Concomitant Use Research Articles

Reactivation of Varicella-Zoster Virus in Patients with Lung Cancer Receiving Immune Checkpoint Inhibitors: Retrospective Nationwide Population-Based Cohort Study from South Korea

Background: This study aimed to determine the association between immune checkpoint inhibitors (ICIs) and the risk of herpes zoster (HZ) incidence in patients with lung cancer. Method: We obtained national claims data of 51,021 patients from South Korea with lung cancer between August 2017 and December 2021. The study population was classified into ICI and non-ICI groups based on the prescription of ICIs at least once during the study period. To estimate the effects of ICIs treatment compared with those without ICIs treatment on HZ incidence, we used the Cox proportional hazards model adjusted for sex, age, comorbidities, and concomitant use of immunosuppressive drugs. Stratified analyses based on sex, age, and comorbidities were conducted to identify corresponding risk factors. Results: Of the 51,021 study participants, 897 (1.8%) were prescribed ICIs and 2262 (4.4%) were diagnosed with HZ. Approximately 75.6% of the patients receiving ICIs were male, and the prevalence of diabetes, cardiovascular disease, and chronic lung disease in the ICI group was significantly lower than that in the non-ICIs group. The Kaplan–Meier plot showed that the probability of incidence of HZ in the ICIs group was lower than that in the non-ICIs group. Additionally, treatment with ICIs was associated with a 31% lower incidence of developing HZ when compared to that seen without ICIs treatment (95% confidence interval [CI], 0.48–1.00). This association was stronger in females (hazard ratio [HR], 0.42; 95% CI, 0.19–0.94) and those less than 68 years of age (HR, 0.58; 95% CI, 0.34–0.99). Conclusions: In these real-world data from an Asian population with lung cancer, ICIs treatment might be associated with a reduced risk of HZ compared to that without ICIs treatment.

Clinical Pharmacology of the Antibody-Drug Conjugate Enfortumab Vedotin in Advanced Urothelial Carcinoma and Other Malignant Solid Tumors.

Enfortumab vedotin is an antibody-drug conjugate comprised of a human monoclonal antibody directed to Nectin-4 and monomethyl auristatin E (MMAE), a microtubule-disrupting agent. The objectives of this review are to summarize the clinical pharmacology of enfortumab vedotin monotherapy and demonstrate that the appropriate dose has been selected for clinical use. Pharmacokinetics (PK) of enfortumab vedotin (antibody-drug conjugate and total antibody) and free MMAE were evaluated in five clinical trials of patients with locally advanced or metastatic urothelial carcinoma (n=748). Intravenous enfortumab vedotin 0.5-1.25 mg/kg on days 1, 8, and 15 of a 28-day cycle showed linear, dose-proportional PK. No significant differences in exposure or safety of enfortumab vedotin and free MMAE were observed in mild, moderate, or severe renal impairment versus normal renal function. Patients with mildly impaired versus normal hepatic function had a 37% increase in area under the concentration-time curve (0-28 days), a 31% increase in maximum concentration of free MMAE, and a similar adverse event profile. No clinically significant PK differences were observed based on race/ethnicity with weight-based dosing, and no clinically meaningful QT prolongation was observed. Concomitant use with dual P-glycoprotein and strong cytochrome P450 3A4 inhibitors may increase MMAE exposure and the risk of adverse events. Approximately 3% of patients developed antitherapeutic antibodies against enfortumab vedotin 1.25 mg/kg. These findings support enfortumab vedotin 1.25 mg/kg monotherapy on days 1, 8, and 15 of a 28-day cycle. No dose adjustments are required for patients with renal impairment or mild hepatic impairment, or by race/ethnicity.

Population Pharmacokinetics and Dosing Simulations for Aripiprazole 2-Month Ready-to-Use Long-Acting Injectable in Adult Patients With Schizophrenia or Bipolar I Disorder.

