Drug Concentration Levels Research Articles

Numerical investigation on the differential injection angle effects of intrathecal anesthetic drug delivery

In lumbar anesthesia surgery, the accurate determination of key parameters such as injection angle and dosage is facilitated by the real-time observation of intrathecal drug distribution. In this study, a non-invasive and visual computational fluid dynamics method was used to simulate drug injections in the “cloverleaf” lumbar thoracic segment with a multiphase mixture model, clarifying the intrathecal unsteady flow behaviors and the drug transport mechanisms. The transport properties of three clinically significant injection angles — [Formula: see text], [Formula: see text] and [Formula: see text]— were compared, determining the fastest and slowest block onset angles based on drug concentration levels in the thoracic vertebral plane. The calculation results are aligned with clinical practice trends, and it is found that significantly different drug amounts are required for different injection angles, with higher doses necessitated for ultrasound-assisted anesthesia. During anesthesia, a trend of increasing and then decreasing local anesthetic concentrations in each vertebral plane was observed, with the presence of a minimum effective dose of local anesthetic at the target block site. Injecting at the “concave” part of the cloverleaf ([Formula: see text] and [Formula: see text]) results in greater drug pulsation, faster diffusion and more efficient mixing than injecting at the positive “convex” part of the cloverleaf cross-section ([Formula: see text]). At the L2 vertebral plane, the flow rate and mixing ratios during injection for angles of [Formula: see text], [Formula: see text] and [Formula: see text] were approximately 1:4:2. Compared with orthostatic [Formula: see text] injections, [Formula: see text] and [Formula: see text] oblique injections resulted in higher drug concentrations in the T12-10 vertebral plane during the pre-transport period, with [Formula: see text] injections being the fastest. However, over a longer period of time, [Formula: see text] injections resulted in the lowest drug concentrations in the target block plane (T10), necessitating a higher dose. A faster anesthetic response was produced by [Formula: see text] injections at the same dose. Valuable insights for the application of appropriate drug dosages in clinical anesthesia practice are offered by the calculations.

Increased risk of adverse drug reactions by higher linezolid dose per weight in multidrug-resistant tuberculosis

Linezolid treatment has a high risk of toxicity and adverse drug reactions (ADR) are frequent. Few studies have investigated risk factors of major ADRs separately, therefore, we aimed to evaluate major ADRs including peripheral neuropathy in relation to risk factors and drug concentration levels of linezolid in a high-resource setting for multidrug-resistant tuberculosis (MDR-TB). We conducted a retrospective cohort study including participants treated with a linezolid-containing MDR-TB regimen in Sweden 1992-2018. Data was collected from medical records. ADRs were classified according to Common Terminology Criteria for Adverse Events (version 5.0). Of all participants (n = 132), 43.2% were female and the median age 28 y. The median linezolid treatment was 6.5 months (IQR 3.0-12.7) with a median daily dose of 9.6 mg/kg/d. Any ADR was seen in 58.3% (n = 77) of participants, with 35.6% having peripheral neuropathy (n = 47), 27.3% anaemia (n = 36), 22.0% leukopenia (n = 36) while 6.1% (n = 8) had optic neuritis. The median time for peripheral neuropathy was 3.6 months (IQR 2.1-5.9) and 8.3 months (6.2-10.7) for optic neuritis. A >2.0 mg/L trough concentration (n = 40) was associated with anaemia (P = 0.0038) and thrombocytopenia (P = 0.009) but not with peripheral neuropathy. In multivariable analysis, a dose ≥12 mg/kg/d was associated with time to peripheral neuropathy (HR 2.89, 95% CI 1.08-7.74, P = 0.035), anaemia (HR 6.62, 95% CI 2.22-19.8, P = 0.001) and leukopenia (HR 5.23, 95% CI 1.48-18.5, P = 0.010). Linezolid ADRs were frequent in a high-resource setting. Structured, regular follow-up for ADRs and adjusting dosing according to body weight followed-up by monitoring of drug concentrations early may reduce toxicity.

