Concurrent Drug Research Articles

Defaulting rate and associated factors among patients attending methadone maintenance clinics in Nairobi City County, Kenya

Background: Defaulting from MMT clinics is a major public health problem affecting people globally resulting in high transmission of HIV, hepatitis B and C, increased crime rate, and reduced productivity of an individual. However, defaulting rate in the MMT clinics in Nairobi City County in Kenya remains understudied. This study was aimed at determining the defaulting rate and its associated factors from MMT clinics in Nairobi City County, Kenya. Methods: A cross-sectional analytical study design was employed. Simple random sampling, purposive sampling and stratified sampling were utilized in this study. A sample size of 388 patients was randomly selected. A semi-structured questionnaire was used for data collection. SPSS V.24 was used for data analysis. Results: A response rate of 95% (369) was achieved. Most were youths aged 18-35yrs (60.7%, n=224), male (76.4%, n=282), married (39%, n=144), Christians (51.8%, n=191). The defaulting rate was 53% with marital status, religion, education level, and income source being significantly associated with defaulting (p<0.05). Conclusions: The defaulting rate from MMT was relatively high in Nairobi City County. Defaulting was linked to education, cocaine use before MMT and concurrent drug use during treatment. A number of interventional strategies were proposed by this study to improve MMT programming.

Behavioral interventions for tobacco use in HIV-infected smokers: systematic review and pairwise, network meta-analysis of randomized trials.

Smoking among persons living with HIV infection (PLWH) is estimated to be 2-3 times greater than that in the general population. Data suggest that cigarette smoking is more common among PLWH because of several factors, including lower socioeconomic status, previous, or concurrent illicit drug and alcohol use, younger age, lower education level, and concomitant depressive symptoms. Cigarette smoking among PLWH has been associated with a higher risk of certain cancers and infections as well as lowered response to antiretroviral therapy. Randomized controlled trials on behavioral interventions for tobacco use among smokers with HIV were searched in the PubMed, Cochrane Library, EMBASE, and Web of Science databases. The retrieval period was from the inception of databases to November 2023. Network meta-analysis (NMA) was performed using the Stata 18.0 software with 19 studies (3190 subjects), of which 15 reported 7-day point prevalence abstinence and seven of which reported continuous abstinence. The NMA results showed that compared with general advice plus self-help brochure, text messaging (relative risk [RR] = 4.60, 95% confidence interval [CI], 1.12-18.81) and cell phone counseling (RR = 3.29, 95% CI, 1.71-6.32) were the most effective for 7-day point prevalence abstinence among smokers with HIV infection. Moreover, the meta-analysis showed that compared with smoking counseling and self-help brochures, continuous abstinence was statistically significantly enhanced after behavioral interventions (RR = 2.52, 95% CI, 1.51-4.20). The study revealed very low-to-high-quality evidence that text messaging, telephone counseling, and smoking cessation websites were effective for smokers with HIV infection.

Assessing the practice of total neoadjuvant therapy for rectal cancer: an online survey among radiation oncology departments in Germany and German-speaking regions of Austria and Switzerland.

