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author:("Ismail, ruili")
1.  Relationship between cold pressor pain-sensitivity and sleep quality in opioid-dependent males on methadone treatment 
PeerJ  2015;3:e839.
Aim. Poor sleep quality due to pain has been reported among opioid-dependent male patients on methadone maintenance therapy (MMT) but objective pain data are lacking. This study aimed to investigate the rate of pain-sensitivity using cold pressor test (CPT) and the relationship between pain-sensitivity and sleep quality in this population.
Methods. A total of 168 male participants were included into the study. Objective pain-tolerance was evaluated at 0 h and at 24 h after the first CPT. Malay version of the Pittsburgh Sleep Quality Index (PSQI) and the subjective opiate withdrawal scale (SOWS) questionnaires were administered to evaluate the quality of sleep and withdrawal symptoms, respectively.
Results. The mean age of study participants was 37.22 (SD 6.20) years old. Mean daily methadone dose was 76.64 (SD 37.63) mg/day, mean global PSQI score was 5.47 (SD 2.74) and mean averaged SOWS score was 5.43 (SD 6.91). The averaged pain-tolerance time ranged from 7 to 300 s with a mean time of 32.16 (SE 2.72) s, slightly below the cut-off score of 37.53 s. More specifically, 78.6% (n = 132) of participants were identified as pain-sensitive (averaged pain-tolerance time ≤37.53 s), and 36 (21.4%) participants were pain-tolerant (averaged pain-tolerance time >37.53 s). The pain-sensitive group reported poorer sleep quality with mean (SD) PSQI of 5.78 (2.80) compared with the pain-tolerant group with mean (SD) PSQI of 4.31 (2.18) (p = 0.005). With analysis of covariance, pain-sensitive group was found to have higher global PSQI scores (adjusted mean 5.76, 95% CI 5.29; 6.22) than pain-tolerant participants (adjusted mean 4.42, 95% CI 3.52; 5.32) (p = 0.010).
Conclusions. Majority of opioid-dependent male patients on methadone treatment are pain-sensitive with CPT. Poor sleep quality is associated with cold pressor pain-sensitivity. Pain and sleep complaints in this male population should not be overlooked.
PMCID: PMC4393806  PMID: 25870765
Methadone maintenance therapy; Pain; Sleep quality; Opioid-dependence; Pain-tolerance; Pain-sensitivity
2.  Inhibitory Potency of 8-Methoxypsoralen on Cytochrome P450 2A6 (CYP2A6) Allelic Variants CYP2A6*15, CYP2A6*16, CYP2A6*21 and CYP2A6*22: Differential Susceptibility Due to Different Sequence Locations of the Mutations 
PLoS ONE  2014;9(1):e86230.
Human cytochrome P450 2A6 (CYP2A6) is a highly polymorphic isoform of CYP2A subfamily. Our previous kinetic study on four CYP2A6 allelic variants (CYP2A6*15, CYP2A6*16, CYP2A6*21 and CYP2A6*22) have unveiled the functional significance of sequence mutations in these variants on coumarin 7-hydroxylation activity. In the present study, we further explored the ability of a typical CYP2A6 inhibitor, 8-methoxypsoralen (8-MOP), in inhibition of these alleles and we hypothesized that translational mutations in these variants are likely to give impact on 8-MOP inhibitory potency. The CYP2A6 variant and the wild type proteins were subjected to 8-MOP inhibition to yield IC50 values. In general, a similar trend of change in the IC50 and Km values was noted among the four mutants towards coumarin oxidation. With the exception of CYP2A6*16, differences in IC50 values were highly significant which implied compromised interaction of the mutants with 8-MOP. Molecular models of CYP2A6 were subsequently constructed and ligand-docking experiments were performed to rationalize experimental data. Our docking study has shown that mutations have induced enlargement of the active site volume in all mutants with the exception of CYP2A6*16. Furthermore, loss of hydrogen bond between 8-MOP and active site residue Asn297 was evidenced in all mutants. Our data indicate that the structural changes elicited by the sequence mutations could affect 8-MOP binding to yield differential enzymatic activities in the mutant CYP2A6 proteins.
PMCID: PMC3903516  PMID: 24475091
3.  Antituberculosis: Synthesis and Antimycobacterial Activity of Novel Benzimidazole Derivatives 
BioMed Research International  2013;2013:926309.
