Displaying publications 1 - 20 of 52 in total

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  1. Shahrir M, Shahdan M, Shahid M, Sulaiman W, Mokhtar AM, Othman M, et al.
    Int J Rheum Dis, 2008;11(3):287-292.
    DOI: 10.1111/j.1756-185X.2008.00379.x
    Aim: This is a rheumatoid arthritis (RA) descriptive study, the first of its kind carried out in Malaysia.
    Methods: This descriptive study involved 1084 RA patients' epidemiological and clinical data taken from Selayang, Putrajaya, Taiping and Seremban hospitals from June 2004 to December 2005.
    Results: One thousand and eighty-four RA patients'data were analysed; 960 (88.6%) patients were female and 124 (11.4%) were male, approximately 8 : 1 M : F ratio. The majority of the patients were Indian (591; 54.5%), followed by the Malays (340; 31.4%), Chinese (126; 11.6%), indigenous (13; 1.2%) and others (14; 1.3%). Mean age was 49.6 ± 11.8 years with the youngest being 15 years and the oldest 88 years of age. Mean age for males was 52.0 ± 12.0 and females 49.3 ± 11.7 years (P =; 0.017). Most of these patients were housewives (565; 52.1%), followed by paid workers (266; 24.5%), retired patients (80; 7.4%), unemployed (76; 7.0%) and others (97; 8.9%). Mean duration of illness was 8.4 ± 6.7 years; 805 (74.3%) patients were relatively new patients (≤ 2 years illness duration) and 279 (25.7%) patients had illness duration > 2 years. Eight hundred and six (74.4%) were seropositive RA patients and 385 (35.5%) had presence of deformity. The majority of patients were treated with methotrexate (178; 16.4%), followed by combination of methotrexate, sulfasalazine and hydroxychloroquine (143; 13.2%), leflunomide (140; 12.9%), sulfasalazine (133; 12.3%) and combination of methotrexate and sulfasalazine (108; 10%).
    Conclusion: In the above study, the majority of patients were female (960; 88.6%), Indian (591; 54.5%), had a mean age of 49.6 ± 11.8 years, most were housewives with a mean duration of illness of 8.4 ± 6.7 years and were treated with methotrexate (178; 16.4%). The results of the study may help Malaysian rheumaologists to understand their patients better and treat RA holistically.
    Comment in: Yeap SS. Comment on: Multicentre survey of rheumatoid arthritis patients from Ministry of Health rheumatology centres in Malaysia. Int J Rheum Dis. 2009 Jul;12(2):177-8; author reply 179. doi: 10.1111/j.1756-185X.2009.01403.x. PubMed PMID: 20374340.
  2. Hasan SS, Yong CS, Babar MG, Naing CM, Hameed A, Baig MR, et al.
    BMC Complement Altern Med, 2011 Oct 13;11:95.
    PMID: 21992582 DOI: 10.1186/1472-6882-11-95
    BACKGROUND: In recent times the basic understanding, perceptions and CAM use among undergraduate health sciences students have become a topic of interest. This study was aimed to investigate the understanding, perceptions and self-use of CAM among pharmacy students in Malaysia.

    METHODS: This cross-sectional study was conducted on 500 systematically sampled pharmacy students from two private and one public university. A validated, self-administered questionnaire comprised of seven sections was used to gather the data. A systematic sampling was applied to recruit the students. Both descriptive and inferential statistics were applied using SPSS® version 18.

    RESULTS: Overall, the students tend to disagree that complementary therapies (CM) are a threat to public health (mean score = 3.6) and agreed that CMs include ideas and methods from which conventional medicine could benefit (mean score = 4.7). More than half (57.8%) of the participants were currently using CAM while 77.6% had used it previously. Among the current CAM modalities used by the students, CM (21.9%) was found to be the most frequently used CAM followed by Traditional Chinese Medicine (TCM) (21%). Most of the students (74.8%) believed that lack of scientific evidence is one of the most important barriers obstructing them to use CAM. More than half of the students perceived TCM (62.8%) and music therapy (53.8%) to be effective. Majority of them (69.3%) asserted that CAM knowledge is necessary to be a well-rounded professional.

