Severe Neurological Side Effects Research Articles

Self-Assembly Nanostructure of Myristoylated ω-Conotoxin MVIIA Increases the Duration of Efficacy and Reduces Side Effects

Chronic pain is one of the most prevalent health problems worldwide. An alternative to suppress or alleviate chronic pain is the use of peptide drugs that block N-type Ca2+ channels (Cav2.2), such as ω-conotoxin MVIIA. Nevertheless, the narrow therapeutic window, severe neurological side effects and low stability associated with peptide MVIIA have restricted its widespread use. Fortunately, self-assembly endows the peptide with high stability and multiple functions, which can effectively control its release to prolong its duration of action. Inspired by this, MVIIA was modified with appropriate fatty acid chains to render it amphiphilic and easier to self-assemble. In this paper, an N-terminal myristoylated MVIIA (Myr-MVIIA, medium carbon chain length) was designed and prepared to undergo self-assembly. The present results indicated that Myr-MVIIA can self-assemble into micelles. Self-assembled micelles formed by Myr-MVIIA at higher concentrations than MVIIA can prolong the duration of the analgesic effect and significantly reduce or even eliminate the side effects of tremor and coordinated motor dysfunction in mice.

Tomato Bushy Stunt Virus Nanoparticles as a Platform for Drug Delivery to Shh-Dependent Medulloblastoma.

Medulloblastoma (MB) is a primary central nervous system tumor affecting mainly young children. New strategies of drug delivery are urgent to treat MB and, in particular, the SHH-dependent subtype—the most common in infants—in whom radiotherapy is precluded due to the severe neurological side effects. Plant virus nanoparticles (NPs) represent an innovative solution for this challenge. Tomato bushy stunt virus (TBSV) was functionally characterized as a carrier for drug targeted delivery to a murine model of Shh-MB. The TBSV NPs surface was genetically engineered with peptides for brain cancer cell targeting, and the modified particles were produced on a large scale using Nicotiana benthamiana plants. Tests on primary cultures of Shh-MB cells allowed us to define the most efficient peptides able to induce specific uptake of TBSV. Immunofluorescence and molecular dynamics simulations supported the hypothesis that the specific targeting of the NPs was mediated by the interaction of the peptides with their natural partners and reinforced by the presentation in association with the virus. In vitro experiments demonstrated that the delivery of Doxorubicin through the chimeric TBSV allowed reducing the dose of the chemotherapeutic agent necessary to induce a significant decrease in tumor cells viability. Moreover, the systemic administration of TBSV NPs in MB symptomatic mice, independently of sex, confirmed the ability of the virus to reach the tumor in a specific manner. A significant advantage in the recognition of the target appeared when TBSV NPs were functionalized with the CooP peptide. Overall, these results open new perspectives for the use of TBSV as a vehicle for the targeted delivery of chemotherapeutics to MB in order to reduce early and late toxicity.

Abstract P221: First-In-Class Anti-Spastic Drug Candidate (MPH-220) Efficiently Relaxes Spastic Muscles and Improves Motor Functions in Gait Disorder in Preclinical Studies

Post-stroke muscle spasticity affects 37% of stroke survivors and disables self-supporting life management. There is a high unmet medical need for an efficient antispastic drug because current muscle relaxants are often of limited efficacy and cause severe neurological and cardiovascular side effects due to targeting the central or peripheral nervous system. We developed a new-generation anti-spastic oral drug, MPH-220, which efficiently relaxes spastic skeletal muscles and lacks cardiovascular and neurological adverse effects because it selectively targets skeletal myosin, the contractile protein of muscles. MPH-220 is an efficient skeletal muscle specific actomyosin relaxant demonstrated on human muscle samples. Orally administered MPH-220 reduces muscle force of living rats without cardiovascular side effects. Brain-damage induced spastic animals showed drastic improvement in gait disorders upon oral MPH-220 treatment resulting in significantly straightened body posture, reduced number of spontaneous falling and cramping, and more ordered limb positions. Due to selective accumulation of MPH-220 in skeletal muscle tissues, antispastic effect was maintained for more than 10 hours. Due to its mechanism of action MPH-220 does not cause complete loss of muscle tone even at high doses. Furthermore, MPH-220 has excellent ADMET properties for oral administration: it is highly absorptive, non-mutagenic and has no effects on hERG channels, kinases, nuclear hormone receptors and GPCRs. Considering these results, MPH-220 is a promising anti-spastic oral drug candidate, which provides potential nervous system-independent therapies for spasticity and muscle stiffness without cardiovascular and neuronal side effects. Phase I clinical trials are scheduled for the beginning of 2021. Funded by the Hungarian National Research, Development and Innovation Office (NVKP 16-1-2016-0051 and PIACI-KFI-2019-00488).

