Adv Pharm Bull. 2023 Nov;13(4):688-700. doi: 10.34172/apb.2023.071. Epub 2023 Jan 23.

ABSTRACT

Glycogen synthase kinase-3 (GSK-3) was discovered to be a multifunctional enzyme involved in a wide variety of biological processes, including early embryo formation, oncogenesis, as well cell death in neurodegenerative diseases. Several critical cellular processes in the brain are regulated by the GSK-3β, serving as a central switch in the signaling pathways. Dysregulation of GSK-3β kinase has been reported in diabetes, cancer, Alzheimer's disease, schizophrenia, bipolar disorder, inflammation, and Huntington's disease. Thus, GSK-3β is widely regarded as a promising target for therapeutic use. The current review article focuses mainly on Alzheimer's disease, an age-related neurodegenerative brain disorder. GSK-3β activation increases amyloid-beta (Aβ) and the development of neurofibrillary tangles that are involved in the disruption of material transport between axons and dendrites. The drug-binding cavities of GSK-3β are explored, and different existing classes of GSK-3β inhibitors are explained in this review. Non-ATP competitive inhibitors, such as allosteric inhibitors, can reduce the side effects compared to ATP-competitive inhibitors. Whereas ATP-competitive inhibitors produce disarrangement of the cytoskeleton, neurofibrillary tangles formation, and lead to the death of neurons, etc. This could be because they are binding to a site separate from ATP. Owing to their interaction in particular and special binding sites, allosteric ligands interact with substrates more selectively, which will be beneficial in resolving drug-induced resistance and also helpful in reducing side effects. Hence, in this review, we focussed on the allosteric GSK-3β inhibitors and discussed their futuristic opportunities as anti-Alzheimer's compounds.

PMID:38022801 | PMC:PMC10676556 | DOI:10.34172/apb.2023.071

Cureus. 2023 Oct 27;15(10):e47807. doi: 10.7759/cureus.47807. eCollection 2023 Oct.

ABSTRACT

Drug-induced autoimmune hepatitis (DIAIH) is a poorly understood form of drug-induced liver injury that presents with features mimicking autoimmune hepatitis. Statins, commonly prescribed for lowering cholesterol and for cardiovascular disease prevention, have been documented in rare cases as being responsible for DIAIH. In this case report, we detail a case where a patient developed DIAIH due to her atorvastatin. We also highlight the diagnostic approach and management strategies for DIAIH.

PMID:38021877 | PMC:PMC10679798 | DOI:10.7759/cureus.47807

Cureus. 2023 Oct 26;15(10):e47742. doi: 10.7759/cureus.47742. eCollection 2023 Oct.

ABSTRACT

INTRODUCTION: Levetiracetam (LEV) and valproic acid (VPA) are two anti-epileptic drugs (AEDs) routinely used for post-traumatic seizure (PTS) prophylaxis at our institution. In our practice, VPA is used for its beneficial effects on behavioral agitation and headaches, but it is also associated with abnormal liver function tests (LFTs). Both medications may be associated with thrombocytopenia. There is less literature comparing the adverse effect profiles and discontinuation rates of LEV and VPA in the context of PTS prophylaxis. We conducted a quality improvement (QI) analysis to determine the safety of LEV and VPA for traumatic brain injury (TBI) patients at our institution. In particular, our QI analysis involved calculating the rates of discontinuation or change of drug regimen due to the adverse effects.

METHODS: Our QI analysis focused on patients treated for TBI at our institution during a six-year period. We recorded the AED used and if the AED was discontinued or switched due to thrombocytopenia, behavioral agitation, headaches, or elevated LFTs (including elevated aspartate aminotransferase or alanine aminotransferase values). We also recorded the incidence of early PTS, defined as seizures within seven days of the TBI.

RESULTS: Our QI analysis included patients with a mean age of approximately 49 years with nearly 75% males. The mean Glasgow Coma Scale (GCS) score was 12.88, with 73.11% of patients having a mild GCS. The three leading injury mechanisms were fall, assault, and motor vehicle collision. The three leading types of TBI were traumatic subarachnoid hemorrhage, subdural hematoma, and cerebral contusion. Among patients with no prior history of seizures, we found an early PTS incidence of 7.28%. For patients administered LEV and VPA, 0.11% (1/898) and 3.85% (4/104) had the medication discontinued or changed because of thrombocytopenia (p < 0.001), respectively. For patients on LEV, 4.01% (36/898) and 1.78% (16/898) had the medication discontinued or changed because of behavioral agitation and headaches, respectively. For patients on VPA, 2.88% (3/104) had the medication discontinued or changed because of hepatotoxicity. In total, 5.90% versus 6.73% (p > 0.5) of patients on LEV and VPA, respectively, had their medication regimens changed due to the adverse effects.