    CONCLUSIONS: This study reveals a high-percentage of pharmacy students who were using or had previously used at least one type of CAM. Students of higher professional years tend to agree that CMs include ideas and methods from which conventional medicine could benefit.

  3. Duong M, Islam S, Rangarajan S, Teo K, O'Byrne PM, Schünemann HJ, et al.
    Lancet Respir Med, 2013 Oct;1(8):599-609.
    PMID: 24461663 DOI: 10.1016/S2213-2600(13)70164-4
    BACKGROUND: Despite the rising burden of chronic respiratory diseases, global data for lung function are not available. We investigated global variation in lung function in healthy populations by region to establish whether regional factors contribute to lung function.

    METHODS: In an international, community-based prospective study, we enrolled individuals from communities in 17 countries between Jan 1, 2005, and Dec 31, 2009 (except for in Karnataka, India, where enrolment began on Jan 1, 2003). Trained local staff obtained data from participants with interview-based questionnaires, measured weight and height, and recorded forced expiratory volume in 1 s (FEV₁) and forced vital capacity (FVC). We analysed data from participants 130-190 cm tall and aged 34-80 years who had a 5 pack-year smoking history or less, who were not affected by specified disorders and were not pregnant, and for whom we had at least two FEV₁ and FVC measurements that did not vary by more than 200 mL. We divided the countries into seven socioeconomic and geographical regions: south Asia (India, Bangladesh, and Pakistan), east Asia (China), southeast Asia (Malaysia), sub-Saharan Africa (South Africa and Zimbabwe), South America (Argentina, Brazil, Colombia, and Chile), the Middle East (Iran, United Arab Emirates, and Turkey), and North America or Europe (Canada, Sweden, and Poland). Data were analysed with non-linear regression to model height, age, sex, and region.

    FINDINGS: 153,996 individuals were enrolled from 628 communities. Data from 38,517 asymptomatic, healthy non-smokers (25,614 women; 12,903 men) were analysed. For all regions, lung function increased with height non-linearly, decreased with age, and was proportionately higher in men than women. The quantitative effect of height, age, and sex on lung function differed by region. Compared with North America or Europe, FEV1 adjusted for height, age, and sex was 31·3% (95% CI 30·8-31·8%) lower in south Asia, 24·2% (23·5-24·9%) lower in southeast Asia, 12·8% (12·4-13·4%) lower in east Asia, 20·9% (19·9-22·0%) lower in sub-Saharan Africa, 5·7% (5·1-6·4%) lower in South America, and 11·2% (10·6-11·8%) lower in the Middle East. We recorded similar but larger differences in FVC. The differences were not accounted for by variation in weight, urban versus rural location, and education level between regions.

    INTERPRETATION: Lung function differs substantially between regions of the world. These large differences are not explained by factors investigated in this study; the contribution of socioeconomic, genetic, and environmental factors and their interactions with lung function and lung health need further clarification.

    FUNDING: Full funding sources listed at end of the paper (see Acknowledgments).

  4. Rizwan K, Zubair M, Rasool N, Ali S, Zahoor AF, Rana UA, et al.
    Chem Cent J, 2014;8:74.
    PMID: 25685184 DOI: 10.1186/s13065-014-0074-z
    It is seen that the regioselective functionalizations of halogenated heterocycles play an important role in the synthesis of several types of organic compounds. In this domain, the Suzuki-Miyaura reaction has emerged as a convenient way to build carbon-carbon bonds in synthesizing organic compounds. Some of the most important applications of these reactions can be seen in the synthesis of natural products, and in designing targeted pharmaceutical compounds. Herein, we present the regioselective synthesis of the novel series of 2-(bromomethyl)-5-aryl-thiophenes 3a-i, via Suzuki cross-coupling reactions of various aryl boronic acids with 2-bromo-5-(bromomethyl)thiophene (2).
