Drug Challenge Research Articles

Technical note: Evaluation of a transportable linear ion trap mass spectrometer for seized drug screening operated under controlled laboratory conditions.

Increasing seized drug casework submissions and challenges with rapidly triaging seized drug evidence have led to interest in the potential use of instruments for on-site or mobile laboratory drug screening. However, before this type of instrumentation can be implemented, it is imperative to evaluate the capabilities and limitations under controlled laboratory conditions. This study evaluates the BaySpec Continuity™ transportable linear ion trap (LIT) mass spectrometer coupled to a thermal desorption-atmospheric pressure chemical ionization (TD-APCI) source for seized drug screening while operated under controlled laboratory conditions. The target compounds chosen for this study were selected based on controlled substances and cutting agents commonly observed in seized drug casework, including cocaine, methamphetamine, heroin, fentanyl, caffeine, acetaminophen, pseudoephedrine, phenacetin, phentermine, and levamisole. A library-based alarm system screening method was developed and validated for rapid compound identification in seized drug mixtures. Selectivity, repeatability, and reproducibility were evaluated using five simulated seized drug mixtures with known compositions, and the limit of detection was evaluated for each compound. Blind and authentic destroyed casework samples were analyzed to determine the efficacy of this method when applied to real-world samples and a 100% correct identification rate of the controlled substance present was achieved. Additionally, the ability to differentiate isobaric species using tandem mass spectrometry (MS/MS) analysis was demonstrated for methamphetamine and phentermine. The validated library-based alarm screening method shows promise for rapid seized drug screening under controlled laboratory conditions, which supports potential usage in a mobile laboratory setting.

Recovery support services as part of the continuum of care for alcohol or drug use disorders.

The definition of 'recovery' has evolved beyond merely control of problem substance use to include other aspects of health and wellbeing (known as 'recovery capital') which are important to prevent relapse to problematic alcohol or other drug (AOD) use. Developing a Recovery Oriented System of Care (ROSC) requires consideration of interventions or services (Recovery Support Services, RSS) designed to build recovery capital which are often delivered alongside established treatment structures. Lived experience and its application to the process of engaging people, changing behaviour and relapse prevention is an essential part of these services. To map out the evidence base for RSS as part of guidance for commissioners of addiction services in each of the 152 local authorities in England. The authors updated the findings of a 2017 systematic review of RSS through a further rapid scoping review, aiming to map out the extent, range and nature of research under six headings: (1) Peer-based recovery support services (P-BRSS); (2) Employment support approaches; (3) Recovery housing; (4) Continuing care and recovery check-ups; (5) Recovery community centres (RCC); and (6) Recovery support services in educational settings. A systematic search of the PubMed, Embase, CINAHL, CENTRAL and PsychINFO databases was conducted. The abstracts of all articles published since 2017 were reviewed by two of the authors, and the full text versions of all relevant articles were obtained and relevant data extracted. A narrative review of the findings was then prepared, mapping them on to the ROSC continuum of care. The review was restricted to adults (over 18 years), but all substances and available outcomes were included. Four of the six forms of RSS were well supported by evidence. RCTs of interventions to increase levels of employment demonstrated large effect sizes, and continuing care interventions that extend treatment intervention into the early recovery phase have shown small but significant benefit. Peer-delivered interventions to link people to ongoing support were associated with decreased rates of relapse and re-admission, increased engagement, and increased social support for change. However, the variability in the design of these studies means that further work is required to clarify the effective components of the intervention. Studies of recovery housing have also shown positive results, including significant differences from standard care. No controlled studies exist to support RCCs or RSS in educational settings, but the complexity of these interventions and the wide range of potential outcome measures mean that other study designs may be more relevant. This monograph provides a structure to help policy makers, commissioners and service providers describe and understand an emerging field of research. Recovery Support Services (RSS) are proving to have clinical, public health and cost utility. A rational social and fiscal response to endemic alcohol or other drug challenges should therefore include the more intensive acute care clinical services linked with more extensive community-based RSS.

Gamma oscillations and excitation/inhibition imbalance: parallel effects of N-methyl D-aspartate receptor antagonism and psychosis.