Proarrhythmic potential of metoclopramide in a sensitive whole-heart model.

Metoclopramide (MCP) is a dopamine D2 -receptor antagonist, mainly used to treat post-operative or chemotherapy-induced nausea. While it is very effective in the cure of gastric symptoms, MCP can cause severe neurologic side effects. Furthermore, there is growing evidence for severe arrhythmic side effects resulting from inhibitory effects on cardiac sodium and potassium channels. Thirteen hearts of New Zealand white rabbits were retrogradely perfused, and electrophysiology studies were performed to obtain action potential duration (APD90 ) and effective refractory period (ERP). After generating baseline data, the hearts were perfused with increasing concentrations of metoclopramide (MCP 10µM, MCP 50µM, MCP 100µM) and the standardized protocol was repeated for each concentration. Perfusion with MCP resulted in a significant prolongation of APD90 and QT interval. In parallel, the incidence of ventricular tachycardias was significantly increased by high doses of MCP. This is the first experimental study that investigated the effect of increasing doses of metoclopramide on a sensitive whole-heart model of proarrhythmia. MCP led to a significant increase in action potential duration and QT interval; meanwhile, the number of ventricular tachycardias was significantly increased.

Single-cell transcriptomic profile reveals macrophage heterogeneity in medulloblastoma and their distinct responses to different treatment modalities

Abstract Tumor-associated macrophages (TAMs) are an important component of the tumor microenvironment (TME). Pro-inflammatory macrophages can suppress while anti-inflammatory macrophages can promote tumor growth. Despite their abundance in many tumors, the origins and diversity of TAMs are not well understood, especially in brain tumors. Our long-term goal is to uncover ways to modulate TAMs for the treatment of pediatric brain tumors. Medulloblastoma (MB) is one of the most common pediatric brain malignancy. MB is heterogeneous with four molecular subgroups: WNT, sonic hedgehog (SHH), group 3, and group 4. Treatment includes surgical resection, cytotoxic chemotherapy, and radiation. Radiation is effective, but severe neurological side-effects limit its use to non-infants (> 3 years). Therefore, treatment choices are even more limited in infants. SHH-MB dominates this age group and is characterized by constitutive activation of the SHH signaling pathway. Ptch1 is a negative regulator of SHH signaling that is often mutated in SHH-MB. In mice, germline deletion of Ptch1 and loss of Tp53 leads generates MB with 100% penetrance. Using single-cell RNA sequencing (ScRNA-Seq) in the genetically engineered mouse model (Ptch+/−:p53−/−) of SHH-MB, we describe macrophage heterogeneity in medulloblastoma, demonstrate differential recruitment and function of macrophages under distinct modalities of tumor therapy (molecular-targeted vs. radiation), and use these insights to uncover potential strategies for immunomodulation as adjunctive therapy.

Identification of a New Chemotype of Anti-Obesity Compounds by Ensemble Screening

Despite the increasing prevalence of overweight or obesity in the global population, most of the approved drugs for obesity are still not ideal for long-term use due to severe cardiovascular and/or neurological side effects. Therefore, we designed a library-implemented virtual screening (VS) approach to discover new anti-obesity agents without significant toxicity. The Bayesian classification and 3D pharmacophore model for the VS process were built by using the screening results of our in-house library of natural piper amide-like compounds, which possess a wide range of biological activities and relatively low toxicities. The VS process identified six compounds of different classes with enhanced inhibitory activities against lipid accumulation and without toxicity. Moreover, the most active compound with an oxadiazole scaffold resulted in weight loss and improved the fatty liver condition of mice with overnutrition in animal experiments.

