Investigating in VigiBase over 6000 cases of pneumonia in clozapine-treated patients in the context of the literature: focus on high lethality and the association with aspiration pneumonia.

BACKGROUND: The literature associates clozapine with pneumonia/aspiration pneumonia. RESEARCH DESIGN AND METHODS: The international pharmacovigilance database (VigiBase™) uses the information component (IC) as statistical signal. VigiBase clozapine reports were analyzed for pneumonia/aspiration pneumonia from introduction to 10 May 2023. RESULTS: There were 6392 cases of all types of pneumonia (5572 cases of pneumonia, 775 of aspiration pneumonia, and 45 combined). The IC was 3.52 for aspiration pneumonia, introduced as a VigiBase label in 2003, and 1.91 for pneumonia. Patients were reclassified as 3628 with no signs of aspiration and 1533 with signs. Signs of aspiration were strongly associated with some co-medications: olanzapine, odds ratio (OR) = 23.8, 95% confidence interval (CI), 14.9-38.0; risperidone OR = 18.6, CI, 11.4-30.4; valproic acid, OR = 5.5, CI, 4.5-6.6; and benzodiazepines OR = 5.5, CI, 4.5-6.6. In 2415 cases with completed data, fatal outcomes made up 45% (signs of aspiration made no difference), but there was wide variability from 0% (females <45 years of age; duration ≤30 days) to 76% (males >64 years of age; duration >1 year). During the first week, pneumonia was associated with 1) very high titration doses, 2) very small doses in Parkinson's disease, and 3) Japan vs other countries. CONCLUSIONS: In clozapine-treated patients: 1) at least 30% of pneumonia cases may be aspiration pneumonia, 2) stopping some co-medications may decrease the risk of aspiration pneumonia, 3) average lethality in pneumonia was 45% but may be around 75% in geriatric patients with long-term treatment, and 4) safer titrations may sometimes require 5-mg tablets.

Effects of induced arterial hypertension for vasospasm on unruptured and unsecured cerebral aneurysms (growth and rupture). A retrospective case-control study.

OBJECTIVES: Unruptured cerebral aneurysms (UCAs) often coexist with the ruptured one but are typically left unsecured during the weeks following aneurysmal subarachnoid hemorrhage (aSAH). We compared the rate of UCAs rupture or volume growth (≥5 mm3) between patients exposed to induced arterial hypertension (iHTN) for vasospasm and those not exposed (control group). MATERIALS AND METHODS: From 2013 to 2021, we retrospectively included consecutive adult patients with aSAH who had ≥1 UCA. Custom software for digital subtraction angiography (DSA) image analysis characterized UCAs volume, going beyond merely considering UCAs long axis. RESULTS: We analyzed 118 patients (180 UCAs): 45 in the iHTN group (64 UCAs) and 73 in the control group (116 UCAs). Systolic blood pressure in the iHTN group was significantly higher than in the control group for several days after aSAH. During the 107 day-monitoring period [interquartile range(IQR):92;128], no UCA rupture occurred in either group. UCA volume analysis was performed in 44 patients (60 UCAs): none of the UCAs in the iHTN group and 3 out of 42 (7%) in the control group had a >5 mm3 volume growth (p=0.55). Other morphologic parameters did not exhibit any variations that might indicate an increased risk of rupture in the iHTN group compared to the control group. CONCLUSION: iHTN did not increase the risk of rupture or volume growth of UCAs within several weeks following aSAH. These reassuring results encourage not to refrain, because of the existence of UCAs, from iHTN as an option to prevent cerebral infarction during cerebral vasospasm.

Glutathione effect on functional and histological recovery after spinal cord injury in rats.

