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1.
Guest-host Relationship of Cyclodextrin and its Pharmacological Benefits.
Alshati, F, Alahmed, TAA, Sami, F, Ali, MS, Majeed, S, Murtuja, S, Hasnain, MS, Ansari, MT
Current pharmaceutical design. 2023;(36):2853-2866
Abstract
Many methods, including solid dispersion, micellization, and inclusion complexes, have been employed to increase the solubility of potent drugs. Beta-cyclodextrin (βCD) is a cyclic oligosaccharide consisting of seven glucopyranoside molecules, and is a widely used polymer for formulating soluble inclusion complexes of hydrophobic drugs. The enzymatic activity of Glycosyltransferase or α-amylase converts starch or its derivatives into a mixture of cyclodextrins. The βCD units are characterized by α -(1-4) glucopyranose bonds. Cyclodextrins possess certain properties that make them very distinctive because of their toroidal or truncated cage-like supramolecular configurations with multiple hydroxyl groups at each end. This allowed them to encapsulate hydrophobic compounds by forming inclusion complexes without losing their solubility in water. Chemical modifications and newer derivatives, such as methylated βCD, more soluble hydroxyl propyl methyl βCD, and sodium salts of sulfobutylether-βCD, known as dexolve® or captisol®, have envisaged the use of CDs in various pharmaceutical, medical, and cosmetic industries. The successful inclusion of drug complexes has demonstrated improved solubility, bioavailability, drug resistance reduction, targeting, and penetration across skin and brain tissues. This review encompasses the current applications of β-CDs in improving the disease outcomes of antimicrobials and antifungals as well as anticancer and anti-tubercular drugs.
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Targeting the Ubiquitin-Proteasome System Using the UBA1 Inhibitor TAK-243 is a Potential Therapeutic Strategy for Small-Cell Lung Cancer.
Majeed, S, Aparnathi, MK, Nixon, KCJ, Venkatasubramanian, V, Rahman, F, Song, L, Weiss, J, Barayan, R, Sugumar, V, Barghout, SH, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2022;(9):1966-1978
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Abstract
PURPOSE Small cell lung cancer (SCLC) is an aggressive disease with an overall 5-year survival rate of less than 10%. Treatment for SCLC with cisplatin/etoposide chemotherapy (C/E) ± radiotherapy has changed modestly over several decades. The ubiquitin-proteasome system is an underexplored therapeutic target for SCLC. We preclinically evaluated TAK-243, a first-in-class small molecule E1 inhibitor against UBA1. EXPERIMENTAL DESIGN We assessed TAK-243 in 26 SCLC cell-lines as monotherapy and combined with C/E, the PARP-inhibitor, olaparib, and with radiation using cell viability assays. We interrogated TAK-243 response with gene expression to identify candidate biomarkers. We evaluated TAK-243 alone and in combination with olaparib or radiotherapy with SCLC patient-derived xenografts (PDX). RESULTS Most SCLC cell lines were sensitive to TAK-243 monotherapy (EC50 median 15.8 nmol/L; range 10.2 nmol/L-367.3 nmol/L). TAK-243 sensitivity was associated with gene-sets involving the cell cycle, DNA and chromatin organization, and DNA damage repair, while resistance associated with cellular respiration, translation, and neurodevelopment. These associations were also observed in SCLC PDXs. TAK-243 synergized with C/E and olaparib in vitro across sensitive and resistant SCLC cell lines. Considerable TAK-243-olaparib synergy was observed in an SCLC PDX resistant to both drugs individually. TAK-243 radiosensitization was also observed in an SCLC PDX. CONCLUSIONS TAK-243 displays efficacy in SCLC preclinical models. Enrichment of gene sets is associated with TAK-243 sensitivity and resistance. TAK-243 exhibits synergy when combined with genotoxic therapies in cell lines and PDXs. TAK-243 is a potential therapeutic strategy to improve SCLC patient outcomes, both as a single agent and in combination with existing therapies.