CONCLUSIONS: The incidence of early PTS in our patients is within the range of what has been reported in the literature. The rate of discontinuation of LEV and VPA on account of adverse events is low in the context of PTS prophylaxis. Both medications had similar overall rates of discontinuation. VPA was discontinued more frequently than LEV due to thrombocytopenia, but discontinuation was not common in either case. LEV is associated with behavioral agitation and headaches, which makes VPA a desirable alternative for patients suffering from these symptoms.

PMID:38021754 | PMC:PMC10676217 | DOI:10.7759/cureus.47742

CNS Drugs. 2023 Nov 29. doi: 10.1007/s40263-023-01042-3. Online ahead of print.

ABSTRACT

INTRODUCTION: Depression, anxiety, and/or panic disorder are often comorbid and have a complex etiology mediated through the same neuronal network. Cholecystokinin-tetrapeptide (CCK-4), a synthetic analog of the endogenous neuropeptide cholecystokinin (CCK), is thought to be implicated in this network. The CCK-4 challenge model is an accepted method of investigating the pathophysiology of panic and has been shown to mediate neuronal activation via the transient receptor potential canonical (TRPC) ion channels.

OBJECTIVES: This study aimed to assess the pharmacodynamic effects of BI 1358894, a small-molecule inhibitor of TRPC ion channel members 4 and 5 (TRPC4/5), on CCK-4-induced anxiety/panic-like symptoms and evaluate circuit engagement.

METHODS: Twenty healthy male CCK-4-sensitive volunteers entered a Phase I, double blind, randomized, two-way cross-over, single dose, placebo-controlled trial. Randomization was to oral BI 1358894 100 mg in the fed state followed by oral placebo in the fed state, or vice versa. Treatments were administered 5 h prior to intravenous CCK-4 50 µg. The primary endpoint was maximum change from baseline of the Panic Symptom Scale (PSS) sum intensity score after CCK-4 injection. Further endpoints included the emotional faces visual analog score (EVAS), the Spielberger State-Trait Anxiety Inventory (STAI), plasma adrenocorticotropic hormone (ACTH), and serum cortisol values. The safety and tolerability of BI 1358894 was assessed based on a number of parameters including occurrence of adverse events (AEs). All pharmacodynamic, pharmacokinetic, and safety endpoints were analyzed using descriptive statistics.

RESULTS: Single oral doses of BI 1358894 were generally well tolerated by the healthy male volunteers included in this study. Adjusted mean maximum change from baseline in PSS sum intensity score was 24.4 % lower in volunteers treated with BI 1358894 versus placebo, while adjusted mean maximum change from baseline of EVAS was reduced by 19.2 % (BI 1358894 vs placebo). The STAI total score before CCK-4 injection was similar in both groups (placebo: 25.1; BI 1358894: 24.3). Relative to placebo, BI 1358894 reduced CCK-4-induced mean maximum plasma ACTH and serum cortisol values by 58.6 % and 27.3 %, respectively. Investigator-assessed drug-related AEs were reported for 13/20 participants (65.0 %). There were no serious or severe AEs, AEs of special interest, AEs leading to discontinuation of trial medication, or deaths.

CONCLUSIONS: Overall, BI 1358894 reduced psychological and physiological responses to CCK-4 compared with placebo, as measured by PSS, subjective EVAS and objectively measured stress biomarkers. BI 1358894 had a positive safety profile, and single oral doses were well tolerated by the healthy volunteers. This trial (NCT03904576/1402-0005) was registered on Clinicaltrials.gov on 05.04.19.

PMID:38019356 | DOI:10.1007/s40263-023-01042-3

CNS Drugs. 2023 Nov 29. doi: 10.1007/s40263-023-01041-4. Online ahead of print.