Total neoadjuvant therapy (TNT) of rectal cancer improves rates of pathological complete remission and progression-free survival. With improved clinical response rates, interest grew in a non-operative approach/watch and wait (WaW) for this disease. In 2020, the working groups of ACO/AIO/ARO published a consensus statement on the use of TNT, including a non-operative approach. However, the best combination scheme remains unclear. Despite the increasing use of TNT, there is a lack of comprehensive data on its current implementation and practices. To address this knowledge gap, a multicenter survey was conducted to capture the use of TNT protocols in German-speaking radiotherapy departments. At the beginning of 2023, a GDPR-compliant online survey was conducted in Germany, Austria, and German-speaking Switzerland. The questionnaire comprised 43 questions covering various aspects of TNT, including chemotherapy and WaW concepts. Most respondents (98.4%) confirmed awareness of the consensus on TNT for rectal cancer. Institutions treated an average of 30.22 rectal cancer patients annually. Most respondents (76.2%) reported treating over 80% of patients neoadjuvantly. Regarding TNT, 33.3% treated 21-50% with such a protocol. No significant association was found between the institution type and TNT application. In 62/63 cases, tumor board discussion was standard before offering TNT. VMAT was the predominant technique (82.5%). For rectal cancer dosing, the 50/50.4Gy scheme was most common, followed by 45Gy with a boost and the 5 × 5Gy scheme. Dosing schemes for TNT varied slightly, with more participants reporting the use of 5 × 5Gy compared to radiation therapy for rectal cancer in general. CBCT was the primary IGRT method (88.9%). Larger hospitals typically administered chemotherapy themselves, while private practices collaborated with medical oncologists (p < 0.0001). The most common concurrent chemotherapy drugs were 5-fluorouracil/capecitabine (64.4%) and oxaliplatin (37.3%). A WaW strategy was reported to be institutional implemented by 63.8%. The timing of offering WaW was split, with 50% offering it after radiochemotherapy and 47% during the informed consent talk. For planned WaW, 62% prefer normofractionated TNT. TNT appears to be widely implemented in the German-speaking radio-oncological community, regardless of the type of institution. Image-guided therapy, multidisciplinary team decisions, and internal guidelines play an important role. TNT seems to have already altered treatment protocols for rectal cancer toward an organ-preserving approach in selected cases. In these WaW cases, normofractionation appears to be preferred over hypofractionation.

Post-COVID-19 condition-Clinical phenotyping in practice

The high number and clinical heterogeneity of neurological impairments in patients with apost-COVID-19 condition (PCC) poses achallenge for outpatient care. Our aim was to evaluate the applicability of the proposed subtypes according to the guidelines "Long/Post-COVID" (30 May 2024) and their phenotyping using clinical and neuropsychological findings from our post-COVID outpatient clinic. The evaluation was based on cross-sectional neurological and psychological test examinations of the patients, which were carried out using standardized questionnaires and test batteries. In addition, adetailed anamnesis of the current symptoms and aretrospective survey of the acute symptoms up to 4 weeks after the confirmed infection was conducted. The subtypes were classified according to the abovementioned guidelines based on the medical history and selected patient questionnaires, to which we added a5th subtype with reference to the previous guidelines "Long/Post-COVID" (as of 5 March 2023). Atotal of 157 patients were included between August 2020 and March 2022. The presentation was at a median of 9.4months (interquartile range, IQR = 5.3) after infection, with amean age of 49.9 years (IQR = 17.2) and more women (68%) presenting, with atotal hospitalization rate of 26%. Subtype1 (postintensive care syndrome) showed the highest proportion of men, highest body mass index (BMI) scores and the highest rates of subjective complaints of word-finding difficulties (70%). Subtype2 (secondary diseases) was dominated by cognitive impairment and had the highest depression scores. Subtype3 (fatigue and exercise-induced insufficiency) was the most common, had the most symptoms and most severe subjective fatigue and the largest proportion of women. Subtype4 (exacerbation) mainly showed affective symptoms. Subtype5 (complaints without relevance to everyday life) had the lowest scores for depression, fatigue and BMI. Neurological and psychological conditions were frequently pre-existing in all groups. The management of PCC can be improved at various levels. Astandardized subtype classification enables early individually tailored treatment concepts. Patients at risk should be identified at the primary care level and informed about risk factors and prevention strategies. Regular monitoring of cardiovascular risk factors and physical activity are essential for PCC treatment. In the case of cognitive deficits and concurrent affective symptoms, psychotherapeutic support and drug treatment with selective serotonin reuptake inhibitors (SSRI) should be provided at an early stage.

Efficacy of Intensified Hygiene Measures with or without the Addition of Doxycycline in the Management of Filarial Lymphedema: A Randomized Double-Blind, Placebo-Controlled Clinical Trial in Tanzania.