Auditory steady-state response (ASSR) abnormalities in the 40-Hz (gamma band) frequency have been observed in schizophrenia and rodent studies of N-methyl D-aspartate glutamate receptor (NMDAR) hypofunction. However, the extent to which 40-Hz ASSR abnormalities in schizophrenia resemble deficits in 40-Hz ASSR induced by acute administration of ketamine, an NMDAR antagonist, is not yet known. To address this knowledge gap, we conducted parallel EEG studies: a crossover, placebo-controlled ketamine drug challenge study in healthy subjects (Study 1) and a comparison of patients with schizophrenia and healthy controls subjects (Study 2). Time-frequency analysis of the ASSR was used to calculate baseline, broadband gamma power, evoked power, total power, phase-locking factor, and phase-locking angle. Relative to healthy controls, schizophrenia patients exhibited increases in pre-stimulus broadband gamma power and reductions in 40-Hz ASSR evoked power, total power, and phase-locking factor, replicating prior studies. However, we failed to replicate previous findings of 40-Hz ASSR phase delay in schizophrenia. Relative to placebo, ketamine: increased pre-stimulus broadband gamma power, reduced 40-Hz ASSR evoked power, total power, and phase-locking factor, and advanced the phase of the 40-Hz ASSR. Normalized by their respective control groups/conditions, direct comparison of these measures between schizophrenia and ketamine data only revealed significant differences in phase, supporting the role of NMDAR hypofunction in mediating gamma oscillation abnormalities in schizophrenia.

Resensitization - Should repeat testing be performed in patients undergoing penicillin allergy evaluations? A Pro-Con Debate.

Evaluating penicillin allergy labels and expanding access to preferred treatment options safely is of critical public health importance. Most patients with penicillin allergy labels are not allergic, and even in those with verified allergy, sensitization wanes over time. However, sensitization is complex and while a patient may have a negative penicillin allergy evaluation (including a drug challenge), resensitization can occur, raising a risk of a subsequent reaction upon exposure. In this pro/con debate we deliberate on whether patients who have had negative penicillin allergy evaluations should undergo retesting for sensitization prior to subsequent administrations. The pro position is presented by Drs. Inmaculada Doña, María Salas, and María Torres, while the con position is described by Drs. Ami Belmont and Roland Solensky.

Polysaccharide-based drug delivery targeted approach for colon cancer treatment: A comprehensive review.

Colon cancer is a leading cause of cancer-related morbidity and mortality worldwide, necessitating advancements in therapeutic strategies to improve outcomes. Current treatment modalities, including surgery, chemotherapy, and radiation, are limited by systemic toxicity, low drug utilization rates, and off-target effects. Colon-targeted drug delivery systems (CDDS) offer a promising alternative by leveraging the colon's unique physiology, such as near-neutral pH and extended transit time, to achieve localized and controlled drug release. Polysaccharide-based CDDS, utilizing natural polymers like chitosan, cyclodextrin, pectin, guar gum, alginate, hyaluronic acid, dextran, chondroitin sulfate, and inulin, have emerged as innovative approaches for improving the specificity and efficacy of colon cancer treatments. These biocompatible and biodegradable polymers enable site-specific drug delivery, enhance tumor apoptosis, reduce systemic side effects, and improve patient compliance. This review evaluates recent advancements in polysaccharide-based CDDS, detailing their drug release mechanisms, therapeutic potential, and challenges in overcoming gastrointestinal transit and pH variability. Studies highlight the successful formulation of nanoparticles, microspheres, and other delivery systems, demonstrating targeted drug delivery, improved bioavailability, and enhanced cytotoxicity against colon cancer cells in-vitro and in-vivo. The review underscores the need for continued research on polysaccharide-based CDDS for colon cancer treatment, offering a path toward more effective, patient-centered oncological care.