Ciprofloxacin: single versus multiple doses in transrectal ultrasound guided prostate biopsy.

IntroductionThere is rising concern regarding overuse of fluoroquinolones due to severe musculoskeletal and neurological side effects, and development of resistant microorganisms. In June 2019, the European Commission recommended fluoroquinolones should not be used routinely for prophylaxis in urological surgical procedures. Methods to reduce unnecessary exposure to fluroquinolones should be investigated.The aim of this article was to determine differences in hospital admission secondary to sepsis following transrectal ultrasound (TRUS) guided prostate biopsies between patients who received single vs. multiple doses of fluoroquinolones.Material and methodsA retrospective analysis (June 2017–September 2018) of 200 consecutive TRUS biopsies at a single centre was undertaken. Group 1 (n = 100) received 750 mg ciprofloxacin 1-hr before their procedure followed by 3 days of ciprofloxacin 250 mg BD. Group 2 (n = 100) received a single dose of 750 mg ciprofloxacin 1-hr before the procedure. Midstream urine (MSU) culture results were examined pre-biopsy and 7 days post-biopsy. Data was also gathered on readmission rates to hospital as a result of urosepsis.ResultsA total of 1% of patients in each group required hospital admission secondary to Escherichia coli sepsis. A further 4% (n = 4) in Group 1 developed a urinary tract infection requiring antibiotic treatment post biopsy compared with 1% (n = 1) in Group 2. There was no statistically significant difference in development of infectious complications post-biopsy between the two groups (p >0.05).ConclusionsA single prophylactic dose of 750 mg of ciprofloxacin 1-hour pre-biopsy is as effective as multiple doses for TRUS guided prostate biopsy. Avoiding an unnecessary and prolonged course of fluoroquinolones has advantages in reducing potential side effects and development of resistant pathogens.

Current Concepts and Treatments of Schizophrenia.

Schizophrenia is a debilitating mental illness which involves three groups of symptoms, i.e., positive, negative and cognitive, and has major public health implications. According to various sources, it affects up to 1% of the population. The pathomechanism of schizophrenia is not fully understood and current antipsychotics are characterized by severe limitations. Firstly, these treatments are efficient for about half of patients only. Secondly, they ameliorate mainly positive symptoms (e.g., hallucinations and thought disorders which are the core of the disease) but negative (e.g., flat affect and social withdrawal) and cognitive (e.g., learning and attention disorders) symptoms remain untreated. Thirdly, they involve severe neurological and metabolic side effects and may lead to sexual dysfunction or agranulocytosis (clozapine). It is generally agreed that the interactions of antipsychotics with various neurotransmitter receptors are responsible for their effects to treat schizophrenia symptoms. In particular, several G protein-coupled receptors (GPCRs), mainly dopamine, serotonin and adrenaline receptors, are traditional molecular targets for antipsychotics. Comprehensive research on GPCRs resulted in the exploration of novel important signaling mechanisms of GPCRs which are crucial for drug discovery: intentionally non-selective multi-target compounds, allosteric modulators, functionally selective compounds and receptor oligomerization. In this review, we cover current hypotheses of schizophrenia, involving different neurotransmitter systems, discuss available treatments and present novel concepts in schizophrenia and its treatment, involving mainly novel mechanisms of GPCRs signaling.

Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma

ABSTRACTPediatric medulloblastomas are the most frequently diagnosed embryonal tumors of the central nervous system. Current therapies cause severe neurological and cognitive side effects including secondary malignancies. Cellular immunotherapy might be key to improve survival and to avoid morbidity. Efficient killing of tumor cells using immunotherapy requires to overcome cancer-associated strategies to evade cytotoxic immune responses. Here, we examined the immune response and immune evasion strategies in pediatric medulloblastomas. Cytotoxic T-cells, infiltrating medulloblastomas with variable activation status, showed no correlation with overall survival of the patients. We found limited numbers of PD1+ T-cells and complete absence of PD-L1 on medulloblastomas. Medulloblastomas downregulated immune recognition molecules MHC-I and CD1 d. Intriguingly, expression of granzyme inhibitors SERPINB1 and SERPINB4 was acquired in 23% and 50% of the tumors, respectively. Concluding, pediatric medulloblastomas exploit multiple immune evasion strategies to overcome immune surveillance. Absence of PD-L1 expression in medulloblastoma suggest limited or no added value for immunotherapy with PD1/PD-L1 blockers.

