Hypersensitivity Reactions to Platinum Agents and Taxanes

Hypersensitivity reactions (HSRs) to chemotherapy agents can present a serious challenge to treating patients with preferred or first-line therapies. Allergic reactions through an immunologic mechanism have been established for platinum and taxane agents, which are used to treat a wide variety of cancers including gynecologic cancers. Platin HSRs typically occur after multiple cycles of chemotherapy, reflecting the development of drug IgE sensitization, while taxane HSRs often occur on first or second exposure. Despite observed differences between platin and taxane HSRs, drug desensitization has been an effective method to reintroduce both chemotherapeutic agents safely. Skin testing is the primary diagnostic tool used to risk-stratify patients after initial HSRs, with more widespread use for platinum agents than taxanes. Different practices exist around the use of skin testing, drug challenge, and choice of desensitization protocol. Here, we review the epidemiology, mechanism, and clinical presentation of HSRs to platinum and taxane agents, as well as key controversies in their evaluation and management.

Chemical peritonitis associated with intraperitoneal vancomycin: A case series

Peritonitis is a serious complication in peritoneal dialysis, usually secondary to an infectious cause. Chemical peritonitis is rarer. No case exclusively attributed to vancomycin has been reported in the last 20 years. Data from 4 consecutive patients diagnosed with culture -negative peritonitis following administration of intraperitoneal vancomycin between May and June 2019 were retrospectively recorded. All patients were treated with 2 grams of intraperitoneal vancomycin after a break in aseptic technique and developed a cloudy effluent. No patient was previously known to be allergic to vancomycin. All had a clear dialysate before vancomycin. All developed an elevated leukocyte count in the dialysate. All had sterile cultures. All resumed a clear effluent with less <100 cells/μL after vancomycin cessation, and in two there were no further administrations. In one, a new drug challenge led to recrudescence of abdominal pain and reappearance of a cloudy sterile effluent. In another, vancomycin from a different lot was administrated 3 days after, no symptoms developed and dialysate cell count remained normal. The pathogenic mechanisms underlying chemical peritonitis are not fully known. The clinical course is typically benign. Management seems to be limited to drug withdrawal. If unrecognized, chemical peritonitis may ultimately lead to unnecessary catheter removal.

Allergic Reaction due to Anti-Tuberculosis Drugs, How to Manage?

Tuberculosis (TB) still becomes a significant health problem in Indonesia. The first-line anti-tuberculosis drug (ATD) is still the most effective TB drug, but it can have some side effects. One of them is allergic skin reactions that can affect a patient's compliance. Allergic reactions due to ATD are found in 4-6% of TB cases and are the third most frequent side effect after gastrointestinal and liver function disorder. All first-line ATD can cause allergic reactions. Allergic reactions due to ATD can be mild, such as itching and reddish rashes, to severe and life-threatening rashes, such as anaphylactic shock, Steven Johnson Syndrome (SJS), and Toxic Epidermal Necrotic (TEN). The most important things in the management are identifying and stopping drugs. It includes drug challenge and desensitization of causing drug. Desensitization must be distinguished from drug challenge or provocation tests, which are diagnostic tools. The proper management of ATD allergic reactions can improve compliance and patient's outcomes.

Fentanyl conjugate vaccine by injected or mucosal delivery with dmLT or LTA1 adjuvants implicates IgA in protection from drug challenge

Fentanyl is a major contributor to the devastating increase in overdose deaths from substance use disorders (SUD). A vaccine targeting fentanyl could be a powerful immunotherapeutic. Here, we evaluated adjuvant and delivery strategies for conjugate antigen vaccination with fentanyl-based haptens. We tested adjuvants derived from the heat-labile toxin of E. coli including dmLT and LTA1 by intramuscular, sublingual or intranasal delivery. Our results show anti-fentanyl serum antibodies and antibody secreting cells in the bone-marrow after vaccination with highest levels observed with an adjuvant (alum, dmLT, or LTA1). Vaccine adjuvanted with LTA1 or dmLT elicited the highest levels of anti-fentanyl antibodies, whereas alum achieved highest levels against the carrier protein. Vaccination with sublingual dmLT or intranasal LTA1 provided the most robust blockade of fentanyl-induced analgesia and CNS penetration correlating strongly to anti-FEN IgA. In conclusion, this study demonstrates dmLT or LTA1 adjuvant as well as mucosal delivery may be attractive strategies for improving the efficacy of vaccines against SUD.

The cognitive and behavioral effects of D-amphetamine and nicotine sensitization in adult zebrafish