Microneedles in transdermal drug delivery system

One such review paper focuses on Minnesota's advanced technologies, highlighting the latest updates on drug delivery methods, challenges, and innovations. Intravenous therapy, a non-invasive and pain-free approach, is often used for drug delivery. This method offers a complete bioactivity with minimal intrusion, enabling the administration of medication through the skin. The effectiveness of this treatment is influenced not only by the transdermal delivery system but also by profiling, which helps optimize the release of active ingredients.The paper discusses various components of intravenous therapy and fabrication techniques, emphasizing their role in managing drug release. For instance, therapies can be administered directly into the epidermis and uveitis area, regulating the release of therapeutic substances over a specific time frame. Several delivery systems, such as polypropylene and nanogels, have been explored for their ability to extend the delivery of active components, improving therapeutic outcomes.Additionally, the review highlights the application of these technologies in treating various medical conditions. Researchers also examine the design requirements for efficient drug delivery systems, including material choice and machine learning simulations to optimize performance. Needle-free methods have been proposed to bypass the skin's lipid barrier, enabling effective nutrient delivery. New technologies in Minneapolis also show promise for conditions such as insulin administration, subcutaneous injections, and gene transfer, demonstrating significant progress in non-invasive healthcare solutions.

Recent advances, strategies, and future perspectives of peptide-based drugs in clinical applications.

Peptide-based therapies have attracted considerable interest in the treatment of cancer, diabetes, bacterial infections, and neurodegenerative diseases due to their promising therapeutic properties and enhanced safety profiles. This review provides a comprehensive overview of the major trends in peptide drug discovery and development, emphasizing preclinical strategies aimed at improving peptide stability, specificity, and pharmacokinetic properties. It assesses the current applications and challenges of peptide-based drugs in these diseases, illustrating the pharmaceutical areas where peptide-based drugs demonstrate significant potential. Furthermore, this review analyzes the obstacles that must be overcome in the future, aiming to provide valuable insights and references for the continued advancement of peptide-based drugs.

Innovative nanocarrier systems for enhanced delivery of phyto-active compounds in cancer therapy.

Millions of people worldwide suffer from cancer, facing challenges such as treatments affecting healthy cells, suboptimal responses, adverse effects, recurrence risk, drug resistance, and nonspecific targeting. Chemoresistance leads to fatalities, but phytoactives show promise in cancer management despite limitations such as high metabolism, poor absorption, and high dosage requirements. Challenges in the large-scale isolation of phytoactive compounds, solubility, bioavailability, and targeting limit their development. Recent developments, including carbohydrate, lipid, and protein-based nanoparticles, have enhanced cancer treatment by improving the bioavailability and targeted delivery of phytoactives such as polyphenols, alkaloids, sulfur-containing compounds, flavonoids, and terpenes. Despite advancements, clinical application faces hurdles such as poor bioavailability and inconsistent immune responses. This article discusses the promise of phytoactive-loaded nanoformulations in cancer management, highlighting targeted drug delivery, unmet needs, and challenges. Further research is needed to overcome these challenges and fully understand the potential of phytoactives in cancer management.

MSR60 Modeling Challenges for Cancer Drugs With Unprecedented Outcomes: Lorlatinib in the First Line Setting of ALK+ aNSCLS As a Case Study

MSR60 Modeling Challenges for Cancer Drugs With Unprecedented Outcomes: Lorlatinib in the First Line Setting of ALK+ aNSCLS As a Case Study

HPR26 Managed Entry Agreements to Mitigate Uncertainties and Reimbursement Challenges for Orphan Drugs: A Matrix to Determine Their Suitability

HPR26 Managed Entry Agreements to Mitigate Uncertainties and Reimbursement Challenges for Orphan Drugs: A Matrix to Determine Their Suitability

Challenges in New Psychoactive Substances and Traditional Drugs of Abuse Testing in Saudi Arabia

Challenges in New Psychoactive Substances and Traditional Drugs of Abuse Testing in Saudi Arabia

A Comprehensive Survey of Studies on Predicting Anatomical Therapeutic Chemical Classes of Drugs

Drug classification plays a crucial role in contemporary drug discovery, design, and development. Determining the Anatomical Therapeutic Chemical (ATC) classes for new drugs is a laborious, costly, and intricate process, often requiring multiple clinical trial phases. Computational models offer significant benefits by accelerating drug evaluation, reducing complexity, and lowering costs; however, challenges persist in the drug classification system. To address this, a literature survey of computational models used for predicting ATC classes was conducted, covering research from 2008 to 2024. This study reviews numerous research articles on drug classification, focusing on drug descriptors, data sources, tasks, computational methods, model performance, and challenges in predicting ATC classes. It also examines the evolution of computational techniques and their application in identifying ATC classes. Finally, the study highlights open problems and research gaps, suggesting areas for further investigation in ATC class prediction.