Calcium channel modulation as a target in chronic pain control.

Neuropathic pain remains poorly treated for large numbers of patients, and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (Prialt™) was developed and approved as a first‐in‐class synthetic version of ω‐conotoxin MVIIA, a peptide blocker of Cav2.2 channels. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide have restricted its use to exceptional circumstances. Ziconotide exhibits no state or use‐dependent block of Cav2.2 channels; activation state‐dependent blockers were hypothesized to circumvent the side effects of state‐independent blockers by selectively targeting high‐frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state‐dependent calcium channel blockers, have displayed efficacy in preclinical models but have subsequently been disappointing in clinical trials. In recent years, it has become more widely acknowledged that trans‐aetiological sensory profiles exist amongst chronic pain patients and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus‐evoked endpoints in preclinical studies and a failure to utilize translatable endpoints, all are likely to have contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant‐based assays provide insight into sensory and affective aspects of pain in animal models and how these may relate to chronic pain patients in order to improve the bench‐to‐bedside translation of calcium channel modulators.Linked ArticlesThis article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc

Severe neurological side effects associated with ipilimumab: A case series

Severe neurological side effects associated with ipilimumab: A case series

TR-15 * USE OF IV N-ACETYLCYSTEINE IN COMBINATION WITH SODIUM THIOSULFATE FOR PREVENTION OF OTOTOXICITY IN PEDIATRIC PATIENTS

Although the childhood cancers medulloblastoma, osteosarcoma, hepatoblastoma, germ cell tumors, and neuroblastoma affect a relatively small number of children, with prevalence under 110,000 in the United States, the impact of these life-threatening illnesses on children and their families is significant. Standard therapy for pediatric cancers typically involves alkylating platinum chemotherapeutics, primarily cisplatin and carboplatin. Platinum chemotherapeutics and other free-radical inducing therapies such as radiotherapy can cause multiple severe systemic and neurological side effects, including permanent ototoxicity. The overall incidence of permanent bilateral hearing loss in children during cisplatin chemotherapy is 60%.(1) Our goal is to decrease the toxic side effects of cisplatin and enhance long-term quality of life by reducing lasting toxicities. Based on our preclinical and clinical studies, we hypothesize that the appropriate timing and dosing of combination chemoprotectants may reduce systemic and neurologic toxicities while maintaining dose intensity, and may even allow for the use of new strategies, such as dose-escalation or chemo-enhancement, for improved cancer control. In particular, our studies have demonstrated that high dose (400 mg/kg) intravenous (IV) N-acetylcysteine (NAC) (Acetadote®) is critical to achieve high plasma concentrations for optimum chemoprotective activity. Recently completed Phase III studies of sodium thiosulfate (STS) otoprotection in children have shown no compromise in efficacy of cisplatin if the tumor is localized (as it is in 50 + % of patients). We have applied for orphan-drug designation of IV NAC in combination with STS for prevention of ototoxicity caused by platinum-based chemotherapeutic agents in children, in addition we are developing a phase I trial of increasing NAC doses in combination with the phase III dose of STS. 1. 1. Brock PR, et al. Platinum-Induced Ototoxicity in Children: A Consensus Review on Mechanisms, Predisposition, and Protection, Including a New International Society of Pediatric Oncology Boston Ototoxicity Scale. J Clin Oncol 30(19), 2408-2417.

Accidental podophyllin poisoning in a 3-year-old child

Accidental poisoning in children remains a common presentation in healthcare centres worldwide, with the highest rates of fatal poisonings occurring in Africa. Podophyllin, commonly used for genital warts, is a rare agent in poisoning cases. A few cases have been reported in the international literature, with serious systemic and neurological side-effects. We report a case of accidental podophyllin poisoning in a 3-year-old boy, which was complicated with organ dysfunction. The case highlights the severe neurological side-effects of podophyllin poisoning and the importance of accident prevention in our communities.