A total of seven novel benzimidazoles were synthesized by a 4-step reaction starting from 4-fluoro-3-nitrobenzoic acid under relatively mild reaction conditions. The synthesized compounds were screened for their antimycobacterial activity against M. tuberculosis H37Rv (MTB-H37Rv) and INH-resistant M. tuberculosis (INHR-MTB) strains using agar dilution method. Three of them displayed good activity with MIC of less than 0.2 μM. Compound ethyl 1-(2-(4-(4-(ethoxycarbonyl)-2-aminophenyl)piperazin-1-yl)ethyl)-2-(4-(5-(4-fluorophenyl)pyridin-3-ylphenyl-1H-benzo[d]imidazole-5-carboxylate (5g) was found to be the most active with MIC of 0.112 μM against MTB-H37Rv and 6.12 μM against INHR-MTB, respectively.
PMCID: PMC3870127  PMID: 24381946
4.  7′-[4-(Trifluoro­meth­yl)phen­yl]-5′,6′,7′,7a’-tetra­hydrodispiro­[indan-2,5′-pyrrolo­[1,2-c][1,3]thia­zole-6′,2′′-indan]-1,3,1′′-trione 
In the title compound, C29H20F3NO3S, the thia­zolidine ringadopts a half-chair conformation. The pyrrolidine and two five-membered carbocyclic rings are in envelope conformations with the spiro C atoms at the flaps. The trifluoro­methyl-substituted benzene ring forms dihedral angles of 62.37 (14) and 87.40 (14)° with the benzene rings of the dihydro-1H-indene units. The two benzene rings form a dihedral angle of 36.94 (15)°. The mol­ecular structure is stabilized by intra­molecular C—H⋯O hydrogen bonds, which generate S(6) ring motifs. In the crystal, mol­ecules are linked into inversion dimers by pairs of inter­molecular C—H⋯O hydrogen bonds, generating R 2 2(10) ring motifs.
PMCID: PMC3238947  PMID: 22199796
5.  4′-(4-Bromo­phen­yl)-1′-methyl­dispiro­[indan-2,2′-pyrrolidine-3′,2′′-indan]-1,3,1′′-trione 
In the title compound, C27H20BrNO3, the pyrrolidine ring adopts a half-chair conformation, while the other five-membered rings adopt flattened envelope conformations with the spiro C atoms as the flap atoms. An intra­molecular C—H⋯O hydrogen bond occurs, generating an S(6) ring. In the crystal, mol­ecules are connected via weak C—H⋯O hydrogen bonds, forming chains along the c axis.
PMCID: PMC3247508  PMID: 22220126
6.  A Nested Allele-Specific Multiplex Polymerase Chain Reaction Method for the Detection of DRD2 Polymorphisms 
The dopamine D2 receptor gene (DRD2) plays a role in many diseases such as schizophrenia, Parkinson’s disease, and addictive behaviour. Methods currently available for the detection of DRD2 polymorphisms are costly and cannot detect all 8 polymorphisms of our research interest simultaneously (Val96Ala, Leu141Leu, Val154Ile, Pro310Ser, Ser311Cys, TaqI A, A-241G, and −141C Ins/Del). Therefore, we developed a nested multiplex polymerase chain reaction (PCR) for simultaneous detection of these polymorphisms.
Genomic DNA was extracted from blood using standardised methods. Primers specific at the 3′-end for the polymorphic sites were designed. A two-step PCR method was developed. In the first PCR, a region from exon 3 to 4, exon 7, the promoter region, and the 3′-region of DRD2 were specifically amplified. The products were subsequently used as templates in the second PCR. Sequencing was performed to validate the test results.
Specific bands corresponding to the amplified product of interest were obtained. The method was reproducible and specific when used to genotype patients with schizophrenia. The amplified sequences showed 100% homology to the DRD2 sequence.
The method was found to be simple, rapid, specific, and reproducible for the simultaneous detection of the DRD2 polymorphisms.
PMCID: PMC3328935  PMID: 22589672
dopamine D2 receptor; genetics; genetic polymorphism; methods; nested PCR; reproducibility of results; specificity
7.  4′-[5-(4-Fluoro­phen­yl)pyridin-3-yl]-1′-methyl­dispiro­[indan-2,2′-pyrrolidine-3′,2′′-indan]-1,3,1′′-trione 
In the title compound, C32H23FN2O3, the pyrrolidine ring adopts an envelope conformation. The monoketo- and diketo-substituted five-membered rings are in envelope and half-chair conformations, respectively. The mol­ecular structure is stabilized by an intra­molecular C—H⋯O hydrogen bond, which generates an S(6) ring motif. In the crystal, mol­ecules are linked via inter­molecular C—H⋯N and C—H⋯O hydrogen bonds into a three-dimensional network. The crystal structure is further consolidated by C—H⋯π inter­actions.