OBJECTIVE: The aim of this study was to evaluate the GSH effect on functional and histological recovery after experimental spinal cord injury in rats. METHODS: Forty Wistar rats were subjected to spinal cord injury through the Multicenter Animal Spinal Cord Injury Study (MASCIS) Impactor system. The rats were sorted and divided into four groups, as follows: Group 1 ‒ Laminectomy and spinal cord injury; Group 2 ‒ Laminectomy, spinal cord injury and Saline Solution (SS) 0.9%; Group 3 ‒ Laminectomy, spinal cord injury, and GSH; and Group 4 ‒ lLaminectomy without spinal cord injury. GSH and SS were administered intraperitoneally. Groups 1 and 4 received no intervention. RESULTS: The rats were evaluated for locomotor function recovery at seven different times by the Basso, Beattie, and Bresnahan (BBB) scale on days 2, 7, 14, 21, 28, 35, and 42 after the spinal cord injury. On day 42, the rats were sacrificed to analyze the histological findings of the injured spinal cord. In the group submitted to GSH, our experimental study revealed better functional scores on the BBB scale, horizontal ladder scale, and cranial and caudal axon count. The differences found were statistically significant in BBB scores and axonal count analysis. CONCLUSION: This study demonstrated that using glutathione in experimental spinal trauma can lead to better functional recovery and improved axonal regeneration rate in Wistar rats submitted to experimental spinal cord injury.

The effects of simultaneous alcohol and cannabis use on subjective drug effects: A narrative review across methodologies.

Over 75% of young adults who use cannabis also report drinking alcohol, leading to increased risks that include impaired cognition, substance use disorders, and more heavy and frequent substance use. Studies suggest that subjective responses to either alcohol or cannabis can serve as a valuable indicator for identifying individuals at risk of prolonged substance use and use disorder. While laboratory studies show additive effects when alcohol and cannabis are used together, the impact of co-using these substances, specifically with respect to cannabidiol, on an individual's subjective experience remains unclear. This narrative review explores the effects of simultaneous alcohol and cannabis (SAM) use on subjective drug effects, drawing from qualitative research, laboratory experiments, and naturalistic studies. Experimental findings are inconsistent regarding the combined effects of alcohol and cannabis, likely influenced by factors such as dosage, method of administration, and individual substance use histories. Similarly, findings from qualitative and naturalistic studies are mixed regarding subjective drug effects following SAM use. These discrepancies may be due to recall biases, variations in assessment methods, and the measurement in real-world contexts of patterns of SAM use and related experiences. Overall, this narrative review highlights the need for more comprehensive research to understand more fully subjective drug effects of SAM use in diverse populations and settings, emphasizing the importance of frequent and nuanced assessment of SAM use and subjective responses in naturalistic settings.

Hematological Complications of Human Immunodeficiency Virus (HIV) Infection: An Update From an HIV-Endemic Setting.

Medical professionals, particularly in regions with a high burden of human immunodeficiency virus (HIV), should be alert to the hematological complications of HIV, which may include cytopenias, malignancy, and coagulation disturbances. Patients may present with these conditions as the first manifestation of HIV infection. Hematological abnormalities are often multifactorial with opportunistic infections, drugs, malignancy, and HIV infection itself contributing to the clinical presentation, and the diagnosis should consider all these factors. Life-threatening hematological complications requiring urgent diagnosis and management include thrombotic thrombocytopenic purpura, superior mediastinal syndrome, spinal cord compression, and tumor lysis syndrome due to aggressive lymphoma. Antiretroviral therapy is the therapeutic backbone, including for patients with advanced HIV, in addition to specific therapy for the complication. This article reviews the impact of HIV on the hematological system and provides a clinical and diagnostic approach, including the role of a bone marrow biopsy, focusing on perspectives from sub-Saharan Africa.

Modeling of Styl'One Evolution Correction Factors for Multicomponent Mixtures Scaling-up to Roller Compaction.