ABSTRACT

INTRODUCTION: The transient receptor potential canonical (TRPC) ion channels have been implicated in the pathophysiology of major depressive disorder (MDD), and TRPC inhibition has been shown to reduce depressive-like behaviour in rodent models of depression. BI 1358894, a small-molecule inhibitor of TRPC ion channels, is currently being developed for the treatment of MDD.

OBJECTIVE: Two phase I studies assessed the safety, tolerability, and pharmacokinetics (PK) of oral BI 1358894 in fed and fasted states following a single ascending dose (SAD) [NCT03210272/1402-0001] and multiple ascending doses (MAD) [NCT03754959/1402-0002] in healthy male volunteers. In addition, any potential food effect was evaluated after a single dose.

METHODS: In both studies, eligible healthy male volunteers (aged 18-45 years; body mass index of 18.5-29.9 kg/m2) were allocated to receive BI 1358894 or placebo. In the SAD study (1402-0001), volunteers were randomised 3:1 to receive BI 1358894 or placebo in fasted (3, 6, 10, 25, 50, 100, or 200 mg) and fed states (200 mg). The food effect part was conducted as an open-label, randomised, two-way crossover study at doses of 50 and 100 mg in fasted and fed states (high-calorie, high-fat breakfast). For the MAD study (1402-0002), volunteers were randomised 4:1 to receive BI 1358894 (10, 25, 50, 100, or 200 mg) or placebo once daily for 14 days under fed conditions. Primary endpoint (both studies): number of volunteers with drug-related adverse events (DRAEs). Secondary PK endpoints for study 1402-0001: area under the concentration-time curve (AUC) from time zero extrapolated to infinity (AUC∞), maximum plasma concentration (Cmax), and AUC from time zero to the last quantifiable data time point (AUC0-tz). Secondary PK endpoints for study 1402-0002: AUC over 0-24 h (AUC0-24), Cmax after the first dose, and steady-state AUC and Cmax over a uniform dosing interval (AUCτ,ss and Cmax,ss, respectively) after the last dose.

RESULTS: BI 1358894 was well tolerated at doses ≤ 200 mg under all tested conditions and no dose dependency was observed in DRAE frequency for either study. In the SAD study, BI 1358894 exposure increased dose proportionally across 3-50 mg in the fasted state and across 50-200 mg in the fed state. A positive food effect was observed at the tested doses. In the MAD study, BI 1358894 exposure increased less than dose proportionally across 10-200 mg.

CONCLUSIONS: These studies demonstrate that BI 1358894 is well tolerated in healthy male volunteers following single and multiple doses, with no dose dependency observed in DRAE frequency. BI 1358894 exposure increased dose dependently in both the SAD and MAD studies, with higher exposure of BI 1358894 observed in the fed state.

CLINICALTRIALS REGISTRATION: These trials have been registered on ClinicalTrials.gov: NCT03210272/1402-0001 (registered on 6 July 2017) and NCT03754959/1402-0002 (registered on 27 November 2018).

PMID:38019355 | DOI:10.1007/s40263-023-01041-4

J Gerontol Nurs. 2023 Dec;49(12):5-10. doi: 10.3928/00989134-20231107-02. Epub 2023 Dec 1.

ABSTRACT

Older adults have an increased risk of adverse drug events related to polypharmacy and potentially inappropriate medication (PIM) use. These patients are even more vulnerable as they transition through different health care settings. In 2023, the American Geriatrics Society published an updated version of the Beers Criteria®, providing updated guidance on identifying and managing PIMs. Nurses and nurse practitioners play important roles in medication management across the continuum of care. The current article aims to illustrate key concepts regarding medication safety and deprescribing for older adult patients during transitions of care. [Journal of Gerontological Nursing, 49(12), 5-10.].

PMID:38015150 | DOI:10.3928/00989134-20231107-02

Ital J Dermatol Venerol. 2023 Dec;158(6):437-444. doi: 10.23736/S2784-8671.23.07542-4.

ABSTRACT

BACKGROUND: Cutaneous adverse events (CAEs) related to oncological therapies are a common scenario in daily clinical practice.

METHODS: This is a retrospective observational study collecting the data regarding CAEs of patients treated with immune checkpoints inhibitors (ICIs) in four different Italian centers.

