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Psychological Medicine Mar 2021Individuals diagnosed with psychiatric disorders who are prescribed antipsychotics have lower rates of violence and crime but the differential effects of specific...
BACKGROUND
Individuals diagnosed with psychiatric disorders who are prescribed antipsychotics have lower rates of violence and crime but the differential effects of specific antipsychotics are not known. We investigated associations between 10 specific antipsychotic medications and subsequent risks for a range of criminal outcomes.
METHODS
We identified 74 925 individuals who were ever prescribed antipsychotics between 2006 and 2013 using nationwide Swedish registries. We tested for five specific first-generation antipsychotics (levomepromazine, perphenazine, haloperidol, flupentixol, and zuclopenthixol) and five second-generation antipsychotics (clozapine, olanzapine, quetiapine, risperidone, and aripiprazole). The outcomes included violent, drug-related, and any criminal arrests and convictions. We conducted within-individual analyses using fixed-effects Poisson regression models that compared rates of outcomes between periods when each individual was either on or off medication to account for time-stable unmeasured confounders. All models were adjusted for age and concurrent mood stabilizer medications.
RESULTS
The relative risks of all crime outcomes were substantially reduced [range of adjusted rate ratios (aRRs): 0.50-0.67] during periods when the patients were prescribed antipsychotics v. periods when they were not. We found that clozapine (aRRs: 0.28-0.44), olanzapine (aRRs: 0.46-0.72), and risperidone (aRRs: 0.53-0.64) were associated with lower arrest and conviction risks than other antipsychotics, including quetiapine (aRRs: 0.68-0.84) and haloperidol (aRRs: 0.67-0.77). Long-acting injectables as a combined medication class were associated with lower risks of the outcomes but only risperidone was associated with lower risks of all six outcomes (aRRs: 0.33-0.69).
CONCLUSIONS
There is heterogeneity in the associations between specific antipsychotics and subsequent arrests and convictions for any drug-related and violent crimes.
PubMed: 33691828
DOI: 10.1017/S0033291721000556 -
European Journal of Drug Metabolism and... May 2021BACKGROUND AND OBJECTIVE: Prior olanzapine population pharmacokinetic (PPK) models have focused on the effects of sex and smoking on olanzapine clearance. This PPK...
UNLABELLED
BACKGROUND AND OBJECTIVE: Prior olanzapine population pharmacokinetic (PPK) models have focused on the effects of sex and smoking on olanzapine clearance. This PPK model in Chinese adult psychiatric patients also investigated the influence of comedications and co-occurrence of infections on olanzapine clearance, and explored how to personalize oral olanzapine dosage in the clinical setting.
METHODS
A total of 1546 serum concentrations from 354 patients were collected in this study. A one-compartment model with first-order absorption was employed to develop the PPK model using a nonlinear mixed-effects modeling approach. Covariates included demographic parameters, co-occurrence of infection and concomitant medications (including dangguilonghui tablets, a Chinese herbal medicine for constipation). Bootstrap validation (1000 runs) and external validation of 50 patients were employed to evaluate the final model. Simulations were performed to explore the personalization of olanzapine dosing after stratification by sex, smoking, and comedication with valproate.
RESULTS
Typical estimates for the absorption rate constant (K), apparent clearance (CL/F), and apparent distribution volume (V/F) were 0.30 h, 12.88 L/h, and 754.41 L, respectively. Olanzapine clearance was increased by the following variables: 1.23-fold by male sex, 1.23-fold by smoking, 1.23-fold by comedication with valproate, 1.16-fold by sertraline, and 2.01-fold by dangguilonghui tablets. Olanzapine clearance was decreased by the following variables: 0.75-fold by co-occurrence of infection, 0.70-fold by fluvoxamine, and 0.78-fold by perphenazine. The model evaluation indicated that the final model's performance was good, stable, and precise.
CONCLUSION
This study contributes to the personalization of oral olanzapine dosing, but further studies should be performed to verify the effects of infection and comedications, including valproate and dangguilonghui.
Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Antipsychotic Agents; Asian People; Computer Simulation; Drug Interactions; Female; Humans; Infections; Male; Mental Disorders; Middle Aged; Models, Biological; Olanzapine; Prospective Studies; Sex Factors; Smoking; Tissue Distribution; Young Adult
PubMed: 33677821
DOI: 10.1007/s13318-021-00673-5 -
Journal of Clinical Medicine Feb 2021To prove the benefits of pelvic floor muscle training with biofeedback (BFB) as a complementary treatment in women with bladder pain syndrome/interstitial cystitis...
OBJECTIVE
To prove the benefits of pelvic floor muscle training with biofeedback (BFB) as a complementary treatment in women with bladder pain syndrome/interstitial cystitis (BPS/IC).
METHODS
Prospective, randomized study in 123 women with BPS/IC. Groups: BFB+ (n = 48): women with oral drug treatment (perphenazine and amitriptyline) plus intravesical instillations (sodium hyaluronate) plus pelvic floor muscle training with BFB; BFB-: (n = 75): women with oral drug treatment plus intravesical instillations.
VARIABLES
age, body mass index (BMI), time of follow-up, length of disease, time free of disease, diseases and health conditions concomitant, and responses to the SF-36 health-related quality of life questionnaire at the first consultation (SF-36 pre-treatment), and at the end of the study (SF-36 post-treatment). The treatment was considered successful when the SF-36 score reached values equal to or greater than 80 points or when the initial value increased by 30 or more points.
RESULTS
Mean age was 51.62 years old (23-82). BMI was higher in BFB-. The mean length of BPS/IC condition was 4.92 years (1-20), shorter in BFB+ than in BFB-. Mean SF-36 score pre-treatment was 45.92 points (40-58), lower in BFB+ than in BFB-. Post-treatment SF-36 score was higher than pre-treatment SF-36 score both in BFB+ and BFB-. SF-36 values were higher in BFB+ compared to BFB- over the follow-up.
CONCLUSIONS
BFB improves quality of life in women with BPS/IC as adjunct therapy to combined oral and intravesical treatment.
PubMed: 33669734
DOI: 10.3390/jcm10040862 -
International Journal of Molecular... Feb 2021Interactions between phospholipid membranes and selected drugs affecting the central nervous system (CNS) were investigated. Small, unilamellar liposomes were used as...
Interactions between phospholipid membranes and selected drugs affecting the central nervous system (CNS) were investigated. Small, unilamellar liposomes were used as biomimetic cell membrane models. Microelectrophoretic experiments on two-component liposomes were performed using the electrophoretic light scattering technique (ELS). The effect of both positively (perphenazine, PF) and negatively (barbituric acid, BA) charged drugs on zwitterionic L-α-phosphatidylcholine (PC) membranes were analyzed. Experimental membrane surface charge density (δ) data were determined as a function of pH. Quantitative descriptions of the adsorption equilibria formed due to the binding of solution ions to analyzed two-component membranes are presented. Binding constants of the solution ions with perphenazine and barbituric acid-modified membranes were determined. The results of our research show that both charged drugs change surface charge density values of phosphatidylcholine membranes. It can be concluded that perphenazine and barbituric acid are located near the membrane surface, interacting electrostatically with phosphatidylcholine polar heads.
Topics: Animals; Anions; Barbiturates; Cations; Central Nervous System; Chickens; Electricity; Isoelectric Point; Liposomes; Membranes, Artificial; Models, Biological; Perphenazine; Phosphatidylcholines; Scattering, Radiation; Solutions; Static Electricity
PubMed: 33668791
DOI: 10.3390/ijms22052270 -
Drug Development and Industrial Pharmacy Mar 2021The main scope of the present investigation was to improve the bioavailability of perphenazine (PPZ) by incorporating it into the nanostructured lipid carriers (NLCs).
OBJECTIVE
The main scope of the present investigation was to improve the bioavailability of perphenazine (PPZ) by incorporating it into the nanostructured lipid carriers (NLCs).