Incentivizing adherence to pre-exposure prophylaxis for HIV prevention: a randomized pilot trial among male sex workers in Mexico.

Low adherence to preventative medications against life-long health conditions is a major contributor to global morbidity and mortality. We implemented a pilot randomized controlled trial in Mexico to measure the extent to which conditional economic incentives help male sex workers increase their adherence to pre-exposure prophylaxis (PrEP) for HIV prevention. We followed n = 110 male sex workers over 6 months. At each quarterly visit (at months 0, 3, and 6), all workers received a $10 transport reimbursement, a free 3-month PrEP supply, and completed socio-behavioral surveys. The primary outcome was an objective biomarker of medication adherence based on tenofovir (TFV) drug concentration levels in hair collected at each visit. Individuals randomized to the intervention received incentives based on a grading system as a function of PrEP adherence: those with high (> 0.043 ng/mg TFV concentration), medium (0.011 to 0.042 ng/mg), or low (< 0.011 ng/mg) adherence received $20, $10, or $0, respectively. Six-month pooled effects of incentives on PrEP adherence were analyzed using population-averaged gamma generalized estimating equation models. We estimated heterogeneous treatment effects by sex worker characteristics. The incentive intervention led to a 28.7% increase in hair antiretroviral concentration levels over 6 months consistent with increased PrEP adherence (p = 0.05). The effect of incentives on PrEP adherence was greater for male sex workers who were street-based (vs. internet) workers (p < 0.10). These pilot findings suggest that modest conditional economic incentives could be effective, at scale, for improving PrEP adherence among male sex workers, and should be tested in larger implementation trials. ClinicalTrials.gov Identifier: NCT03674983.

Evaluation of anti-seizure medications and their serum concentration with regard to cardiovascular risk parameters: A cross-sectional study

Epilepsy is a chronic disease that requires long-term monitoring and treatment. It is suspected that there is a interaction between the use of anti-seizure medications and the risk of cardiovascular disease. The aim of the study is to investigate the association between the intake of phenobarbital, carbamazepine and valproic acid and their serum drug concentrations (SDC) with various cardiovascular risk parameters (homocysteine, folic acid, vitamin B12, total cholesterol (TC), triglycerides, high- and low-density lipoprotein (LDL)). This is a cross-sectional study. Data (demographic characteristics and laboratory results) of patients treated for epilepsy in a tertiary care hospital between January 2020 and February 2022 were analyzed retrospectively (n=2014). Kruskal Wallis, Mann-Whitney U, correlation analysis was used, p<0.05 was considered statistically significant. The median age of patients was 15years (IQR:8-31) and 48.3% were women. The highest homocysteine level was found in patients receiving valproic acid, but it was not statistically significant. Patients receiving phenobarbital had the highest levels of folic acid and B12 and the lowest levels of total cholesterol and low-density lipoprotein cholesterol, which was statistically significant. In patients receiving carbamazepine, a moderately negative significant association was found between serum drug concentration and folic acid levels and a moderately positive significant association was found between TC and LDL levels. In our study, the majority of patients were children and adolescents. Regular monitoring of drug serum concentrations and metabolic parameters may be useful to select the safest drug in terms of cardiovascular disease risk. Randomized controlled trials on the long-term effects of anti-seizure treatment are needed.

Preparation of a β-cyclodextrin grafted magnetic biochar for efficient extraction of four antiepileptic drugs in plasma samples

Simultaneous monitoring of plasma concentration levels of multiple antiepileptic drugs (AEDs) is essential for dose adjustment in comprehensive epilepsy treatment, necessitating a sensitive technique for accurate extraction and determination of AEDs. Herein, a magnetic solid-phase extraction (MSPE) technique on the basis of modified biochar (BC) is investigated to extract four AEDs from plasma, in conjunction with high performance liquid chromatography. BC derived from Zizyphus jujuba seed shells was activated by phosphoric acid (PBC) and magnetized via coprecipitation to produce MPBC. The MPBCCD obtained after modification with β-cyclodextrin (CD) was characterized and evaluated for adsorption. It exhibited fast adsorption kinetics based on second-order kinetics and satisfactory adsorption capacity for AEDs. Then it was employed as the MSPE adsorbent and the influencing parameters were optimized. The enrichment factor was 18.75. The validation analysis revealed a favorable linearity that ranged from 0.04 to 20 μg·mL-1 along with a low limit of detection of 6.85 to 10.19 ng·mL-1. The recovery of the AEDs ranged from 78.7 to 109.2 %, with relative standard deviations below 6.7 %. Using quantum chemistry theory calculations and experimental results analysis, the adsorption mechanism was investigated. It disclosed that the suggested strategy built upon MPBCCD was appropriate for the assessment of AEDs in plasma and expanded the usage of BC as the environmentally favorable matrix for the analysis of biological samples.

