Clinical experience with bromocriptine for central hyperthermia after brain insult.

INTRODUCTION: Bromocriptine is a dopamine receptor agonist used for central hyperthermia with limited data. We describe our single-center experience utilizing bromocriptine for central hyperthermia, including the population treated, most common dosing regimens, adverse events, and discontinuation reasons. METHODS: A retrospective study was conducted screening patients who were admitted to intensive care units for acute neurological insults and administered bromocriptine for central hyperthermia between April 2016 and September 2022. Baseline characteristics, disease severity markers, and bromocriptine doses were collected. Body temperatures prior to the first dose of bromocriptine, at the time of dose, and after each dose were recorded. Co-administration of additional hyperthermia management therapies was noted. RESULTS: Thirty patients were included. The most common diagnosis was traumatic brain injury (TBI) (N = 14). The most common reason for discontinuation was resolution of indication (N = 14). Discontinuation due to mild adverse effects occurred in four patients; hepatotoxicity was the most common. There was a paired mean difference of -0.37°C (p = 0.005) between temperatures before and after bromocriptine initiation. CONCLUSION: Bromocriptine is a potential therapy for the management of central hyperthermia in patients with severe acute neurologic insults who have failed other therapies. Bromocriptine was well tolerated and associated with a low incidence of adverse events.

Switching from zonisamide to perampanel improved the frequency of seizures caused by hyperthermia in Dravet syndrome: a case report.

BACKGROUND: Dravet syndrome is a severe epilepsy disorder characterized by drug-resistant seizures and cognitive dysfunction, often caused by SCN1A gene mutations. It leads to neurodevelopmental delays and motor, behavioral, and cognitive impairments, with a high mortality rate. Treatment options include sodium valproate, clobazam, and newer agents such as cannabidiol and fenfluramine. Zonisamide, which is used in some cases, can cause hyperthermia and oligohydrosis. Herein, we present a case of a patient with Dravet syndrome whose seizures were controlled by treating infections and switching from zonisamide to perampanel. CASE PRESENTATION: A 24-year-old Japanese man with Dravet syndrome presented to our department with aspiration pneumonia. The patient had been treated with valproate, sodium bromide, and zonisamide for a long time. His seizures were triggered by hyperthermia. The patient was experiencing a sustained pattern of hyperthermia caused by infection, zonisamide, and persistent convulsions, which caused a vicious cycle of further seizures. In this case, the control of infection and switching from zonisamide to perampanel improved seizure frequency. CONCLUSION: Dravet syndrome usually begins with generalized clonic seizures in its infancy because of fever and progresses to various seizure types, often triggered by fever or seizure-induced heat due to mutations in the SCN1A gene that increases neuronal excitability. Seizures usually diminish with age, but the heat sensitivity remains. In this case, seizures were increased by repeated infections, and hyperthermia was induced by zonisamide, resulting in status epilepticus. Perampanel, an aminomethylphosphonic acid receptor antagonist, decreased seizures but caused psychiatric symptoms. It was effective in suppressing seizures of Dravet syndrome in this patient.

[A 70-year-old male exhibiting parkinsonism-hyperpyrexia syndrome during levodopa carbidopa intestinal gel (LCIG) treatment and suspected carbidopa allergy due to positive drug-induced lymphocyte stimulation test (DLST)].

A 70-year-old male who has medical history of Parkinson's disease for 26 years admitted to our hospital for trial of levodopa carbidopa intestinal gel (LCIG) therapy because of severe dyskinesia and frequent wearing-off. He developed deterioration when he was treated with one of the levodopa (LD) decacrboxylase inhibitor compounds in the past. Five days after LD had changed into equivalent dose of LD/carbidopa (CD), high fever with hyperCKemia appeared. He was diagnosed as having Parkinsonism-hyperpyrexia syndrome (PHS). Exchange of LD/CD to LD drugs improved the symptoms quickly. Four days after LCIG administration, PHS reappeared. Simultaneously, the patient developed sepsis and disseminated intravascular coagulation (DIC). Thrombocytopenia did not improve after recovery from infection and DIC. Anti-PA IgG and drug-induced lymphocyte stimulation test (DLST) against LCIG showed positive. Exchange of LCIG to LD drugs and intravenous methylprednisolone administration improved the symptoms and thrombocytopenia. CD induced type II and type IV allergy were suspected. This case offers a caution that physicians should be aware of drug allergy in cases of which unexpected symptoms occurred in altering one LD compound to another.