Carence en vitamine B12 par toxicité du protoxyde d’azote : une cause méconnue de sclérose combinée de la moelle

IntroductionNitrous oxide is widely used in anesthesia. It is usually safe but may be associated with severe side effects when it is used repeatedly or on a prolonged time. Here, we report a case of drug-induced subacute combined spinal cord degeneration related to cobalamin deficiency. Case reportA 20-year-old man with sickle-cell disease (SS) who was followed for severe recurrent vaso-occlusive crisis with repeated hospital admissions presented with ascending motor and sensitive neurological deficits that were later associated with bladder dysfunction. He was first considered to develop Guillain-Barre syndrome. However, persisting neurological signs despite adequate treatment lately led to diagnose subacute combined medullar degeneration due to abnormal cobalamin (vitamin B12) metabolism induced by repeated use of nitrous oxide during painful episodes of sickle-cell disease. ConclusionInhaled nitric oxide is widely used in the treatment of vaso-occlusive crisis. Clinicians should be aware of possible severe neurologic side effects.

The invention of the swine-flu pandemic

coming from Vietnam brought the virus as the so called Asian swine flu to the US. In 1976 a vaccination campaign started and about 40 million US-citizens were vaccinated, because the Centres for Disease Control and Prevention (CDC) feared, that the A/H1N1 virus might be similar to the virus of the Spanish influenza in 1918-1920 with 25-40 million deaths [1]. A/H1N1 vaccination campaign stopped abruptly when it realized that the virus produced only a mild disease, while the vaccine produced a number of severe neurological side effects, namely Guillain-Barre-Syndrome [2]. In their report The epidemic that never was Neustadt and Fineberg [3, 4] concluded that

Severe neurologic side effects in patients being treated for hemophagocytic lymphohistiocytosis

Hemophagocytic Lymphohistiocytosis (HLH) is characterized by uncontrolled inflammation that is generally fatal without immune modulating chemotherapy. At Texas Children's Hospital, we have observed significant central nervous system (CNS) toxicity in several patients treated for HLH according to the Histiocyte Society protocol HLH-2004 in which cyclosporine is given early in the treatment regimen. Patients diagnosed with HLH at Texas Children's Hospital between April 2004 and October 2007 were identified and charts were reviewed. A reference group of patients treated between August 2001 and March 2004, prior to the introduction of HLH-2004, was also evaluated. Five of 17 patients in the study group developed severe neurotoxicity. Four had new onset seizures associated with significant MRI abnormalities, while the fifth died of intracerebral hemorrhage. Timing of the development of neurologic side effects ranged from day 5 to week 6 of therapy. Cyclosporine levels were outside the therapeutic range (200-300 ng/ml) prior to the onset of symptoms in two of the five patients. Systolic blood pressures for all five patients were greater than the 95th percentile for age on at least one measurement within 24 hr of the onset of neurologic symptoms. MRI scans obtained within 24 hr of seizure activity in four patients were consistent with posterior reversible encephalopathy syndrome (PRES). By comparison only one patient in the reference group (n = 15) had neurotoxicity (PRES). Patients being treated for HLH appear to be at risk for neurotoxicity, particularly PRES. Elevated blood pressure, worsening renal and liver function, increased cyclosporine levels, and CNS involvement of HLH may be triggers for the neurotoxic side effects of treatment. Patients being treated on HLH-2004 require close monitoring of their neurologic status and modifiable risk factors such as hypertension should managed aggressively. If larger studies validate our observations, it will be important to determine if up-front cyclosporine in HLH protocols confers a survival benefit that outweighs the potential risk of increased neurotoxicity.

Late-onset Tacrolimus-associated Cerebellar Atrophia in a Heart Transplant Recipient

Tacrolimus is a macrolide immunosuppressant frequently used after solid-organ transplantation. Moderate and severe neurologic side effects have been reported in patients receiving tacrolimus. Cerebral neurotoxicity is a rare but fatal calcineurin inhibitor-related complication, especially in kidney and liver transplant recipients. Often a reduction or a change in immunosuppressive regimen is the only means of clinical management. Herein we report a case of a 31-year-old man who developed cerebellar atrophia while under immunosuppressive therapy 9 years after heart transplantation. His neurologic constitution ameliorated after an immunosuppressant switch from tacrolimus to sirolimus.