Adiponectin may play a crucial role in the metabolic effects of GLP-1RAs treatment in patients with Type 2 Diabetes Mellitus: a preliminary longitudinal study.

Type 2 diabetes mellitus (T2DM) stands as the most prevalent metabolic disorder globally. T2DM entails numerous cardiovascular complications, which contribute significantly to morbidity, mortality, and increased public spending worldwide. The real challenge for new diabetes drugs lies not only in reducing blood glucose levels and glycated hemoglobin but also in preventing cardiovascular risk. Emerging receptor agonists for glucagon-like peptide-1 (GLP-1RAs) have demonstrated a pivotal role in diabetes management and mitigating cardiovascular risk. We conducted a 12-month longitudinal investigation evaluating the cardio-metabolic effects of GLP-1RAs on a cohort of 65 Caucasian patients diagnosed with T2DM who were scheduled for treatment with GLP-1RAs. Fifty-four T2DM patients successfully completed the 12-month study period, with 30 receiving dulaglutide and 24 receiving semaglutide. In our study population, GLP-1RAs resulted in several positive changes beyond the observed weight loss: a shift in fat distribution, indicated by a reduction in the percentage of visceral fat (1.21 vs. 1.17, p < 0.05); a significant decrease in LDL cholesterol levels (p < 0.05) and triglycerides (p < 0.01); and a significant increase in serum adiponectin levels (p < 0.05), potentially indicating a reduction in insulin resistance and inflammation. Additionally, we observed a significant decrease in microalbuminuria and media-intimal thickness at the carotid vessel level (p < 0.05). In patients with T2DM 1-year therapy with GLP-1RAs has a positive effect on the main determinants of cardiovascular risk including body weight, visceral fat, dyslipidemia, and atherosclerosis. Moreover, the increase in adiponectin may play a pivotal role in controlling the inflammatory state and the mechanisms of vascular damage.

Chemical Probes Review: Choosing the Right Path Towards Pharmacological Targets in Drug Discovery, Challenges and Future Perspectives.

Chemical probes are essential for academic research and target validation for disease identification. They facilitate drug discovery, target function investigation, and translation studies. A chemical probe provides starting material that can accelerate therapeutic values and safety measures for identifying any biological target in drug discovery. Essential read outs depend on their versatility in biochemical testing, proving the hypothesis, selectivity, specificity, affinity towards the target site, and valuable in new therapeutic approaches. Disease management will depend upon chemical probes as a primitive tool to ascertain the physicochemical stability for in vivo and in vitro studies useful for clinical trials and industrial application in the future. For cancer research, bacterial infection, and neurodegenerative disorders, chemical probes are integrated circuits which are on pipeline for the drug discovery process Furthermore, pharmacological modulators incorporate activators, crosslinkers, degraders, and inhibitors. Reports accessed depend on their structural, mechanical, biochemical, and pharmacological characterization in drug discovery research. The perspective for designing any chemical probes concludes with the utilization of drug discovery and identification of the potential target. It focuses mainly on evidence-based studies and produces promising results in successfully delivering novel therapeutics to treat cancers and other disorders at the target site. Moreover, natural product pharmacophores like rapamycin, cephalosporin, and α-lactamase are utilized for drug discovery. Chemical probes revolutionize computational-based study design depending on identifying novel targets within the database framework. Chemical probes are the clinical answers for drug development and goforward tools in solving other riddles for scientists and researchers working in this industries.