Calcium dobesilate-induced hyperpyrexia: A case report.

RATIONALE: Calcium dobesilate, a vasoprotective and antioxidant agent, is gradually being used for the treatment of chronic kidney disease. Calcium dobesilate-induced hyperpyrexia is a rare clinical event, and few studies have reported it. PATIENT CONCERNS: The patient took calcium dobesilate, which caused high fever. After stopping calcium dobesilate, his body temperature returned to normal. DIAGNOSES: Based on the medical history, symptoms and signs, the patient was diagnosed with drug fever caused by calcium dobesilate. INTERVENTIONS: Calcium dobesilate was stopped, and supportive treatment was given at the same time. OUTCOMES: The present case was initially misdiagnosed as a fever caused by a bacterial infection, but treatment with the antibiotic moxifloxacin was ineffective. Based on the patient's medical history, laboratory and examination results, body temperature changes, and Naranjo Advanced Drug Response Scale, calcium dobesilate-induced hyperpyrexia was diagnosed. After discontinuation of calcium dobesilate, the patient's body temperature normalized, and no additional episode of fever was observed at follow-up. LESSON: Moreover, misdiagnosis and mistreatment of this condition can deteriorate the patient's condition. Herein, we report a case of calcium dobesilate-induced hyperpyrexia that occurred during the treatment of chronic renal insufficiency. Subsequently, a systematic analysis of the patient's diagnosis and treatment was reviewed. If unexplained high fever develops during the use of calcium dobesilate, calcium dobesilate-induced hyperpyrexia should be considered. Accordingly, calcium dobesilate should be discontinued.

Antipyretic and antinociceptive potential of Ricinus communis L. and Withania somnifera L. hydroalcoholic extracts in Wistar rats: A comparative study.

The present study was designed to evaluate the antipyretic and antinociceptive activities of R. communis leaves and W. somnifera roots hydroalcoholic extracts in Wistar rats. To assess the antipyretic activity, Brewer's yeast suspension was used to induce hyperthermia. Antinociceptive activity was observed using acetic acid-induced abdominal writhing, formalin-induced paw licking reflex and heat-induced pain models. R. communis and W. somnifera extracts were used at 150, 250 and 500mg/kg. Results showed that administration of both plants significantly (p<0.001) lowered rectal temperature (°C) in a dose-dependent manner from 1h to 4h of study. R. communis and W. somnifera extracts showed a dose-dependent reduction in abdominal writhing induced by acetic acid and decreased the paw licking reflex in formalin-induced nociceptive response. In the heat test, R. communis and W. somnifera extracts exhibited significant (p<0.001) analgesic effects evidenced as an increase in latency time. However, R. communis exhibited prominent antipyretic and antinociceptive activities at 250 and 500mg/kg as compared to W. somnifera. Conclusively, R. communis and W. somnifera could be a potential source of antipyretic and analgesic agents which require further studies.

Photoactivatable Nitric Oxide-Releasing Gold Nanocages for Enhanced Hyperthermia Treatment of Biofilm-Associated Infections.

With the increasing clinical use of invasive medical devices, various healthcare-associated infections (HAIs) caused by bacterial biofilm colonization of biomedical devices have posed serious threats to patients. The formation of biofilms makes it much more difficult and costly to treat infections. Here, we report a nitric oxide (NO)-releasing gold nanocage (AuNC@NO) that is stimulated by near-infrared (NIR) irradiation to deliver NO and generate hyperthermia for biofilm elimination. AuNC@NO was prepared by immobilizing a temperature-responsive NO donor onto gold nanocages (AuNCs) through thiol-gold interactions. AuNC@NO possesses stable and excellent photothermal conversion efficiency, as well as the characteristics of slow NO release at physiological temperature and on-demand quick NO release under NIR irradiation. Based on these features, AuNC@NO exhibits enhanced in vitro bactericidal and antibiofilm efficacy compared with AuNCs, which could achieve 4 orders of magnitude bacterial reduction and 85.4% biofilm elimination under NIR irradiation. In addition, we constructed an implant biofilm infection model and a subcutaneous biofilm infection model to evaluate the anti-infective effect of AuNC@NO. The in vivo results indicated that after 5 min of 0.5 W cm-2 NIR irradiation, NO release from AuNC@NO was significantly accelerated, which induced the dispersal of methicillin-resistant Staphylococcus aureus (MRSA) biofilms and synergized with photothermal therapy (PTT) to kill planktonic MRSA that had lost its biofilm protection. Meanwhile, the surrounding tissues showed little damage because of controlled photothermal temperature and toxicity. In view of the above-mentioned results, the AuNC@NO nanocomposite developed in this work reveals potential application prospects as a useful antibiofilm agent in the field of biofilm-associated infection treatment.

