Genetic Variants of the NF-κB Pathway: Unraveling the Genetic Architecture of Psoriatic Disease

Psoriasis is a multifactorial genetic disease for which the genetic factors explain about 70% of disease susceptibility. Up to 30–40% of psoriasis patients develop psoriatic arthritis (PsA). However, PsA can be considered as a “disease within a disease”, since in most cases psoriasis is already present when joint complaints begin. This has made studies that attempt to unravel the genetic basis for both components of psoriatic disease enormously difficult. Psoriatic disease is also accompanied by a high burden of comorbid conditions, mainly of the cardiometabolic type. It is currently unclear whether these comorbidities and psoriatic disease have a shared genetic basis or not. The nuclear factor of kappa light chain enhancer of activated B cells (NF-κB) is a transcription factor that regulates a plethora of genes in response to infection, inflammation, and a wide variety of stimuli on several cell types. This mini-review is focused on recent findings that highlight the importance of this pathway both in the susceptibility and in the determinism of some features of psoriatic disease. We also briefly review the importance of genetic variants of this pathway as biomarkers of pharmacological response. All the above may help to better understand the etiopathogenesis of this complex entity.

Neuroacting drugs and its pharmacological response in relation to different stress status: A review

This article intended to review many methods and types of stressors in the previous works of literaturethat describe the role of these stressors to induce modifications and alterations in the pharmacological response of the drugs acting on the nervous system (neuroacting drugs) in human and animal models. The current review focus on the different methods for inducing stress status which categorized as chemical, physical and miscellaneous stressors that affect on the well-known pharmacological response of the neuroacting drugs and by which mechanism can the stressor induce a modification in the drug target response with mentioning the findings related to changes in the pharmcologiacal response of the neuroacting drugs in previous literature. In conclusion, most studies suggest an alteration of the pharmacological response of neuroacting drugs, commonly by potentiating their efficacy and subsequent toxicity, due to different stressful methods, which may be obligated to the direct and indirect receptor modification (pharmacodynamic interaction) in addition to the direct pharmacokinetic influence on the essential parameters of absorption, distribution, metabolism, and excretion of the neuroacting drugs.

Development and evaluation of buccal patches of theophylline

Buccal patches are the types of formulations in which the drug is administered through buccal mucosa. these patches are or placed in between the gums and the for the pharmacological response. The main advantage of these patches is there is no first pass metabolism takes place and easily absorb in systemic circulation through themucosa .the main objective of this drug delivery system is to elevate or increase the bioavailability of the drug. the review informs about the steps involve in the preparation of buccal patch and to promote the awareness towards this type of drug delivery system. This article intends to analyze the overall profile of Buccal Patches and scope of future advances.

Dose-dependent Pharmacological Response to Rituximab in the Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculiti

Objective Rituximab (RTX) is effective in induction and maintenance of remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, uncertainty remains regarding the optimal maintenance dosing regimen. This work evaluates the relationship between variability in RTX dosing and pharmacological response in AAV. Methods A prospective cohort of AAV patients (n=28) with either GPA (n=23) or MPA (n=5) receiving maintenance RTX therapy were followed in a single tertiary care academic medical center over a 2-year period. Patient demographics, RTX dosing information, and trough plasma RTX levels were collected along with laboratory measures of pharmacologic response, including B-cell counts and ANCA titers. Results RTX dosing information from 94 infusions with 59 trough samples were collected with a mean±SD dose of 640±221 mg, dosing interval of 210±88 days, and trough plasma RTX concentration of 622±548 ng/mL. RTX trough concentrations were associated with RTX dose (ρ=0.60, p<0.0001) and dosing interval (ρ=-0.55, p<0.0001). RTX dosing intensity (mg/d) was associated with RTX trough concentrations (ρ=0.57, p<0.0001). Higher dosing intensities were associated with undetectable B-cell repopulation (p<0.0001), but not negative ANCA titers (p=0.6). Stratification of dosing intensities based on the standard dosing regimen of 500 mg every six months (2.4 to 3.3 mg/d) demonstrated that this regimen was associated with B-cell repopulation in 8 of 17 doses (47%) compared to 0 of 23 doses (0%) with the high-dose regimen (>3.3 mg/d) (p<0.0001). Conclusion RTX maintenance dosing of 500 mg every six months may be inadequate to maintain B-cell depletion in the treatment of AAV.

Progressing our understanding of the impacts of nutrition on the brain and behaviour in anorexia nervosa: a tyrosine case study example

Anorexia nervosa is a severe and complex illness associated with a lack of efficacious treatment. The effects of nutrition on the brain and behaviour is of particular interest, though an area of limited research. Tyrosine, a non-essential amino acid, is a precursor to the catecholamines dopamine, noradrenaline and adrenaline. Ongoing tyrosine administration has been proposed as an adjunct treatment through increasing blood tyrosine sufficiently to facilitate brain catecholamine synthesis. The effects of tyrosine supplementation in adolescents with anorexia nervosa remain to be tested. This study had approval from the Hunter New England Human Research Ethics Committee (06/05/24/3.06). We aimed to explore the pharmacokinetics of tyrosine loading in adolescents with anorexia nervosa (n = 2) and healthy peers (n = 2). The first stage of the study explored the pharmacological response to a single, oral tyrosine load in adolescents (aged 12–15 years) with anorexia nervosa and healthy peers. Participants with anorexia nervosa then continued tyrosine twice daily for 12 weeks. There were no measured side effects. Peak tyrosine levels occurred at approximately two to three hours and approached baseline levels by eight hours. Variation in blood tyrosine response was observed and warrants further exploration, along with potential effects of continued tyrosine administration in anorexia nervosa.