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Role of Vitamin D Supplementation in Improving Cytokine Profile in Patients of Non-ST-Elevation Acute Coronary Syndrome.
Jabeen, S, Khan, HF, Ali, S, Siddique, AH, Majeed, S, Safder, S, Shamshad, F
Journal of nutritional science and vitaminology. 2022;(1):1-7
Abstract
Sub endothelial infarcts leads to non-ST-elevation acute coronary syndrome. Proinflammatory cytokines are raised in serum, the severity of which is a poor prognostic sign. Vitamin D deficiency is prevalent among patients of ACS. Vitamin D has immunomodulatory roles having effects on various aspects of inflammation. A total of 40 patients were divided into experimental (n=20) and control (n=20) groups. Experimental group was given single dose of vitamin D 200,000 IU. They were assessed for baseline C-reactive protein, interleukin-6, tumor necrosis factor-α levels by using sandwich ELISA technique. Four months after intervention resampling was done for the same parameters. Findings were expressed as mean±SD. Independent sample t-test was used to compare effect of vitamin D intervention between control group and intervention group. p-value of ≤0.05 was considered to be significant. The serum C-reactive protein showed significant reduction (p=0.028*) after intervention with vitamin D. Serum interleukin-6 (p=0.848), tumor necrosis factor-α (p=0.20) were decreased non-significantly in experimental as compared to the control group. It was concluded that a single large dose of vitamin D was able to reduce the C-reactive protein in non-ST-elevation acute coronary syndrome patients while non-significant reductions in interleukin-6 and tumor necrosis factor-α were observed.
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The science of resveratrol, formulation, pharmacokinetic barriers and its chemotherapeutic potential.
Robertson, I, Wai Hau, T, Sami, F, Sajid Ali, M, Badgujar, V, Murtuja, S, Saquib Hasnain, M, Khan, A, Majeed, S, Tahir Ansari, M
International journal of pharmaceutics. 2022;:121605
Abstract
Chemopreventive properties of resveratrol has been studied for decades. Despite its potential for chemotherapeutic advancement, the compound has pharmaceutical limitations, such as, the drug has a poor pharmacokinetic profile and low bioavailability. Studies have comforting results that that the nano-formulations may aid the future resveratrol drug development. Resveratrol can also be encapsulated as co-drug with an anticipation of gaining improved targeting and pharmacokinetic parameters, as well as achieving desired therapeutic plasma levels. It has been envisaged that the nanoformulations can also address the issue of drug accumulation, which may lead to hepatotoxicity. Nanoformulations can bring a major improvement in the bioavailability of resveratrol but still the formulation still suffers with pharmacokinetics issues clinically. This review encompasses the pharmacokinetics barriers associated with resveratrol and a possible suggestion to overcome those barriers for improving absorbance, reducing toxicity andimproving the drug releaseand encapsulation efficiency. The article also suggest that co-administration of resveratrol with chemotherapeutic drugsmust be tested in vivo on a wide range of cancers to avoid accidental proliferation exacerbation. The review's focusses on the resveratrol formulation and make suggestions for improvements in order to overcome the pharmacokinetic and toxicity issues.
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Lesser Investigated Natural Ingredients for the Management of Obesity.
Majeed, M, Majeed, S, Nagabhushanam, K, Gnanamani, M, Mundkur, L
Nutrients. 2021;(2)
Abstract
Obesity, an epidemiological disorder, is related to various complications in both the developed and developing world. It epitomizes a crucial risk factor for health, decreasing productivity and life expectancy while increasing health care costs worldwide. Conventional therapies with synthetic drugs or bariatric surgery, associated with numerous side effects, recurrence, and surgical complexity, have been restricted in their use. Lifestyle changes and dietary restrictions are the proven methods for successful weight loss, although maintaining a strict lifestyle is a challenge. Multiple natural products have been explored for weight management with varied efficacy. The current review explores less explored natural herbs, their active constituents, and their mechanisms of action against obesity.