Lymphedema, hydrocele, and acute adenolymphangitis (ADL) are chronically disabling consequences in patients with lymphatic filariasis (LF). Provision of morbidity management and disability prevention and concurrent mass drug administration of anthelmintics are two pillars for elimination of LF. This study assessed the impact of strict hygiene protocols with or without doxycycline on the progression of filarial lymphedema. A randomized, placebo-controlled, double-blind trial was conducted in two regions in Tanzania. We enrolled 362 participants with lymphedema stages 1-3 assigned into three treatment groups of doxycycline 200 mg once daily, doxycycline 100 mg once daily, or matching placebo for 42 days in addition to hygiene measures. The participants were followed every 2 months for 2 years. Twenty-four months after treatment onset, 17.7% of participants displayed improved limb conditions, including 15/104 (14.4%) in the doxycycline 200 mg group, 16/105 (15.2%) in the doxycycline 100 mg group, and 25/107 (23.4%) in the placebo group. During the first 6 months after treatment, the number of participants experiencing an ADL attack was significantly lower in the doxycycline groups than in the placebo group. The study also found that hygiene was one of the factors associated with preventing the occurrence of acute attacks over the whole study period. Doxycycline 100 mg was a significant factor for the halt of progression (odds ratio: 0.53, P = 0.0239) when both legs if affected at baseline were considered. These findings emphasize the importance of practicing hygiene in reducing the occurrence of ADL attacks and the benefits of doxycycline with regards to acute attacks and halt of progression.

Characteristics of patients who are initiated on long-acting buprenorphine (Buvidal®) in France: A retrospective cross-sectional study

The long-acting buprenorphine Buvidal® is a recent type of opioid agonist treatment (OAT) used for opioid use disorder (OUD). It was initially suggested to preferentially use Buvidal® for specific OUD populations, including people in prison, or patients in recovery and on sublingual buprenorphine. We conducted a national study to examine whether the profile of patients treated with Buvidal® in France matched these initial recommendations. A retrospective cross-sectional study was conducted in 13 national addiction centers (outside prison), using the individual medical records of patients initiated on Buvidal®. Baseline characteristics were collected and described, including sociodemographic features, comorbid medical conditions, concurrent substance use and prescription drug misuse, and OAT features before Buvidal® initiation, respectively. In total 101 patients (72.3% males, mean age 43.9±11.3years) were identified, which corresponded to one sixth of all patients treated with Buvidal® in France at the time of the study. Of them, 36 (36.4%) of them were professionally active, 35 (35.4%) were durably inactive, and the rest in an intermediary situation. Furthermore, 90 (90.0%) patients had at least one medical comorbidity (all types), and 83 (83.0%) at least one psychiatric comorbidity. Most frequent non-psychiatric comorbidities were chronic pain (n=20, 20.0%) and chronic viral infection (n=16, 17.8%). Current use of psychoactive substances included cocaine and crack (n=43, 42.6%), heroin (n=19, 18.8%), but also misuse of prescription drugs (n=20, 20%), mainly opioid analgesics. Moreover, 99 (98.0%) patients had an OAT before Buvidal® initiation, including 7 (8.1%) patients on methadone. The profile of patients initiated on Buvidal® in France was extremely similar to that of patients treated for OUD in France, either in terms of social or clinical features. While initial recommendations essentially underlined the interest of Buvidal® for some niche populations, the on-the-ground practice reveals a more widespread use, including for unrecovered patients, or patients treated with methadone.

Is general practitioner involvement in the initiation of opioids for chronic non-cancer pain associated with opioid dose and concurrent drug use?

Objective Is the involvement of the regular general practitioner (GP) in the decision to initiate opioid treatment for chronic non-cancer pain (CNCP) associated with two main risk factors for serious adverse events: increased opioid dose and the concomitant use of prescribed benzodiazepines or benzodiazepine-related medications? Design and setting An anonymous web-based survey was conducted in the county of Rogaland, Norway, during the spring of 2021. Subjects GPs who self-reported applying at least once for reimbursement of opioids prescribed to treat CNCP. They were asked to answer the survey based on the last patient for whom they recalled submitting a reimbursement application. Main outcome measures 1) Total opioid dose in daily oral morphine equivalents (OMEQ). 2) Concurrent use of benzodiazepines and/or benzodiazepine-related drugs. Results The daily opioid dose was lower when the surveyed GPs initiated the opioid treatment (36 OMEQ, n = 25), than when others had initiated the treatment (108 OMEQ, n = 31, p = 0.001). For concurrent use of benzodiazepine or benzodiazepine-related drugs, no significant difference was found (33%, n = 9 with GP involvement vs. 47%, n = 16, p = 0.279 with no GP involvement). Conclusions GP involvement in the initiation of opioid medication for CNCP was associated with a lower opioid dose being prescribed. Implications GP involvement in the initiation of opioid prescriptions may facilitate safer prescribing.