RESULTS: Of 323 patients included, 305 were evaluable for this analysis; 182 patients (59.7%) had metastatic cutaneous melanoma (CM), 99 (32.5%) non-small cell lung cancer (NSCLC) and 24 (7.8%) renal cell carcinoma (RCC). The most frequent CAEs that we found, considering all the 305 patients, were pruriginous maculopapular rash (10.2% of the patients), vitiligo-like areas (7.2% of the patients), psoriasiform rash (6.2% of the patients), asymptomatic maculopapular rash (4.6% of the patients), and lichenoid rash (4.3% of the patients). Vitiligo-like areas occurred more frequently in patients with CM, while a lichenoid rash was more frequently observed in patients with RCC. Treatment interruption was related to drug-induced CAEs in 15.4% of melanoma patients and 0.0% of lung and kidney patients. Patients developing a cutaneous adverse event had better overall response rate and higher progression free survival and overall survival than the patients without CAEs.

CONCLUSIONS: Our study brings new information on the characteristics of CAEs related to ICIs treatment in three different types of cancers, CM, NSCLC and RCC.

PMID:38015482 | DOI:10.23736/S2784-8671.23.07542-4

Expert Opin Drug Saf. 2023 Nov 28. doi: 10.1080/14740338.2023.2289176. Online ahead of print.

ABSTRACT

INTRODUCTION: Acute myeloid leukemia (AML) treatment has primarily focused on 7 + 3 chemotherapy, but in the last decade there has been a significant increase in new therapies, mostly targeted agents, approved for the treatment of AML. We performed a comparative analysis of the unique safety profile of each of these new agents.

AREAS COVERED: We conducted a review of the current literature on public databases (PubMed, ClinicalTrials.gov, and U.S. Food and Drug Administration) regarding new AML drugs that were approved from 2017 to 2023.

EXPERT OPINION: The diagnosis of AML typically carries a poor prognosis but with an increase in the number of drugs that are now available, patients' outcomes are improving. With novel mechanisms of action, the use of these agents introduces different safety profiles, occasionally with adverse events not previously seen with standard chemotherapy or at different frequencies. An understanding of the drugs available and the safety concerns associated with each one is crucial to selecting the best available option for each patient, and early recognition and appropriate management of drug-related adverse effects.

PMID:38014918 | DOI:10.1080/14740338.2023.2289176

Women Health. 2023 Nov 28:1-9. doi: 10.1080/03630242.2023.2286264. Online ahead of print.

ABSTRACT

Cyclophosphamide is a drug used in chemotherapy. However, it has side effects, including changes in reproductive system functioning. Some herbal compounds can reduce the harmful effects of cyclophosphamide. This study aims to investigate the protective role of crocin against changes caused by Cyclophosphamide in ovarian tissue through changes in the expression of genes involved in the hypothalamic-pituitary-gonadal axis. This experimental study was performed on 24 adult female Wistar rats. Mice were divided into four groups (normal saline, 30 mg/kg cyclophosphamide, 100 mg/kg crocin and 30 mg/kg cyclophosphamide, and 200 mg/kg crocin and 30 mg/kg cyclophosphamide). At the end of the treatment period, the hypothalamus and ovaries were also removed to evaluate ob-Rb, ob-Ra, and NPY genes expression using real-time PCR and histological changes in the ovaries. Data were analyzed by SPSS statistical software. The expression of genes, number of follicles, and follicle diameter significantly decreased in the cyclophosphamide-treated groups compared with the control group. In the crocin and cyclophosphamide-treated groups, drug-induced reproductive complications were mitigated. The current findings indicate that by increasing the expression of genes ob-Rb, ob-Ra, and NPY, crocin could modulate the harmful effects of cyclophosphamide.

PMID:38014433 | DOI:10.1080/03630242.2023.2286264

Curr J Neurol. 2020 Jul 5;19(3):103-106. doi: 10.18502/cjn.v19i3.5422.