Roll compaction (RC) is a cost-effective dry granulation method, widely implemented in the pharmaceutical industry. In early formulation development however, when the material availability is limited, being able to predict the most important parameters in RC, like gap width and specific compaction force (SCF), to obtain a target ribbon solid fraction (SF) would significantly improve the formulation development efficiency as it would avoid the need of performing experiments on the roller compactor itself. However, at the present state of things, experiments on RC mechanical simulators present an overestimation of the target SF, when compared to roller compactor SF values. Although numerous correction approaches have been developed to improve the predictive performance of different mathematical models applied to the simulation experimental results, no study has collected a database wide enough to demonstrate the validity of a correction factor that allows to accurately simulate the compaction behavior of multicomponent mixtures. Here, 25 different formulations at 40 % drug load are compacted at different SCFs, both on a RC mimicking device (Styl'One Evolution) and on an actual roller compactor (Gerteis Mini-Pactor): following a similar approach as Reimer et al. and implementing a simplified version of the Johanson's mathematical model, 4 different correction factors are calculated, depending on how their material properties and pressure dependencies are considered. In conclusion, one correction factor is identified as the optimal trade-off between the SF prediction accuracy on the Gerteis Mini-Pactor and its applicability to a wide range of formulations, as it is independent of the material properties. This finding is particularly relevant when applied to scale-up to this specific roller compactor or early development processes of new formulations that have not been mechanically characterized yet.

Discordance Between Psychiatric Diagnoses and Medication Use in Children and Adults With Autism Presenting in Crisis.

Autistic individuals experience high rates of behavioral crises that present to healthcare providers for medication management. Co-occurring psychiatric conditions and psychotropic medication use are common among this patient population. Particularly for those with limited expressive language, evaluating for the presence of psychiatric and medical conditions that could contribute to distress is a critical component of crisis management. A records review study was completed on 126 autistic individuals for whom medical decision-making support was requested from The Huntsman Mental Health Institute Neurobehavior Consultation Service. Crisis manifestations and historical information were provided by the parent or caregiver through an online questionnaire. Nearly all individuals presented with behavioral (96.8%) and emotional (96.8%) symptoms; 97.6% received at least one co-occurring psychiatric diagnosis. Additionally, 75.4% of parents or caregivers endorsed the presence of a medical condition that they believed could be contributing to the crisis presentation. Most individuals (92.1%) were prescribed at least one psychotropic medication; 69.8% were taking an antipsychotic, suggesting a history of treatment resistance. The alignment between psychotropic medications and psychiatric diagnoses was evaluated in the context of prior studies and reviews on psychiatric management in autistic and neurotypical populations. Several individuals were taking a combination of medications that included both indicated and contraindicated medications for the psychiatric disorder diagnosed, likely contributing to treatment resistance. Identifying discordance between psychotropic medication use and psychiatric conditions present offers an opportunity to pursue better treatment outcomes for autistic individuals, particularly for those experiencing treatment-resistant agitation.

Bone quality in zebrafish vertebrae improves after alendronate administration in a glucocorticoid-induced osteoporosis model.

Glucocorticoid-induced osteoporosis (GIOP) changes the microarchitecture of bones and often leads to the reduction of bone-mineral density (BMD) and increased fracture rates. Zebrafish has been used as an alternative model for GIOP, however, the interaction of GIOP, and its treatment, with zebrafish bone morphometrics and mechanical properties, remains a challenge. Thus, this study aimed to evaluate the effects of prednisolone and alendronate on the properties of zebrafish vertebrae. Adult 7-month-old zebrafish were distributed into four groups: control (CTRL), prednisolone-only (PN), alendronate-only (ALN), and the sequential use of both medicines (PN + ALN). Fish skeletons were scanned via micro-tomography (n = 3) to obtain vertebra morphometrics (e.g., BMD). Bone morphology was assessed using scanning electron microscopy (n = 4) and the biomechanical behaviour with nanoindentation technique (n = 3). The BMD decreased in PN (426.08 ± 18.58 mg/cm3) and ALN (398.23 ± 10.20 mg/cm3) groups compared to the CTRL (490.43 ± 41.96 mg/cm3) (p < 0.001); however, administering the medicines in sequence recovered the values to healthy levels (495.43 ± 22.06 mg/cm3) (p > 0.05). The bone layered structures remain preserved in all groups. The vertebrae of the groups that received ALN and PN + ALN, displayed higher modulus of elasticity (27.27 ± 1.59 GPa and 25.68 ± 2.07 GPa, respectively) than the CTRL (22.74 ± 1.60 GP) (p < 0.001). ALN alone increased the hardness of zebrafish vertebrae to the highest value among the treatments (1.32 ± 0.13 GPa) (p < 0.001). Conversely, PN + ALN (1.25 ± 0.11 GPa) showed unaltered hardness from the CTRL (1.18 ± 0.13 GPa), but significantly higher than the PN group (1.08 ± 0.12 GPa) (p < 0.001). ALN administered after GIOP development, rescued osteoporotic condition by recovering the BMD and bone hardness in zebrafish vertebrae.