  5. Ikhsan NI, Rameshkumar P, Pandikumar A, Mehmood Shahid M, Huang NM, Vijay Kumar S, et al.
    Talanta, 2015 Nov 1;144:908-14.
    PMID: 26452907 DOI: 10.1016/j.talanta.2015.07.050
    In this report, silver nanoparticles (Ag NPs) were successfully deposited on graphene oxide (GO) sheets to form GO-Ag nanocomposite using garlic extract and sunlight and the nanocomposite modified glassy carbon (GC) electrode was applied as an electrochemical sensor for the detection of nitrite ions. The formation of GO-Ag nanocomposite was confirmed by using UV-visible absorption spectroscopy, TEM, XRD and FTIR spectroscopy analyses. Further, TEM pictures showed a uniform distribution Ag on GO sheets with an average size of 19 nm. The nanocomposite modified electrode produced synergistic catalytic current in nitrite oxidation with a negative shift in overpotential. The limit of detection (LOD) values were found as 2.1 µM and 37 nM, respectively using linear sweep voltammetry (LSV) and amperometric i-t curve techniques. The proposed sensor was stable, reproducible, sensitive and selective toward the detection nitrite and could be applied for the detection of nitrite in real water sample.
  6. Othman AS, Marin-Mogollon C, Salman AM, Franke-Fayard BM, Janse CJ, Khan SM
    Expert Rev Vaccines, 2017 Jul;16(7):1-13.
    PMID: 28525963 DOI: 10.1080/14760584.2017.1333426
    INTRODUCTION: Transgenic malaria parasites expressing foreign genes, for example fluorescent and luminescent proteins, are used extensively to interrogate parasite biology and host-parasite interactions associated with malaria pathology. Increasingly transgenic parasites are also exploited to advance malaria vaccine development. Areas covered: We review how transgenic malaria parasites are used, in vitro and in vivo, to determine protective efficacy of different antigens and vaccination strategies and to determine immunological correlates of protection. We describe how chimeric rodent parasites expressing P. falciparum or P. vivax antigens are being used to directly evaluate and rank order human malaria vaccines before their advancement to clinical testing. In addition, we describe how transgenic human and rodent parasites are used to develop and evaluate live (genetically) attenuated vaccines. Expert commentary: Transgenic rodent and human malaria parasites are being used to both identify vaccine candidate antigens and to evaluate both sub-unit and whole organism vaccines before they are advanced into clinical testing. Transgenic parasites combined with in vivo pre-clinical testing models (e.g. mice) are used to evaluate vaccine safety, potency and the durability of protection as well as to uncover critical protective immune responses and to refine vaccination strategies.
  7. Rubab K, Abbasi MA, Rehman A, Siddiqui SZ, Shah SAA, Ashraf M, et al.
    Pak J Pharm Sci, 2017 Jul;30(4):1263-1274.