Drug development of lyso-thermosensitive liposomal doxorubicin: Combining hyperthermia and thermosensitive drug delivery.

We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be utilized in human clinical trials. This class of compounds is designed to carry a payload of a cytotoxic agent and adequately circulate in order to accumulate at a tumor that is being heated. At the target the carrier is activated by heat and releases its contents at high concentrations. We summarize the preclinical and clinical experience of LTLD including its successes and challenges in the development process.

Near infrared light fluorescence imaging-guided biomimetic nanoparticles of extracellular vesicles deliver indocyanine green and paclitaxel for hyperthermia combined with chemotherapy against glioma.

BACKGROUND: We investigated the therapeutic effect of targeting extracellular vesicles (EVs) loaded with indocyanine green (ICG) and paclitaxel (PTX) on glioma. METHODS: Raw264.7 cells were harvested to extract EVs for the preparation of ICG/PTX@RGE-EV by electroporation and click chemistry. We evaluated the success of modifying Neuropilin-1 targeting peptide (RGE) on the EV membrane of ICG/PTX@RGE-EV using super-resolution fluorescence microscopy and flow cytometry. Spectrophotometry and high performance liquid chromatography (HPLC) were implemented for qualitative and quantitative analysis of the ICG and PTX loaded in EVs. Photothermal properties of the vesicles were evaluated by exposing to 808-nm laser light. Western blot analysis, cell counting kit 8 (CCK-8), Calcein Acetoxymethyl Ester/propidium iodide (Calcein-AM/PI) staining, and flow cytometry were utilized for assessing effects of vesicle treatment on cellular behaviors. A nude mouse model bearing glioma was established to test the targeting ability and anti-tumor action of ICG/PTX@RGE-EV in vivo. RESULTS: Under exposure to 808-nm laser light, ICG/PTX@RGE-EV showed good photothermal properties and promotion of PTX release from EVs. ICG/PTX@RGE-EV effectively targeted U251 cells, with activation of the Caspase-3 pathway and elevated apoptosis in U251 cells through chemotherapy combined with hyperthermia. The anti-tumor function of ICG/PTX@RGE-EV was confirmed in the glioma mice via increased accumulation of PTX in the ICG/PTX@RGE-EV group and an increased median survival of 48 days in the ICG/PTX@RGE-EV group as compared to 25 days in the PBS group. CONCLUSION: ICG/PTX@RGE-EV might actively target glioma to repress tumor growth by accelerating glioma cell apoptosis through combined chemotherapy-hyperthermia.

Self-synergistic effect of Prussian blue nanoparticles for cancer therapy: driving photothermal therapy and reducing hyperthermia-induced side effects.

BACKGROUND: Photothermal therapy (PTT), involving application of localized hyperthermia to kill cancer cells, has attracted wide attention in cancer therapy. The production of reactive oxygen species (ROS) during PTT may cause irreversible damage to healthy tissues around the tumor. Simultaneously, hyperthermia can stimulate inflammatory response, thus promoting tumor recurrence and metastasis. Therefore, it is of paramount importance to reduce the undesired side effects for further development of PTT. RESULTS: Using a hydrothermal method, spherical Prussian blue nanoparticles (PBs) with uniform size were prepared. The PBs exhibited good dispersion and stability in saline with an average hydrodynamic size of 110 nm. The prepared PBs had a high photothermal conversion efficiency and photothermal stability. The PBs showed intrinsic ROS scavenging properties in vitro. Antioxidant and anti-inflammatory effects of PBs were also observed in vivo. Assessment of toxicity and endoplasmic reticulum stress-inducing ability showed that PBs did not induce an inflammatory response. Tissues of major organs of mice stained with hematoxylin-eosin showed no significant damage, indicating good biocompatibility and safety of PBs. CONCLUSION: The designed single-component PBs with intrinsic ROS scavenging and anti-inflammatory properties could avoid inflammatory response and heat stress-induced ROS during PTT. Thus, further research on PBs is worthwhile to achieve their clinical translation and promote the development of PTT.