The Impact of Drug Interactions with Tyrosine Kinase Inhibitors on Adverse Event Development based on the changes of drug concentration level: Meta-analysis

The Impact of Drug Interactions with Tyrosine Kinase Inhibitors on Adverse Event Development based on the changes of drug concentration level: Meta-analysis

P1080 Real-world Study on Early Predictors of Infliximab Treatment Efficacy in Crohn's disease

Abstract Background Infliximab (IFX) can effectively induce and maintain the clinical remission of Crohn's disease (CD). However, a substantial number of CD patients experience primary or secondary nonresponse to IFX during treatment. Therefore, it is essential to identify early predictors of IFX treatment efficacy. Methods This study included 147 CD patients. Based on clinical outcomes, patients were categorized into IFX nonresponse and response group. We collected and compared laboratory data on blood routine examination, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), fecal calprotectin and post-induction IFX drug concentration and antibody levels in both groups. Logistic regression models were employed to identify potential factors associated with the risk of IFX nonresponse. Machine learning using random forest analysis was utilized to quantitatively assess the predictive features for IFX treatment efficacy and ROC curves was used to evaluate the model’s accuracy. Additionally, we performed HE staining and double immunofluorescence staining for CD64 and CD206 on intestinal biopsy tissues obtained before IFX treatment to compare the difference of macrophage subtypes between the nonresponse and response groups. Results Data from both cohorts revealed that patients in the IFX nonresponse group had lower drug concentration (P &amp;lt; 0.001), higher antibody levels (P &amp;lt; 0.001), and increasing ESR during the induction therapy (P &amp;lt; 0.001). Univariate and multivariate Logistic regression models demonstrated that IFX drug concentration and the ratio of ESR before and after induction therapy were associated with the risk of nonresponse. After the induction period, for each unit increase in drug concentration (1 μg/ml), the risk of IFX nonresponse decreased by 23% (RR= 0.77, 95% CI = 0.68-0.89), while each doubling of the ESR ratio after induction was associated with a 1.43-fold increase in the risk of nonresponse (RR= 2.43, 95% CI = 1.48-4.00). After combining data from the two cohorts, random forest machine learning analysis revealed that drug concentration below 1.5 μg/ml and an increase in ESR during induction could predict IFX nonresponse, with ROC curve areas of 0.740 and 0.651, respectively. Furthermore, immunofluorescence staining of intestinal mucosal biopsy tissues before IFX treatment showed a higher proportion of M1-type macrophages in the nonresponse group compared to the response group (P &amp;lt; 0.05). Conclusion Our study suggests that lower post-induction IFX drug concentrations and an increase in ESR during the induction phase are predictive of IFX nonresponse. Additionally, a higher proportion of M1-type macrophages in the intestinal mucosa before IFX treatment is associated with IFX nonresponse.