Plasma Instead of Serum Avoids Critical Confounding of Clinical Metabolomics Studies by Platelets.

Metabolomics is an emerging and powerful bioanalytical method supporting clinical investigations. Serum and plasma are commonly used without rational prioritization. Serum is collected after blood coagulation, a complex biochemical process involving active platelet metabolism. This may affect the metabolome and increase the variance, as platelet counts and function may vary substantially in individuals. A multiomics approach systematically investigating the suitability of serum and plasma for clinical studies demonstrated that metabolites correlated well (n = 461, R2 = 0.991), whereas lipid mediators (n = 83, R2 = 0.906) and proteins (n = 322, R2 = 0.860) differed substantially between specimen. Independently, analysis of platelet releasates identified most biomolecules significantly enriched in serum compared to plasma. A prospective, randomized, controlled parallel group metabolomics trial with acetylsalicylic acid administered for 7 days demonstrated that the apparent drug effects significantly differ depending on the analyzed specimen. Only serum analyses of healthy individuals suggested a significant downregulation of TXB2 and 12-HETE, which were specifically formed during coagulation in vitro. Plasma analyses reliably identified acetylsalicylic acid effects on metabolites and lipids occurring in vivo such as an increase in serotonin, 15-deoxy-PGJ2 and sphingosine-1-phosphate and a decrease in polyunsaturated fatty acids. The present data suggest that plasma should be preferred above serum for clinical metabolomics studies as the serum metabolome may be substantially confounded by platelets.

Enriching the FIDEO ontology with food-drug interactions from online knowledge sources.

The increasing number of articles on adverse interactions that may occur when specific foods are consumed with certain drugs makes it difficult to keep up with the latest findings. Conflicting information is available in the scientific literature and specialized knowledge bases because interactions are described in an unstructured or semi-structured format. The FIDEO ontology aims to integrate and represent information about food-drug interactions in a structured way. This article reports on the new version of this ontology in which more than 1700 interactions are integrated from two online resources: DrugBank and Hedrine. These food-drug interactions have been represented in FIDEO in the form of precompiled concepts, each of which specifies both the food and the drug involved. Additionally, competency questions that can be answered are reviewed, and avenues for further enrichment are discussed.

Beneficial effects of simultaneously targeting calorie intake and calorie efficiency in diet-induced obese mice.

Semaglutide is an anti-diabetes and weight loss drug that decreases food intake, slows gastric emptying, and increases insulin secretion. Patients begin treatment with low-dose semaglutide and increase dosage over time as efficacy plateaus. With increasing dosage, there is also greater incidence of gastrointestinal side effects. One reason for the plateau in semaglutide efficacy despite continued low food intake is due to compensatory actions whereby the body becomes more metabolically efficient to defend against further weight loss. Mitochondrial uncoupler drugs decrease metabolic efficiency, therefore we sought to investigate the combination therapy of semaglutide with the mitochondrial uncoupler BAM15 in diet-induced obese mice. Mice were fed high-fat western diet (WD) and stratified into six treatment groups including WD control, BAM15, low-dose semaglutide without or with BAM15, and high-dose semaglutide without or with BAM15. Combining BAM15 with either semaglutide dose decreased body fat and liver triglycerides, which was not achieved by any monotherapy, while high-dose semaglutide with BAM15 had the greatest effect on glucose homeostasis. This study demonstrates a novel approach to improve weight loss without loss of lean mass and improve glucose control by simultaneously targeting energy intake and energy efficiency. Such a combination may decrease the need for semaglutide dose escalation and hence minimize potential gastrointestinal side effects.

An audit of postoperative haemodynamic stability after intraoperative labetalol administration in non-cardiac surgery patients.