    PMID: 29039324
    The undertaken research was initiated by transforming 2-(1H-Indol-3-yl)acetic acid (1) in catalytic amount of sulfuric acid and ethanol to ethyl 2-(1H-Indol-3-yl)acetate (2), which was then reacted with hydrazine monohydrate in methanol to form 2-(1H-Indol-3-yl)acetohydrazide (3). Further, The reaction scheme was designed into two pathways where, first pathway involved The reaction of 3 with substituted aromatic aldehydes (4a-o) in methanol with few drops of glacial acetic acid to generate 2-(1H-Indol-3-yl)-N'-[(un)substitutedphenylmethylidene]acetohydrazides (5a-o) and in second pathway 3 was reacted with acyl halides (6a-e) in basic aqueous medium (pH 9-10) to afford 2-(1H-Indol-3-yl)-N'-[(un)substitutedbenzoyl/2-thienylcarbonyl]acetohydrazides (7a-e). All The synthesized derivatives were characterized by IR, EI-MS and 1H-NMR spectral techniques and evaluated for their anti-bacterial potentials against Gram positive and Gram negative bacterial strains and it was found that compounds 7a-d exhibited antibacterial activities very close to standard Ciprofloxacin. The synthesized derivatives demonstrated moderate to weak anti-enzymatic potential against α-Glucosidase and Butyrylcholinesterase (BChE) where, compounds 7c and 5c exhibited comparatively better inhibition against these enzymes respectively. Compounds 7a, 7d and 7e showed excellent anti-enzymatic potentials against Lipoxygenase (LOX) and their IC50 values were much lower than the reference standard Baicalein. Enzyme inhibitory activities were also supported by computational docking results. Compounds 5c, 7a, 7b and 7c also showed low values of % hemolytic activity as well, showing that these molecules were not toxic, indicating that these molecules can be utilized as potential therapeutic agents against inflammatory ailments.
  8. Hussain G, Abbasi MA, Rehman A, Siddiqui SZ, Shah SAA, Ahmad I, et al.
    Pak J Pharm Sci, 2018 May;31(3):857-866.
    PMID: 29716866
    In this work, a new series of 2-[4-(2-furoyl)-1-piperazinyl]-N-aryl/aralkyl acetamides has been synthesized and evaluated for their antibacterial potential. The synthesis was initiated by the reaction of different aryl/aralkyl amines (1a-u) with 2-bromoacetylbromide (2) to obtain N-aryl/aralkyl-2-bromoacetamides (3a-u). Equimolar quantities of different N-aryl/aralkyl-2-bromoacetamides (3a-u) and 2-furoyl-1-piperazine (4) was allowed to react in acetonitrile and in the presence of K2CO3, to form 2-[4-(2-furoyl)-1-piperazinyl]-N-aryl/aralkyl acetamides (5a-u). The structural elucidation was done by EI-MS, IR and 1H-NMR techniques of all the synthesized compounds. All of the synthesized molecules were active against various Gram positive and Gram negative bacterial strains. Among them 5o and 5c showed very excellent MIC values. The cytotoxicity of the molecules was also checked to find their utility as possible therapeutic agents, where 5c (0.51%) and 5g (1.32%) are found to be least toxic in the series.
  9. Marin-Mogollon C, van Pul FJA, Miyazaki S, Imai T, Ramesar J, Salman AM, et al.
    Malar J, 2018 Aug 09;17(1):288.
    PMID: 30092798 DOI: 10.1186/s12936-018-2431-1
    BACKGROUND: Rodent malaria parasites where the gene encoding circumsporozoite protein (CSP) has been replaced with csp genes from the human malaria parasites, Plasmodium falciparum or Plasmodium vivax, are used as pre-clinical tools to evaluate CSP vaccines in vivo. These chimeric rodent parasites produce sporozoites in Anopheles stephensi mosquitoes that are capable of infecting rodent and human hepatocytes. The availability of chimeric P. falciparum parasites where the pfcsp gene has been replaced by the pvcsp would open up possibilities to test P. vivax CSP vaccines in small scale clinical trials using controlled human malaria infection studies.

    METHODS: Using CRISPR/Cas9 gene editing two chimeric P. falciparum parasites, were generated, where the pfcsp gene has been replaced by either one of the two major pvcsp alleles, VK210 or VK247. In addition, a P. falciparum parasite line that lacks CSP expression was also generated. These parasite lines have been analysed for sporozoite production in An. stephensi mosquitoes.

    RESULTS: The two chimeric Pf-PvCSP lines exhibit normal asexual and sexual blood stage development in vitro and produce sporozoite-containing oocysts in An. stephensi mosquitoes. Expression of the corresponding PvCSP was confirmed in oocyst-derived Pf-PvCSP sporozoites. However, most oocysts degenerate before sporozoite formation and sporozoites were not found in either the mosquito haemocoel or salivary glands. Unlike the chimeric Pf-PvCSP parasites, oocysts of P. falciparum parasites lacking CSP expression do not produce sporozoites.

