The effectiveness of Colchicine as an anti-inflammatory drug in the treatment of coronavirus disease 2019: Meta-analysis.

A recently discovered coronavirus, SARS-CoV-2, caused a global respiratory disease pandemic called COVID-19. Many studies have shown the excessive activation of the innate immune response that leads to the adverse outcomes of COVID-19, and anti-inflammatory drugs are very useful in the treatment and management of this infection. The activities of Colchicine, one of the anti-inflammatory drugs, target several pathways related to excessive inflammation of COVID-19. This study aimed to evaluate the efficacy of Colchicine in the treatment of COVID-19 using a meta-analysis approach. Scopus, Pubmed, Google scholars, Web of Science, and Science direct were used to search all the randomized controlled trials, case-control, and cross-sectional studies that have evaluated the efficacy of Colchicine as a treatment for COVID-19 (up to 28 May 2021). The overall effect of Colchicine versus the control group was determined using a random-effects model meta-analysis where we compared changes (i.e. mean differences-Colchicine group vs Control group) between the two conditions in test scores indicative of hospitalization time (day) and mortality rate. The results illustrated Colchicine therapy is associated with a decreased mortality rate in COVID-19 patients and associated with a decrease in hospitalization time (day) in COVID-19 patients. Present preliminary data shows that Colchicine has a beneficial effect on coronavirus disease care in 2019. Therefore, Colchicine can be a good suggestion in the management of COVID-19.

Prediction of pharmacokinetic values of two various dosages of caffeine in premature neonates with apnea.

OBJECTIVES: Despite extensive caffeine use in preterm infants, the pharmacokinetics (PKs) data are limited because of the studies are complicated to do in these patients. This research was investigated the PK profile of two various dosages of caffeine in premature neonates. MATERIALS AND METHODS: The PK values of caffeine in premature neonates with Apnea were predicted by using all of computer-based simulation (Simcyp®), population-based PK, and modeling (P-Pharm®). We assayed the plasma levels of caffeine in two groups. The information was analyzed utilizing nonlinear mixed-effects modeling approach. The PK parameters were assessed simulating virtual clinical considers with subjects got 20 mg. kg-1 of caffeine in both groups, which was followed by a 5 mg. kg-1 once daily in Group 1 or 2.5 mg. kg-1 twice daily in Group 2. All statistical analysis was executed utilizing SSPS issue 19 and a P value of 0.05 was chosen significance. RESULTS: In the present study, the means CL, volume of distribution, and T1/2 of caffeine in preterm infants were 0.0476 L. h-1, 1.1081 L, 16.2284 h, respectively. Whereas our simulated means by Simcyp were 0.090 L. h-1, 1.841 L, and 14.653 h in Group 1 and 16.223 h in Group 2, respectively. CONCLUSIONS: There was overall good agreement between predicted and measured PK values in our study. This study provides an initial demonstration of Simcyp simulation advantage on anticipating of PK parameters.

Simvastatin prevents morphine antinociceptive tolerance and withdrawal symptoms through antioxidative effect and nitric oxide pathway in mice.

Oxidative stress and the nitric oxide (NO) pathway are involved in the development of opioid analgesic tolerance and dependence. Simvastatin modulates NO and oxidative stress, so the present study aimed to investigate its effect on the development and expression of morphine analgesic tolerance and withdrawal signs in mice. Morphine tolerance and dependence were induced by twice daily morphine injection (10 mg/kg, s.c.) for 5 consecutive days. Tolerance was assessed by the hot-plate test and dependence by naloxone challenge, on the sixth day. To determine if the NO is involved in the effects of simvastatin, mice were pre-treated with l-arginine (200 mg/kg) or the NO synthesis inhibitors (L-NAME; 30 mg/kg) along with simvastatin (300 mg/kg). The results showed that acute and chronic administration of simvastatin reversed the antinociceptive tolerance of morphine and attenuated withdrawal signs in morphine-dependent mice, and this effect is reversed by l-arginine and augmented by l-NAME. Also, the concentration of NO and oxidative stress factors such as malondialdehyde content, total thiol, and glutathione peroxidase (GPx) activity in brain tissues was evaluated. Chronic administration of simvastatin reduced NO and malondialdehyde, and increased total thiol and GPx levels in the cerebral cortex and hippocampus of morphine-dependent mice which were antagonized by l-arginine, and augmented by l-NAME. In summary, simvastatin attenuates morphine-induced antinociceptive tolerance and withdrawal symptoms, at least partly, through antioxidative properties and nitric oxide pathway.