SIGNIFICANCE
As a result of lipophilic nature and poor aqueous solubility, as well as extensive hepatic metabolism, PPZ has low systemic bioavailability via the oral route. NLCs have shown potentials to surmount the oral delivery drawbacks of poorly water-soluble drugs.
METHODS
The PPZ-NLCs were prepared by the emulsification-solvent evaporation method and subjected for particle size, zeta potential, and entrapment efficiency (EE) analysis. The optimized NLCs were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffractometry (PXRD). Besides, release behavior, storage stability, and pharmacokinetic studies followed by a single-dose oral administration in rats were performed.
RESULTS
Optimized PPZ-NLCs showed a particle size of less than 180 nm with appropriate EE of more than 95%. Microscopic images captured with SEM and TEM exhibited that NLCs were approximately spherical in shape. DSC and PXRD analysis confirmed reduced crystallinity of PPZ after incorporation in NLCs. FTIR spectra demonstrated no chemical interactions between PPZ and NLC components. release studies confirmed the extended-release properties of NLC formulations. PPZ-NLCs exhibited good stability at 4 °C within three months. The oral bioavailability of NLC-6 and NLC-12 was enhanced about 3.12- and 2.49-fold, respectively, compared to the plain drug suspension.
CONCLUSION
NLC can be designated as an effective nanocarrier for oral delivery of PPZ.
Topics: Administration, Oral; Animals; Biological Availability; Drug Carriers; Lipids; Nanostructures; Particle Size; Perphenazine; Rats
PubMed: 33650445
DOI: 10.1080/03639045.2021.1892745 -
Langmuir : the ACS Journal of Surfaces... Mar 2021Bile colloids containing taurocholate and lecithin are essential for the solubilization of hydrophobic molecules including poorly water-soluble drugs such as...
Bile colloids containing taurocholate and lecithin are essential for the solubilization of hydrophobic molecules including poorly water-soluble drugs such as Perphenazine. We detail the impact of Perphenazine concentrations on taurocholate/lecithin colloids using analytical ultracentrifugation, dynamic light scattering, small-angle neutron scattering, nuclear magnetic resonance spectroscopy, coarse-grained molecular dynamics simulations, and isothermal titration calorimetry. Perphenazine impacted colloidal molecular arrangement, structure, and binding thermodynamics in a concentration-dependent manner. At low concentration, Perphenazine was integrated into stable and large taurocholate/lecithin colloids and close to lecithin. Integration of Perphenazine into these colloids was exothermic. At higher Perphenazine concentration, the taurocholate/lecithin colloids had an approximately 5-fold reduction in apparent hydrodynamic size, heat release was less exothermic upon drug integration into the colloids, and Perphenazine interacted with both lecithin and taurocholate. In addition, Perphenazine induced a morphological transition from vesicles to wormlike micelles as indicated by neutron scattering. Despite these surprising colloidal dynamics, these natural colloids successfully ensured stable relative amounts of free Perphenazine throughout the entire drug concentration range tested here. Future studies are required to further detail these findings both on a molecular structural basis and in terms of in vivo relevance.
PubMed: 33587852
DOI: 10.1021/acs.langmuir.0c02282 -
Cancers Jan 2021Targeting a tumor's metabolic dependencies is a clinically actionable therapeutic approach; however, identifying subtypes of tumors likely to respond remains difficult....