Leptin and its receptor gene polymorphism as a target for pharmacotherapy in T2DM and COPD

Combined pathology is a real problem for rational pharmacotherapy due to multiple organ damage. The need to affect simultaneously several pathogenesis processes leads to polypharmacy that can appear to be less effective, toxic and unacceptable in some time. For comorbid patients with long - term ongoing type 2 diabetes mellitus (T2DM), the problem of drug interactions is as relevant as the selection of optimal hypoglycemic therapy. This review aims to identify opportunities to optimize drug therapy in comorbid pathology to increase the effectiveness of pharmacotherapy, improve the prognosis and outcomes of concomitant diseases, and slow the progression of one or a combination of diseases. One of the ways to individualize pharmacotherapy is to identify polymorphic genes that can account not only to the predisposition to the disease, but also to the formation of a pharmacological response, thus determining the effectiveness of drug therapy. A peptide hormone leptin along with its receptors in various tissues could be the milestone of unifying pathology that contributes both to the development of diseases - chronic obstructive pulmonary disease (COPD) and T2DM. This modality potentially forms the pharmacological response to prescribed drug therapy of such. Gene polymorphism determines the development of pathologies such as leptin and insulin resistance. These deteriorations are in turn likely to be the targets of many oral antidiabetic drugs. The review suggests potential associations and directions for research in the field of pharmacogenetics of drugs used for the treatment of comorbid patients. The duly identified mutations involved in the general pathogenesis of type 2 diabetes and COPD will account to the approach toward tailored medicine and contribute to proper control of both diseases.

Cannabis Use in People With Obsessive-Compulsive Symptomatology: Results From a Mexican Epidemiological Sample

Recent studies suggest that the endocannabinoid system could play an important role in the physiopathology of obsessive-compulsive disorder (OCD). There are reports of effective treatment with derivatives of tetrahydrocannabinol (THC). The study of the genetic factor associated with psychiatric disorders has made possible an exploration of its contribution to the pharmacological response. However, very little is known about the genetic factor or the prevalence of cannabis use in the Mexican population with OCD. The objective of this study is to compare the prevalence of use and dependence on cannabis in individuals with obsessive-compulsive symptomatology (OCS) with that of individuals with other psychiatric symptoms (psychosis, depression, and anxiety), and to explore the association between genetic risk and use. The study includes a total of 13,130 individuals evaluated in the second stage of the 2016 National Survey of Drug, Alcohol, and Tobacco Use (Encodat 2016), with genetic analysis (polygenic risk scoring) of a subsample of 3,521 individuals. Obsessive symptomatology had a prevalence of 7.2% and compulsive symptomatology a prevalence of 8.6%. The proportion of individuals with OCS who had ever used cannabis was 23.4%, and of those with cannabis dependency was 2.7%, the latter figure higher than that in individuals with other psychiatric symptoms (hypomania, 2.6%; anxiety, 2.8%; depression, 2.3%), except psychosis (5.9%). Individuals with OCS who reported using cannabis had an increased genetic risk for cannabis dependence but not for OCD. We thus cannot know how the increased genetic risk of cannabis dependence in people with OCD is influenced by their pharmacological response to derivatives of THC. The results, however, suggest paths for future studies.

Pharmacological validation of SSc-ILD mouse model bleomycin-induced by osmotic minipump

Systemic sclerosis (SSc) is an autoimmune disease characterized by an excessive production and accumulation of collagen in the skin and internal organs often associated with interstitial lung disease (ILD). The unknown pathogenetic mechanisms of SSc-ILD and the lack of animal models mimicking the features of the human disease contribute to create a gap between the selection of antifibrotic drug candidates and effective therapies. Nintedanib (NINT) was used as a tool compound to validate the pharmacological response either on lung or skin fibrosis in a SSc-ILD mouse model. The model is based on the continuous infusion of bleomycin (BLM) by osmotic minipumps for 1 week in the C57BL/6 female mice. Longitudinal Micro-CT analysis highlighted a significant slowdown in lung fibrosis progression after NINT treatment, then confirmed by histology. However, no significant effect was observed on lung hydroxyproline content, inflammatory infiltrate and skin lipoatrophy. The modest pharmacological effect reported reflects the clinical outcome, lighting up the reliability of this model to serve as secondary screening to profile the best clinical drug candidates. Moreover, we have underlined the pivotal role of Micro-CT imaging, together describing the relevant readouts and the importance of their validation prior to use for drug discovery.

Publisher Correction: MLIP genotype as a predictor of pharmacological response in primary open-angle glaucoma and ocular hypertension

An amendment to this paper has been published and can be accessed via a link at the top of the paper.