The efficacy and safety of two different doses of caffeine in respiratory function of preterm infants.

BACKGROUND: Caffeine is widely used for prevention of apnea and helps successful extubation from mechanical ventilation. It facilitates the transition from invasive to noninvasive support and reduces duration of continuous positive airway pressure (CPAP) in preterm infants. The optimum caffeine dose in preterm infants has not been well-studied in terms of benefits and risks. We compared efficacy and safety of once versus twice-daily caffeine dose in premature infants. METHODS: This study was a randomized clinical trial conducted in Bu-Ali Sina Teaching Hospital, Sari. Patients with gestational age of <37 weeks were included. Both groups received 20 mg/kg loading dose of caffeine intravenously followed by maintenance dose of 5 mg/kg/day in group 1 or 2.5 mg/kg every 12 hours in group 2. Extubation failure, CPAP failure and possibly adverse reactions were evaluated. RESULTS: The mean of gestational age and birth weight were 32.27±3.23 (weeks) and 1824.5±702.54 (gr), respectively. The rate of extubation and CPAP failure and length of NICU stay were lower in twice-daily-group with no statistically significant difference. The means of O2 saturations on the first three days of caffeine therapy were higher in twice-daily-group. Caffeine was generally safe and well tolerated. CONCLUSIONS: This study, which assayed short-term effects of caffeine, showed that twice daily caffeine maintenance dose was related to more benefits in facilitating extubation or prevention of CPAP failure in preterm infants. However, there was not statistically significant difference between two groups.

Pharmacokinetic Parameters and Over-Responsiveness of Iranian Population to Propranolol.

Purpose: Propranolol is the most widely used treatment for cardiovascular diseases. Dosage range in our patients is usually less than the amount mentioned in references. The aim of the present study was to clarify whether pharmacokinetic differences are able to justify the need for the fewer doses in our patients or not. Methods: Twenty healthy volunteers (10 male) at heart center of Mazandaran University of Medical Sciences were studied. Samples of blood were collected before a single oral dose (40 mg) of Propranolol. Blood samples were taken up to 9 hours after dose. Total plasma concentration of Propranolol was measured by HPLC. Population Pharmacokinetic analysis was performed using population pharmacokinetics modeling software P-Pharm. Results: The mean value for oral plasma clearance (CL/F) was 126.59 ml/hr. The corresponding values for apparent volume of distribution (V/F), t1/2 beta, maximum blood concentration (C max), and time to reach the maximum blood concentration (T max) were 334.12 Lit, 1.98 hr, 40.25 ng/ml, and 1.68 hr, respectively. The observed mean values of V/F of propranolol in the present study were comparable with those reported in the literature. However, the mean values of CL/F of propranolol in current study was significantly higher than those reported in other population (P-value<0.001). Conclusion: This study has confirmed that the pharmacokinetic differences are not able to justify over-responsiveness of Iranian population to propranolol. Pharmacodynamic differences in responding to beta blocker drugs by Renin secretion or having a different sensibility to beta receptors might play a role in making our population have a different response to propranolol.

"Influence of methadone on clopidogrel in addicts on methadone maintenance therapy" Drug interaction between methadone and clopidogrel.

