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

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Mate Gyimesi ◽  
Adam Horvath ◽  
Demeter Turos ◽  
Mate Penzes ◽  
Csilla Kurdi ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Nervous System ◽  
Side Effects ◽  
Hormone Receptors ◽  
Muscle Tone ◽  
Muscle Stiffness ◽  
Oral Drug ◽  
Drug Candidate ◽  
Phase I Clinical Trials ◽  
Cardiovascular Side Effects

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).

Fluoxetine Hydrochloride (Prozac) Toxicity in a Neonate

PEDIATRICS ◽  
1993 ◽  
Vol 92 (5) ◽  
pp. 721-722 ◽  
Author(s):  
MARY J. SPENCER
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Side Effects ◽  
Cord Blood ◽  
Parent Compound ◽  
Total Drug ◽  
Therapeutic Level ◽  
Fluoxetine Hydrochloride ◽  
Cardiovascular Side Effects ◽  
The Central Nervous System

A case of fluoxetine toxicity in a newborn of 38 weeks' gestation has been presented. The total drug concentration in cord blood was 80 ng/mL. The fluoxetine level, 26 ng/mL, is below the adult therapeutic level; the norfluoxetine cord blood level, 54 ng/mL, is at the adult therapeutic level. At 96 hours the fluoxetine level was not measurable and the norfluoxetine level was 55 ng/mL. The parent compound is fluoxetine, which is metabolized in the liver to norfluoxetine. The half-life of fluoxetine is 2 to 3 days, and that of norfluoxetine is 7 to 9 days. Interestingly, in our patient the fluoxetine was absent in the blood at 4 days, but norfluoxetine was present. The most common side effects of Prozac in adult patients involve primarily the central nervous system and include nervousness, tremor, jitteriness, and occasionally seizures. Central nervous system symptoms were most prominent in this newborn. He also had an increased heart rate. Cardiovascular side effects are less prominent in adults who are taking Prozac. The neonate in this case was asymptomatic at 96 hours of age, indicating that the parent compound, fluoxetine, may be the active part of the drug and side effects may be caused by the parent compound.

Cardiovascular side-effects of antipsychotic drugs: The role of the autonomic nervous system

2012 ◽  
Vol 135 (2) ◽  
pp. 113-122 ◽  
Author(s):  
Joanne Y.T. Leung ◽  
Alasdair M. Barr ◽  
Ric M. Procyshyn ◽  
William G. Honer ◽  
Catherine C.Y. Pang
Keyword(s):  
Nervous System ◽  
Autonomic Nervous System ◽  
Side Effects ◽  
Antipsychotic Drugs ◽  
Autonomic Nervous ◽  
Cardiovascular Side Effects

Intramuscular β2-agonist administration enhances early regeneration and functional repair in rat skeletal muscle after myotoxic injury

2008 ◽  
Vol 105 (1) ◽  
pp. 165-172 ◽  
Author(s):  
James G. Ryall ◽  
Jonathan D. Schertzer ◽  
Tammy M. Alabakis ◽  
Stefan M. Gehrig ◽  
David R. Plant ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Side Effects ◽  
Cardiac Hypertrophy ◽  
Muscle Mass ◽  
Intramuscular Injection ◽  
Therapeutic Potential ◽  
Cardiovascular Effects ◽  
Skeletal Muscle Regeneration ◽  
Cardiovascular Side Effects ◽  
The Right