    CONCLUSIONS: Chimeric P. falciparum parasites expressing P. vivax circumsporozoite protein fail to produce salivary gland sporozoites. Combined, these studies show that while PvCSP can partially complement the function of PfCSP, species-specific features of CSP govern full sporozoite maturation and development in the two human malaria parasites.

  10. Othman AS, Lin JW, Franke-Fayard BM, Kroeze H, van Pul FJA, Chevalley-Maurel S, et al.
    Mol Biochem Parasitol, 2018 Sep;224:44-49.
    PMID: 30053393 DOI: 10.1016/j.molbiopara.2018.07.009
    The transmission-blocking vaccine candidate Pfs48/45 from the human malaria parasite Plasmodium falciparum is known to be difficult to express in heterologous systems, either as full-length protein or as correctly folded protein fragments that retain conformational epitopes. In this study we express full-length Pfs48/45 in the rodent parasite P. berghei. Pfs48/45 is expressed as a transgene under control of the strong P. berghei schizont-specific msp1 gene promoter (Pfs48/45@PbMSP1). Pfs48/45@PbMSP1 schizont-infected red blood cells produced full-length Pfs48/45 and the structural integrity of Pfs48/45 was confirmed using a panel of conformation-specific monoclonal antibodies that bind to different Pfs48/45 epitopes. Sera from mice immunized with transgenic Pfs48/45@PbMSP1 schizonts showed strong transmission-reducing activity in mosquitoes infected with P. falciparum using standard membrane feeding. These results demonstrate that transgenic rodent malaria parasites expressing human malaria antigens may be used as means to evaluate immunogenicity and functionality of difficult to express malaria vaccine candidate antigens.
  11. Marin-Mogollon C, van de Vegte-Bolmer M, van Gemert GJ, van Pul FJA, Ramesar J, Othman AS, et al.
    Sci Rep, 2018 10 08;8(1):14902.
    PMID: 30297725 DOI: 10.1038/s41598-018-33236-x
    Two members of 6-cysteine (6-cys) protein family, P48/45 and P230, are important for gamete fertility in rodent and human malaria parasites and are leading transmission blocking vaccine antigens. Rodent and human parasites encode a paralog of P230, called P230p. While P230 is expressed in male and female parasites, P230p is expressed only in male gametocytes and gametes. In rodent malaria parasites this protein is dispensable throughout the complete life-cycle; however, its function in P. falciparum is unknown. Using CRISPR/Cas9 methodology we disrupted the gene encoding Pfp230p resulting in P. falciparum mutants (PfΔp230p) lacking P230p expression. The PfΔp230p mutants produced normal numbers of male and female gametocytes, which retained expression of P48/45 and P230. Upon activation male PfΔp230p gametocytes undergo exflagellation and form male gametes. However, male gametes are unable to attach to red blood cells resulting in the absence of characteristic exflagellation centres in vitro. In the absence of P230p, zygote formation as well as oocyst and sporozoite development were strongly reduced (>98%) in mosquitoes. These observations demonstrate that P230p, like P230 and P48/45, has a vital role in P. falciparum male fertility and zygote formation and warrants further investigation as a potential transmission blocking vaccine candidate.
  12. Abbasi MA, Nazeer MM, Rehman A, Siddiqui SZ, Hussain G, Shah SA, et al.
    Pak J Pharm Sci, 2018 Nov;31(6):2477-2485.