BACKGROUND: Clopidogrel is a prodrug that converts in the liver to an active thiol metabolite, which irreversibly inhibits the platelet P2Y12 adenosine diphosphate receptor. It seems that methadone as CYP2C19 inhibitor affects ticlopidine activity in vivo. This study aimed to test the ability of methadone in changing ticlopidine pharmacokinetics. METHODS: We conducted a case-control study in 10 subjects. The cases (5 subjects) in our study were addicts who were receiving methadone maintenance treatment (MMT) for preventing opium withdrawal symptoms. The control group were opiate users before starting MMT. In both groups, the patients received clopidogrel (75mg/day) for 5 days. On the 6(th) day, the subjects returned to the clinic, blood samples were taken up to 12 hours following clopidogrel dosing in case and control groups. Plasma concentration of clopidogrel was measured by GC-MAS. Noncompartmental pharmacokinetic analysis was performed using Microsoft Excel software to estimate PK parameters. RESULTS: In this study, methadone decreased clopidogrel clearance by 25% and increased the AUC0-inf nearly 1.3 fold during the coadministration of clopidogrel as an antiplatelet drug. CONCLUSION: A significant decrease in the clearance of clopidogrel during the coadministration of methadone consistent with a decrease in clopidogrel conversion to its active metabolite and this may decrease its efficacy and may have life-threatening consequences for the patients undergoing clopidogerel maintenance therapy.

Non-invasive prenatal diagnosis of ß-thalassemia by detection of the cell-free fetal DNA in maternal circulation: a systematic review and meta-analysis.

The discovery of fetal DNA (f-DNA) opens the possibility of early non-invasive procedure for detection of paternally inherited mutation of beta-thalassemia. Since 2002, some studies have examined the sensitivity and specificity of this method for detection of paternally inherited mutation of thalassemia in pregnant women at risk of having affected babies. We conducted a systematic review of published articles that evaluated using this method for early detection of paternally inherited mutation in maternal plasma. A sensitive search of multiple databases was done in which nine studies met our inclusion criteria. The sensitivity and specificity was 99 and 99 %, respectively. The current study found that detection of paternally inherited mutation of thalassemia using analysis of cell-free fetal DNA is highly accurate. This method could replace conventional and invasive methods.

Opium tincture versus methadone syrup in management of acute raw opium withdrawal: A randomized, double-blind, controlled trial.

The aim of this study was to evaluate the effectiveness of opium tincture versus methadone syrup in the management of acute withdrawal syndrome in opium dependent patients during the detoxification period. In this double-blind randomized controlled study, a total of 74 adult male raw opium dependent patients were treated with opium tincture or methadone syrup 2 times daily for 5 consecutive days. Detoxification was initiated by tapered dose reductions to reach abstinence. At the end of the 10th day, the medications were discontinued. The Objective Opioid Withdrawal Scale was used to assess withdrawal symptoms every day. Significant decreases on the Objective Opioid Withdrawal Scale were found for both treatment methods during the study period (p < .0001). However, there was no significant difference between groups on the total Objective Opioid Withdrawal Scale, and adverse effects existed. Opium tincture can be considered as a potential substitute for methadone syrup for suppression of raw opium withdrawal symptoms, with minimal adverse effects.

Pharmacokinetic-pharmacodynamic modeling of mood and withdrawal symptoms in relation to plasma concentrations of methadone in patients undergoing methadone maintenance treatment.