Randomized Clinical Trial of High-Dose Levamisole Combined with 5-Fluorouracil and Leucovorin as Surgical Adjuvant Therapy for High-Risk Colon Cancer

Levamisole combined with 5-fluorouracil (5-FU) was previously shown to significantly reduce tumor relapses and improve patient survival when given postoperatively in patients with resected stage III colon cancer. Laboratory investigations subsequently documented a direct dose-dependent enhancement of 5-FU cytotoxicity with increasing concentrations of levamisole against human cancer cell lines. A clinical trial was designed to test the value of levamisole given at its maximum tolerated dose in combination with 5-FU-based chemotherapy. Eight hundred seventy-eight patients who had undergone complete surgical resection of high-risk stage II/III colon cancer were stratified by known prognostic factors and randomized to receive 1 of 2 treatment regimens: standard-dose levamisole combined with 5-FU and leucovorin; or high-dose levamisole combined with the same chemotherapy. Serum neopterin was monitored in a cohort of patients to evaluate immune function. Severe vomiting and neurologic side effects required reduction in the dose of levamisole that could be safely administered on the high-dose levamisole regimen. There were no significant differences in disease-free survival, overall survival, or levels of serum neopterin between the treatment regimens. It was not possible to improve the efficacy of surgical adjuvant chemotherapy for patients with high-risk colon cancer by giving levamisole at its maximum tolerated dose in combination with 5-FU and leucovorin. High rates of severe gastrointestinal and neurologic side effects were observed with the high-dose levamisole regimen.

Parkinsonism and/or Cognitive Impairment with Valproic Acid Therapy: A Report of Ten Cases

Valproic acid (VPA) is commonly prescribed and is generally considered to have a good safety profile. Severe neurological side effects, such as acute encephalopathy or tremor, are well-known. Parkinsonian syndromes and cognitive impairment have been very rarely reported with this drug. Ten cases of reversible parkinsonism associated with VPA in 6 women and 4 men, associated with marked cognitive impairment in six cases, are described. These side effects sometimes occurred after several years of good tolerability. All patients had serum levels within the therapeutic range (50-100 microg/ml). Symptoms improved several weeks or months after discontinuation of VPA therapy in every case. Several cases of parkinsonian syndromes have been reported in the literature, but usually in children or young adults. These symptoms had an insidious and progressive onset. Clinical features can mimic Parkinson's disease and may be confusing, especially when they occur in older patients. The mechanism of these disorders is currently unknown, but several hypotheses have been proposed. Despite the good safety of VPA therapy for several years, a drug-induced mechanism of parkinsonism or cognitive impairment must be considered in all patients treated with VPA, as discontinuation of the drug can induce significant improvement of the patient's neurological and mental status.

The life-threatening complications of dermatologic therapies

Dermatologists use a variety of systemic drugs, some of which can cause severe adverse reactions and even fatalities. Ivermectin, a well-tolerated drug, can cause severe neurological side effects, whereas metronidazole, in high cumulative doses, has been associated with convulsions and rarely with hepatotoxicity. Dapsone is associated with frequent hematologic side effects, such as methemoglobinemia, hemolysis, and anemia. Although hepatotoxicity is rare and usually mild and reversible with the new antifungal agents, severe cutaneous reactions (such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and anaphylaxis) have been reported. Even a relatively safe drug such as acyclovir has been reported to be the cause of renal failure and neurotoxicity. Retinoids can cause not so benign “benign” intracranial hypertension. Methotrexate can cause not only liver toxicity, but also myelosuppression and pancytopenia, which may be acute and life threatening. Nephrotoxicity is a well-recognized side effect of cyclosporine, whereas thrombotic thrombocytopenic purpura, which is associated with high morbidity and mortality, is less well known. Dermatologists should be familiar with these and other severe adverse reactions of the most popular and most used systemic medications of our trade.