    PMID: 30473521
    The aim of the present research work was synthesis of some 2-furyl[(4-aralkyl)-1-piperazinyl]methanone derivatives and to ascertain their antibacterial potential. The cytotoxicity of these molecules was also checked to find out their utility as possible therapeutic agents. The synthesis was initiated by reacting furyl(-1-piperazinyl)methanone (1) in N,N-dimethylformamide (DMF) and lithium hydride with different aralkyl halides (2a-j) to afford 2-furyl[(4-aralkyl)-1-piperazinyl]methanone derivatives (3a-j). The structural confirmation of all the synthesized compounds was done by IR, EI-MS, 1H-NMR and 13C-NMR spectral techniques and through elemental analysis. The results of in vitro antibacterial activity of all the synthesized compounds were screened against Gram-negative (S. typhi, E. coli, P. aeruginosa) and Gram-positive (B. subtilis, S. aureus) bacteria and were found to be decent inhibitors. Amongst the synthesized molecules, 3e showed lowest minimum inhibitory concentration MIC = 7.52±0.μg/mL against S. Typhi, credibly due to the presence of 2-bromobenzyl group, relative to the reference standard, ciprofloxacin, having MIC = 7.45±0.58μg/mL.
  13. Abbasi MA, Hassan M, Ur-Rehman A, Siddiqui SZ, Hussain G, Shah SAA, et al.
    Comput Biol Chem, 2018 Dec;77:72-86.
    PMID: 30245349 DOI: 10.1016/j.compbiolchem.2018.09.007
    The heterocyclic compounds have been extensively reported for their bioactivity potential. The current research work reports the synthesis of some new multi-functional derivatives of 2-furoic piperazide (1; 1-(2-furoyl)piperazine). The synthesis was initiated by reacting the starting compound 1 with 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (2) in a basic, polar and protic medium to obtain the parent sulfonamide 3 which was then treated with different electrophiles, 4a-g, in a polar and aprotic medium to acquire the designed molecules, 5a-g. These convergent derivatives were evaluated for their inhibitory potential against α-glucosidase, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Acarbose was used as a reference standard for α-glucosidase inhibition while eserine for AChE and BChE inhibition. Some of the synthesized compounds were identified as promising inhibitors of these three enzymes and their bioactivity potentials were also supported by molecular docking study. The most active compounds among the synthetic analogues might be helpful in drug discovery and development for the treatment of type 2 diabetes and Alzhiemer's diseases.
  14. Hassan M, Abbasi MA, Aziz-Ur-Rehman, Siddiqui SZ, Hussain G, Shah SAA, et al.
    J Theor Biol, 2018 12 07;458:169-183.
    PMID: 30243565 DOI: 10.1016/j.jtbi.2018.09.018
    A new series of multifunctional amides has been synthesized having moderate enzyme inhibitory potentials and mild cytotoxicity. 2-Furyl(1-piperazinyl)methanone (1) was coupled with 3,5-dichloro-2-hydroxybenzenesulfonyl chloride (2) to form {4-[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]-1-piperazinyl}(2-furyl)methanone (3). Different elecrophiles were synthesized by the reaction of various un/substituted anilines (4a-o) with 2-bromoacetylbromide (5), 2‑bromo‑N-(un/substituted-phenyl)acetamides (6a-o). Further, equimolar ratios of 3 and 6a-o were allowed to react in the presence of K2CO3 in acetonitrile to form desired multifunctional amides (7a-o). The structural confirmation of all the synthesized compounds was carried out by their EI-MS, IR, 1H NMR and 13C NMR spectral data. Enzyme inhibition activity was performed against acetyl and butyrylcholinestrase enzymes, whereby 7e showed very good activity having IC50 value of 5.54 ± 0.03 and 9.15 ± 0.01 μM, respectively, relative to eserine, a reference standard. Hemolytic activity of the molecules was checked to asertain their cytotoxicity towards red blood cell membrance and it was observed that most of the compounds were not toxic up to certain range. Moreover, chemoinformatic protepties and docking simulation results also showed the significance of 7e as compared to other compounds. Based on in vitro and in silico analysis 7e could be used as a template for the development of new drugs against Alzheimer's disease.
  15. Ullah I, Subhan F, Alam J, Shahid M, Ayaz M
    Front Pharmacol, 2018;9:231.