Long‐Lasting Simultaneous Epidermal and Dermal Microneedle‐Enabled Drug Delivery

AbstractDifferent skin diseases, such as cancers, inflammatory conditions, and bacterial infections, manifest at distinct skin depths. Microneedle arrays, recognized for their painless and minimally invasive drug administration, can be customized to penetrate these layers simultaneously. Here, the design of the microneedles (MNs) in nonlinear ways with diverse needle heights on the array enabling concurrent drug delivery to various skin layers is engineered. Additionally, varying the base diameter of the needles in the array facilitates prolonged or intermittent drug release, depending on the biodegradation kinetics of these needles. MNs, microfabricated with a biocompatible and biodegradable polymer, are validated by skin administration. The nonlinear design of the MNs on the array introduces a novel perspective on addressing skin diseases at varying depths of the skin.

The incidence and trends of proteinuria, azotemia and hypertension in cats receiving toceranib phosphate.

This retrospective study aimed to determine the incidence and trends of proteinuria, elevations in serum creatinine and urea, and systolic blood pressure in cats undergoing treatment with toceranib. In total, 32 cats treated with toceranib for malignancies were analyzed. Cats were included if urinalysis and urine protein:creatinine ratio (UPC) measurements were available at 28 days (T1) and 56 days (T2) after starting the treatment. Cats with concurrent lower urinary tract disease, including urinary tract malignancy, were excluded. Friedman's ANOVA compared variables between time points, and the Spearman test assessed the correlation between treatment duration and UPC. The median starting dose of toceranib was 2.68 mg/kg (range 1.7-3.9). In total, 15 (46.9%) cats received concurrent non-steroidal anti-inflammatory drugs. The most commonly treated tumors were oral squamous cell carcinoma (n = 10) and mast cell tumor (n = 5). None of the 32 cats developed progressive proteinuria or azotemia during the follow-up period (median 56 days; range 56-336). Notably, UPC and serum creatinine were significantly lower at T2 compared with baseline (P = 0.012 and 0.001, respectively). Among the four cats with baseline proteinuria, UPC decreased over time with or without concurrent telmisartan treatment (n = 2). All four of these cats experienced a reduction in tumor size with toceranib concurrently with their decreased UPC. There was no significant correlation between UPC and the duration of toceranib treatment (P = 0.089). Blood pressure was not significantly different over the assessed time points. The incidence of proteinuria, renal azotemia and hypertension in cats treated with toceranib for neoplasia appears to be low. Toceranib may be a viable treatment option even in cats with pre-existing proteinuria or renal disease, with careful monitoring of trends recommended.

A multicenter, open-label, parallel-group, randomized controlled trial of Tongluo-Qutong rubber plaster for the treatment of cervical spondylotic radiculopathy.

In China, Tongluo-Qutong rubber plaster (TQRP) is commonly used for cervical spondylotic radiculopathy, but lacks high-quality trials. This study aimed to conduct a multicenter, open-label, parallel-group, randomized controlled trial in China to investigate the practical efficacy and safety of TQRP in the treatment of CSR. A total of 240 patients diagnosed with CSR were recruited for the investigation from multiple hospitals in Gansu province, China. The patients were randomly assigned to either an experimental or a control group. The experimental group received treatment with TQRP, whereas the control group was administered a diclofenac sodium patch (DSP) for a maximum duration of 21 days. The visual analogue scale (VAS) score for pain, the proportion of patients experiencing 50% or more pain relief, the neck disability index (NDI), changes as per the Eaton trial, and recurrence during the follow-up period were evaluated for both groups. The safety and adverse events associated with the concurrent drug therapy were also evaluated. At each time point, the mean VAS and NDI scores of both groups demonstrated a downward trend. The experimental group exhibited a greater decline in VAS score at each time point compared to the control group (P< 0.01). In the Eaton trial, both the percentage of patients experiencing pain relief of 50% or more and the number of abnormal results exhibited improvement. However, the outcomes in the 21 ± 3d experimental group were significantly superior to those in the control group (P< 0.01). During the follow-up period, the recurrence events in the experimental group were reduced compared to the control group. The difference between the two groups was statistically significant (P< 0.05). The incidence of adverse reactions was 1.74% for TQRP and 3.54% for DSP. TQRP is effective and safe in the treatment of CSR.