Formulation and Evaluation of Linagliptin Buccal Films

Achieving steady concentration levels of drugs in the plasma for diabetics is important for an extended period. Thestudy focussed on developing mucoadhesive buccal films incorporating linagliptin, aiming to achieve controlled drug delivery foreffective type 2 diabetes management towards steady level plasma concentration. The research utilizes various mucoadhesivepolymers, specifically HPMC K100, HPMC E5LV, and Eudragit RL100, exploring their potential in formulating optimized filmsthrough solvent casting technique. Our primary aim was to identify the most effective formulation, that would ensure controlleddrug release over an extended period. We formulated various formulations and evaluated drug content, swelling index, in-vitrodrug discharge, and ex-vivo mucoadhesive strength. The formulation, incorporated linagliptin, HPMC E5LV, HPMC K100,Eudragit RL100, glycerol, and polyethylene glycol. Results from our comprehensive evaluations showcased favorable dissolutiontime, robust mechanical properties, and impressive mucoadhesive characteristics in the buccal films. The sustained drugdischarge and mucoadhesive strength exhibited by formulation F7 indicate its potential for effective type 2 diabetes managementwith a single film administration lasting up to 8 hours. This research represents a significant step forward in the field ofpharmaceuticals, offering a promising avenue for developing mucoadhesive buccal films to control drug delivery precisely forenhanced therapeutic outcomes in the management of type 2 diabetes.

Salt-assisted liquid–liquid microextraction for determination of haloperidol in human plasma by LC-MS/MS

Haloperidol is an antipsychotic used in the treatment of schizophrenia. Compared to other antipsychotics, it is widely used in developing countries due to its affordable price. Haloperidol has a narrow therapeutic range and variable pharmacokinetics; therefore, therapeutic drug monitoring (TDM) is recommended. For this reason, in this study, an easily applicable, fast, selective, accurate, reliable, and economical LC-MS/MS method was developed for the determination of haloperidol in human plasma for use in TDM and also method was validated according to European Medicines Agency (EMA) Bioanalytical method validation guidelines. In the developed method, analyte and internal standard were extracted from plasma by salt-assisted liquid-liquid microextraction (SALLME) technique and after that injected to the LC system. The limit of quantification of haloperidol was determined as 1 ng/ml. The calibration curve was validated between 1-15 ng/ml, with correlation coefficients &gt;0.99. In addition, the developed method was used to determine drug concentration levels in the plasma of real patients.

Assessing immune hepatotoxicity of troglitazone with a versatile liver-immune-microphysiological-system.

Drug-induced liver injury is a prevalent adverse event associated with pharmaceutical agents. More significantly, there are certain drugs that present severe hepatotoxicity only during the clinical phase, consequently leading to the termination of drug development during clinical trials or the withdrawal from the market after approval. The establishment of an evaluation model that can sensitively manifest such hepatotoxicity has always been a challenging aspect in drug development. In this study, we build a liver-immune-microphysiological-system (LIMPS) to fully demonstrate the liver injury triggered by troglitazone (TGZ), a drug that was withdrawn from the market due to hepatotoxicity. Leveraging the capabilities of organ-on-chip technology allows for the dynamic modulation of cellular immune milieu, as well as the synergistic effects between drugs, hepatocytes and multiple immune cells. Through the LIMPS, we discovered that 1) TGZ can promote neutrophils to adhered hepatocytes, 2) the presence of TGZ enhances the crosstalk between macrophages and neutrophils, 3) the induction of damage in hepatocytes by TGZ at clinically relevant blood concentrations not observed in other in vitro experiments, 4) no hepatotoxicity was observed in LIMPS when exposed to rosiglitazone and pioglitazone, structurally similar analogs of TGZ, even at the higher multiples of blood drug concentration levels. As an immune-mediated liver toxicity assessment method, LIMPS is simple to operate and can be used to test multiple drug candidates to detect whether they will cause severe liver toxicity in clinical settings as early as possible.

Combining solubilization and controlled release strategies to prepare pH-sensitive solid dispersion loaded with albendazole: in vitro and in vivo studies.