Safety and Low Incidence of Anaphylaxis in Performing Oral Drug and Food Challenges in Mastocytosis

BackgroundPatients with mastocytosis (MC) have an increased risk of severe anaphylaxis. They report hypersensitivity reactions to drugs and food, but causality often remains questionable. Most allergy centers avoid oral challenge tests (OCT) in MC patients. ObjectiveTo determine the safety of food and drug OCT in patients with MC. MethodsTo retrospectively evaluate the safety and outcome of challenges to drugs and food including food additives, out of 126 adult MC inpatients, 83 patients had a suspicion of food or drug hypersensitivity and 445 OCTs were performed. History, clinical data and allergy test results highlighting OCTs were analyzed. ResultsOnly 10 of 445 OCTs (2.2%) in 9 patients resulted in anaphylaxis. Drugs elicited reactions in 4/170 (2.4 %) patients: two patients to acetylsalicylic acid (2/39 tested patients, 5.1%), one to tramadol (1/12, 8.3%) and one to flurbiprofen (1/1). Anaphylaxis to food was recorded in 6/275 OCTs (2.2%); two out of 48 (4.1%) to α-gal, two to other foods and two to sulfites. Flushing or diarrhea occurred to histamine in 5/48 (10.4%), but also in 5/50 (10.0%) placebo challenges strongly questioning its relevance. Patients with proven anaphylaxis had more bone marrow MC and higher basal serum tryptase (71.3 vs. 44.3ug/l; p<0.05). ConclusionsChallenge-confirmed food and drug anaphylaxis was rare in MC patients. Results have to be interpreted cautiously as placebo reactions did occur. Severe anaphylaxis was seldom, but may occur and should be met by emergency preparedness.

Effects of Sex and Gender in Immediate Beta-Lactam Antibiotic Allergy: A Systematic Review and Meta-analysis

BackgroundBeta-lactams are the most common antibiotic class reported to cause allergic drug reactions. Previous literature suggests an increased prevalence of penicillin drug allergy in female patients in both inpatient and outpatient settings. However, the effects of sex and gender have not been well characterized regarding the entire class of beta-lactam antibiotics. ObjectiveThis systematic review and meta-analysis aimed to identify sex and gender-based differences in the prevalence of immediate beta-lactam allergy. MethodsWe performed an electronic search of Ovid MEDLINE/PubMed, Embase, Web of Science, Scopus, and the Cochrane Library between 2013-2023. Patients with a documented beta-lactam allergy who underwent allergy testing with skin testing, oral drug challenge, or serum-specific IgE were included. We quantitatively assessed sex- and gender-based differences in beta-lactam allergy with meta-analysis. ResultsWe included 69 primary studies, assessing 53,989 participants from outpatient and inpatient cohorts. 7,558 patients had a confirmed beta-lactam allergy. There was no difference in the prevalence of positive beta-lactam allergy test between males and females. Sub-group analysis of studies that performed oral challenges did show a higher risk of beta-lactam allergy in females than males (RR 1.40, 95% CI 1.18-1.66, p < 0.001, I2 =77.8%). Finally, there was a higher proportion of females (64.8%) than males enrolled in beta-lactam allergy studies. ConclusionsOur findings suggest both sex-based and gender-based differences in the prevalence of immediate beta-lactam allergy. Both biological factors, such as sex hormones, and gender-based behaviors, including increased healthcare utilization, may contribute to higher rates of beta-lactam allergy diagnosis in females.

Prospects of universal influenza virus vaccine and the current challenges of new antiviral drugs

The profound impact of influenza viruses on human health persists as a significant burden, given their potent capacity to cause morbidity and mortality. Despite efforts to mitigate the annual burden of influenza, the effectiveness of current seasonal vaccines in providing substantial protection falls short, leaving undesirable pandemic of influenza viruses. The challenges posed by the influenza pandemic lies from the constant changes inherent in the virus itself, as well as the limitations of current immunization approaches in achieving sufficient immunogenicity. Influenza viruses exhibit antigenic drift and shift, undergoing antigenic evolution by altering the surface glycoproteins. These changes contribute to the persistent and dynamic nature of the influenza virus, posing formidable challenges to effective prevention and control strategies. Currently, there is growing recognition of unique viral targets that hold promise development of broad-protective vaccines against influenza. These targets are distinct from traditional vaccine targets and offer the potential for more comprehension protection against diverse strains of the virus. Here, we present a review about the novel drugs and vaccines that target the influenza virus would signify the unique immune correlates of protection that need to be initiated to accelerate the vaccine efficacy.

