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1.  Inhibition of Human Cytochrome P450 2c8-catalyzed Amodiaquine N-desethylation: Effect of Five Traditionally and Commonly Used Herbs 
Pharmacognosy Research  2016;8(4):292-297.
Background:
In Southeast Asia and many parts of the world, herbal products are increasingly used in parallel with modern medicine.
Objective:
This study aimed to investigate the effects of herbs commonly used in Southeast Asia on activity of cytochrome P450 2C8 (CYP2C8), an important human hepatic enzyme in drug metabolism.
Materials and Methods:
The selected herbs, such as Eurycoma longifolia Jack (ELJ), Labisia pumila (LP), Echinacea purpurea (EP), Andrographis paniculata (AP), and Ginkgo biloba (GB), were subjected to inhibition studies using an in vitro CYP2C8 activity marker, amodiaquine N-desethylase assay. Inhibition parameters, inhibitory concentration 50% (IC50), and Ki values were determined to study the potency and mode of inhibition.
Results:
All herbs inhibited CYP2C8 with the following order of potency: LP > ELJ > GB > AP > EP. LP and ELJ inhibited potently at Ki's of 2 and 4 times the Ki of quercetin, the positive control. The inhibition by LP was uncompetitive in nature as compared to competitive or mixed type inhibition observed with other herbs. GB exhibited moderate inhibitory effect at a Ki6 times larger than quercetin Ki. AP and EP, on the other hand, showed only weak inhibition.
Conclusion:
The herbs we chose represented the more commonly used herbs in Southeast Asia where collision of tradition and modernization in healthcare, if not properly managed, may lead to therapeutic misadventures. We conclude that concurrent consumption of some herbs, in particular, LP and ELJ, may have relevance in drug-herb interactions via CYP2C8 inhibition in vivo.
SUMMARY
Herbs are increasingly used in parallel with modern medicines nowadays. In this study five commonly used herbs in Southeast Asia region, ELJ, LP, EP, AP and GB, were investigated for their in vitro inhibitory potency on CYP2C8, an important drug-metaboliz-ing human hepatic enzyme. All herbs inhibited CYP2C8 activity marker, amodiaquine N-desethylation, with potency order of LP > ELJ > GB >AP > EP. LP, ELJ and GB exhibited Ki values of 2, 4 and 6 times the Ki of quercetin, the positive control, indicating potent to moderate degree of enzyme inhibition. AP and EP, on the other hand, showed only weak inhibition. In summary, concurrent consumption of some herbs especially LP and ELJ may have relevance in drug-herb interactions via CYP2C8 inhibition in vivo.
Abbreviations Used: AQ: Amodiaquine, AP: Andrographis paniculata, CYP: Cytochrome P450, DEAQ: Desethylamodiaquine, EP: Echinacea purpurea, ELJ: Eurycoma longifolia Jack, GB: Ginkgo biloba, Ki: Inhibition constant, LP: Labisia pumila, Vmax: Maximal velocity, Km: Michaelis-Menten constant.
doi:10.4103/0974-8490.188886
PMCID: PMC5004522  PMID: 27695271
Cytochrome P450; cytochrome P450 2C8; drug-herb interaction; inhibition
2.  The AC/AG Diplotype for the 118A>G and IVS2 + 691G>C Polymorphisms of OPRM1 Gene is Associated with Sleep Quality Among Opioid-Dependent Patients on Methadone Maintenance Therapy 
Pain and Therapy  2016;5(1):43-54.
Introduction
Methadone is a full agonist of the opioid receptor mu 1 which is encoded by the OPRM1 gene. Sleep disorders were frequently reported by opioid-dependent patients during methadone maintenance therapy (MMT). It is possible, therefore, that genetic polymorphisms in OPRM1 influence sleep quality among patients on MMT. This study investigated the association of OPRM1 polymorphisms with sleep quality among opioid-dependent patients on MMT.
Methods
The sleep quality of 165 male opioid-dependent patients receiving MMT was evaluated using the Pittsburgh Sleep Quality Index (PSQI). DNA was extracted from whole blood and subjected to polymerase chain reaction (PCR) genotyping.