ABSTRACT

Background: The study aimed to judge the safety and possible side effects of rituximab (RTX) drug in patients with multiple sclerosis (MS). Methods: This retrospective observational study was performed on 91 patients with MS who had been treated with RTX between 2016 and 2019. Each patient was visited and examined a minimum of once. The side effects of the drug and therefore the drug-related reactions to the injection were asked via phone calls, which were recorded separately as mild, moderate, and severe modes with the necessity for hospitalization. Results: A total of 91 patients were enrolled within the study: 80 patients with relapsing-remitting MS (RRMS), 6 patients with secondary progressive MS (SPMS), and 5 patients with primary progressive MS (PPMS). The mean age of the patients was 32.18 ± 8.71 years (18 to 60 years). The injection-related side effects occurred in 30.8% of the injections, most of which were mild and one of the mild complications was urinary tract infection (UTI). Two cases of complications with moderate severity were recorded. Conclusion: The observations from this study demonstrated that RTX did not cause serious complications in patients with MS.

PMID:38011421 | PMC:PMC8185590 | DOI:10.18502/cjn.v19i3.5422

Shock. 2023 Nov 22. doi: 10.1097/SHK.0000000000002277. Online ahead of print.

ABSTRACT

AIMS: We conducted a systemic review and meta-analysis to evaluate the therapeutic efficacy and safety of soluble guanylate cyclase(sGC) stimulators in patients with heart failure with preserved ejection fraction(HFpEF).

METHODS: We systematically searched PubMed, EMBASE and Cochrane Library databases for original randomized controlled trials comparing sGC stimulators with placebo in HFpEF patients. A random-effects model was applied to evaluate the mortality, quality of life and drug-related adverse events. This meta-analysis is registered in PROSPERO under the number CRD42023457382.

RESULTS: We included five studies involving 1600 HFpEF patients. Comprehensively, the combined risk ratio (RR) for mortality was not significant(RR(95% CI) = 1.44 (0.71-2.91), p = 0.31). Furthermore, there were no statistically significant differences in the Kansas City Cardiomyopathy Questionnaire (KCCQ) results, including the Clinical Summary Score(CSS) (WMD (95% CI) =0.32( -7.38-8.02), p = 0.94) and the Overall Summary Score(OSS) (WMD (95% CI) = -0.87( -8.87-7.14), P = 0.83). Similarly, there was no significant improvement in the 6-minute walk distance(6MWD) (WMD(95% CI) = -6.22(-18.56-6.12), p = 0.32). Additionally, drug-related adverse events were more common in patients treated with sGC stimulators(RR(95%CI) = 1.63,(1.25-2.14), p < 0.05).

CONCLUSIONS: Oral sGC stimulators do not significantly improve mortality outcomes, functional capacity and quality of life in HFpEF patients but are associated with increased drug-related adverse events. Therefore, we should consider using sGC stimulators in HFpEF patients carefully.

PMID:38010279 | DOI:10.1097/SHK.0000000000002277

Australas J Dermatol. 2023 Nov 27. doi: 10.1111/ajd.14190. Online ahead of print.

NO ABSTRACT

PMID:38009895 | DOI:10.1111/ajd.14190

Clin J Oncol Nurs. 2023 Nov 16;27(6):644-652. doi: 10.1188/23.CJON.644-652.

ABSTRACT

BACKGROUND: Despite advances in antiemetic regimens, uncontrolled chemotherapy-induced nausea and vomiting (CINV) remains a problem for patients receiving oncology treatment, leading to decreased quality of life and worse treatment outcomes.

OBJECTIVES: The purpose of this pilot project was to use follow-up telephone calls to identify barriers related to successful management and prevention of CINV on a single-center outpatient chemotherapy infusion unit.

METHODS: A mixed-methods descriptive design was used for this project. Quantitative data were used to assess barriers to management and prevention of CINV. Secondary multiple regression analysis was used to determine whether barriers could predict CINV. Qualitative data were used to analyze common barriers and themes.

FINDINGS: Of the patients called (N = 132), 50% identified a barrier to managing and treating CINV, with the most common barrier being knowledge gaps related to proper use of antiemetics.

PMID:38009878 | DOI:10.1188/23.CJON.644-652

Therapie. 2023 Nov 17:S0040-5957(23)00183-X. doi: 10.1016/j.therap.2023.10.015. Online ahead of print.

