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Movement Disorders Clinical Practice Sep 2023Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by widespread accumulation of hyperphosphorylated tau that typically occurs in people...
BACKGROUND
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by widespread accumulation of hyperphosphorylated tau that typically occurs in people who have suffered repetitive head impacts. To date, very few cases have been reported in association football players.
OBJECTIVES
To describe the clinicopathological features of a case of CTE in an 84-year-old former football player who was clinically diagnosed as having dementia with Lewy bodies (DLB).
METHODS
A retrospective review of the patient's primary care and hospital medical records was performed along with a comprehensive neuropathological examination.
RESULTS
This patient presented at age 84 with symmetrical parkinsonism and cognitive impairment that was exacerbated by prochlorperazine. His condition was rapidly progressive with recurrent falls within 1 year. Other features included headaches, depression, anxiety, suicidal ideation, disturbed sleep and aggression. He received a clinical diagnosis of DLB and died approximately 2 years after the onset of symptoms. A post-mortem examination revealed stage 4 CTE.
CONCLUSIONS
While the contemporaneous onset of parkinsonism and cognitive symptoms in the context of possible neuroleptic sensitivity is suggestive of DLB, the additional symptoms of aggressive behavior, depression and suicidality in a former football player are consistent with the neuropathological diagnosis of CTE. This case, which is notable for the late presentation, demonstrates that CTE may masquerade as other dementias and highlights the importance of seeking a history of repetitive head impacts.
PubMed: 37772307
DOI: 10.1002/mdc3.13829 -
Journal of the American Society of... Jun 2024In hemodialysis, ondansetron initiation versus initiation of lesser QT-prolonging antiemetics associated with higher 10-day sudden cardiac death risk. Analyses...
KEY POINTS
In hemodialysis, ondansetron initiation versus initiation of lesser QT-prolonging antiemetics associated with higher 10-day sudden cardiac death risk. Analyses considering additional cardiac outcomes had consistent findings.
BACKGROUND
Individuals receiving hemodialysis have a high incidence of sudden cardiac death and are susceptible to QT interval–prolonging medication–related cardiac complications. Ondansetron, an antiemetic with known QT-prolonging potential, is associated with fatal arrhythmias in the general population when administered intravenously. The cardiac safety of ondansetron in the hemodialysis population is unknown.
METHODS
We conducted a new-user, active-comparator, cohort study using United States Renal Data System data (2012–2019) to examine the association between the initiation of oral ondansetron versus antiemetics with lesser QT-prolonging potential (promethazine, metoclopramide, or prochlorperazine) and the 10-day risk of sudden cardiac death among individuals receiving hemodialysis. We used inverse probability of treatment-weighted survival models to estimate adjusted hazard ratios, risk differences, and 95% confidence intervals (CIs). We used an intention-to-treat approach in which non-sudden cardiac death was considered a competing event. We examined additional cardiac outcomes in secondary analyses.
RESULTS
Of 119,254 study patients, 64,978 (55%) initiated ondansetron and 54,276 (45%) initiated a comparator antiemetic. Initiation of ondansetron versus a comparator antiemetic was associated with higher relative and absolute 10-day risks of sudden cardiac death (adjusted hazard ratio, 1.44 [95% CI, 1.08 to 1.93]; adjusted risk difference, 0.06% [95% CI, 0.01% to 0.11%]). The number needed to harm was 1688. Analyses of additional cardiac outcomes yielded similar findings.
CONCLUSIONS
Compared with initiation of antiemetics with lesser QT-prolonging potential, initiation of ondansetron was associated with higher short-term cardiac risks among people receiving hemodialysis.
Topics: Humans; Renal Dialysis; Death, Sudden, Cardiac; Ondansetron; Male; Female; Middle Aged; Kidney Failure, Chronic; Antiemetics; Aged
PubMed: 38409683
DOI: 10.1681/ASN.0000000000000336 -
Current Issues in Molecular Biology Jun 2023Skeletal muscle disuse leads to pathological muscle activity as well as to slow-to-fast fiber-type transformation. Fast-type fibers are more fatigable than slow-type, so...