Defining Cardiomyocyte Repolarization Response to Pharmacotherapy in Long-QT Syndrome Type 3.

Long-QT syndrome is a primary cardiac ion channelopathy predisposing a patient to ventricular arrhythmia through delayed repolarization on the resting ECG. We aimed to establish a patient-specific, human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes model of long-QT syndrome type 3 (LQT3) using clustered regularly interspaced palindromic repeats (CRISPR/Cas9), for disease modeling and drug challenge. HiPSCswere generated from a patient with LQT3 harboring an SCN5A pathogenic variant (c.1231G>A; p.Val411Met), and an unrelated healthy control. The same SCN5A pathogenic variant was engineered into the background healthy control hiPSCs via CRISPR/Cas9gene editing to generate a second disease model of LQT3 for comparison with an isogenic control. All 3 hiPSC lines were differentiated into cardiomyocytes. Both the patient-derived LQT3 (SCN5A+/-) and genetically engineered LQT3 (SCN5A+/-) hiPSC-derived cardiomyocytesshowed significantly prolonged cardiomyocyte repolarization compared with the healthy control. Mexiletine, a cardiac voltage-gated sodium channel (NaV1.5) blocker, shortened repolarization in both patient-derived LQT3 and geneticallyengineered LQT3 hiPSC-derived cardiomyocytes, but had no effect in the control. Notably, calcium channel blockers nifedipine and verapamil showed a dose-dependent shortening of repolarization, rescuing the phenotype. Additionally, therapeutic drugs known to prolong the corrected QT in humans (ondansetron, clarithromycin, and sotalol) demonstrated this effect invitro, but the LQT3 clones were not more disproportionately affected compared with the control. We demonstrated that patient-derived and genetically engineered LQT3 hiPSC-derived cardiomyocytesfaithfully recapitulate pathologic characteristics of LQT3. The clinical significance of such an invitro model is in the exploration of novel therapeutic strategies, stratifying drug adverse reaction risk and potentially facilitating a more targeted, patient-specific approach in high-risk patients with LQT3.

A Review on Ocular Nanoformulation Based Formulations with Highlights on Pediatric Ocular Pharmacokinetics.

The potential use of nanoparticle-based formulations is being explored rapidly for drug delivery in ocular treatment. Despite having several advancements in the area of ocular therapy, the pharmacokinetics-based formulation development for pediatric ocular treatment is still not in proper focus. There are an inadequate number of degenerative ocular ailments with childhood onset. The purpose of this review is to focus on the pharmacokinetics studies of nanoparticle- based formulations for treating ocular diseases and problems associated with the ocular treatment of the pediatric population. Recent studies on pharmaceutical modeling of ocular formulations have also been discussed. Nanoparticle-based formulations were collected by conducting a literature survey on PubMed, Science Direct, and other portals. In this review, we have explored in detail the explanation behind the inequality among available ocular treatment regimens for youngsters as well as adults by specifically focusing on those diseases that can be distressing for children. Latest innovative developments and advancements in drug delivery systems and challenges in their usage particularly for young infant patients were also discussed. It can be concluded that the bioavailability of ocular formulations and their effect on ocular cells can be further enhanced manifolds by the development of nanoparticles-based formulations.

Diagnosis of Brugada Syndrome With a Sodium-Channel-Blocker Test: Who Should Be Tested? Who Should Not?

Intravenous infusion of sodium-channel blockers (SCB) with either ajmaline, flecainide, procainamide, or pilsicainide to unmask the ECG of Brugada syndrome is the drug challenge most commonly used for diagnostic purposes when investigating cases possibly related to inherited arrhythmia syndromes. For a patient undergoing an SCB challenge, the impact of a positive result goes well beyond its diagnostic implications. It is, therefore, appropriate to question who should undergo a SCB test to diagnose or exclude Brugada syndrome and, perhaps more importantly, who should not. We present a critical review of the benefits and drawbacks of the SCB challenge when performed in cardiac arrest survivors, patients presenting with syncope, family members of probands with confirmed Brugada syndrome, and asymptomatic patients with suspicious ECG.