Results
Patients with IVS2 + 691 CC genotype had higher PSQI scores [mean (SD) = 5.73 (2.89)] compared to those without the IVS2 + 691 CC genotype (IVS2 + 691 GG/GC genotype) [4.92 (2.31)], but the difference did not reach statistical significance (p = 0.081). Patients with combined 118 AA genotype and IVS2 + 691 GC genotype (AC/AG diplotype) had significantly lower PSQI scores [mean (SD) = 4.25 (2.27)] compared to those without the diplotype [5.68 (2.77)] (p = 0.018).
Conclusion
Our study indicates that the AC/AG diplotype for the 118A>G and IVS2 + 691G>C polymorphisms of OPRM1 gene is associated with better sleep quality among males with opioid dependence on MMT.
doi:10.1007/s40122-016-0044-3
PMCID: PMC4912965  PMID: 26792136
AC/AG diplotype; Male patients; Methadone; Methadone maintenance therapy; Opioid dependence; Opioid receptor; Opioid receptor, mu 1 gene; OPRM1; Pittsburgh Sleep Quality Index; Sleep quality
3.  The Opposing Roles of IVS2+691 CC Genotype and AC/AG Diplotype of 118A>G and IVS2+691G>C of OPRM1 Polymorphisms in Cold Pain Tolerance Among Opioid-Dependent Malay Males on Methadone Therapy 
Pain and Therapy  2015;4(2):179-196.
Introduction
We recently reported that a majority of opioid-dependent Malay males on methadone therapy are cold pain sensitive. It is postulated that common OPRM1 polymorphisms may be responsible. This study investigated the association between 118A>G (dbSNP rs1799971) and IVS2+691G>C (dbSNP rs2075572) variants on cold pain responses among opioid-dependent Malay males on methadone maintenance therapy.
Methods
Cold pain responses including pain threshold, pain tolerance, and pain intensity were measured using the cold pressor test. DNA was extracted from the venous blood before polymerase chain reaction genotyping. Repeated measures analysis of variance was used to compare the cold pain responses and OPRM1 polymorphisms (118A>G and IVS2+691G>C) using models including genotype dominant and recessive models, allelic additive models, and analysis of haplotypes and diplotypes.
Results
A total of 148 participants were recruited. With the recessive model, those with IVS2+691 homozygous CC genotype had a shorter cold pain tolerance time than those without CC genotype (i.e., GG/GC genotype; 29.81 vs. 43.08 s, respectively, P = 0.048). On the other hand, with diplotype analysis, participants with combined homozygous 118 AA genotype and heterozygous IVS2+691 GC genotype (i.e., AC/AG diplotype) had a longer cold pain tolerance time than those without this diplotype (49.34 vs. 31.48 s, respectively, P = 0.043). Cold pain threshold was not associated with any of the 118A>G and IVS2+691G>C variations despite being analyzed using various models (all P > 0.05).
Conclusion
The IVS2+691 CC genotype and AC/AG diplotype of 118A>G and IVS2+691G>C seem to have opposing roles in pain tolerance among opioid-dependent Malay males on methadone therapy. Haplotypes of OPRM1 may be associated with altered binding affinity.
Electronic supplementary material
The online version of this article (doi:10.1007/s40122-015-0041-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s40122-015-0041-y
PMCID: PMC4676768  PMID: 26581429
Cold pain; Malays; Methadone maintenance; Opioid dependence; Pain tolerance; Polymorphism
4.  Prevalence and Correlates of HIV and Hepatitis C Virus Infections and Risk Behaviors among Malaysian Fishermen 
PLoS ONE  2015;10(8):e0118422.