Skeletal muscle disuse leads to pathological muscle activity as well as to slow-to-fast fiber-type transformation. Fast-type fibers are more fatigable than slow-type, so this transformation leads to a decline in muscle function. Prochlorperazine injections previously were shown to attenuate autonomous rat soleus muscle electrical activity under unloading conditions. In this study, we found that prochlorperazine blocks slow-to-fast fiber-type transformation in disused skeletal muscles of rats, possibly through affecting calcium and ROS-related signaling.
PubMed: 37504270
DOI: 10.3390/cimb45070354 -
Bioelectrochemistry (Amsterdam,... Aug 2024We present a novel application of a nanocrystalline boron-doped diamond electrode (B-NCDE) for the construction of an electrochemical DNA biosensor based on...
We present a novel application of a nanocrystalline boron-doped diamond electrode (B-NCDE) for the construction of an electrochemical DNA biosensor based on double-stranded DNA (dsDNA) for various bioanalytical applications. Surface characterization of the transducer surface (prior and after the fabrication of negatively charged O-terminated surface - O-B-NCDE) was performed by scanning electron microscopy (SEM), Raman spectroscopy, and linear sweep voltammetry (LSV) that was further used for the voltammetric determination, scan rate dependence investigation, and repeatability examination of dsDNA electrochemical oxidation at the O-B-NCDE. The fabrication of a dsDNA/O-B-NCDE biosensor via electrostatic adsorption of dsDNA involved a thorough optimization process of deposition potential (E), deposition time (t), and optimal saturation concentration (c) with optimal values of 0.3 V, 3 min, and 10 mg/mL. The bioanalytical applicability of the fabricated dsDNA/O-B-NCDE biosensor was verified by examining the nature of the interaction between dsDNA and five selected DNA intercalators - namely thioridazine hydrochloride (TR), trimipramine maleate (TRIM), levomepromazine maleate (LEV), imipramine hydrochloride (IMI), and prochlorperazine maleate (PER) - where intercalation was proven for all of the five tested compounds. Moreover, the proposed novel bioanalytical test offers the possibility to selectively distinguish between the phenothiazine representatives (TR, LEV, and PER) and representatives of tricyclic antidepressants group (TRIM and IMI).
Topics: Biosensing Techniques; DNA; Diamond; Boron; Electrodes; Electrochemical Techniques; Nanoparticles
PubMed: 38574451
DOI: 10.1016/j.bioelechem.2024.108691 -
Molecular Pharmaceutics Sep 2023Dynamin II (dynII) plays a significant role in the internalization pathways of endocytic cells, by allowing membrane invaginations to "bud off". An important class of...
Dose-Dependent Effect of Phenothiazines as Dynamin II Inhibitors on the Uptake of PEGylated Liposomes by Endocytic Cells and In Vivo Pharmacokinetics of PEGylated Liposomal Doxorubicin in Rats.
Dynamin II (dynII) plays a significant role in the internalization pathways of endocytic cells, by allowing membrane invaginations to "bud off". An important class of dynII inhibitors that are used clinically are phenothiazines, such as prochlorperazine (PCZ). PCZ is an antipsychotic drug but is also currently in clinical trials at higher concentrations as an adjuvant in cancer patients that increases the efficacy of monoclonal antibodies at high intravenous doses. It is unknown, however, whether high-dose dynII inhibitors have the potential to alter the pharmacokinetics of co-administered chemotherapeutic nanomedicines that are largely cleared via the mononuclear phagocyte system. This work therefore sought to investigate the impact of clinically relevant concentrations of phenothiazines, PCZ and thioridazine, on in vitro liposome endocytosis and in vivo liposome pharmacokinetics after PCZ infusion in rats. The uptake of fluorescently labeled PEGylated liposomes into differentiated and undifferentiated THP-1 and RAW246.7 cells, and primary human peripheral white blood cells, was investigated via flow cytometry after co-incubation with dynII inhibitors. The IV pharmacokinetics of PEGylated liposomes were also investigated in rats after a 20 min infusion with PCZ. Phenothiazines and dyngo4a reduced the uptake of PEGylated liposomes by THP-1 and RAW264.7 cells in a concentration-dependent manner in vitro. However, dynII inhibitors did not alter the mean uptake of liposomes by human peripheral white blood cells, but endocytic white cells from some donors exhibited sensitivity to phenothiazine exposure. When a clinically relevant dose of PCZ was co-administered with PEGylated liposomal doxorubicin (Caelyx/Doxil) in rats, the pharmacokinetics and biodistribution of liposomes were unaltered. These data suggest that while clinically relevant doses of dynII inhibitors can inhibit the uptake of liposomes by endocytic cells in vitro, they are unlikely to significantly affect the pharmacokinetics of long-circulating, co-administered liposomes.