The aims of the present study were to characterize the relationship between plasma racemic methadone and its enantiomers' concentrations with respect to their pharmacodynamic effects and to investigate the influence of potential covariates on the pharmacodynamic parameters in patients on methadone maintenance treatment (MMT). Eighty-eight regular subjects at the Sheffield Care Trust Substance Misuse Services were studied. Samples of blood and urine were collected before the daily dose of methadone. Blood samples were taken up to 5 hours after dose. Total plasma concentrations of (RS)-methadone and total and unbound plasma concentrations of both enantiomers were measured by liquid chromatography-mass spectrometry. The Total Mood Disturbance Score (TMDS), the Objective Opioid Withdrawal Scale (OOWS), and the Subjective Opioid Withdrawal Scale (SOWS) were used as measures of mood and withdrawal. Population pharmacokinetic/pharmacodynamic analysis and subsequent multiple regression analysis were used to determine the factors influencing the pharmacodynamic effects of methadone. Significant decreases (P ≤ 0.04) were observed in the scores for the TMDS, SOWS, and OOWS for 5 hours after methadone dosage. The TMDS had returned to baseline by 10 hours after dose (P = 0.98), at which time the SOWS remained significantly below baseline (P = 0.001). Multiple regression analysis revealed that 33% of the overall variation in unbound (R)-methadone EC50 was explained by 3 variables, namely CYP3A activity (9%), age (16%), and sex (8%). Age also accounted for 8% and 9% of the variation in total (rac)- and (R)-methadone EC50. The present study has confirmed that the duration of mood change in the present study was shorter than the effect of methadone in stabilizing withdrawal symptoms. Thus, it is likely that a once-daily dose of methadone, albeit effective for preventing withdrawal, may not be sufficient to improve mood in some patients. Finally, it was established that CYP3A activity, years of dependent use, sex, and age are major determinants of methadone EC50 with respect to TMDS.

Tramadol versus methadone for treatment of opiate withdrawal: a double-blind, randomized, clinical trial.

The aim of this study was to compare the efficacy and safety of tramadol versus methadone for treatment of opiate withdrawal. Seventy patients randomly were assigned in two groups to receive either prescribed methadone (60 mg/day) or tramadol (600 mg/day). The withdrawal syndrome of patients was evaluated before and after rapid opiate detoxification using the Objective Opioid Withdrawal Scale (OOWS). No significant differences existed in overall OOWS scores between two groups (P = 0.11). Dropout rates were similar in both groups. Side effects in the tramadol group were as or less common than in the methadone group, with the exception of perspiration. Tramadol may be as effective as methadone in the control of withdrawal and could be considered as a potential substitute for methadone to manage opioids withdrawal.

Allele and genotype frequencies of CYP2C9 within an Iranian population (Mazandaran).

Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme responsible for the metabolism of different drugs, some with low therapeutic index. The frequency of functionally important mutations and alleles of the gene coding for CYP2C9 shows wide ethnic variations. The present study aimed to determine the prevalence of the most common allelic variants of the CYP2C9 enzyme and to predict the genotype frequency in the Mazandarani ethnic group among the Iranian population. Genotyping of CYP2C9 allelic variants was carried out in 103 unrelated subjects by polymerase chain reaction and restriction fragment length pattern analysis. The frequencies for CYP2C9 alleles *1, *2, and *3 were 78%, 12%, and 10%, respectively. No subjects were found carrying the CYP2C19*11 allele. The frequencies of CYP2C9 genotypes *1/*1, *1/*2, *1/*3, *2/*2, *2/*3, and *3/*3 were 61%, 19%, 16%, 1.5%, 2.5%, and 0.0%, respectively. The result of the present study showed that the two inactive alleles of CYP2C9 accounted for 22% of CYP2C9 alleles in our sample versus 1.5%-29% reported in other populations. The frequencies of the studied alleles resulted in significant differences between our sample and African and Eastern Asian populations.

Frequencies of three CYP2D6 nonfunctional alleles (CYP2D6*3, *4, and *6) within an Iranian population (Mazandaran).

Although the frequencies of CYP2D6 nonfunctional alleles have been extensively studied in most populations worldwide, limited information is available for those of the Iranian population. The present study aimed to determine the frequency of three CYP2D6 nonfunctional alleles (CYP2D6*3, *4, and *6) in the Mazandarani ethnic group among the Iranian population. A total of 100 unrelated healthy subjects living in Mazandaran, a Caspian province in the north of Iran, were selected. Lymphocytic genomic DNA was genotyped by a polymerase chain reaction amplification method for detection of three nonfunctional alleles. Finally, the obtained data were used to determine the frequencies of the three alleles, and the results were compared with published data from other populations. The frequencies for CYP2D6 alleles *3, *4, and *6 were 0.5%, 9%, and 0.5%, respectively. Homozygous or compound heterozygous genotypes that predict poor metabolizer phenotype, that is, *4/*4 or *4/*6, were not found in this study. The result of the present study showed that CYP2D6*4 is the major nonfunctional allele found in Mazandarani subjects. In addition, the three inactive alleles of CYP2D6 accounted for 10% of CYP2D6 alleles in our sample versus 0.2%-25.2% reported in other populations. The frequencies of the studied alleles resulted in significant differences between our sample and East Asians, Black-Tanzanians, Saudi Arabians, and Caucasians.