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Lipid Membrane Mimetics in Functional and Structural Studies of Integral Membrane Proteins.
Majeed, S, Ahmad, AB, Sehar, U, Georgieva, ER
Membranes. 2021;(9)
Abstract
Integral membrane proteins (IMPs) fulfill important physiological functions by providing cell-environment, cell-cell and virus-host communication; nutrients intake; export of toxic compounds out of cells; and more. However, some IMPs have obliterated functions due to polypeptide mutations, modifications in membrane properties and/or other environmental factors-resulting in damaged binding to ligands and the adoption of non-physiological conformations that prevent the protein from returning to its physiological state. Thus, elucidating IMPs' mechanisms of function and malfunction at the molecular level is important for enhancing our understanding of cell and organism physiology. This understanding also helps pharmaceutical developments for restoring or inhibiting protein activity. To this end, in vitro studies provide invaluable information about IMPs' structure and the relation between structural dynamics and function. Typically, these studies are conducted on transferred from native membranes to membrane-mimicking nano-platforms (membrane mimetics) purified IMPs. Here, we review the most widely used membrane mimetics in structural and functional studies of IMPs. These membrane mimetics are detergents, liposomes, bicelles, nanodiscs/Lipodisqs, amphipols, and lipidic cubic phases. We also discuss the protocols for IMPs reconstitution in membrane mimetics as well as the applicability of these membrane mimetic-IMP complexes in studies via a variety of biochemical, biophysical, and structural biology techniques.
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A pilot, randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of a novel Boswellia serrata extract in the management of osteoarthritis of the knee.
Majeed, M, Majeed, S, Narayanan, NK, Nagabhushanam, K
Phytotherapy research : PTR. 2019;33(5):1457-1468
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Osteoarthritis (OA) is an age-related, degenerative joint disorder which affects many people worldwide. It causes pain, most frequently in the large joints such as knee and hips and is characterised by pain, decreased mobility and negative effects on the quality of life. This randomised, double-blind placebo controlled trial of 48 adults between the age of 35 and 75, aimed to evaluate the safety and efficacy of Boswellia serrata extract on newly diagnosed or untreated patients with OA of the knee. 340mg of Boswellia serrata extract was administered daily in 2 doses to the treatment group for 120 days. Outcome measures were WOMAC scores on pain, stiffness and physical function; a 6 min walk test assessing distance; physician assessment of range of motion, strength, stability and tenderness; x-ray images of joint space and growths; and hs-CRP, a blood marker of inflammation. The researchers found that the treatment group significantly improved, with reduced pain and stiffness compared to placebo. X-ray assessment also showed significantly improved knee join space and reductions in abnormal bone spur growth in the treatment group. Additionally, the treatment group had significantly lower hs-CRP compared to placebo. No adverse effects were reported. Whilst this is a small trial, Nutrition Practitioners working with patients with OA could consider the use of Boswellia serrata extract in their supplement protocols.
Abstract
A double-blind, placebo-controlled human trial was conducted to evaluate the safety and efficacy of a standardized oral supplementation of Boswellin®, a novel extract of Boswellia serrata extract (BSE) containing 3-acetyl-11-keto-β-boswellic acid (AKBBA) with β-boswellic acid (BBA). A total of 48 patients with osteoarthritis (OA) of the knee were randomized and allocated to the BSE and placebo groups for intervention. Patients were administered BSE or placebo for a period of 120 days. The trial results revealed that BSE treatment significantly improved the physical function of the patients by reducing pain and stiffness compared with placebo. Radiographic assessments showed improved knee joint gap and reduced osteophytes (spur) confirming the efficacy of BSE treatment. BSE also significantly reduced the serum levels of high-sensitive C-reactive protein, a potential inflammatory marker associated with OA of the knee. No serious adverse events were reported. This is the first study with BSE conducted for a period of 120 days, longer than any other previous clinical trial on patients with OA of the knee. The findings provide evidence that biologically active constituents of BSE, namely, AKBBA and BBA, act synergistically to exert anti-inflammatory/anti-arthritic activity showing improvement in physical and functional ability and reducing the pain and stiffness.