A ready-to-use (RTU) long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, available in 960 mg (Ari 2MRTU 960) or 720 mg doses, has been developed for the treatment of schizophrenia or bipolar I disorder. A previously developed and validated population pharmacokinetic model for characterizing aripiprazole plasma concentrations following administration of oral aripiprazole or aripiprazole once-monthly (AOM) intramuscular injection was expanded to include the RTU LAI formulation of aripiprazole (Ari RTU LAI). Overall, 8899aripiprazole pharmacokinetic samples from 1191 adults from 10 clinical trials were included in the final combined analysis data set. Aripiprazole plasma concentration-time profiles were simulated for various Ari RTU LAI initiation and maintenance scenarios in 1000 virtual patients. Diagnostic plots demonstrated that the final population pharmacokinetic model, which incorporated data for oral aripiprazole, AOM, and Ari RTU LAI, adequately described aripiprazole concentrations following Ari RTU LAI administration. Absorption of Ari RTU LAI was modeled by a parallel zero-order and lagged first-order process. Simulations across multiple scenarios were performed to inform dosing recommendations, including various treatment initiation regimens for a 2-monthly formulation of Ari RTU LAI in patients with or without prior stabilization on oral aripiprazole, and for patients switching from AOM. Additional simulations accounted for missed/delayed doses, cytochrome (CYP) 2D6 metabolizer status, and concomitant use of CYP2D6 or CYP3A4 inhibitors. Overall, simulations across a variety of scenarios demonstrated an Ari RTU LAI pharmacokinetic exposure profile that was comparable to AOM, with a longer dosing interval.

The prevalence of constipation in adult psychiatric out-patients on clozapine treatment at a regional public hospital in Hong Kong.

To determine the occurrence of constipation in local patients on clozapine treatment, and to compare the demographical and clinical characteristics of patients on clozapine treatment with or without constipation. This is a cross-sectional, observational study. All adult psychiatric out-patients on clozapine treatment attending follow-up at a regional hospital were recruited for clinical interview and medical record review. The Enhanced Asian Rome III Questionnaire (EAR3Q) was used to define patients with constipation. The Bristol Stool Form Scale (BSFS) was used to assess stool form. The Brief Psychiatric Rating Scale-Anchored (BPRS-A) was used to measure psychiatric symptoms. The Brief Medication Adherence Scale (BMAS) was used to assess treatment adherence. Logistic regression was conducted to identify independent associating factors of constipation in patients on clozapine treatment. The prevalence of constipation in patients on clozapine treatment was 26.3%, (95% CI [21.5%, 31.6%]). Independent associating factors included disorder of psychological development (aOR=6.98, 95% CI [1.24, 39.18]), anxiety (very mild: aOR=9.23, 95% CI [2.59, 32.87]; mild: aOR=2.66, 95% CI [1.26, 5.62]), prescription with combination of laxatives (aOR=0.40, 95% CI [0.17, 0.95]), and concomitant use of amisulpride (aOR=2.52, 95% CI [1.09, 5.82]), quetiapine (aOR=5.92, 95% CI [1.11, 31.56]) and metamucil (aOR=9.30, 95% CI [1.53, 56.58]). This study examined the prevalence of clozapine-associated constipation in Hong Kong using a validated questionnaire. The identification of independent factors associated with constipation could facilitate better risk stratification and risk modification in clinical practice.

Concomitant use of interleukin-2 and tacrolimus suppresses follicular helper T cell proportion and exerts therapeutic effect against lupus nephritis in systemic lupus erythematosus-like chronic graft versus host disease