    PMID: 29615907 DOI: 10.3389/fphar.2018.00231
    Cannabis sativa
    (CS, familyCannabinaceae) has been reported for its anti-emetic activity against cancer chemotherapy-induced emesis in animal models and in clinics. The current study was designed to investigateCSfor potential effectiveness to attenuate cisplatin-induced vomiting in healthy pigeons and to study the impact on neurotransmitters involved centrally and peripherally in the act of vomiting. High-performance liquid chromatography system coupled with electrochemical detector was used for the quantification of neurotransmitters 5-hydroxytryptamine (5HT), dopamine (DA) and their metabolites; Di-hydroxy Phenyl Acetic acid (Dopac), Homovanillic acid (HVA), and 5-hydroxy indole acetic acid (5HIAA) centrally in specific brain areas (area postrema and brain stem) while, peripherally in small intestine. Cisplatin (7 mg/kg i.v.) induce emesis without lethality across the 24 h observation period.CShexane fraction (CS-HexFr; 10 mg/kg) attenuated cisplatin-induced emesis ∼ 65.85% (P< 0.05); the reference anti-emetic drug, metoclopramide (MCP; 30 mg/kg), produced ∼43.90% reduction (P< 0.05). At acute time point (3rdh), CS-HexFr decreased (P< 0.001) the concentration of 5HT and 5HIAA in the area postrema, brain stem and intestine, while at 18thh (delayed time point) CS-HexFr attenuated (P< 0.001) the upsurge of 5HT caused by cisplatin in the brain stem and intestine and dopamine in the area postrema.CS-HexFr treatment alone did not alter the basal neurotransmitters and their metabolites in the brain areas and intestine except 5HIAA and HVA, which were decreased significantly. In conclusion the anti-emetic effect ofCS-HexFr is mediated by anti-serotonergic and anti-dopaminergic components in a blended manner at the two different time points, i.e., 3rdand 18thh in pigeons.
  16. Othman AS, Franke-Fayard BM, Imai T, van der Gracht ETI, Redeker A, Salman AM, et al.
    PMID: 30073152 DOI: 10.3389/fcimb.2018.00247
    Protection against a malaria infection can be achieved by immunization with live-attenuated Plasmodium sporozoites and while the precise mechanisms of protection remain unknown, T cell responses are thought to be critical in the elimination of infected liver cells. In cancer immunotherapies, agonistic antibodies that target T cell surface proteins, such as CD27, OX40 (CD134), and 4-1BB (CD137), have been used to enhance T cell function by increasing co-stimulation. In this study, we have analyzed the effect of agonistic OX40 monoclonal antibody treatment on protective immunity induced in mice immunized with genetically attenuated parasites (GAPs). OX40 stimulation enhanced protective immunity after vaccination as shown by an increase in the number of protected mice and delay to blood-stage infection after challenge with wild-type sporozoites. Consistent with the enhanced protective immunity enforced OX40 stimulation resulted in an increased expansion of antigen-experienced effector (CD11ahiCD44hi) CD8+ and CD4+ T cells in the liver and spleen and also increased IFN-γ and TNF producing CD4+ T cells in the liver and spleen. In addition, GAP immunization plus α-OX40 treatment significantly increased sporozoite-specific IgG responses. Thus, we demonstrate that targeting T cell costimulatory receptors can improve sporozoite-based vaccine efficacy.
  17. Ndlovu ST, Ullah N, Khan S, Ramharack P, Soliman M, de Matas M, et al.
    Drug Deliv Transl Res, 2019 Feb;9(1):284-297.