Anaesthesiologists commonly use intravenous labetalol to adjust patient haemodynamics during surgical procedures. Cases of profound hypotension after continuous labetalol infusions have been reported; however, there is limited evidence regarding the safety of intraoperative labetalol boluses. This audit examined the frequency of postoperative hypotension and bradycardia in 292 adult non-cardiac surgery patients treated with intraoperative labetalol boluses. Blood pressure and heart rate data were collected from the post-anaesthesia care unit and on the floor units for 24 hours after surgery. The median total intraoperative labetalol dose was 10mg. A total of 30/292 patients had all-cause postoperative hypotension within 24 hours of surgery, 26 of which had other medical or surgical precipitants. Fifteen patients developed bradycardia. There were no deaths or intensive care unit admissions attributed to labetalol. This audit demonstrates a low risk of all-cause postoperative hypotension (10%) and bradycardia (5%) after the use of small IV doses of intraoperative labetalol.

Brain Glutamate Dynamics Predict Positive Agency in Healthy Women: Insights from Combined Application of Pharmacological Challenge, Comprehensive Affective Assessment, and Magnetic Resonance Spectroscopy.

Contributions of brain glutamate (Glu) to conscious emotion are not well understood. Here, we evaluate the relationship of experimentally induced change in neocortical Glu (ΔGlu) and subjective states in well individuals, using combined application of pharmacological challenge, magnetic resonance spectroscopy (MRS), and comprehensive affective assessment. Drug challenge with d-amphetamine (AMP) (20 mg oral), methamphetamine (MA) (Desoxyn, 20 mg oral), and placebo (PBO) was conducted on three separate test days in a within-subjects double blind design. Proton MRS quantified neurometabolites in the right dorsal anterior cingulate cortex 140-150 min post-drug and PBO. Subjective states were assessed at half hour intervals over 5.5 h on each session, yielding 3792 responses per participant (91,008 responses overall, N = 24 participants), with self-reports reduced by principal components analysis (PCA). PCA produced a primary factor score of AMP- and MA-induced positive agency (ΔPA). MRS indicated drug-induced ΔGlu related positively to ΔPA (ΔGluMA r = +0.44, p < 0.05, N = 21), with large effects in females (ΔGluMA r = +0.52, p < 0.05; ΔGluAMP r = +0.61, p < 0.05, N = 11). Subjective states related to ΔGlu included rise in subjective stimulation, vigor, friendliness, elation, positive mood, positive affect (r's = +0.51 to +0.74, p < 0.05), and alleviation of anxiety in females (r = -0.61, p < 0.05, N = 11). These self-reports correlated with ΔGlu to the extent they loaded on ΔPA (r = 0.95 AMP, p = 5 × 10-10; r = 0.63 MA, p = 0.0015, N = 11), indicating the coherence of ΔGlu effects on emotional states. Timing data indicated Glu shaped positive emotion both concurrently and prospectively, with no relationship with pre-MRS emotion (ΔGluAMP r = +0.59 to +0.65, p's < 0.05; ΔGluMA r = +0.53, p < 0.05, N = 11). Together these findings indicate substantive, mechanistic contributions of neocortical Glu to positive agentic states in healthy individuals, which are most readily observed in women. The findings illustrate the promise of combined application of pharmacological challenge, comprehensive affective assessment, and MRS neuroimaging techniques in basic and clinical studies.

Necrólisis epidérmica tóxica debido a un fármaco a base de caléndula más acetilcisteína: presentación de caso / Toxic Epidermal Necrolysis Induced by a Drug Combination of Calendula and Acetylcysteine: A Case Report / Necrólise epidermal tóxica por medicamento à base de calêndula mais acetilcisteína: relato de caso