IntroductionDefective interleukin-2 (IL-2) production contributes to immune system imbalance in patients with systemic erythematosus lupus (SLE). Recent clinical studies suggested that low-dose IL-2 treatment is beneficial for SLE and the therapeutic effect is associated with regulatory T cell (Treg) expansion. Pharmacological calcineurin inhibition induces a reduction in the number of Tregs because they require stimulation of T cell receptor signaling and IL-2 for optimal proliferation. However, the activation of T cell receptor signaling is partially dispensable for the expansion of Tregs, but not for that of conventional T cells if IL-2 is present.AimWe examined whether addition of IL-2 restores the Treg proportion even with concurrent use of a calcineurin inhibitor and if the follicular helper T cell (Tfh) proportion is reduced in an SLE-like murine chronic graft versus host disease model.MethodsUsing a parent-into-F1 model, we investigated the effect of IL-2 plus tacrolimus on Treg and Tfh proportions and the therapeutic effect.ResultsTreatment with a combination of IL-2 and tacrolimus significantly delayed the initiation of proteinuria and decreased the urinary protein concentration, whereas tacrolimus or IL-2 monotherapy did not significantly attenuate proteinuria. Phosphorylation of signal transducer and activator of transcription 3, a positive regulator of Tfh differentiation, was reduced by combination treatment, whereas phosphorylation of signal transducer and activator of transcription 5, a negative regulator, was not reduced.ConclusionAddition of calcineurin inhibitors as adjunct agents may be beneficial for IL-2-based treatment of lupus nephritis.

Impact of Polypharmacy and Risk Factors for Exacerbation of Lower Urinary Tract Symptoms in Patients with Urological Conditions: A Retrospective Study in a Japanese Municipal Hospital.

Polypharmacy exacerbates lower urinary tract symptoms (LUTS). Japan exhibits a higher prevalence of concomitant medication use in drug therapy than other countries. Previous age- and sex-specific reports exist; however, none include patients of all ages. Therefore, this retrospective study determined the impact of polypharmacy and its associated risk factors on LUTS exacerbation in outpatients with urological conditions. We included patients receiving medication who visited the Department of Urology at the Gifu Municipal Hospital (Gifu, Japan) between January, 2018 and December, 2018. The association between LUTS and polypharmacy and the risk factors for LUTS exacerbation were investigated. Patients were categorized into two groups according to their polypharmacy status. We performed propensity score matching and compared the International Prostate Symptom Score (IPSS) between the groups using the unpaired t-test. Multiple logistic regression analysis was performed to examine the risk factors, including "polypharmacy" and "taking multiple anticholinergic medications" for LUTS exacerbation. When comparing the IPSS between the groups, the polypharmacy group was found to have significantly higher scores than the non-polypharmacy group in six items, including "total score" and "storage score." Multiple logistic regression analysis results showed high significance in three items, including "polypharmacy" (odds ratio (OR) = 1.67, 95% confidence interval (CI): 1.03-2.71) and "taking multiple anticholinergic medications" (OR = 8.68, 95% CI: 1.05-71.7). In conclusion, this study revealed that "polypharmacy" and "taking multiple anticholinergic medications" were risk factors for LUTS. Particularly, "polypharmacy" is associated with storage symptom exacerbation. Therefore, eliminating "polypharmacy" and "taking multiple anticholinergic medications" is expected to improve LUTS.

Potential drug-drug interactions in outpatient lung cancer patients in a university hospital.

Concomitant use of drugs in the same or different indications can sometimes lead to undesirable interactions. The prevalence of drug interactions is high in cancer patients. In this study, we aimed to determine the frequency and clinical severity of drug interactions in outpatient lung cancer patients. The drugs used, kidney and liver blood analysis results of 160 outpatient lung cancer patients over the age of 18 who received chemotherapy between October 2020 and July 2021 were evaluated. The Lexi-Interact online database was used to identify the types of clinically significant drug interactions, frequently interacting drugs, and clinical outcomes predicted by the databases. The average number of drugs per patient was 4.2±2.3. It was determined that there was a relationship between multi-drug use and comorbidity, and the number of drugs used increased as the number of diagnoses increased. A relationship was also found between potential drug-drug interactions (pDDI), which we observed in 52.5% of the patients, and the number of drugs used and age. The most common clinically significant C (36.9%), D (16.9%) and X (10.6%) type pDDI were detected between conventional paclitaxel-hydrochlorothiazide, conventional paclitaxel-carboplatin, and ipratropium-tiotropium, respectively. The use of frequently interacting drugs in outpatient lung cancer patients can lead to pDDI. In these patients, the application of therapy by observing the drug-drug interaction may improve the quality of life.

Identification of Risk Factors for Gliptin-associated Bullous Pemphigoid among Diabetic Patients.