Topics: Rats; Humans; Animals; Liposomes; Dynamin II; Tissue Distribution; Doxorubicin; Polyethylene Glycols; Phenothiazines; Prochlorperazine
PubMed: 37548597
DOI: 10.1021/acs.molpharmaceut.3c00102 -
Nanomedicine : Nanotechnology, Biology,... Feb 2024Anti-cancer monoclonal antibodies often fail to provide therapeutic benefit in receptor-positive patients due to rapid endocytosis of antibody-bound cell surface...
A PEGylated liposomal formulation of prochlorperazine that limits brain exposure but retains dynamin II activity: A potential adjuvant therapy for cancer patients receiving chemotherapeutic mAbs.
Anti-cancer monoclonal antibodies often fail to provide therapeutic benefit in receptor-positive patients due to rapid endocytosis of antibody-bound cell surface receptors. High dose co-administration of prochlorperazine (PCZ) inhibits endocytosis and sensitises tumours to mAbs by inhibiting dynamin II but can also introduce neurological side effects. We examined the potential to use PEGylated liposomal formulations of PCZ (LPCZ) to retain the anti-cancer effects of PCZ, but limit brain uptake. Uncharged liposomes showed complete drug encapsulation and pH-dependent drug release, but cationic liposomes showed limited drug encapsulation and lacked pH-dependent drug release. Uncharged LPCZ showed comparable inhibition of EGFR internalisation to free PCZ in KJD cells. After IV administration to rats, LPCZ reduced the plasma clearance and brain uptake of PCZ compared to IV PCZ. The results suggest that LPCZ may offer some benefit over PCZ as an adjunct therapy in cancer patients receiving mAb treatment.
Topics: Humans; Rats; Animals; Prochlorperazine; Dynamin II; Liposomes; Neoplasms; Antineoplastic Agents; Antibodies, Monoclonal; Brain; Polyethylene Glycols
PubMed: 38199450
DOI: 10.1016/j.nano.2024.102733 -
CEN Case Reports Apr 2024Carcinoid syndrome is caused by the release of serotonin and other substances, which commonly occurs due to liver metastasis of neuroendocrine tumors. It rarely occurs...
Carcinoid syndrome is caused by the release of serotonin and other substances, which commonly occurs due to liver metastasis of neuroendocrine tumors. It rarely occurs due to liver metastasis of neuroendocrine carcinoma. We report the case of a patient with liver metastasis of neuroendocrine carcinoma who suffered from acute abdominal pain and diarrhea triggered by hemodialysis. Various differential diagnoses were considered, but we concluded these symptoms to be probably caused by exacerbation of carcinoid syndrome, as the serum 5HIAA level was markedly elevated, and a drug with anti-serotonin activity was effective. Prochlorperazine maleate, which has anti-serotonin activity, was effective for these symptoms, and the patient was able to continue maintenance hemodialysis, which contributed to his quality of life and prognosis. We speculated the mechanism of carcinoid exacerbation was that substances such as serotonin had entered the systemic circulation via the increased extrahepatic shunt of the portal venous blood flow, entering the inferior vena cava and that this condition had been triggered by hemodialysis via the same mechanism as portal systemic encephalopathy.
Topics: Humans; Prochlorperazine; Serotonin; Quality of Life; Carcinoid Tumor; Renal Dialysis; Carcinoma, Neuroendocrine; Liver Neoplasms
PubMed: 37606883
DOI: 10.1007/s13730-023-00814-6