Current status and usefulness of therapeutic drug monitoring implementation of theophylline in elderly patients based on a nationwide database study and modeling approach.

Theophylline is used in the treatment of chronic obstructive pulmonary disease but readily causes symptoms of intoxication and exhibits high risks in elderly patients. However, there have only been a few recent reports on the significance of therapeutic drug monitoring (TDM) implementation, especially in elderly patients. To examine the usefulness of theophylline TDM, we evaluated the current status of prescriptions containing theophylline and its side effects and assessed the influence of aging, sex, drug formulation, and concurrent drugs use on theophylline exposure using data from various nationwide databases and a pharmacokinetic modeling approach. We utilized sampling data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Using the data of patients aged ≥80 years, we conducted an association analysis of theophylline and concurrent drugs. The transition in plasma theophylline concentration levels of elderly patients was estimated based on a previously reported physiological-based pharmacokinetic model. Altogether, 3973 patients using theophylline were registered in our dataset, and about 50% were over 70 years old and used theophylline. Therapeutic drug monitoring implementation was confirmed in only 1.13% of patients. The association analysis confirmed a frequent co-occurrence with allopurinol and famotidine, which increase theophylline exposure, in elderly patients aged ≥80 years. The physiologically based pharmacokinetic model indicated that theophylline trough concentrations were 1.65-fold higher in elderly patients aged 80 years compared to those aged 30 years and 1.35-fold higher in females compared to males. This study effectively combined information on the nationwide health care database and modeling approach, indicating the importance of proactive TDM and dose justification for female and elderly patients.

Arrhythmogenic effects of acute electronic cigarette compared to tobacco cigarette smoking in people living with HIV.

The leading cause of death in people living with HIV (PLWH) is cardiovascular disease, and the high prevalence of tobacco cigarette (TC) smoking is a major contributor. Switching to electronic cigarettes (ECs) has been promoted as a harm reduction strategy. We sought to determine if acute EC compared to TC smoking had less harmful effects on arrhythmogenic risk factors including acute changes in hemodynamics, heart rate variability (HRV), and ventricular repolarization (VR). In PLWH who smoke, changes in hemodynamics, HRV, and VR were compared pre/post acutely using an EC, TC, or puffing on an empty straw on different days in random order, in a crossover study. Thirty-seven PLWH (36 males, mean age 40.5 ± 9.1 years) participated. Plasma nicotine was greater after TC versus EC use (10.12 ± 0.96 vs. 6.18 ± 0.99 ng/mL, respectively, p = 0.004). HR increased significantly, and similarly, after acute EC and TC smoking compared to control. Changes in HRV that confer increased cardiac risk (LF/HF ratio) were significantly smaller after acute EC versus TC use, consistent with a harm reduction effect. In a post-hoc analysis of PLWH with and without positive concurrent recreational drug use as indicated by point of care urine toxicology testing, this differential effect was only seen in PLWH not currently using recreational drugs. Changes in VR were not different among the three exposures. In PLWH who smoke, EC compared to TC smoking resulted in smaller adverse changes in HRV. This differential effect was accompanied by a smaller increase in plasma nicotine, and was negated by concurrent recreational drug use. Additional studies are warranted in this vulnerable population disproportionately affected by tobacco-related health disparities.

Role of renin angiotensin system inhibitors and metformin in Glioblastoma Therapy: a review.