Introducción: la hipersensibilidad por fármacos es inducida por una respuesta aberrante del sistema inmune; por lo general, impredecible, dosis independiente y amenazante para la vida del paciente. Las reacciones de hipersensibilidad por fármacos con compromiso mucocutáneo se dan en alrededor del 2 %-3 % de los pacientes hospitalizados. Objetivo: describir un caso de necrólisis tóxica epidérmica por un fármaco a base de caléndula y acetilcisteína como los presuntos desencadenantes. Presentación del caso: hombre de 39 años, quien asistió a emergencias, por malestar general, artralgias, mialgias, astenia y adinamia de un día de evolución. Tres días después refirió la aparición de lesiones purpúricas progre-sivas que se extendieron por cara, extremidades y glúteos; delimitadas; no dolorosas, y sin desaparecer a la digitopresión, asociado con disnea, inestabilidad hemodinámica y cardiovascular. Al sexto día de hos-pitalización, se interrogó al paciente, quien se había automedicado un fármaco de origen desconocido, presuntamente de extracto herbal a base de caléndula más acetilcisteína para artralgias, osteomialgias y disfagia. A la mañana siguiente, presentó lesiones purpúricas y ulcerativas extensas. Se observaron lesiones purpúricas progresivas y ulcerativas en cara extremidades y glúteos. Mediante la sospecha clínica y la evaluación histopatológica, se confirmó la necrólisis tóxica epidérmica. Conclusiones: las reacciones adversas medicamentosas severas que amenazan la vida del paciente son relativamente raras, pero representan un verdadero desafío diagnóstico y terapéutico. Es necesario profundizar en la investigación para esclarecer la causa de este tipo de reacción medicamentosa.

Introduction: Drug hypersensitivity is induced by an aberrant response from the immune system. It is usually unpredictable, dose-independent, and can be life-threatening to the patient. Drug-induced hypersensitivity reactions with mucocutaneous involvement occur in approximately 2­3% of hospitalized patients. However, Toxic Epidermal Necrolysis is a rare case. Aim: To describe a case of drug-induced toxic epidermal necrolysis triggered by Calendula officinalis and acetylcysteine. Case report: A 39-year-old male was pre-sented to the emergency room with malaise, arthralgia, myalgia, asthenia, and adynamia since day one. Three days later, he developed progressive purpuric lesions that spread to the face, extremities, and buttocks. These lesions were painless, not delineate, and did not blanch under pressure. They were asso-ciated with dyspnea and hemodynamic and cardiovascular instability. On the sixth day of hospitaliza-tion, the patient admitted to self-medicating with an unknown drug, presumably a herbal extract based on calendula and acetylcysteine, for arthralgia, myalgia, and dysphagia. The morning after the drug consumption, the patient developed extensive purpuric and ulcerative lesions. A diagnosis of toxic epi-dermal necrolysis was made based on clinical suspicion and histopathological confirmation. Conclusion:Severe adverse drug reactions that threaten a patient's life are relatively rare. However, they represent a real diagnostic and therapeutic challenge when they do occur

Introdução: a hipersensibilidade a drogas é induzida por uma resposta aberrante do sistema imunoló-gico; geralmente imprevisível, independente da dose e com risco de vida para o paciente. As reações de hipersensibilidade a drogas com comprometimento mucocutâneo estão em torno dos 2-3% dos pacien-tes hospitalizados. Objetivo: descrever um caso de necrólise epidérmica tóxica causada por uma droga à base de Calendula officinalis e acetilcisteína como os supostos desencadeantes. Apresentação do caso:homem, 39 anos, deu entrada no pronto-socorro manifestando mal-estar, artralgia, mialgia, astenia e adinamia há um dia. Posteriormente, três dias depois, relatou o aparecimento de lesões purpúricas pro-gressivas que se espalharam para a face, extremidades e nádegas; que são delimitadas, não dolorosas e não desaparecem com a acupressão associada a dispnéia, instabilidade hemodinâmica e cardiovascular. No sexto dia de internação, o paciente foi questionado, y disse que tinha se automedicado com uma droga de origem desconhecida, presumivelmente extrato de ervas à base de calêndula mais acetilcis-teína para artralgia, osteomialgia e disfagia. Na manhã seguinte, apresentou extensas lesões purpúricas e ulcerativas. Observam-se lesões purpúricas progressivas e ulcerativas que se estendem à face, extre-midades e nádegas. Pela suspeita clínica e confirmação histopatológica, confirma-se a necrólise epidér-mica tóxica. Conclusões: reações adversas graves a medicamentos que ameaçam a vida do paciente são relativamente raras, mas quando ocorrem representam um verdadeiro desafio a nível diagnóstico e terapêutico. São precisas mais pesquisas para esclarecer a causa desse tipo de reação medicamentosa.

