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.
Methadone maintenance therapy; Pain; Sleep quality; Opioid-dependence; Pain-tolerance; Pain-sensitivity
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.
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.
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(10) ring motifs.
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.
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.
dopamine D2 receptor; genetics; genetic polymorphism; methods; nested PCR; reproducibility of results; specificity
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.
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.
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.
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.
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.
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.
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.
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.
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  via intermolecular C—H⋯O hydrogen bonds. The crystal structure is further consolidated by C—H⋯π interactions.
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.
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.
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  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.
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.
Cytochrome P450 CYP2D6; schizophrenia; treatment outcomes; neurosciences