A Smart Hyperthermia Nanofiber-Platform-Enabled Sustained Release of Doxorubicin and 17AAG for Synergistic Cancer Therapy.

This study demonstrates the rational fabrication of a magnetic composite nanofiber mesh that can achieve mutual synergy of hyperthermia, chemotherapy, and thermo-molecularly targeted therapy for highly potent therapeutic effects. The nanofiber is composed of biodegradable poly(ε-caprolactone) with doxorubicin, magnetic nanoparticles, and 17-allylamino-17-demethoxygeldanamycin. The nanofiber exhibits distinct hyperthermia, owing to the presence of magnetic nanoparticles upon exposure of the mesh to an alternating magnetic field, which causes heat-induced cell killing as well as enhanced chemotherapeutic efficiency of doxorubicin. The effectiveness of hyperthermia is further enhanced through the inhibition of heat shock protein activity after hyperthermia by releasing the inhibitor 17-allylamino-17-demethoxygeldanamycin. These findings represent a smart nanofiber system for potent cancer therapy and may provide a new approach for the development of localized medication delivery.

Fabrication of monodisperse magnetic nanorods for improving hyperthermia efficacy.

BACKGROUND: Hyperthermia is one of the promising cancer treatment strategies enabled by local heating with the use of tumor-targeting magnetic nanoparticles (MNP) under a non-invasive magnetic field. However, one of the remaining challenges is how to achieve therapeutic levels of heat (without causing damages to regular tissues) in tumors that cannot be effectively treated with anti-tumor drug delivery. RESULTS: In this work, we report a facile method to fabricate magnetic nanorods for hyperthermia by one-step wet chemistry synthesis using 3-Aminopropyltrimethoxysilane (APTMS) as the shape-controlling agent and ferric and ferrous ions as precursors. By adjusting the concentration of APTMS, hydrothermal reaction time, ratios of ferric to ferrous ions, magnetic nanorods with aspect ratios ranging from 4.4 to 7.6 have been produced. At the clinically recommended field strength of 300 Oe (or less) and the frequency of 184 kHz, the specific absorption rate (SAR) of these nanorods is approximately 50 % higher than that of commercial Bionized NanoFerrite particles. CONCLUSIONS: This increase in SAR, especially at low field strengths, is crucial for treating deep tumors, such as pancreatic and rectal cancers, by avoiding the generation of harmful eddy current heating in normal tissues.

Impact of elevated core temperature on cognition in hot environments within a military context.

PURPOSE: Cognition can be impaired during exercise in the heat, potentially contributing to military casualties. To our knowledge, the independent role of elevated core temperature during exercise has not been determined. The aim of the current study was to evaluate effects of elevated core temperature on cognition during physically encumbering, heated exercise, and to determine whether the perceptual cooling effects of menthol preserves cognition. METHODS: Eight participants complete three trials in randomised order: one normothermic (CON) and two with elevated (38.5°C) core temperature, induced by prior immersion in neutral versus hot water The CON trial and one hot trial (HOT) used a water mouth-rinse following each cognitive task of the trial, (HOT) while the other used a menthol mouth-rinse (MENT). Participants walked in humid heat (33°C, 75% relative humidity) in military clothing, completing a cognitive battery of reaction time, perceptual processing, working memory, executive function, cognitive flexibility, vigilance, and declarative memory. RESULTS: No differences in cognitive performance were observed between any conditions. Near-infrared spectroscopy showed greater oxygenated haemoglobin tissue content in HOT and MENT compared to CON (ΔO2Hb-deO2Hb: 2.3 ± 4.5 µM, p < .024), and lower deoxygenated haemoglobin in MENT than in CON or HOT (p = .017), suggesting higher brain metabolism during the more stressful conditions. CONCLUSION: Moderately elevated core (38.5°C) and skin temperature does not appear to impair cognitive performance during exercise despite mildly elevated cerebral metabolism. The effects of menthol remain undetermined due to the lack of heat-mediated cognitive impairment.