Albendazole (ABZ), classified as a class II basic drug under the Biopharmaceutics Classification System (BCS), is widely recognized for its therapeutic efficacy in treating and preventing trichuriasis. However, despite its clinical relevance, ABZ's oral administration presents challenges due to its poor solubility and pH sensitivity, which diminish its therapeutic effectiveness. Additionally, high dosing regimens of ABZ pose risks of developmental toxicity in animal models. This study developed a pH-sensitive solid dispersion of albendazole (ABZ-pHs-SD) using Glyceryl Monostearate (GM) in conjunction with Hypromellose Acetate Succinate (HPMC-AS). Characterization via Scanning Electron Microscopy (SEM), Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), and Fourier Transform Infrared Spectroscopy (FT-IR) confirmed the high dispersion of ABZ in a crystalline state within the carrier. Furthermore, we compared the in vitro dissolution profile, pharmacokinetics, and intestinal drug concentration of ABZ-pHs-SD with commercially available formulations. Our findings demonstrated that ABZ-pHs-SD exhibited an excellent dissolution profile, significantly increasing the solubility of ABZ in water by 3.15 times. The formulation effectively prevented drug release in acidic environments while maintaining a slow release in weakly alkaline conditions. Additionally, compared to commercial formulations, ABZ-pHs-SD showed significantly lower Cmax (4.70 ± 1.16 vs. 6.83 ± 0.66 μg/mL) and higher Tmax (5.5 ± 0.93 vs. 3.75 ± 0.71 h) in vivo, achieving elevated drug concentration levels in the cecal and colonic environments (p < 0.01) without significantly decreasing bioavailability. Overall, our research findings indicate that ABZ-pHs-SD serves as a promising drug delivery strategy for the poorly soluble and pH-sensitive ABZ. Particularly, the simple preparation of solid dispersion demonstrates strong industrial feasibility.

Triple hit on ocular surface inflammation – case reports

In everyday medical practice, finding the exact cause of conjunctivitis can be difficult without thorough laboratory testing. Therefore, the paper presents cases of treating ocular surface disorders of unknown etiology with the help of combination preparations in the form of a suspension, which allows a wide range of therapeutic effects including bacteria, chlamydia and allergic inflammation and provides a more stable and longer-lasting drug concentration level compared to drugs in the form of aqueous solutions.

Characterisation of populations at risk of sub-optimal dosing of artemisinin-based combination therapy in Africa.

Selection of resistant malaria strains occurs when parasites are exposed to inadequate antimalarial drug concentrations. The proportion of uncomplicated falciparum malaria patients at risk of being sub-optimally dosed with the current World Health Organization (WHO) recommended artemisinin-based combination therapies (ACTs) is unknown. This study aims to estimate this proportion and the excess number of treatment failures (recrudescences) associated with sub-optimal dosing in Sub-Saharan Africa. Sub-populations at risk of sub-optimal dosing include wasted children <5 years of age, patients with hyperparasitaemia, pregnant women, people living with HIV, and overweight adults. Country-level data on population structure were extracted from openly accessible data sources. Pooled adjusted Hazard Ratios for PCR-confirmed recrudescence were estimated for each risk group from published meta-analyses using fixed-effect meta-analysis. In 2020, of the estimated 153.1 million uncomplicated P. falciparum malaria patients in Africa, the largest risk groups were the hyperparasitaemic patients (13.2 million, 8.6% of uncomplicated malaria cases) and overweight adults (10.3 million, 6.7% of uncomplicated cases). The estimated excess total number of treatment failures ranged from 0.338 million for a 98% baseline ACT efficacy to 1.352 million for a 92% baseline ACT efficacy. Our study shows that an estimated nearly 1 in 4 people with uncomplicated confirmed P. falciparum malaria in Africa are at risk of receiving a sub-optimal antimalarial drug dosing. This increases the risk of antimalarial drug resistance and poses a serious threat to malaria control and elimination efforts. Changes in antimalarial dosing or treatment duration of current antimalarials may be needed and new antimalarials development should ensure sufficient drug concentration levels in these sub-populations that carry a high malaria burden.