Background Zebrafish are growing in use as a model for understanding drug dependence and addiction. Sensitization paradigms have been a useful tool in identifying mechanisms involved in drug-induced behavioral and neurological changes, but in zebrafish have tended to focus on locomotor, rather than cognitive, endpoints. Methods Here, we used a novel method, the FMP Y-maze, which measures continuous performance through a series of repeated binary choices (L vs R), to establish a model for assessing parameters associated with psychostimulant-induced behavioral and cognitive sensitization in adult zebrafish. Results Repeat, intermittent exposure to d-amphetamine (AMPH) for 14 days increased alternations (LRLR) in the maze, suggesting improved working memory, which was enhanced further following drug challenge after a short withdrawal period, suggesting behavioral sensitization. However, this cognitive enhancement coincided with a reduction in the use of other exploration strategies, hypolocomotion, and inhibition of cognitive flexibility. Like AMPH, exposure to nicotine (NIC) increased alternations following drug challenge after chronic treatment. Repeat NIC exposure appeared to induce both cognitive and psychomotor sensitization, as evidenced by increased working memory performance (alternations) and locomotor activity, without negatively impacting other search strategies or cognitive flexibility. Conclusion Chronic treatment with AMPH or NIC boosts cognitive performance in adult zebrafish. Cognitive sensitization occurred with both drugs, resulting in enhanced working memory; however, repeat AMPH exposure, following a withdrawal period, resulted in inhibited cognitive flexibility, an effect not evident with repeat NIC exposure. Cognitive and behavioral sensitization paradigms in zebrafish could serve as a useful tool for assessing cognitive states which result in cognitive enhancing or impairing effects of drugs.

PATTERNS OF RESPONSE AND DRUGS INVOLVED IN HYPERSENSITIVITY REACTIONS TO BETA-LACTAMS IN CHILDREN.

Background Beta-lactams generate different allergenic determinants that induce selective or cross-reactive drug hypersensitivity reactions (DHRs). We aimed to identify the drugs involved, the selectivity of the response, the mechanism, and the value of the different diagnostic tests for establishing a diagnosis in children evaluated for DHRs to beta-lactams. Methods Prospective study evaluating children aged under 16 years reporting DHRs to beta-lactams. Reactions were classified as immediate and nonimmediate reactions. The work-up included sIgE, skin testing and drug provocation tests (DPTs) for immediate reactions and patch testing and DPTs for nonimmediate ones. Results Of the 510 included children, 133 were evaluated for immediate reactions and confirmed in 8.3%. Skin test/in vitro IgE contributed to diagnosing half of the cases. Selective reactions occurred with amoxicillin (63%), followed by common penicillin determinants (27%) and cephalosporins (0.9%). Among nonimmediate reactions (11,4% of the 377 children evaluated), most required DPTs, 52.7% of which were positive at 6–7 days of drug challenge. Selective reactions were identified with amoxicillin (80%), penicillin G (7.5%), cephalosporins (7.5%), and clavulanic acid (5%). Urticaria and maculopapular exanthema were the most frequent entities. Conclusions There were few confirmed cases of either type of reaction. Skin testing proved less valuable in nonimmediate reactions, over half of which would also have been lost in a short DPT protocol. Selective responders to amoxicillin were more likely to have nonimmediate reactions, while clavulanic acid-selectivity was exclusive to the nonimmediate typology. Over half the cases with DPTs required 6-7 days of treatment for DHR confirmation.

Spanish Society vision of Drug challenge tests

The controlled drug exposure test (DPT) is currently considered the gold standard for the diagnosis of drug allergy. Drug-induced adverse reactions (ADRs) are a growing reason for consultation in both primary and specialized care. Allergology consultations in Spain are the ones that usually study these ADRs and rule out immunological mechanisms involved in up to 90% of the cases consulted. An adequate approach to these cases has an obvious impact on the costs and efficacy of the treatments required by other specialists, so that if we did not use DPTs, patients would require more expensive, more toxic and less effective treatments in most of the cases. In recent years, a large number of new drugs have been developed and this document is intended to be a practical guide in the management of PDT with the vision of the Spanish Allergology Society. Diagnostic work begins with a detailed history of the patient. Skin tests are only useful for some medications, and in most cases the diagnosis can only be confirmed by DPT. Although there is usually cross-reactivity, DPTs can confirm the diagnosis and also help to find a tolerable alternative drug. The individual management of patients in a programmed way, taking into account both the type of drug to be studied and the patient's comorbidities, usually allows a solution to be found for the majority of patients.

Cannabinoids, reward processing, and psychosis

Background Evidence suggests that an overlap exists between the neurobiology of psychotic disorders and the effects of cannabinoids on neurocognitive and neurochemical substrates involved in reward processing. Aims We investigate whether the psychotomimetic effects of delta-9-tetrahydrocannabinol (THC) and the antipsychotic potential of cannabidiol (CBD) are underpinned by their effects on the reward system and dopamine. Methods This narrative review focuses on the overlap between altered dopamine signalling and reward processing induced by cannabinoids, pre-clinically and in humans. A systematic search was conducted of acute cannabinoid drug-challenge studies using neuroimaging in healthy subjects and those with psychosis Results There is evidence of increased striatal presynaptic dopamine synthesis and release in psychosis, as well as abnormal engagement of the striatum during reward processing. Although, acute THC challenges have elicited a modest effect on striatal dopamine, cannabis users generally indicate impaired presynaptic dopaminergic function. Functional MRI studies have identified that a single dose of THC may modulate regions involved in reward and salience processing such as the striatum, midbrain, insular, and anterior cingulate, with some effects correlating with the severity of THC-induced psychotic symptoms. CBD may modulate brain regions involved in reward/salience processing in an opposite direction to that of THC. Conclusions There is evidence to suggest modulation of reward processing and its neural substrates by THC and CBD. Whether such effects underlie the psychotomimetic/antipsychotic effects of these cannabinoids remains unclear. Future research should address these unanswered questions to understand the relationship between endocannabinoid dysfunction, reward processing abnormalities, and psychosis.