Hydration Methods for Cisplatin Containing Chemotherapy: A Systematic Review.

INTRODUCTION: Cisplatin-induced nephrotoxicity (CIN) can be prevented by fluid hydration, electrolyte supplementation, or forced diuresis; however, the best way to prevent CIN is still unknown. The aim of this study was to provide objective evidence on the optimal design of hydration schemes to prevent CIN based on an update of the literature. METHODS: A Pubmed and Embase search were conducted in December 2021 and repeated in April 2022 and March 2023. Two independent reviewers screened the articles. The included articles were categorized and reviewed per category. RESULTS: Twenty-seven articles met the inclusion criteria. The included studies varied widely. Four out of seven studies investigating diuretics found a protective effect of adding mannitol to the hydration scheme. All six studies investigating duration and amount of volume of hydration found that a short-hydration scheme resulted in less CIN than a longer hydration scheme. Seven out of nine articles evaluating the role of electrolytes found that magnesium supplementation reduced the risk of nephrotoxicity. Three studies investigated the safety of oral hydration and concluded that nephrotoxicity did not occur more frequently after oral hydration. CONCLUSION: The hydration scheme of cisplatin should be short and consist of a relatively small amount of volume. The scheme should include mannitol and magnesium supplementation. Head-to-head studies are needed to investigate the safety of furosemide compared with mannitol and the dose of mannitol and magnesium.

Novel pyridyl-substituted nitronyl nitroxides as potential antiarrhythmic and hypotensive agents with low toxicity and enhanced stability in aqueous solutions.

This study explores the antiarrhythmic and hypotensive potential of pyridyl-substituted nitronyl nitroxides derivatives, uncovering the crucial role of a single carbon moiety of the pyridine cycle alongside radical and charged oxygen centers of the imidazoline fragment. Notably, the introduction of fluorine atoms diminished the antiarrhythmic effect, while the most potent derivatives featured the nitronyl nitroxide pattern positioned at the third site of the pyridine cycle. Gender-dependent responses were observed in lead compounds LCF3 and LMe, with LMe inducing temporary bradycardia and hypotension specifically in female rats, and LCF3 causing significant blood pressure reduction followed by rebound in females compared to milder effects in males. Mechanistic insights point towards ß1 adrenoceptor blockade as an underlying mechanism, supported by experiments on isolated rat atria. This research underscores the interplay between structure, cardiovascular effects and gender-specific responses, offering insights for therapeutic strategies for treating free radical-associated cardiovascular disorders.

Use of non-steroidal anti-inflammatory drugs in pregnancy and oligohydramnios: a review.

OBJECTIVE: The aim of this review is to evaluate the relationship between the use of non-steroidal anti-inflammatory drugs (NSAIDs) during last trimesters of the pregnancy and the reduction of amniotic fluid. METHODS: Electronic databases were searched (PubMed, Medline, and Scopus). Selection criteria included studies reporting the relationship between oligohydramnios and use of NSAID during pregnancy. We analyzed the median age of women, weeks of pregnancy at the beginning of the drug administration, kind of medication, period of exposure and dosage, deepest vertical pocket (DVP), and amniotic fluid index (AFI). RESULTS: Of the 68 records identified, we analyzed 29 studies investigating the administration of NSAIDs, including 11 studies examined the administration of the Indomethacin, four articles have focused on the use of Nimesulide, and only two manuscripts considered the use of Diclofenac. We found a strict correlation between the development of oligohydramnios and the use of NSAIDs. The oligohydramnios is reversible, and the normal amount of amniotic fluid is restored after the interruption of the treatment. CONCLUSIONS: The use of NSAIDs should be considered when maternal benefits outweigh the potential fetal risk, at the lowest effective dose for shortest duration. Beyond 48 h of NSAIDs treatment, we consider ultrasound monitoring of amniotic fluid, and we suggest stopping therapy if a decline AFI is present.