Finasteride and Dutasteride for the Treatment of Male Androgenetic Alopecia: A Review of Efficacy and Reproductive Adverse Effects

Finasteride and dutasteride are 5-α-reductase inhibitors (5-ARIs) used to treat androgenetic alopecia (AGA). This review evaluates the efficacy of 5-ARIs for treatment of men with AGA and the potential adverse effects on reproduction including sexual dysfunction, infertility, and teratogenicity. A broad literature review was conducted to search for publications on 5-ARI treatment in men with AGA. Hair counts, hair growth assessments, sexual adverse effects (erectile dysfunction, ejaculatory dysfunction, and decreased libido), change in sperm parameters (decreased sperm count, semen volume, sperm motility), and teratogenic drug concentration levels in semen were the measured outcomes of studies included in this literature review. Both finasteride and dutasteride are effective at treating hair loss in male AGA, with studies finding dutasteride was more efficacious than finasteride. Many studies reported sexual adverse effects of 5-ARIs that are uncommon and resolve spontaneously, although there remains no consensus with respect to the presence, severity, and duration of sexual adverse effects. 5-ARIs may have a negative impact on spermatogenesis although the clinical significance of this is unclear and discontinuation of these medications results in improved sperm parameters for most patients. Teratogenicity after paternal exposure is unlikely due to the low concentration of 5-ARIs absorbed in semen. Further research is needed to evaluate the effects of 5-ARI use on reproduction.

A comparative study between conventional chemotherapy and photothermal activated nano-sized targeted drug delivery to solid tumor

Delivery of chemotherapeutic medicines to solid tumors is critical for optimal therapeutic success and minimal adverse effects. We mathematically developed a delivery method using thermosensitive nanocarriers activated by light irradiation. To assess its efficacy and identify critical events and parameters affecting therapeutic response, we compared this method to bolus and continuous infusions of doxorubicin for both single and multiple administrations. A hybrid sprouting angiogenesis approach generates a semi-realistic microvascular network to evaluate therapeutic drug distribution and microvascular heterogeneity. A pharmacodynamics model evaluates treatment success based on tumor survival cell percentage. The study found that whereas bolus injection boosted extracellular drug concentration levels by 90%, continuous infusion improved therapeutic response due to improved bioavailability. Cancer cell death increases by 6% with several injections compared to single injections due to prolonged chemotherapeutic medication exposure. However, responsive nanocarriers supply more than 2.1 times more drug than traditional chemotherapy in extracellular space, suppressing tumor development longer. Also, controlled drug release decreases systemic side effects substantial through diminishing the concentration of free drug in the circulation. The primary finding of this work highlights the significance of high bioavailability in treatment response. The results indicate that responsive nanocarriers contribute to increased bioavailability, leading to improved therapeutic benefits. By including drug delivery features in a semi-realistic model, this numerical study sought to improve drug-bio interaction comprehension. The model provides a good framework for understanding preclinical and clinical targeted oncology study outcomes.

Development, optimization and in vitro-in vivo evaluation of solid lipid microparticles for improved pharmacokinetic profile of bisoprolol

Development, optimization and in vitro-in vivo evaluation of solid lipid microparticles for improved pharmacokinetic profile of bisoprolol

Drug Diffusion from the Gastrointestinal Tract through the Body, Bloodstream, and Urinary Compartments: Mathematical Modeling Approach

This research involved the formulation of a mathematical system that mimics the diffusion of drug concentration from the gastrointestinal tract to the body and bloodstream compartments and the elimination through the urinary tract. The models are formulated separately as ordinary differential equations for the aforementioned compartments, where some pertinent entry parameters in the form of rates were obtained. We applied the Laplace method of solution to solve the formulated mathematical models for the drug concentration in the various compartments as mentioned. In order to investigate the effect of the drug concentration in the urinary and gastrointestinal tracts on the concentration in the body and bloodstream compartments, we solved the urinary tract and gastrointestinal models and substituted the results into the models representing the drug concentration in the body and bloodstream compartments, and those models were later solved to obtain the function representing the body and bloodstream compartments. The research further involved the numerical simulation of the various functions obtained by varying the various rates of diffusion on the drug concentration in the body and bloodstream compartments. The results revealed that the various diffusion rate changes affect the drug concentration level in the body and bloodstream compartments, respectively. The novelty of this research is the fact that we’ve been able to incorporate drug administration and concretion in the gastrointestinal and urinary tracts, which were not considered previously. This research is recommended for application by mathematicians and scientists alike who could be interested in understanding drug diffusion from one compartment to another with different rate constants.