ABSTRACT

Admissions of the elderly related to medication errors are frequent in hospital, more than half would be avoidable, but there is currently no validated method in French to identify them. The objective of this work was to validate the French version of the AT-HARM10 tool in order to use it for patients admitted in our healthcare facilities. The tool has 10 questions. A positive response to any of the first 3 questions identify admissions that are unlikely to be drug-related. A positive response to one of the following 7 questions identify possible medication-related admissions. For semantic and linguistic validation, we performed cross-validation with forward-backward translation. To clinically validate the method, we conducted a retrospective study including patients over 65 admitted to short-stay units (UHCD) and to orthopedic surgery units in two French hospitals. Two hundred and sixty-six (266) patients were included ; 166 patients admitted to UHCD (mean age 86.0±5.7 years; sex ratio 0.66; mean number of drugs prescribed 7.7±3.8) and 100 patients admitted to orthopedic units (mean age 85.2±6.1 years; sex ratio 0.43; mean number of prescribed drugs 6.4±3.6). We identified 55 % of admissions probably related to medication in UHCD and 76 % in orthopedic units (p<0.05). The most represented item was P5 in both groups (Might [side] effects of the medications the patient was taking [prescribed or not prescribed] prior to hospitalization have caused the admission [including over-treatment] ? The validated AT-HARM10 tool is now integrated into our clinical pharmacy practices and medication reviews are offered as a priority to patients admitted for iatrogenic reasons.

PMID:38008600 | DOI:10.1016/j.therap.2023.10.015

Complement Med Res. 2023 Nov 24. doi: 10.1159/000535437. Online ahead of print.

ABSTRACT

Background Osteoarthritis has a tremendous socioeconomic impact in terms of drug spending, hospital admissions, work productivity and temporary or permanent incapacity. Mud therapy has been discussed as a potential conservative treatment options for osteoarthritis. However, findings from several trials still remain controversial. Methods We conducted a systematic review of the literature on mud-therapy in the treatment of osteoarthritis in order to investigate the evidence of efficiency of this treatment. Results Of the 19 studies included, 15 examined the effects of mud-bath therapy in knee osteoarthritis treatment. We finally systematically reviewed the data obtained from literature and summarized the results on the basis of the main outcomes. The results show significant improvements in function, quality of life and perceived pain for patients with osteoarthritis. Conclusion Results of randomized controlled trials suggest that mud therapy is part of a promising integrated and synergistic multidisciplinary approach in combination with other treatment forms like pharmacotherapy or physiotherapy. Impressing drug- reduction of conventional treatment dosage was reported, possibly resulting in lesser costs and drug-related adverse events.

PMID:38008065 | DOI:10.1159/000535437

G Ital Nefrol. 2023 Oct 3;40(Suppl 81):2023-S81.

ABSTRACT

The introduction of innovative therapies has changed the scenario of complications. The delay in the recognition of kidney adverse effects is partly due to the timing of the development of the kidney damage which occurs later than the observation period of registration studies, and partly to the exclusion of patients with known kidney impairment from registration trials. Renal disease has a significant impact on the management of cancer patients and often leads to discontinuation of therapy. Histological evaluations of kidney disorders induced by targeted/immunotherapy are very limited. Renal biopsy is critical for the management of renal toxicities and should be especially encouraged for patients showing adverse renal effects to novel cancer agents. We recently examined the histological features of patients treated with new cancer agents who underwent renal biopsy for new onset renal failure and/or urinary abnormalities. The cohort included 42 patients. The most frequently administered therapies were immunotherapy (54.8%) and anti-angiogenic treatments (45.2%). The most common adverse effect was tubular interstitial nephritis in the first group and thrombotic microangiopathy in the second one. Based on histological findings, definitive discontinuation of treatment could be restricted to a very limited number of patients. All of them had anti-VEGF-related TMA. Treatment discontinuation was unneeded in patients treated with ICIs. In patients treated with multidrug therapy, the histological findings made it possible to identify the weight of drug-related specific injury. Based on this data, renal biopsy should be considered in every cancer patient who develops urinary abnormalities or shows a worsening of renal function during treatment with immunotherapy or targeted therapy.

PMID:38007829

An Bras Dermatol. 2023 Nov 24:S0365-0596(23)00242-8. doi: 10.1016/j.abd.2023.05.005. Online ahead of print.