Glioblastoma multiforme (GBM) is a highly aggressive and incurable disease accounting for about 10,000 deaths in the USA each year. Despite the current treatment approach which includes surgery with chemotherapy and radiation therapy, there remains a high prevalence of recurrence. Notable improvements have been observed in persons receiving concurrent antihypertensive drugs such as renin angiotensin inhibitors (RAS) or the antidiabetic drug metformin with standard therapy. Anti-tumoral effects of RAS inhibitors and metformin have been observed in in vitro and in vivo studies. Although clinical trials have shown mixed results, the potential for the use of RAS inhibitors and metformin as adjuvant GBM therapy remains promising. Nevertheless, evidence suggest that these drugs exert multimodal antitumor actions; by particularly targeting several cancer hallmarks. In this review, we highlight the results of clinical studies using multidrug cocktails containing RAS inhibitors and or metformin added to standard therapy for GBM. In addition, we highlight the possible molecular mechanisms by which these repurposed drugs with an excellent safety profile might elicit their anti-tumoral effects. RAS inhibition elicits anti-inflammatory, anti-angiogenic, and immune sensitivity effects in GBM. However, metformin promotes anti-migratory, anti-proliferative and pro-apoptotic effects mainly through the activation of AMP-activated protein kinase. Also, we discussed metformin's potential in targeting both GBM cells as well as GBM associated-stem cells. Finally, we summarize a few drug interactions that may cause an additive or antagonistic effect that may lead to adverse effects and influence treatment outcome.

Factors influencing serum concentrations of levetiracetam in dogs with epilepsy.

Factors affecting serum concentrations of levetiracetam in dogs are unknown and could affect the efficacy of levetiracetam in controlling seizures in dogs with epilepsy. Higher PO doses of levetiracetam will be needed in dogs to achieve serum concentrations shown to be effective in humans. Determine factors that could influence serum levetiracetam concentrations and justify dose adjustment in some epileptic dogs. Sixty-nine client-owned dogs with epilepsy treated with levetiracetam alone or in combination, based on 127 trough serum concentration measurements of levetiracetam. Retrospective cohort study. Linear mixed models were used to assess the effect of patient signalment and concurrent drug administration on serum concentrations of levetiracetam and the effect of serum concentration of levetiracetam on seizure frequency reduction. The PO dose of levetiracetam significantly explained changes in serum levetiracetam concentration, and this causal link was stronger with monotherapy (R2 = 0.59, P < .001). Phenobarbital significantly decreased serum levetiracetam concentration in a dose dependent manner (R2 = 0.30, P = .003). Based on our model, a levetiracetam dosage of 99-216 mg/kg/day is necessary to obtain a serum levetiracetam concentration of 20 μg/mL when used alone or concurrently with 7 mg/kg/day of phenobarbital. No other factors were found to influence serum levetiracetam concentrations. No therapeutic range could be identified. Our data suggest that a dosage of 99-216 mg/kg/day of levetiracetam is needed to achieve a serum concentration known to be therapeutically effective in humans, especially when administered concomitantly with phenobarbital.

Development and validation of machine-learning algorithms predicting retention, overdoses, and all-cause mortality among US military veterans treated with buprenorphine for opioid use disorder

Background Buprenorphine for opioid use disorder (B-MOUD) is essential to improving patient outcomes; however, retention is essential. Objective To develop and validate machine-learning algorithms predicting retention, overdoses, and all-cause mortality among US military veterans initiating B-MOUD. Methods Veterans initiating B-MOUD from fiscal years 2006-2020 were identified. Veterans’ B-MOUD episodes were randomly divided into training (80%;n = 45,238) and testing samples (20%;n = 11,309). Candidate algorithms [multiple logistic regression, least absolute shrinkage and selection operator regression, random forest (RF), gradient boosting machine (GBM), and deep neural network (DNN)] were used to build and validate classification models to predict six binary outcomes: 1) B-MOUD retention, 2) any overdose, 3) opioid-related overdose, 4) overdose death, 5) opioid overdose death, and 6) all-cause mortality. Model performance was assessed using standard classification statistics [e.g., area under the receiver operating characteristic curve (AUC-ROC)]. Results Episodes in the training sample were 93.0% male, 78.0% White, 72.3% unemployed, and 48.3% had a concurrent drug use disorder. The GBM model slightly outperformed others in predicting B-MOUD retention (AUC-ROC = 0.72). RF models outperformed others in predicting any overdose (AUC-ROC = 0.77) and opioid overdose (AUC-ROC = 0.77). RF and GBM outperformed other models for overdose death (AUC-ROC = 0.74 for both), and RF and DNN outperformed other models for opioid overdose death (RF AUC-ROC = 0.79; DNN AUC-ROC = 0.78). RF and GBM also outperformed other models for all-cause mortality (AUC-ROC = 0.76 for both). No single predictor accounted for >3% of the model’s variance. Conclusions Machine-learning algorithms can accurately predict OUD-related outcomes with moderate predictive performance; however, prediction of these outcomes is driven by many characteristics.