Pharmacological activity and flavonoids constituents of Artemisia judaica L aerial parts.

ETHNO-PHARMACOLOGICAL RELEVANCE: Artemisia judaica L is an aromatic medicinal plant growing widely in Saint Katherine, Sinai, Egypt, and used in traditional medicine as a herbal remedy for antibacterial, anthelmintic, antidiabetic, analgesic and anti-inflammatory activities. Additionally, other Arabic regions commonly used it in their folk medicines for the treatment of fungal infections, atherosclerosis, cancer, diabetes, arthritis, and inflammatory-related diseases. AIM OF THE STUDY: Based on the traditional medicinal uses of A. judaica, the present study was designed to validate some of the traditional uses as the analgesic, anti-inflammatory, antipyretic, hepatoprotective, antidiabetic, and antioxidant activities of 80% aqueous methanol extract (AME) of A. judaica aerial parts as well as isolation and identification of its flavonoid content. MATERIALS AND METHODS: AME of A. judaica aerial parts was fractionated using column chromatography and the structures of the isolated compounds were established using different spectroscopic data. Analgesic activity was evaluated using acetic acid-induced writhing in mice; antipyretic activity was assessed using yeast suspension-induced hyperthermia in rats; anti-inflammatory activity was evaluated using carrageenan-induced paw edema; the hepatoprotective effect was studied by measuring liver enzymes in carbon tetrachloride(CCl4)-induced hepatotoxicity rats while antidiabetic activity was estimated in alloxan hyperglycemia. RESULTS: Eight flavone compounds namely luteolin 4' methyl ether 7-O-ß-D-4C1-glucopyranoside (1), 8-methoxyapigenin 7-O-ß-D-4C1-galactopyranoside (2), isovitexin (3), 8-methoxyluteolin 7-O-ß-D-4C1-glucopyranoside (4), diosmetin (5), cirsimaritin (6), luteolin (7), and apigenin (8) were identified from AME of A. judaica. The AME was found to be non-toxic to mice up to 5 g/kg b.w. Moreover, it exhibits significant analgesic antipyretic, anti-inflammatory, antidiabetic, hepatoprotective, and antioxidant activities in a dose-dependent manner. CONCLUSION: The AME was nontoxic; it exhibits significant analgesic, antipyretic, anti-inflammatory, antidiabetic, hepatoprotective, and antioxidant activities. Moreover, the isolated flavone was identified from AME for the first time.

Mitochondria and Endoplastic Reticulum Targeting Strategy for Enhanced Phototherapy.

To ensure improved efficacy and minimized toxicity of therapeutic molecules, it is generally accepted that specifically delivering them to the subcellular site of their action will be attractive. Phototherapy has received considerable attention because of its noninvasiveness, high temporal-spatial resolution, and minimal drug resistance. As important functional organelles in cells, mitochondria and endoplasmic reticulum (ER) participate in fundamental cellular processes, which make them much more sensitive to reactive oxygen species (ROS) and hyperthermia. Thus, mitochondria- or ER-targeted phototherapy will be rational strategies for synergetic cancer therapy. In this review, we focus on the latest advances in molecules and nanomaterials currently used for mitochondria- and ER-targeted phototherapy.

Postembolization syndrome in endovascular interventions on the gonadal veins.