    PMID: 30387048 DOI: 10.1007/s13346-018-00596-w
    The aim of this study was to employ experimental and molecular modelling approaches to use molecular level interactions to rationalise the selection of suitable polymers for use in the production of stable domperidone (DOMP) nanocrystals with enhanced bioavailability. A low-energy antisolvent precipitation method was used for the preparation and screening of polymers for stable nanocrystals of DOMP. Ethyl cellulose was found to be very efficient in producing stable DOMP nanocrystals with particle size of 130 ± 3 nm. Moreover, the combination of hydroxypropyl methylcellulose and polyvinyl alcohol was also shown to be better in producing DOMP nanocrystals with smaller particle size (200 ± 3.5 nm). DOMP nanosuspension stored at 2-8 °C and at room temperature (25 °C) exhibited better stability compared to the samples stored at 40 °C. Crystallinity of the unprocessed and processed DOMP was monitored by differential scanning calorimetry and powder X-ray diffraction. DOMP nanocrystals gave enhanced dissolution rate compared to the unprocessed drug substance. DOMP nanocrystals at a dose of 10 mg/kg in rats showed enhanced bioavailability compared to the raw drug substance and marketed formulation. A significant increase in plasma concentration of 2.6 μg/mL with a significant decrease in time (1 h) to reach maximum plasma concentration was observed for DOMP nanocrystals compared to the raw DOMP. Molecular modelling studies provided underpinning knowledge at the molecular level of the DOMP-polymer nanocrystal interactions and substantiated the experimental studies. This included an understanding of the impact of polymers on the size of nanocrystals and their associated stability characteristics.
  18. Abbasi MA, Nazir M, Ur-Rehman A, Siddiqui SZ, Hassan M, Raza H, et al.
    Arch Pharm (Weinheim), 2019 Mar;352(3):e1800278.
    PMID: 30624805 DOI: 10.1002/ardp.201800278
    Novel bi-heterocyclic benzamides were synthesized by sequentially converting 4-(1H-indol-3-yl)butanoic acid (1) into ethyl 4-(1H-indol-3-yl)butanoate (2), 4-(1H-indol-3-yl)butanohydrazide (3), and a nucleophilic 5-[3-(1H-indol-3-yl)propyl]-1,3,4-oxadiazole-2-thiol (4). In a parallel series of reactions, various electrophiles were synthesized by reacting substituted anilines (5a-k) with 4-(chloromethyl)benzoylchloride (6) to afford 4-(chloromethyl)-N-(substituted-phenyl)benzamides (7a-k). Finally, the nucleophilic substitution reaction of 4 was carried out with newly synthesized electrophiles, 7a-k, to acquire the targeted bi-heterocyclic benzamides, 8a-k. The structural confirmation of all the synthesized compounds was done by IR, 1 H NMR, 13 C NMR, EI-MS, and CHN analysis data. The inhibitory effects of these bi-heterocyclic benzamides (8a-k) were evaluated against alkaline phosphatase, and all these molecules were identified as potent inhibitors relative to the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver-Burk plots, which revealed that compound 8b inhibited alkaline phosphatase non-competitively to form an enzyme-inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 1.15 μM. The computational study was in full agreement with the experimental records and these ligands exhibited good binding energy values. These molecules also exhibited mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds to render normal calcification of bones and teeth.
  19. Butt ARS, Abbasi MA, Aziz-Ur-Rehman, Siddiqui SZ, Raza H, Hassan M, et al.
    Bioorg Chem, 2019 05;86:459-472.
    PMID: 30772647 DOI: 10.1016/j.bioorg.2019.01.036
    The present research was designed for the selective synthesis of novel bi-heterocyclic acetamides, 9a-n, and their tyrosinase inhibition to overwhelm the problem of melanogenesis. The structures of newly synthesized compounds were confirmed by spectral techniques such as 1H NMR, 13C NMR, and EI-MS along with elemental analysis. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against tyrosinase and all these molecules were recognized as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which explored that compound, 9h, inhibited tyrosinase competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0027 µM. The computational study was coherent with the experimental records and these ligands exhibited good binding energy values (kcal/mol). The hemolytic analysis revealed their mild cytotoxicity towards red blood cell membranes and hence, these molecules can be pondered as nontoxic medicinal scaffolds for skin pigmentation and related disorders.
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