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Evaluation of the Safety and Efficacy of a Multienzyme Complex in Patients with Functional Dyspepsia: A Randomized, Double-Blind, Placebo-Controlled Study.
Majeed, M, Majeed, S, Nagabhushanam, K, Arumugam, S, Pande, A, Paschapur, M, Ali, F
Journal of medicinal food. 2018;(11):1120-1128
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Abstract
Functional dyspepsia (FD) is a highly prevalent disorder having nonspecific symptoms and varied pathophysiology. Its treatment remains a challenge as therapeutic options are limited, unsatisfactory, and elusive. Thus, safety and efficacy of DigeZyme®, a proprietary multienzyme complex (MEC), was evaluated as a dietary supplement in FD patients. In this randomized, double-blind, placebo-controlled, parallel-group study, 40 patients were randomly assigned (1:1 ratio) to receive either MEC (50 mg, TID; n = 20) or placebo (n = 20) for 60 days. Reports of adverse or serious adverse events (AEs), abnormal results of vital signs, abnormal findings during physical examination, and abnormal laboratory investigations were monitored closely. Efficacy measures were change in Short-Form Leeds Dyspepsia Questionnaire (SF-LDQ), Nepean Dyspepsia Index-Short Form (NDI-SF), Visual Analog Scale (VAS), Clinical Global Impression Severity Rating Scale (CGI-S), and Glasgow Dyspepsia Severity Score (GDSS) at baseline and follow-up visits on day 15, 30, and 60. Supplementation with MEC was associated with statistically significant differences (P value ranging from .0401 to .0033) in all efficacy parameters compared with placebo. The between-group comparison also revealed that MEC supplement had a significantly greater effect (P < .001) versus placebo. No investigation product-related AEs were reported. There were no clinically significant abnormalities in physical findings and no statistically significant changes in biochemical and hematological parameters, vital signs, body weight, and body mass index observed between the two groups at baseline and follow-up visits. MEC supplementation represents an effective and safe alternative to manage dyspepsia symptoms in FD patients.
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Bacillus coagulans MTCC 5856 for the management of major depression with irritable bowel syndrome: a randomised, double-blind, placebo controlled, multi-centre, pilot clinical study.
Majeed, M, Nagabhushanam, K, Arumugam, S, Majeed, S, Ali, F
Food & nutrition research. 2018;62
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Bacillus coagulans, also known as Lactobacillus sporogenes, is a probiotic bacterium in spore form that "opens up" in the small intestine, thereby enduring minimal damage by the acidity of the stomach pH. Bacillus coagulans MTCC 5856 supplemented orally in doses of 2 billion spores twice per day (a total of 4 billion per day) has been shown previously to help in the management of diarrhoea. The current study is randomised and controlled, and focused on finding out what effect this probiotic would have on the depressive symptoms often experienced by people with irritable bowel syndrome or IBS. A total of 40 participants were randomised to the probiotic group, which means that 20 of them just took an empty capsule without any Bacillus coagulans to figure out whether the effects of the supplementation were just due to chance or placebo. Neither the clinician administering the probiotic or the participants knew whether they were taking the probiotic or an empty capsule. The study lasted for 90 days. Those who did take the probiotic at 4 billion spores per day (2 billion morning and 2 billion evening) experienced an improvement in both depression and IBS symptoms that was statistically significant and clinically meaningful. Even though this was a small study, it is worth taking into account that the safety of supplementation with Bacillus coagulans has been documented in previous studies. Therefore, nutrition and lifestyle practitioners looking to support their patients' mental health by working upstream from the gut may wish to consider adding this probiotic bacterium to their recommendations on the basis of its potential psychobiotic properties.