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008-2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer's disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer's and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.

Effect of a Declined Plasma Concentration of Valproic Acid Induced by Meropenem on the Antiepileptic Efficacy of Valproic Acid.

This study aimed to indicate whether a declined plasma concentration of valproic acid (VPA) induced by co-administration of meropenem (MEPM) could affect the antiepileptic efficacy of VPA. We retrospectively reviewed data of hospitalized patients who were diagnosed with status epilepticus or epilepsy between 2010 and 2019. Patients co-administered VPA and MEPM during hospitalization were screened and assigned to the exposure group, while those co-administerd VPA and other broad-spectrum antibiotics were allocated to the control group. The exposure group and control group included 50 and 11 patients, respectively. With a similar dosage of VPA, the plasma concentration of VPA significantly decreased during co-administration (24.6 ± 4.3 μg/mL) compared with that before co-administration (88.8 ± 13.6 μg/mL, p < 0.0001), and it was partly recovered with the termination of co-administration (39.8 ± 13.2 μg/mL, p = 0.163) in the exposure group. The inverse probability of treatment weighting estimated the treatment efficacy via changes in seizure frequency, seizure duration, and concomitant use of antiepileptic drugs, which were not significantly different between the exposure and control groups. In the exposure group, there was no significant differences in seizure frequency between the periods of before-during and before-after (p = 0.074 and 0.153, respectively). Seizure duration during VPA-MEPM co-administration was not significantly different from that before co-administration (p = 0.291). In this study, the reduced plasma concentration of VPA induced by the co-administration of MEPM did not affect the antiepileptic efficacy of VPA. This conclusion should be interpreted with caution, and more research is warranted. Chinese Clinical Trial Registry: ChiCTR2000034567. Registered on 10 July 2020.

Acute Methotrexate Toxicity Managed with Leucovorin and Pegylated Granulocyte Colony-stimulating Factor: A Report of Two Cases and Review of Literature

Acute methotrexate (MTX) toxicity is most commonly due to overdose of the drug, which may be due to the patient's noncompliance to doctor's orders or physician's prescription error. Other causes include acute renal failure, concomitant use of other drugs, and genetic susceptibility. MTX toxicity presents with pancytopenia, mucositis, hepatotoxicity, pulmonary toxicity, and acute renal failure. Treatment involves a polypragmatic approach which includes vigorous hydration, urinary alkalinization, administration of leucovorin, and glucarpidase. Administration of granulocyte colony-stimulating factor should be considered in cases of severe neutropenia. Here, we present two cases of acute MTX toxicity in chronic plaque psoriasis presenting with ulceration of psoriatic lesions and mucosal ulceration successfully treated with leucovorin and pegylated granulocyte colony-stimulating factor (G-CSF). This case report demonstrates that G-CSF might be lifesaving by contributing to rapid reconstitution of leukopoiesis.

Intravenous Administration of Recombinant Phα1β: Antinociceptive Properties and Morphine Tolerance Reversal in a Cancer-Associated Pain Model

Cancer-related pain is considered one of the most prevalent symptoms for those affected by cancer, significantly influencing quality of life and treatment outcomes. Morphine is currently employed for analgesic treatment in this case, however, chronic use of this opioid is limited by the development of analgesic tolerance and adverse effects, such as digestive and neurological disorders. Alternative therapies, such as ion channel blockade, are explored. The toxin Phα1β has demonstrated efficacy in blocking calcium channels, making it a potential candidate for alleviating cancer-related pain. This study aims to assess the antinociceptive effects resulting from intravenous administration of the recombinant form of Phα1β (r-Phα1β) in an experimental model of cancer-related pain in mice, tolerant or not to morphine. The model of cancer-induced pain was used to evaluate these effects, with the injection of B16F10 cells, followed by the administration of the r-Phα1β, and evaluation of the mechanical threshold by the von Frey test. Also, adverse effects were assessed using a score scale, the rotarod, and open field tests. Results indicate that the administration of r-Phα1β provoked antinociception in animals with cancer-induced mechanical hyperalgesia, with or without morphine tolerance. Previous administration of r-Phα1β was able to recover the analgesic activity of morphine in animals tolerant to this opioid. r-Phα1β was proved safe for these parameters, as no adverse effects related to motor and behavioral activity were observed following intravenous administration. This study suggests that the concomitant use of morphine and r-Phα1β could be a viable strategy for pain modulation in cancer patients.