PMCID: PMC3200886  PMID: 22058982
8.  (E)-2-(4-Bromo­benzyl­idene)indan-1-one 
In the title compound, C16H11BrO, the dihydro­indene ring system is approximately planar, with a maximum deviation of 0.008 (2) Å. The mean plane of this ring system forms a dihedral angle of 3.73 (11)°, with the bromo-substituted benzene ring. In the crystal, weak inter­molecular C—H⋯O hydrogen bonds link the mol­ecules into sheets parallel to the ab plane and further stabilization is provided by weak C—H⋯π inter­actions involving the bromo-substituted benzene rings.
PMCID: PMC3200602  PMID: 22058940
9.  (E)-2-[4-(Trifluoro­meth­oxy)benzyl­idene]indan-1-one 
In the title compound, C17H11F3O2, the dihydro­indene ring is approximately planar with a maximum deviation of 0.024 (2) Å and makes a dihedral angle of 3.17 (8) Å with the adjacent benzene ring. In the crystal, mol­ecules are inter­connected by C—H⋯O inter­actions, forming an infinite chain along the c axis.
PMCID: PMC3213585  PMID: 22091162
10.  2-[(E)-4-(Dimethyl­amino)­benzyl­idene]indan-1-one 
In the title compound, C18H17NO, the dihydro­indene ring system is approximately planar, with a maximum deviation of 0.041 (2) Å. This ring system is almost coplanar with the benzene ring, making a dihedral angle of 5.22 (9)°. In the crystal, inter­molecular C—H⋯O hydrogen bonds link the mol­ecules into chains along the b axis.
PMCID: PMC3213440  PMID: 22091019
11.  Ethyl 1-[2-(morpholin-4-yl)eth­yl]-2-[4-(morpholin-4-yl)phen­yl]-1H-1,3-benzimidazole-5-carboxyl­ate 
The asymmetric unit of the title compound, C26H32N4O4, consists of two independent mol­ecules. In both mol­ecules, the eth­oxy groups are each disordered over two sets of sites with occupancies of 0.695 (4):0.305 (4) and 0.877 (2):0.123 (2). The dihedral angles between the benzimidazole ring system and the adjacent benzene ring in the two mol­ecules are 41.41 (5) and 31.46 (5)°. In the crystal, mol­ecules are linked by C—H⋯O and C—H⋯N inter­actions.
PMCID: PMC3152030  PMID: 21837149
12.  Better retention of Malaysian opiate dependents treated with high dose methadone in methadone maintenance therapy 
Methadone is a synthetic opiate mu receptor agonist that is widely used to substitute for illicit opiates in the management of opiate dependence. It helps prevent opiate users from injecting and sharing needles which are vehicles for the spread of HIV and other blood borne viruses. This study has the objective of determining the utility of daily methadone dose to predict retention rates and re-injecting behaviour among opiate dependents.
Subjects comprised opiate dependent individuals who met study criteria. They took methadone based on the Malaysian guidelines and were monitored according to the study protocols. At six months, data was collected for analyses. The sensitivity and specificity daily methadone doses to predict retention rates and re-injecting behaviour were evaluated.
Sixty-four patients volunteered to participate but only 35 (54.69%) remained active and 29 (45.31%) were inactive at 6 months of treatment. Higher doses were significantly correlated with retention rate (p < 0.0001) and re-injecting behaviour (p < 0.001). Of those retained, 80.0% were on 80 mg or more methadone per day doses with 20.0% on receiving 40 mg -79 mg.
We concluded that a daily dose of at least 40 mg was required to retain patients in treatment and to prevent re-injecting behaviour. A dose of at least 80 mg per day was associated with best results.
PMCID: PMC3019202  PMID: 21167035
13.  (E)-2-(3-Chloro­benzyl­idene)-5,6-dimeth­oxy-2,3-dihydro-1H-inden-1-one 
In the title compound, C18H15ClO3, the dihydro­indenone group makes a dihedral angle of 8.56 (6)° with the bezene ring. In the crystal, the mol­ecules are inter­connected into a three-dimensional network via inter­molecular C—H⋯O hydrogen bonds. Weak C—H⋯π and π⋯π [centroid–centroid distances 3.6598 (9)–3.6913 (9) Å] inter­actions are also observed.
PMCID: PMC3008978  PMID: 21589046
14.  (E)-2-[4-(Piperidin-1-yl)benzyl­idene]-2,3-dihydro-1H-inden-1-one 
In the title compound, C21H21NO, the indene ring system is essentially planar with a maximum deviation of 0.066 (1) Å and makes dihedral angles of 7.93 (6) and 2.43 (6)°, respectively, with the benzene plane and the mean plane of the piperidine ring. These latter two planes make a dihedral angle of 7.61 (7)°. In the crystal, mol­ecules are linked by C—H⋯O inter­actions, forming infinite chains along the b axis.