Cognitive performance as a behavioral phenotype associated with cocaine self-administration in female and male socially housed monkeys

Considerable research has suggested that certain cognitive domains may contribute to cocaine misuse. However, there are gaps in the literature regarding whether cognitive performance before drug exposure predicts susceptibility to cocaine self-administration and how cognitive performance relates to future cocaine intake. Thus, the present study aimed to examine cognitive performance, as measured using automated CANTAB cognitive battery, prior to and following acquisition of cocaine self-administration under a concurrent drug vs. food choice procedure in female and male socially housed cynomolgus macaques. The cognitive battery consisted of measures of associative learning (stimulus and compound discrimination tasks), behavioral flexibility (intradimensional and extradimensional tasks), and behavioral inhibition (stimulus discrimination reversal, SDR, and extra-dimensional reversal tasks). After assessing cognitive performance, monkeys were trained to self-administer cocaine (saline, 0.01–0.1 mg/kg/injection) under a concurrent cocaine vs. food schedule of reinforcement. After a history of cocaine self-administration across 3-4 years, the cognitive battery was re-assessed and compared with sensitivity to cocaine reinforcement. Results showed drug-naïve monkeys that were less accurate on the SDR task, measuring behavioral inhibition, were more sensitive to cocaine reinforcement under the concurrent cocaine vs. food choice procedure. Furthermore, following chronic cocaine self-administration, cocaine intake was a negative predictor of accuracy on the SDR behavioral inhibition task. After cocaine maintenance, monkeys with higher cocaine intakes required more trials to complete the SDR behavioral inhibition task and made more incorrect responses during these trials. No sex or social rank differences were noted. Overall, these findings suggest that cognitive performance may influence vulnerability to cocaine misuse. Also, chronic cocaine may decrease levels of behavioral inhibition as measured via the SDR task in both females and males.

Impact of concurrent medications on the outcome of immunotherapy in non-small cell lung carcinoma.

There have been reports on the impact of concurrent drugs on the outcome of immunotherapy for non-small cell lung carcinoma (NSCLC). However, the effect of some drugs, such as antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs), has not been clarified in patients with NSCLC. In the present study, we aimed to assess the association between concurrent drugs and the outcomes of immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy for patients with advanced NSCLC. We retrospectively assessed patients with advanced NSCLC who underwent ICI treatment between September 2017 and December 2021 at Kobe University Hospital. We evaluated the data regarding the use of antibiotics within 30 days before ICI initiation, as well as the use of proton pump inhibitors (PPIs) and NSAIDs during ICI initiation. A total of 127 patients were assessed, among whom 28 (22.0%) patients received antibiotics, 39 (30.7%) PPIs, and 36 (28.3%) NSAIDs. No significant differences were observed between the patients with and without antibiotic use. However, patients using NSAIDs had significantly worse objective response rates (ORR) and progression-free survival (PFS) with ICI alone or in combination with chemotherapy compared to those who did not (ORR, 47.2% vs. 67.0%; p = 0.045. PFS, 6.3 months vs. 10.8 months; p = 0.02). Patients using PPIs demonstrated a worse ORR of ICI in combination with chemotherapy compared to those who did not (ORR, 45.2% vs. 72.6%; p = 0.013). The unnecessary use of NSAIDs along with immunotherapy should be discouraged.