Topological Optimisation Structure Design for Personalisation of Hydrogel Controlled Drug Delivery System.

Personalised controlled drug delivery systems (CDDSs) can adjust drug concentration levels according to patient needs, which has enormous research prospects in precision medicine. In this study, the topological optimisation method was utilised in the structural design of a hydrogel CDDS to achieve a parameter-based adjustment of the drug average concentration in the hydrogel. A polyacrylamide/sodium alginate dual-network hydrogel was selected as a drug carrier, and tetracycline hydrochloride was used as a model drug. The topological optimisation model of the hydrogel CDDS was developed. The effects of the mesh size, target concentration, and volume factor on the optimised results were investigated. Hydrogel flow channel structures were obtained, which satisfied the different target concentrations. To verify the rationality of the optimisation model, in vitro drug release experiments were carried out. The results show that the hydrogel CDDS can control drug release within 7 days, and the drug release tends to follow zero-order release behaviour. The adjustable average concentration of tetracycline hydrochloride in hydrogel CDDS is recommended in the range of 20.79 to 31.04 mol/m3. This novel method provides a reference for personalised structure design of CDDS in the context of precision medicine.

The Progress and Pitfalls of Pharmacogenetics-Based Precision Medicine in Schizophrenia Spectrum Disorders: A Systematic Review and Meta-Analysis

The inadequate efficacy and adverse effects of antipsychotics severely affect the recovery of patients with schizophrenia spectrum disorders (SSD). We report the evidence for associations between pharmacogenetic (PGx) variants and antipsychotics outcomes, including antipsychotic response, antipsychotic-induced weight/BMI gain, metabolic syndrome, antipsychotic-related prolactin levels, antipsychotic-induced tardive dyskinesia (TD), clozapine-induced agranulocytosis (CLA), and drug concentration level (pharmacokinetics) in SSD patients. Through an in-depth systematic search in 2010-2022, we identified 501 records. We included 29 meta-analyses constituting pooled data from 298 original studies over 69 PGx variants across 39 genes, 4 metabolizing phenotypes of CYP2D9, and 3 of CYP2C19. We observed weak unadjusted nominal significant (p < 0.05) additive effects of PGx variants of DRD1, DRD2, DRD3, HTR1A, HTR2A, HTR3A, and COMT (10 variants) on antipsychotic response; DRD2, HTR2C, BDNF, ADRA2A, ADRB3, GNB3, INSIG2, LEP, MC4R, and SNAP25 (14 variants) on weight gain; HTR2C (one variant) on metabolic syndrome; DRD2 (one variant) on prolactin levels; COMT and BDNF (two variants) on TD; HLA-DRB1 (one variant) on CLA; CYP2D6 (four phenotypes) and CYP2C19 (two phenotypes) on antipsychotics plasma levels. In the future, well-designed longitudinal naturalistic multi-center PGx studies are needed to validate the effectiveness of PGx variants in antipsychotic outcomes before establishing any reproducible PGx passport in clinical practice.

Quantitative systems pharmacology of the eye: Tools and data for ocular QSP.

Good eyesight belongs to the most-valued attributes of health, and diseases of the eye are a significant healthcare burden. Case numbers are expected to further increase in the next decades due to an aging society. The development of drugs in ophthalmology, however, is difficult due to limited accessibility of the eye, in terms of drug administration and in terms of sampling of tissues for drug pharmacokinetics (PKs) and pharmacodynamics (PDs). Ocular quantitative systems pharmacology models provide the opportunity to describe the distribution of drugs in the eye as well as the resulting drug-response in specific segments of the eye. In particular, ocular physiologically-based PK (PBPK) models are necessary to describe drug concentration levels in different regions of the eye. Further, ocular effect models using molecular data from specific cellular systems are needed to develop dose-response correlations. We here describe the current status of PK/PBPK as well as PD models for the eyes and discuss cellular systems, data repositories, as well as animal models in ophthalmology. The application of the various concepts is highlighted for the development of new treatments for postoperative fibrosis after glaucoma surgery.