420 Decrease in Post-Coiling Aneurysm Recanalization With Regular Aspirin Use

INTRODUCTION: Endovascular coiling has remained an efficacious mechanism for aneurysm treatment. While continued biomechanical advancements in coil design have led to improved aneurysm embolization rates (1), aneurysm recanalization is estimated to remain between 21-33% (2, 3, 4). Post-occlusion, cerebral aneurysm sac growth has been identified as one of the driving components of aneurysm recurrence (2, 5). Recently, antiplatelet agents such as aspirin (ASA) have been shown to be significantly associated with decreased aneurysm growth and rupture (6, 7, 8). METHODS: All aneurysms treated by a single surgeon over 10 years (n = 2236) were screened for adherence to inclusion criteria. The primary endpoint was follow-up more than 12 months from the original intervention. Of 525 treated with coils only, 109 patients reported regular ASA use (defined as = 3x/ week, irrespective of dose). No significant demographic differences were identified between patients with regular ASA use and those without. While there were no significant differences in aneurysm size, location, or history of rupture, there was an increased presence of daughter sacs in patients without regular ASA. Rates of aneurysm recanalization, defined as a change of Raymond-Roy occlusion classification =1, were compared between ASA-treated and non-ASA-treated groups. RESULTS: Of the 109 coiled aneurysms with concomitant regular ASA use, only 9.2% underwent recanalization compared to 23.6% in patients without regular ASA use (P = 0.001, OR = 0.33, 95% CI = 0.15–0.66). Furthermore, when specifically considering cases of recanalization that only demonstrated sac growth, 5.5% occurred with regular ASA use compared to 18% without (P = 0.001, OR = 0.26, 95% CI = 0.09–0.63). CONCLUSIONS: ASA use significantly decreased the odds of post-coiling aneurysm sac growth and recanalization 12 months post-original intervention when compared to those without regular ASA use.

[Exploration of Risk Factors of the Onset of Antibiotics-induced Acute Kidney Injury and Its Transfer to Chronic Kidney Disease Using the Medical Information Database].

Drug-induced acute kidney injury (AKI) is a serious adverse drug reaction, which results in a significant decline in renal function and is known to progress to chronic kidney disease (CKD). Therefore, appropriate drug therapy is important to avoid the risk of drug-induced AKI and CKD, which are serious concerns in clinical practice. In this study, using the medical information database of Hamamatsu University Hospital, we investigated the risk factors that accelerate the onset of drug-induced AKI or its progression to CKD in patients who received aminoglycoside antibiotics (AGs) or glycopeptide antibiotics (GPs), which are strongly associated with drug-induced AKI and CKD. We performed logistic regression analysis using patients' background, laboratory test results, and concomitant drug use, among other such factors as explanatory variables and drug-induced AKI or CKD onset as objective variables to explore the risk factors for drug-induced AKI and CKD. Our results showed that co-administration of amphotericin B, piperacillin-tazobactam and other AGs and GPs, increased serum creatinine (Scr) and chloride concentrations, serum lactate dehydrogenase activity, and decreased serum albumin concentration were risk factors for drug-induced AKI onset. Moreover, a reduced blood urea nitrogen:Scr ratio at drug-induced AKI onset served as a risk factor for CKD. These results suggest that careful monitoring of the aforementioned factors is important to ensure appropriate usage of these drugs in patients treated with AGs and GPs.