Potentially inappropriate prescribing for people with dementia in ambulatory care: a cross-sectional observational study

BackgroundStudies have shown that potentially inappropriate prescribing (PIP) is highly prevalent among people with dementia (PwD) and linked to negative outcomes, such as hospitalisation and mortality. However, there are limited data on prescribing appropriateness for PwD in Saudi Arabia. Therefore, we aimed to estimate the prevalence of PIP and investigate associations between PIP and other patient characteristics among PwD in an ambulatory care setting.MethodsA cross-sectional, retrospective analysis was conducted at a tertiary hospital in Saudi Arabia. Patients who were ≥ 65 years old, had dementia, and visited ambulatory care clinics between 01/01/2019 and 31/12/2021 were included. Prescribing appropriateness was evaluated by applying the Screening Tool of Older Persons Potentially Inappropriate Prescriptions (STOPP) criteria. Descriptive analyses were used to describe the study population. Prevalence of PIP and the prevalence per each STOPP criterion were calculated as a percentage of all eligible patients. Logistic regression analysis was used to investigate associations between PIP, polypharmacy, age and sex; odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Analyses were conducted using SPSS v27.ResultsA total of 287 PwD were identified; 56.0% (n = 161) were female. The mean number of medications prescribed was 9.0 [standard deviation (SD) ± 4.2]. The prevalence of PIP was 61.0% (n = 175). Common instances of PIP were drugs prescribed beyond the recommended duration (n = 90, 31.4%), drugs prescribed without an evidence-based clinical indication (n = 78, 27.2%), proton pump inhibitors (PPIs) for > 8 weeks (n = 75, 26.0%), and acetylcholinesterase inhibitors with concurrent drugs that reduce heart rate (n = 60, 21.0%). Polypharmacy was observed in 82.6% (n = 237) of patients and was strongly associated with PIP (adjusted OR 24.1, 95% CI 9.0–64.5).ConclusionsFindings have revealed a high prevalence of PIP among PwD in Saudi Arabia that is strongly associated with polypharmacy. Future research should aim to explore key stakeholders’ experiences and perspectives of medicines management to optimise medication use for this vulnerable patient population.

Risky Sexual Behaviours and Knowledge on Contraceptive Use and Family Planning Among Women Who Use Drugs (WWUDs) in Malaysia

Women who use drugs (WWUDs) face elevated risk of intimate partner violence (IPV) and unsafe sexual behaviours. This prevalence study, involving 200 WWUDs in a mandated drug rehabilitation program, examined risky sexual behaviours, family planning knowledge among IPV victims, and barriers to contraceptives or condoms use. The majority were Malays (86%, n = 171/200), averaging 32.3 years of age (SD = 8.61). Over half had experienced IPV in their lifetime (53%, n = 105/200). IPV victims had higher odds of unwanted pregnancies, prior abortions, concurrent drug use with partners, drug use before sex, and cohabitation with male partners who used drugs. Sixty percent were uninformed of female condoms, and most disliked using male condoms due to performance concerns. Despite better family planning knowledge among IPV victims, WWUDs had limited awareness of contraceptive use. Interventions should prioritize empowering and educating WWUDs, particularly IPV victims, on IPV prevention and the risks associated with unsafe sexual behaviour during rehabilitation.

Ultrasensitive Response Explains the Benefit of Combination Chemotherapy Despite Drug Antagonism.

Most aggressive lymphomas are treated with combination chemotherapy, commonly as multiple cycles of concurrent drug administration. Concurrent administration is in theory optimal when combination therapies have synergistic (more than additive) drug interactions. We investigated pharmacodynamic interactions in the standard 4-drug "CHOP" regimen in peripheral T-cell lymphoma (PTCL) cell lines and found that CHOP consistently exhibits antagonism and not synergy. We tested whether staggered treatment schedules could improve tumor cell kill by avoiding antagonism, using in vitro models of concurrent or staggered treatments. Surprisingly, we observed that tumor cell kill is maximized by concurrent drug administration despite antagonistic drug-drug interactions. We propose that an ultrasensitive dose response, as described in radiology by the linear-quadratic (LQ) model, can reconcile these seemingly contradictory experimental observations. The LQ model describes the relationship between cell survival and dose, and in radiology has identified scenarios favoring hypofractionated radiotherapy-the administration of fewer large doses rather than multiple smaller doses. Specifically, hypofractionated treatment can be favored when cells require an accumulation of DNA damage, rather than a "single hit," to die. By adapting the LQ model to combination chemotherapy and accounting for tumor heterogeneity, we find that tumor cell kill is maximized by concurrent administration of multiple drugs, even when chemotherapies have antagonistic interactions. Thus, our study identifies a new mechanism by which combination chemotherapy can be clinically beneficial that is not contingent on positive drug-drug interactions.