Targeting a tumor's metabolic dependencies is a clinically actionable therapeutic approach; however, identifying subtypes of tumors likely to respond remains difficult. The use of lipids as a nutrient source is of particular importance, especially in breast cancer. Imaging techniques offer the opportunity to quantify nutrient use in preclinical tumor models to guide development of new drugs that restrict uptake or utilization of these nutrients. We describe a fast and dynamic approach to image fatty acid uptake in vivo and demonstrate its relevance to study both tumor metabolic reprogramming directly, as well as the effectiveness of drugs targeting lipid metabolism. Specifically, we developed a quantitative optical approach to spatially and longitudinally map the kinetics of long-chain fatty acid uptake in in vivo murine models of breast cancer using a fluorescently labeled palmitate molecule, Bodipy FL c16. We chose intra-vital microscopy of mammary tumor windows to validate our approach in two orthotopic breast cancer models: a MYC-overexpressing, transgenic, triple-negative breast cancer (TNBC) model and a murine model of the 4T1 family. Following injection, Bodipy FL c16 fluorescence increased and reached its maximum after approximately 30 min, with the signal remaining stable during the 30-80 min post-injection period. We used the fluorescence at 60 min (Bodipy), the mid-point in the plateau region, as a summary parameter to quantify Bodipy FL c16 fluorescence in subsequent experiments. Using our imaging platform, we observed a two- to four-fold decrease in fatty acid uptake in response to the downregulation of the MYC oncogene, consistent with findings from in vitro metabolic assays. In contrast, our imaging studies report an increase in fatty acid uptake with tumor aggressiveness (6NR, 4T07, and 4T1), and uptake was significantly decreased after treatment with a fatty acid transport inhibitor, perphenazine, in both normal mammary pads and in the most aggressive 4T1 tumor model. Our approach fills an important gap between in vitro assays providing rich metabolic information at static time points and imaging approaches visualizing metabolism in whole organs at a reduced resolution.
PubMed: 33466329
DOI: 10.3390/cancers13010148 -
Anesthesia and Analgesia Feb 2021
Topics: Antiemetics; Humans; Perphenazine; Postoperative Nausea and Vomiting
PubMed: 33449568
DOI: 10.1213/ANE.0000000000005279 -
Oncology Letters Feb 2021Sezary syndrome is a rare type of non-Hodgkin lymphoma. Protein phosphatase 2A (PP2A) is an important tumor suppressor whose activity is widely inhibited in a variety of...
Sezary syndrome is a rare type of non-Hodgkin lymphoma. Protein phosphatase 2A (PP2A) is an important tumor suppressor whose activity is widely inhibited in a variety of tumors. Recently, reactivation of PP2A has attracted increasing attention as a promising approach for cancer therapy. Phenothiazine anti-psychotic perphenazine (PPZ) exerts antitumor effects by reactivating PP2A. The present study investigated the molecular mechanism underling the antitumor effects of PPZ in the neuroblastoma rat sarcoma oncogene (-mutated Sezary syndrome cell line, HUT78. The results of the present study demonstrated that PPZ induced the dephosphorylation of Akt and ERK1/2, and triggered apoptosis in HUT78 cells. In addition, a PP2A inhibitor blocked the PPZ-mediated dephosphorylation of Akt but did not affect that of ERK1/2. The pharmacological inhibition of Akt and ERK1/2 signaling revealed that Akt activity serves an important role in the survival of HUT78 cells. The present data suggested that suppressing Akt activity by PP2A activation may be an attractive antitumor strategy for -mutated Sezary syndrome.
PubMed: 33376545
DOI: 10.3892/ol.2020.12374 -
Journal of Controlled Release :... Feb 2021Poorly water-soluble drugs frequently solubilize into bile colloids and this natural mechanism is key for efficient bioavailability. We tested the impact of...
Poorly water-soluble drugs frequently solubilize into bile colloids and this natural mechanism is key for efficient bioavailability. We tested the impact of pharmaceutical polymers on this solubilization interplay using proton nuclear magnetic resonance spectroscopy, dynamic light scattering, and by assessing the flux across model membranes. Eudragit E, Soluplus, and a therapeutically used model polymer, Colesevelam, impacted the bile-colloidal geometry and molecular interaction. These polymer-induced changes reduced the flux of poorly water-soluble and bile interacting drugs (Perphenazine, Imatinib) but did not impact the flux of bile non-interacting Metoprolol. Non-bile interacting polymers (Kollidon VA 64, HPMC-AS) neither impacted the flux of colloid-interacting nor colloid-non-interacting drugs. These insights into the drug substance/polymer/bile colloid interplay potentially point towards a practical optimization parameter steering formulations to efficient bile-solubilization by rational polymer selection.
Topics: Bile; Colloids; Polymers; Solubility; Water
PubMed: 33333120
DOI: 10.1016/j.jconrel.2020.12.016