Efficacy and Safety of Weight-based Dosing of Daptomycin in Obese Patients: A Systematic Review

Purpose: To provide a comprehensive review of daptomycin weight-based dosing methods for obese patients. Methods: PubMed, Embase, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched through December 31, 2022. Studies relevant to daptomycin weight-based dosing methods in obese adult patients were included. Results: Sixteen studies were included, of which five were case reports and 11 were cohort studies. Obese patients were included in all case reports, of which one was pregnant. The infections improved after receiving a daptomycin dose based on actual body weight (ABW) in all cases. Seven studies demonstrated that ABW, ideal body weight (IBW), and adjusted body weight (AjBW)-based daptomycin dosing differed in terms of treatment success, microbiological clearance, and creatinine phosphokinase (CPK) elevation. However, AjBW was not statistically equivalent to ABW in all evaluated outcomes, except for treatment success. Three studies showed a higher area under the concentration-time curve (AUC) by 60% in obese patients, whereas two studies indicated a higher maximum plasma concentration (Cmax) of ~2 folds. One study demonstrated that obese patients had higher levels of total clearance and volume of distribution, whereas other pharmacokinetic parameters were comparable between obese and non-obese patients. Conclusion: While most of the available evidence reported daptomycin dosing based on actual or total body weight, a few other studies have reported the use of ideal or adjusted body weight. A significant elevation in CPK was observed when daptomycin was administered based on AdjBW, but not with ABW and IBW. Further research is required to determine the optimal daptomycin weight-based dosing method in obese patients (AU)

Guía internacional para una dosificación más segura de la clozapina en adultos mediante el uso de 6 titulaciones personalizadas de dosis basados en la etnicidad, la proteína C reactiva y los niveles de clozapina / An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels

Esta guía internacional propone mejorar los prospectos de la clozapina en todo el mundo mediante la inclusion de información sobre la titulación del fármaco en función de la ascendencia del paciente. Las bases de datos de reacciones adversas a medicamentos (RAM) sugieren que la clozapina es el tercer fármaco más tóxico en los Estados Unidos de América (EE. UU.) y que produce una mortalidad por neumonía en todo el mundo 4 veces mayor que la correspondiente a la agranulocitosis o la miocarditis. El rango terapéutico de referencia para las concentraciones séricas estables de clozapina es estrecho, de 350 a 600 ng/ml, con potencial de toxicidad y reacciones adversas más fecuentes a medida que aumentan las concentraciones. La clozapina se metaboliza principalmente por CYP1A2 (las mujeres no fumadoras requieren la dosis más baja y los hombres fumadores la dosis más alta). A través de la conversión fenotípica, la prescripción conjunta de inhibidores del metabolismo de la clozapina (incluidos los anticonceptivos orales y el valproato), la obesidad o la inflamación con elevaciones de la proteína C reactiva (PCR), pueden convertir al paciente en un metabolizador lento/pobre (MP). Las personas de ascendencia asiática (de Pakistán a Japón) o los habitantes originarios de las Américas tienen menor actividad de CYP1A2 y requieren dosis más bajas de clozapina para alcanzar concentraciones de 350 ng/ml. En los EE. UU. se recomiendan dosis diarias de 300-600 mg/día. La dosificación personalizada lenta puede prevenir RAM tempranas (incluidos el síncope, la miocarditis y la neumonía). La esencia de esta guía se fundamenta en 6 esquemas de titulaciones personalizadas para pacientes hospitalizados...(AU)

This is the Spanish translation of an international guideline which proposes improving clozapine package inserts worldwide by using ancestry-based: 1) dosing and 2) titration. Adverse drug reaction (ADR) databases suggest clozapine: 1) is the third most toxic drug in the United States (US), and 2) produces worldwide pneumonia mortality four times greater than that of agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers require the lowest dose and male smokers the highest dose). Poor metabolizer (PM) status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity or inflammation with C-reactive protein (CRP) elevations. People with ancestry from Asia (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/ml. Daily doses of 300-600 mg/day are recommended in the US. Slow personalized titration may prevent early ADRs (including syncope, myocarditis and pneumonia). The core of this guideline consists of six personalized titration schedules for inpatients...(AU)