Cardiotoxicity of Doxorubicin in Acute Leukemia

Abstract: Doxorubicin, an anthracycline chemotherapeutic agent, is widely utilized in the treatment of acute leukemia due to its potent anti-neoplastic properties. However, its clinical utility is limited by the occurrence of dose-dependent cardiotoxicity, which may manifest as cardiomyopathy, heart failure, or arrhythmias. This review provides an overview of the mechanisms underlying doxorubicin-induced cardiotoxicity, including oxidative stress, mitochondrial dysfunction, and DNA damage. Additionally, it discusses risk factors predisposing patients to cardiotoxicity, such as cumulative dose, age, pre-existing cardiac conditions, and concomitant use of other cardiotoxic agents. Furthermore, this review highlights various strategies for the prevention and management of doxorubicin-induced cardiotoxicity, including the use of cardioprotective agents, cardiac monitoring protocols, and lifestyle modifications. Finally, future directions for research aimed at minimizing cardiotoxicity while preserving the antineoplastic efficacy of doxorubicin in acute leukemia treatment are discussed.

Plasmapheresis in thyrotoxicosis: a single-center case series

BackgroundPlasmapheresis represent an alternative therapeutic option for hyperthyroidism with thyroid storm or refractory cases. It provides a rapid decrease in plasma thyroid hormones and anti-thyroid antibodies. The aim of this paper was to report our single center’s experience in managing particular situations of hyperthyroidism using apheresis.Cases presentationThe following case series describes three young African patients (two females, one male) aged 29, 37, and 25 years old, respectively, with Graves’ disease who presented with drug ineffectiveness, drug-induced agranulocytosis, and thyroid storm with multi-organ failure. The three patients underwent plasmapheresis sessions leading to effective decline of thyroid hormone levels and offering a window for processing total thyroidectomy.Discussion/conclusionThe standard management of thyrotoxicosis and thyroid storm was usually codified by the concomitant use of antithyroid medication, iodine, beta-blockers, and corticosteroids. This medical preparation can be effective in most cases. However, drug toxicity or ineffectiveness can limit the use of such therapeutics. Our paper supports the efficiency and safety of therapeutic plasma exchange in the preoperative management of thyrotoxicosis.

An LC-MS/MS Method for Quantification of Lamotrigine and Its Main Metabolite in Dried Blood Spots

Background: The antiepileptic drug lamotrigine (LTG) shows high pharmacokinetic variability due to genotype influence and concomitant use of glucuronidation inducers and inhibitors, both of which may be frequently taken by elderly patients. Our goal was to develop a reliable quantification method for lamotrigine and its main glucuronide metabolite lamotrigine-N2-glucuronide (LTG-N2-GLU) in dried blood spots (DBS) to enable routine therapeutic drug monitoring and to identify altered metabolic activity for early detection of drug interactions possibly leading to suboptimal drug response. Results: The analytical method was validated in terms of selectivity, accuracy, precision, matrix effects, haematocrit, blood spot volume influence, and stability. It was applied to a clinical study, and the DBS results were compared to the concentrations determined in plasma samples. A good correlation was established for both analytes in DBS and plasma samples, taking into account the haematocrit and blood cell-to-plasma partition coefficients. It was demonstrated that the method is suitable for the determination of the metabolite-to-parent ratio to reveal the metabolic status of individual patients. Conclusions: The clinical validation performed confirmed that the DBS technique is a reliable alternative for plasma lamotrigine and its glucuronide determination.

The Incidence of Thrombotic Events After the Concomitant Use of Andexanet alfa and 4-Factor Prothrombin Complex Concentrate

Limited data exists on the safety and efficacy with the concomitant use of 4 factor prothrombic complex concentrate (4F-PCC) and andexanet alfa (AA). This case series describes 7 patients at our institution who received both 4F-PCC and AA for the management of life-threatening bleeding associated with apixaban or rivaroxaban. Four patients received AA due to worsening bleeding after 4F-PCC. Of the 7 patients in this case series, 1 had a documented thrombotic event which was an acute ischemic stroke. The thrombotic event rate in our case series was similar to the incidence of thrombotic events reported with the use of AA alone. In-hospital mortality occurred in 2 of 7 patients with 1 additional patient discharged to hospice care.