PMCID: PMC3009073  PMID: 21589059
15.  (E)-2-(3,4-Dimeth­oxy­benzyl­idene)-5,6-dimeth­oxy-2,3-dihydro-1H-inden-1-one 
In the title compound, C20H20O5, the 2,3-dihydro-1H-indene ring system is essentially planar [maximum deviation = 0.010 (1) Å] and is inclined at an angle of 4.09 (4)° with respect to the phenyl ring. The C=C bond has an E configuration. In the crystal, the mol­ecules are linked into chains propagating in [102] via inter­molecular C—H⋯O hydrogen bonds. The crystal structure is further consolidated by C—H⋯π inter­actions.
PMCID: PMC3009320  PMID: 21589057
16.  (E)-5,6-Dimeth­oxy-2-(pyridin-4-yl­methyl­idene)-2,3-dihydro-1H-inden-1-one 
The mol­ecule of the title compound, C17H15NO3, is slightly twisted, with a dihedral angle of 12.12 (3)° between the dihydro­indenone group and the pyridine ring. In the crystal, mol­ecules are connected into layers parallel to the ab plane via inter­molecular C—H⋯O hydrogen bonds. Weak π–π [centroid–centroid distance = 3.5680 (6) Å] inter­actions are also observed.
PMCID: PMC3009365  PMID: 21588957
17.  (2E)-2-Benzyl­idene-5,6-dimethoxy­indan-1-one 
The mol­ecular structure of the title compound, C18H16O3, is roughly planar; the maximum deviation of the indanone ring system is 0.027 (1) Å and it makes a dihedral angle of 2.69 (3)° with the phenyl ring. The torsion angles between the two meth­oxy groups and the ­indanone ring are −14.67 (11) and −1.11 (12)°. In the crystal, mol­ecules are connected into a ribbon along the a axis via weak inter­molecular C—H⋯O hydrogen bonds. Weak inter­molecular C—H⋯π and π–π [centroid–centroid distance = 3.7086 (6) Å] inter­actions are also observed.
PMCID: PMC2983266  PMID: 21587524
18.  5,6-Dimeth­oxy-4′,5′-diphenyl­indane-2-spiro-3′-pyrrolidine-2′-spiro-3′′-indoline-1,2′′-dione 
In the title compound, C33H28N2O4, the central pyrrolidine ring adopts a half-chair conformation. Both the indolinone and indanone groups are twisted, with their five-membered rings adopting a half-chair and an envelope conformation, respectively. The two benzene rings and the mean plane of the indolinone and indanone groups make dihedral angles of 71.98 (10), 84.32 (10), 86.26 (9) and 78.50 (9)°, respectively, with the central pyrrolidine ring. Intra­molecular C—H⋯O hydrogen bonds stabilize the mol­ecular conformation. In the crystal, pairs of inter­molecular N—H⋯O hydrogen bonds link the mol­ecules into centrosymmetric dimers. The dimers are inter­connected into ribbons propagating along [110] via weak inter­molecular C—H⋯O hydrogen bonds. Weak inter­molecular C—H⋯π and π–π [centroid–centroid distance = 3.6509 (11) Å] inter­actions are also observed.
PMCID: PMC2983396  PMID: 21587525
19.  Influence of CYP2D6 polymorphisms on symptomatology and side-effects of patients with schizophrenia in Malaysia 
Our objective was to investigate the association of CYP2D6 polymorphisms with symptoms and side-effects of patients with schizophrenia.
The subjects were 156 patients with schizophrenia undergoing antipsychotic treatment at a psychiatric clinic. Patients with co-morbid diagnoses of substance abuse or mental retardation were excluded from the study. Psychopathology was evaluated using the Positive and Negative Symptoms Scale (PANSS). Extrapyramidal side-effects and akathisia were assessed with the Simpson Angus Scale (SAS) and the Barnes Akathisia Rating Scale (BARS), respectively. DNA was extracted from blood and subjected to PCR-genotyping.
We found that CYP2D6 polymorphisms were significantly associated with a subtotal negative PANSS score. In addition, CYP2D6 is not related to side-effects of antipsychotic therapy, or SAS and BARS scores. The results suggest that CYP2D6 polymorphisms may have implications in treatment response.
Therefore, CYP2D6 may be a predictor for treatment outcomes of patients with schizophrenia. However, further investigation is required to confirm these findings in a larger sample.
PMCID: PMC3329140  PMID: 22589660
Cytochrome P450 CYP2D6; schizophrenia; treatment outcomes; neurosciences

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