Abstract
BACKGROUND The modification of microbial ecology in human gut by supplementing probiotics may be an alternative strategy to ameliorate or prevent depression. OBJECTIVE The current study was conducted to assess the safety and efficacy of the probiotic strain Bacillus coagulans MTCC 5856 for major depressive disorder (MDD) in IBS patients. METHOD Patients (n = 40) diagnosed for MDD with IBS were randomized (1:1) to receive placebo or B. coagulans MTCC 5856 at a daily dose of 2 × 109 cfu (2 billion spores) and were maintained to the end of double-blind treatment (90 days). Changes from baseline in clinical symptoms of MDD and IBS were evaluated through questionnaires. RESULTS Significant change (p = 0.01) in favour of the B. coagulans MTCC 5856 was observed for the primary efficacy measure Hamilton Rating Scale for Depression (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), Center for Epidemiological Studies Depression Scale (CES-D) and Irritable bowel syndrome quality of life questionnaire (IBS-QOL). Secondary efficacy measures i.e. Clinical Global Impression-Improvement rating Scale (CGI-I), Clinical Global Impression Severity rating Scale (CGI-S), Gastrointestinal Discomfort Questionnaire (GI-DQ) and Modified Epworth Sleepiness Scale (mESS) also showed significant results (p = 0.01) in B. coagulans MTCC 5856 group compared to placebo group except dementia total reaction scoring. Serum myeloperoxidase, an inflammatory biomarker was also significantly reduced (p < 0.01) when compared with the baseline and end of the study. All the safety parameters remained well within the normal clinical range and had no clinically significant difference between the screening and at the end of the study. CONCLUSION B. coagulans MTCC 5856 showed robust efficacy for the treatment of patients experiencing IBS symptoms with major depressive disorder. The improvement in depression and IBS symptoms was statistically significant and clinically meaningful. These findings support B. coagulans MTCC 5856 as an important new treatment option for major depressive disorder in IBS patients.
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Hope, Symptoms, and Palliative Care.
Davis, MP, Lagman, R, Parala, A, Patel, C, Sanford, T, Fielding, F, Brumbaugh, A, Gross, J, Rao, A, Majeed, S, et al
The American journal of hospice & palliative care. 2017;(3):223-232
Abstract
BACKGROUND Hope is important to patients with cancer. Identifying factors that influence hope is important. Anxiety, depression, fatigue, and pain are reported to impair hope. The objective of this study was to determine whether age, gender, marital status, duration of cancer, symptoms, or symptom burden measured by the sum of severity scores on the Edmonton Symptom Assessment Scale (ESAS) correlated with hope measured by the Herth Hope Index (HHI). METHODS Patients with advanced cancer in a palliative care unit participated. Demographics including age, gender, marital status, cancer site, and duration of cancer were collected. Individuals completed the ESAS and HHI. Spearman correlation and linear regression were used to assess associations adjusting for gender (male vs female), age (< 65 vs ≥ 65 years), marital status (married or living with a partner vs other), and duration of cancer (≤ 12 vs > 12 months). RESULTS One hundred and ninety-seven were participated in the study, of which 55% were female with a mean age of 61 years (standard deviation 11). Hope was not associated with gender, age, marital status, or duration of cancer. In univariable analysis, hope inversely correlated with ESAS score (-0.28), lack of appetite (-0.22), shortness of breath (-0.17), depression (-0.39), anxiety (-0.32), and lack of well-being (-0.33); only depression was clinically relevant. In multivariable analysis, total symptom burden weakly correlated with hope; only depression remained clinically significant. DISCUSSION This study found correlation between symptom burden and hope was not clinically relevant but was so for depression. CONCLUSION Among 9 ESAS symptoms, only depression had a clinically relevant correlation with hope.