Epstein-Barr Virus-Positive Mucosal Skin Ulcer Resulting in Oral Lesions During Concomitant Use of Tacrolimus and Prednisolone

Epstein-Barr Virus-Positive Mucosal Skin Ulcer Resulting in Oral Lesions During Concomitant Use of Tacrolimus and Prednisolone

Association of Premorbid GLP-1RA and SGLT-2i Prescription Alone and in Combination with COVID-19 Severity.

People with type 2 diabetes are at heightened risk for severe outcomes related to COVID-19 infection, including hospitalization, intensive care unit admission, and mortality. This study was designed to examine the impact of premorbid use of glucagon-like peptide-1 receptor agonist (GLP-1RA) monotherapy, sodium-glucose cotransporter-2 inhibitor (SGLT-2i) monotherapy, and concomitant GLP1-RA/SGLT-2i therapy on the severity of outcomes in individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Utilizing observational data from the National COVID Cohort Collaborative through September 2022, we compared outcomes in 78,806 individuals with a prescription of GLP-1RA and SGLT-2i versus a prescription of dipeptidyl peptidase 4 inhibitors (DPP-4i) within 24months of a positive SARS-CoV-2 PCR test. We also compared concomitant GLP-1RA/SGLT-2i therapy to GLP-1RA and SGLT-2i monotherapy. The primary outcome was 60-day mortality, measured from the positive test date. Secondary outcomes included emergency room (ER) visits, hospitalization, and mechanical ventilation within 14days. Using a super learner approach and accounting for baseline characteristics, associations were quantified with odds ratios (OR) estimated with targeted maximum likelihood estimation (TMLE). Use of GLP-1RA (OR 0.64, 95% confidence interval [CI] 0.56-0.72) and SGLT-2i (OR 0.62, 95% CI 0.57-0.68) were associated with lower odds of 60-day mortality compared to DPP-4i use. Additionally, the OR of ER visits and hospitalizations were similarly reduced with GLP1-RA and SGLT-2i use. Concomitant GLP-1RA/SGLT-2i use showed similar odds of 60-day mortality when compared to GLP-1RA or SGLT-2i use alone (OR 0.92, 95% CI 0.81-1.05 and OR 0.88, 95% CI 0.76-1.01, respectively). However, lower OR of all secondary outcomes were associated with concomitant GLP-1RA/SGLT-2i use when compared to SGLT-2i use alone. Among adults who tested positive for SARS-CoV-2, premorbid use of either GLP-1RA or SGLT-2i is associated with lower odds of mortality compared to DPP-4i. Furthermore, concomitant use of GLP-1RA and SGLT-2i is linked to lower odds of other severe COVID-19 outcomes, including ER visits, hospitalizations, and mechanical ventilation, compared to SGLT-2i use alone. Graphical abstract available for this article.

Clinical and pharmacological factors influencing serum clozapine and norclozapine levels.

Clozapine (CLO) is a very effective antipsychotic, whose use is associated with dose-dependent risk of complications. Due to high interindividual variability in CLO metabolism, there is a need to identify factors affecting the blood concentrations of CLO and its active metabolite, norclozapine (NCLO). A total of 446 blood samples (collected from 233 women and 213 men, aged from 18 to 77 years) were included in this study and analyzed for CLO and NCLO concentrations. The patients were treated at a psychiatric hospital in Warsaw in the years 2016-2021. Serum CLO and NCLO concentrations were determined with high-performance liquid chromatography coupled to UV. The following factors were shown to increase serum CLO and NCLO levels: higher CLO dose (p < 0.001), female sex (p < 0.001), nonsmoker status (p < 0.001), the use of more than two additional psychotropic drugs (only in the case of CLO; p = 0.046), concomitant use of beta-blockers (for CLO p = 0.049; for NCLO p < 0.001), and older age (for CLO p < 0.001; for NCLO p = 0.011). Despite the use of CLO at daily doses within the recommended range (200-450mg), the evaluated serum CLO and NCLO levels were within the therapeutic ranges in only 37% and 75% of cases, respectively, with 5.6% of cases exceeding the CLO toxicity threshold. The use of CLO at recommended doses does not guarantee achieving therapeutic concentrations of CLO or NCLO. Women and nonsmokers were at the highest risk of having toxic CLO levels.