ABSTRACT

In dermatologists' clinical practice, the use of systemic glucocorticoids is recurrent for the management of different comorbidities that require chronic immunosuppression. The prescription of this medication requires caution and basic clinical knowledge due to the several adverse effects inherent to the treatment. However, different doubts may arise or inappropriate conduct may be adopted due to the lack of objective and specific guidelines for the screening, prophylaxis and management of complications from chronic corticosteroid therapy. Considering this problem, the authors carried out a narrative review of the literature to gather up-to-date data on adverse effects secondary to the chronic use of systemic glucocorticoids. The broad approach to this topic made it possible to review the pathophysiology and risk factors for these complications, as well as to develop updated orientation that can be used as a learning tool and quick reference for dermatologists during their clinical practice with glucocorticoids.

PMID:38007314 | DOI:10.1016/j.abd.2023.05.005

Pharmaceuticals (Basel). 2023 Nov 13;16(11):1596. doi: 10.3390/ph16111596.

ABSTRACT

Polymorphisms of genes encoding drug metabolizing enzymes and transporters can significantly modify pharmacokinetics, and this can be associated with significant differences in drug efficacy, safety, and tolerability. Moreover, genetic variants of some components of the immune system can explain clinically relevant drug-related adverse events. However, the implementation of drug dose individualization based on pharmacogenomics remains scarce. In this narrative review, the impact of genetic variations on the disposition, safety, and tolerability of the most commonly prescribed drugs is reported. Moreover, reasons for poor implementation of pharmacogenomics in everyday clinical settings are discussed. The literature analysis showed that knowledge of how genetic variations can modify the effectiveness, safety, and tolerability of a drug can lead to the adjustment of usually recommended drug dosages, improve effectiveness, and reduce drug-related adverse events. Despite some efforts to introduce pharmacogenomics in clinical practice, presently very few centers routinely use genetic tests as a guide for drug prescription. The education of health care professionals seems critical to keep pace with the rapidly evolving field of pharmacogenomics. Moreover, multimodal algorithms that incorporate both clinical and genetic factors in drug prescribing could significantly help in this regard. Obviously, further studies which definitively establish which genetic variations play a role in conditioning drug effectiveness and safety are needed. Many problems must be solved, but the advantages for human health fully justify all the efforts.

PMID:38004461 | DOI:10.3390/ph16111596

Antioxidants (Basel). 2023 Oct 30;12(11):1930. doi: 10.3390/antiox12111930.

ABSTRACT

Aripiprazole has fewer metabolic side effects than other antipsychotics; however, there are some severe ones in the liver, leading to drug-induced liver injury. Repeated treatment with aripiprazole affects cell division. Since this process requires a lot of energy, we decided to investigate the impact of aripiprazole on rat liver cells and mitochondria as the main source of cellular energy production by measuring the mitochondrial membrane potential, respiration, adenosine triphosphate (ATP) production, oxidative stress, antioxidative response, and human blood haemolysis. Here, we report that mitochondrial hyperpolarisation from aripiprazole treatment is accompanied by higher reactive oxygen species (ROS) production and increased antioxidative response. Lower mitochondrial and increased glycolytic ATP synthesis demand more glucose through glycolysis for equal ATP production and may change the partition between the glycolysis and pentose phosphate pathway in the liver. The uniform low amounts of the haemolysis of erythrocytes in the presence of aripiprazole in 25 individuals indicate lower quantities of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH+H+), which is in accordance with a decreased activity of glucose 6-phosphate dehydrogenase and the lower dehydrogenase activity upon aripiprazole treatment. The lower activity of glucose 6-phosphate dehydrogenase supports a shift to glycolysis, thus rescuing the decreased mitochondrial ATP synthesis. The putative reduction in NADPH+H+ did not seem to affect the oxidised-to-reduced glutathione ratio, as it remained equal to that in the untreated cells. The effect of aripiprazole on glutathione reduction is likely through direct binding, thus reducing its total amount. As a consequence, the low haemolysis of human erythrocytes was observed. Aripiprazole causes moderate perturbations in metabolism, possibly with one defect rescuing the other. The result of the increased antioxidant enzyme activity upon treatment with aripiprazole is increased resilience to oxidative stress, which makes it an effective drug for schizophrenia in which oxidative stress is constantly present because of disease and treatment.

PMID:38001783 | DOI:10.3390/antiox12111930

BMJ. 2023 Nov 24;383:2784. doi: 10.1136/bmj.p2784.

NO ABSTRACT

PMID:38000791 | DOI:10.1136/bmj.p2784