., Binley, Coventry, CV2 2DX UK.

Transient auditory dysfunction (TAD) is a previously undescribed symptom complex of unknown cause. It is characterized by short-lasting sensorineural hearing loss (unilateral or bilateral), it is associated with tinnitus, it resolves completely within minutes, and it is not accompanied by vestibular symptoms. We conducted a cross-sectional prospective study to define TAD, find its prevalence, and discuss its significance. Two hundred healthy subjects between the ages of 16 and 49 years were surveyed using a questionnaire. Of these subjects, 41 (20.5%) reported experiencing symptoms of TAD. The mean number of episodes was 5.9 times per month, the mean duration was 41 seconds, and 80% experienced concomitant tinnitus. We conclude that TAD is a common finding in a healthy population. This may have implications for the pathogenesis of sudden-onset sensorineural hearing loss. Further longitudinal studies and detailed audiologic evaluation of patients with TAD are required to ascertain the significance, etiology, and pathophysiology of this condition.
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http://dx.doi.org/10.1177/014556131309200809DOI Listing
August 2013

Formulation of niosomal gel for enhanced transdermal lopinavir delivery and its comparative evaluation with ethosomal gel.

AAPS PharmSciTech 2012 Dec 27;13(4):1502-10. Epub 2012 Oct 27.

Centre for Research in Pharmaceutical Sciences, The M.S. University of Baroda, Shri G.H. Patel Pharmacy Building, Vadodara, 390002, India.

The aim was to develop niosomal gel as a transdermal nanocarrier for improved systemic availability of lopinavir. Niosomes were prepared using thin-film hydration method and optimized for molar quantities of Span 40 and cholesterol to impart desirable characteristics. Comparative evaluation with ethosomes was performed using ex vivo skin permeation, fluorescence microscopy, and histopathology studies. Clinical utility via transdermal route was acknowledged using in vivo bioavailability study in male Wistar rats. The niosomal formulation containing lopinavir, Span 40, and cholesterol in a molar ratio of 1:0.9:0.6 possessed optimally high percentage of drug entrapment with minimum mean vesicular diameter. Ex vivo skin permeation studies of lopinavir as well as fluorescent probe coumarin revealed a better deposition of ethosomal carriers but a better release with niosomal carriers. Histopathological studies indicated the better safety profile of niosomes over ethosomes. In vivo bioavailability study in male Wistar rats showed a significantly higher extent of absorption (AUC(0→∞), 72.87 h × μg/ml) of lopinavir via transdermally applied niosomal gel as compared with its oral suspension. Taken together, these findings suggested that niosomal gel holds a great potential of being utilized as novel, nanosized drug delivery vehicle for transdermal lopinavir delivery.
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http://dx.doi.org/10.1208/s12249-012-9871-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513445PMC
December 2012

Features of testicular epidermoid cysts on contrast-enhanced sonography and real-time tissue elastography.

J Ultrasound Med 2012 Jan;31(1):115-22

Department of Radiology, King's College London, King's College Hospital, London, England.

A series of 7 testicular epidermoid cysts were imaged by contrast-enhanced sonography to assess internal vascularity and by real-time tissue elastography to grade stiffness by a visual and strain ratio quantification scoring system. No internal vascular enhancement was seen on contrast-enhanced sonography; the 3 largest lesions showed rim enhancement. On the real-time elastographic color display, all lesions were predominantly blue ("hard"), and the lesions analyzed for the strain ratio had a mean value of 43.57. Contrast-enhanced sonography depicts the absence of vascular flow, and real-time elastography shows that the epidermoid cysts are hard. This combination of information will help further characterize these lesions.
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http://dx.doi.org/10.7863/jum.2012.31.1.115DOI Listing
January 2012

Vincristine-sulphate-loaded liposome-templated calcium phosphate nanoshell as potential tumor-targeting delivery system.

J Liposome Res 2012 Jun 8;22(2):139-47. Epub 2011 Dec 8.

Center for Post Graduate Studies and Research in Pharmaceutical Sciences, The Maharaja Sayajirao University of Baroda, Vadodara, India.

Vincristine-sulfate-loaded liposomes were prepared with an aim to improve stability, reduce drug leakage during systemic circulation, and increase intracellular uptake. Liposomes were prepared by the thin-film hydration method, followed by coating with calcium phosphate, using the sequential addition approach. Prepared formulations were characterized for size, zeta potential, drug-entrapment efficiency, morphology by transmission electron microscopy (TEM), in vitro drug-release profile, and in vitro cell cytotoxicity study. Effect of formulation variables, such as drug:lipid ratio as well as nature and volume of hydration media, were found to affect drug entrapment, and the concentration of calcium chloride in coating was found to affect size and coating efficiency. Size, zeta potential, and TEM images confirmed that the liposomes were effectively coated with calcium phosphate. The calcium phosphate nanoshell exhibited pH-dependent drug release, showing significantly lower release at pH 7.4, compared to the release at pH 4.5, which is the pH of the tumor interstitium. The in vitro cytotoxicity study done on the lung cancer cell line indicated that coated liposomes are more cytotoxic than plain liposomes and drug solution, indicating their potential for intracellular drug delivery. The cell-uptake study done on the lung cancer cell line indicated that calcium-phosphate-coated liposomes show higher cell uptake than uncoated liposomes.
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http://dx.doi.org/10.3109/08982104.2011.633266DOI Listing
June 2012
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