Fishermen in Southeast Asia have been found to be highly vulnerable to HIV, with research evidence highlighting the role of sexual risk behaviors. This study aims to estimate the rate of HIV as well as hepatitis C virus (HCV) infections among Malaysian fishermen, and the risky sexual and injection drug use behaviors that may contribute to these infections. The study also includes an assessment of socio-demographic, occupational and behavioral correlates of testing positive for HIV or HCV, and socio-demographic and occupational correlates of risk behaviors. The study had a cross-sectional design and recruited 406 fishermen through respondent-driven sampling (RDS). Participants self-completed a questionnaire and provided biological specimens for HIV and HCV testing. We conducted and compared results of analyses of both unweighted data and data weighted with the Respondent-Driven Sampling Analysis Tool (RDSAT). Of the participating fishermen, 12.4% were HIV positive and 48.6% had HCV infection. Contrary to expectations and findings from previous research, most fishermen (77.1%) were not sexually active. More than a third had a history of injection drug use, which often occurred during fishing trips on commercial vessels and during longer stays at sea. Of the fishermen who injected drugs, 42.5% reported unsafe injection practices in the past month. Reporting a history of injection drug use increased the odds of testing HIV positive by more than 6 times (AOR = 6.22, 95% CIs [2.74, 14.13]). Most fishermen who injected drugs tested positive for HCV. HCV infection was significantly associated with injection drug use, being older than 25 years, working on a commercial vessel and spending four or more days at sea per fishing trip. There is an urgent need to strengthen current harm reduction and drug treatment programs for Malaysian fishermen who inject drugs, especially among fishermen who work on commercial vessels and engage in deep-sea fishing.
doi:10.1371/journal.pone.0118422
PMCID: PMC4526636  PMID: 26244844
5.  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.
doi:10.7717/peerj.839
PMCID: PMC4393806  PMID: 25870765
Methadone maintenance therapy; Pain; Sleep quality; Opioid-dependence; Pain-tolerance; Pain-sensitivity
6.  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.
doi:10.1371/journal.pone.0086230
PMCID: PMC3903516  PMID: 24475091
7.  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.
doi:10.1155/2013/926309
PMCID: PMC3870127  PMID: 24381946
8.  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.
doi:10.1107/S1600536811047118
PMCID: PMC3238947  PMID: 22199796
9.  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.
doi:10.1107/S1600536811044515
PMCID: PMC3247508  PMID: 22220126
10.  A Nested Allele-Specific Multiplex Polymerase Chain Reaction Method for the Detection of DRD2 Polymorphisms 
Background:
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.
Methods:
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.
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.
Conclusion:
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
11.  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.
doi:10.1107/S1600536811032946
PMCID: PMC3200886  PMID: 22058982
12.  (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.
doi:10.1107/S1600536811031746
PMCID: PMC3200602  PMID: 22058940
13.  (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.
doi:10.1107/S1600536811028698
PMCID: PMC3213585  PMID: 22091162
14.  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.
doi:10.1107/S160053681102664X
PMCID: PMC3213440  PMID: 22091019
15.  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.
doi:10.1107/S1600536811023294
PMCID: PMC3152030  PMID: 21837149
16.  Better retention of Malaysian opiate dependents treated with high dose methadone in methadone maintenance therapy 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1477-7517-7-30
PMCID: PMC3019202  PMID: 21167035
17.  (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.
doi:10.1107/S1600536810040869
PMCID: PMC3008978  PMID: 21589046
18.  (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.
doi:10.1107/S1600536810041723
PMCID: PMC3009073  PMID: 21589059
19.  (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.
doi:10.1107/S1600536810041619
PMCID: PMC3009320  PMID: 21589057
20.  (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.
doi:10.1107/S1600536810039486
PMCID: PMC3009365  PMID: 21588957
21.  (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.
doi:10.1107/S1600536810035695
PMCID: PMC2983266  PMID: 21587524
22.  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.
doi:10.1107/S1600536810035865
PMCID: PMC2983396  PMID: 21587525
23.  Influence of CYP2D6 polymorphisms on symptomatology and side-effects of patients with schizophrenia in Malaysia 
Background:
Our objective was to investigate the association of CYP2D6 polymorphisms with symptoms and side-effects of patients with schizophrenia.
Methods:
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.
Results:
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.
Conclusions:
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

Results 1-24 (24)