OBJECTIVE: The present study evaluated the incidence of postembolization syndrome (PES) after endovascular coil embolization of the gonadal veins (EEGV) in patients with pelvic congestion syndrome and investigated the appropriate medical treatment. METHODS: EEGV was performed in 70 female patients with pelvic congestion syndrome (left-sided in 58, right-sided in 3, and bilateral in 9 patients). For embolization, 0.035-in. coils with an 8- to 12-mm diameter and 10- to 20-cm length were used. Assessments of the EEGV results and possible PES symptoms were performed on days 1, 5, 10, 20, and 30 after the procedure and included transvaginal and transabdominal duplex ultrasound scanning of the pelvic veins and at the embolization site. RESULTS: PES had manifested with increased pelvic pain, tenderness along the embolized vein, and hyperthermia ≤37.5°C to 37.8°C and had developed in 14 patients (20%). For PES treatment, a nonsteroidal anti-inflammatory drug (diclofenac, 75 mg daily for 3-7 days; mean, 4.2 ± 1.1 days) and a venoactive drug (micronized purified flavonoid fraction, 1000 mg daily for 2 months) were used. Medical treatment was associated with a significant reduction in PES symptoms in all patients within 14 days and complete resolution by day 30 after embolization. duplex ultrasound scanning revealed thrombosis of parametrial veins in 12 of 56 patients (21.4%) with successful EEGV and 3 of 14 patients (21.4%) with PES. CONCLUSIONS: In patients who have undergone EEGV, increased pelvic pain, the occurrence of tenderness along the embolized vein, and the presence of hyperthermia should be considered as PES manifestations. In our study, PES occurred in 20% of the treated patients.

MTX-Loaded Dual Thermoresponsive and pH-Responsive Magnetic Hydrogel Nanocomposite Particles for Combined Controlled Drug Delivery and Hyperthermia Therapy of Cancer.

In recent years, the exploitation of magnetic nanoparticles in smart polymeric matrices have received increased attention in several fields as site-specific drug delivery systems. Here, ultrasonic-assisted emulsion copolymerization of N-isopropylacrylamide (NIPAM) and 2-(N,N-diethylaminoethyl) methacrylate (DEAEMA) in the presence of Fe3O4 nanoparticles was employed to prepare pH- and temperature-responsive magnetite nanocomposite particles (MNCPs). The obtained MNCPs were fully characterized by TEM, DSC, FT-IR, VSM, and XRD techniques. They had an average particle size of 70 nm with a lower critical solution temperature of 42 °C and superparamagnetic properties. In addition, MNCPs were loaded with methotrexate (MTX) as an anticancer drug, and their in vitro drug release was studied in different pH values and temperatures and in the presence of an alternating magnetic field. Noteworthy that the highest rate of MTX release was observed at pH 5.5 and 42 °C. Cell viability of the treated MCF-7 human breast cancer cell line with free MTX, MNCPs, and MTX-loaded MNCPs or in combination with magnetic hyperthermia (MHT) and water-based hyperthermia was comparatively studied. The obtained results showed about 17% higher antiproliferative activity for the MTX-loaded MNCPs accompanied by MHT relative to that of free MTX.

Ameliorating effects of curcumin-loaded superparamagnetic iron oxide nanoparticles (SPIONs) on the mouse testis exposed to the transient hyperthermia: A molecular and stereological study.

BACKGROUND: Testicular hyperthermia can have negative effects on male fertility. Despite reported therapeutic benefits of curcumin, several factors often limit its application such as low water solubility and instable structure. Curcumin-loaded superparamagnetic iron oxide nanoparticles (SPIONs) were designed to solve its limitation of use. In the present study, we evaluated the effect of curcumin-loaded SPIONs on transient testicular hyperthermia in mouse. MATERIALS AND METHOD: A total of 18 adult male NMRI mice were divided into three groups (n = 6): I. Controls (Cont), II. Scrotal hyperthermia (Hyp), III. Scrotal hyperthermia + curcumin-loaded iron particles (240 µL) (Hyp + Cur). After seventy days, the animals were sacrificed and used for further molecular and stereological evaluations. RESULTS: Sperm count, motility and viability significantly decreased in group hyp as compared to cont group. Furthermore, Sperm DNA fragmentation and cell apoptosis in testes increased remarkably in group hyp, compared with group cont. Stereological study showed a reduction in number of spermatogenic and Leydig cells, as well as reduced weight and volume of testes in hyp group. Degenerative appearance of testes exposed to hyperthermia was also observed. In addition, higher mRNA expression of inflammatory cytokines (IL1-α, IL6, and TNF-α) was detected in group hyp compared to cont group. However, curcumin-loaded SPIONs alleviated all of the pathologic changes in the Hyp + Cur group compared to the hyp group. CONCLUSION: Here, we used nanoparticle form of curcumin in testicular hyperthermia model and showed its ameliorating effects on testes damages caused by heat stress, which can be an appropriate method to overcome the problems that limit curcumin application in cases with increased intra testicular temperature.