Population pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of methadone in a sample of Iranian (mazandarani) opiate users undergoing methadone maintenance treatment.

OBJECTIVE: To investigate the pharmacokinetics (PK) and PK- pharmacodynamic (PD) relationship of methadone in a cohort of outpatients undergoing methadone maintenance treatment (MMT). METHODS: Sixty male patients undergoing MMT with a mean ±SD methadone daily dosage of 58 ± 34 mg were enrolled in this study. A 5-ml blood sample was collected before the daily intake of methadone. As a PD measure, the Subjective Opioid Withdrawal Scale (SOWS) form was completed immediately after obtaining the blood sample. Blood samples were taken and the forms were completed 4-5 times more (up to 24 hr) after the daily intake of methadone. Plasma methadone was analyzed using HPLC. Population PK/PD analysis was performed using population pharmacokinetics modeling software P-Pharm. RESULTS: Significant decreases (p< 0.05) were observed in the SOWS scores during 10 hours after methadone intake. The SOWS had returned to baseline by 24 hr after using methaodone (p= 0.98). A considerable interindividual variability in the CL/F (16 fold), EC50 (3 fold) and Emax (6 fold) for methadone was observed. CONCLUSION: Withdrawal symptoms were significantly improved in MMT patients after taking methadone and the PD measure was substantially affected by fluctuations in plasma methadone concentration. However, The SOWS had returned to baseline by 24 hr after using mathadone. Thus, a once daily dosing of methadone may not be suitable for those MMT patients who experience a significant withdrawal disturbance in the latter part of the interdose interval. This may increase the perceived severity of withdrawal and induce a craving for additional opioids.

Contribution of the activities of CYP3A, CYP2D6, CYP1A2 and other potential covariates to the disposition of methadone in patients undergoing methadone maintenance treatment.

AIMS: To investigate the influence of different cytochrome P450 (CYP) activities and other potential covariates on the disposition of methadone in patients on methadone maintenance therapy (MMT). METHODS: Eighty-eight patients (58 male; 21-55 years; 84 White) on MMT were studied. CYP2D6 activity [3 h plasma metabolic ratio of dextromethorphan (DEX) to dextrorphan (DOR)] was determined in 44 patients (29 male; 24-55 years), CYP1A2 activity (salivary caffeine elimination half-life) in 44 patients (21 male; 24-55 years) and CYP3A activity (oral clearance of midazolam) in 49 patients (33 male; 23-55 years). Data on all three CYPs were obtained from 32 subjects. Total plasma concentrations of (RS)-methadone and total and unbound plasma concentrations of both enantiomers were measured by LC/MS. Population pharmacokinetics and subsequent multiple regression analysis were used to calculate methadone oral clearance and to identify its covariates. RESULTS: Between 61 and 68% of the overall variation in total plasma trough concentrations of (RS)-, (R)- and (S)-methadone was explained by methadone dose, duration of addiction before starting MMT, CYP3A activity and illicit morphine use. CYP3A activity explained 22, 16, 15 and 23% of the variation in unbound (R)-, unbound (S)-, total (RS)- and total (S)-methadone clearances, respectively. Neither CYP2D6 nor CYP1A2 activity was related to methadone disposition. CONCLUSIONS: CYP3A activity has a modest influence on methadone disposition. Inhibitors and inducers of this enzyme should be monitored in patients taking methadone.