Risperidone and 5-HT2A Receptor Antagonists Attenuate and Reverse Cocaine-Induced Hyperthermia in Rats.

BACKGROUND: Cocaine (benzoylmethylecgonine) is one of the most widely used illegal psychostimulant drugs worldwide, and mortality from acute intoxication is increasing. Suppressing hyperthermia is effective in reducing cocaine-related mortality, but a definitive therapy has not yet been found. In this study, we assessed the ability of risperidone to attenuate acute cocaine-induced hyperthermia and delineated the mechanism of its action. METHODS: Rats were injected i.p. with saline, risperidone, ketanserin, ritanserin, haloperidol, or SCH 23 390 before and after injection of cocaine (30 mg/kg) or with WAY-00 635, SB 206 553, or sulpiride before cocaine injection; thereafter, the rectal temperature was measured every 30 minutes for up to 4 hours. In vivo microdialysis was used to reveal the effect of risperidone on cocaine-induced elevation of dopamine (DA), serotonin (5-HT), and noradrenaline concentrations in the anterior hypothalamus. For post-administration experiments, saline or risperidone (0.5 mg/kg) were injected into rats, and cocaine (30 mg/kg) was injected 15 minutes later. For every 30 minutes thereafter, DA, 5-HT, and noradrenaline levels were measured for up to 240 minutes after cocaine administration. RESULTS: Risperidone, 5-HT2A receptor antagonists, and D1 receptor antagonistic drugs prevented and reversed cocaine-induced hyperthermia. In contrast, receptor antagonists for 5-HT1A, 5-HT2B/2C, and D2 did not alter cocaine-induced hyperthermia. Risperidone treatment further attenuated cocaine-induced elevation of DA. CONCLUSIONS: Our results indicate that risperidone attenuates cocaine-induced hyperthermia primarily by blocking the activities of the 5-HT2A and D1 receptors and may be potentially useful for treating cocaine-induced acute hyperthermia in humans.

A novel pipeline of 2-(benzenesulfonamide)-N-(4-hydroxyphenyl) acetamide analgesics that lack hepatotoxicity and retain antipyresis.

Although acetaminophen (ApAP) is one of the most commonly used medicines worldwide, hepatotoxicity is a risk with overdose or in patients with compromised liver function. ApAP overdose is the most common cause of acute fulminant hepatic failure. Oxidation of ApAP to N-acetyl-p-benzoquinone imine (NAPQI) is the mechanism for hepatotoxicity. 1 is a non-hepatotoxic, metabolically unstable lipophilic ApAP analog that is not antipyretic. The newly synthesized 3 is a non-hepatotoxic ApAP analog that is stable, lipophilic, and retains analgesia and antipyresis. Intraperitoneal or po administration of the new chemical entities (NCEs), 3b and 3r, in concentrations equal to a toxic dose of ApAP did not result in the formation of NAPQI. Unlike livers from NCE-treated mice, the livers from ApAP-treated mice demonstrated large amounts of nitrotyrosine, a marker of mitochondrial free radical formation, and loss of hepatic tight junction integrity. Given the widespread use of ApAP, hepatotoxicity risk with overuse, and the ongoing opioid epidemic, these NCEs represent a novel, non-narcotic therapeutic pipeline.

The efficacy of steroids in reducing morbidity and mortality from extreme hyperthermia and heatstroke-A systematic review.

Severe hyperthermia from classical or exertional heatstroke, or from drug ingestion or other noninfective pyrogens, is associated with a high mortality and morbidity. A systemic pro-inflammatory response occurs during heatstroke, characterized by elevated cytokines with endotoxemia from elevated lipopolysaccharide (LPS) levels. Corticosteroids reduce LPS and cytokine levels, suggesting that they may improve outcome. A systematic review searching Embase, MEDLINE, and PubMed from the earliest date available until September 2019 was conducted, according to the PRISMA guidelines, with five papers identified. In four studies, systemic steroids administered before or at the onset of heat stress improved mortality or reduced organ dysfunction. Survival time was greatest when steroid administration preceded heat stress. In one study, a nonsignificant increase in mortality was seen. A dose response was observed, with higher doses extending survival time. Animal studies suggest that steroids improve mortality and/or organ dysfunction after an episode of heat stress or extreme hyperthermia.