Systemic administration of β2-adrenoceptor agonists (β2-agonists) can improve skeletal muscle regeneration after injury. However, therapeutic application of β2-agonists for muscle injury has been limited by detrimental cardiovascular side effects. Intramuscular administration may obviate some of these side effects. To test this hypothesis, the right extensor digitorum longus (EDL) muscle from rats was injected with bupivacaine hydrochloride to cause complete muscle fiber degeneration. Five days after injury, half of the injured muscles received an intramuscular injection of formoterol (100 μg). Muscle function was assessed at 7, 10, and 14 days after injury. A single intramuscular injection of formoterol increased muscle mass and force-producing capacity at day 7 by 17 and 91%, respectively, but this effect was transient because these values were not different from control levels at day 10. A second intramuscular injection of formoterol at day 7 prolonged the increase in muscle mass and force-producing capacity. Importantly, single or multiple intramuscular injections of formoterol did not elicit cardiac hypertrophy. To characterize any potential cardiovascular effects of intramuscular formoterol administration, we instrumented a separate group of rats with indwelling radio telemeters. Following an intramuscular injection of formoterol, heart rate increased by 18%, whereas systolic and diastolic blood pressure decreased by 31 and 44%, respectively. These results indicate that intramuscular injection can enhance functional muscle recovery after injury without causing cardiac hypertrophy. Therefore, if the transient cardiovascular effects associated with intramuscular formoterol administration can be minimized, this form of treatment may have significant therapeutic potential for muscle-wasting conditions.

scholarly journals Myopathy in Primary Systemic Amyloidosis

1988 ◽  
Vol 15 (3) ◽  
pp. 314-316 ◽  
Author(s):  
M.E. Roke ◽  
W.F.E. Brown ◽  
D. Boughner ◽  
L.C. Ang ◽  
G.P.A. Rice
Keyword(s):  
Skeletal Muscle ◽  
Nervous System ◽  
Blood Vessels ◽  
Peripheral Nervous System ◽  
Basal Lamina ◽  
Cardiac Amyloidosis ◽  
Muscle Fibers ◽  
Muscle Stiffness ◽  
Systemic Amyloidosis

ABSTRACT:Involvement of the peripheral nervous system by amyloidosis is common. It is less well recognized that amyloid can directly infiltrate and weaken skeletal muscle. We report a case of a 73-year-old woman, known to have cardiac amyloidosis, who developed profound weakness secondary to amyloid myopathy. Review of the 8 other well documented cases in the literature has revealed a rather homogeneous syndrome. Proximal weakness, muscle stiffness, pseudohypertrophy and myalgia constitute the principal features. This syndrome usually develops in cases with well recognized generalized amyloidosis. Amyloid is deposited within the basal lamina of blood vessels and muscle fibers.

scholarly journals Cardiooncology—dealing with modern drug treatment, long-term complications, and cancer survivorship

2021 ◽  
Author(s):  
Claudia de Wall ◽  
Johann Bauersachs ◽  
Dominik Berliner
Keyword(s):  
Side Effects ◽  
Checkpoint Inhibitors ◽  
Heart Diseases ◽  
Tumor Therapy ◽  
Treatment Strategies ◽  
Tumor Treatment ◽  
Cardiac Side Effects ◽  
Cardiovascular Side Effects ◽  
Modern Drug

AbstractModern treatment strategies have improved prognosis and survival of patients with malignant diseases. The key components of tumor treatment are conventional chemotherapy, radiotherapy, targeted therapies, and immunotherapy. Cardiovascular side-effects may occur in the early phase of tumor therapy or even decades later. Therefore, knowledge and awareness of acute and long-lasting cardiac side effects of anti-cancer therapies are essential. Cardiotoxicity impairs quality of life and overall survival. The new cardiologic subspecialty ‘cardio-oncology’ deals with the different cardiovascular problems arising from tumor treatment and the relationship between cancer and heart diseases. Early detection and treatment of cardiotoxicity is of crucial importance. A detailed cardiac assessment of patients prior to administration of cardiotoxic agents, during and after treatment should be performed in all patients. The current review focusses on acute and long-term cardiotoxic side effects of classical cytotoxic and selected modern drug treatments such as immune checkpoint inhibitors and discusses strategies for the diagnosis of treatment-related adverse cardiovascular effects in cancer patients.

scholarly journals The electrophysiological effects of cannabidiol on action potentials and transmembrane potassium currents in rabbit and dog cardiac ventricular preparations

2021 ◽  
Author(s):  
Leila Topal ◽  
Muhammad Naveed ◽  
Péter Orvos ◽  
Bence Pászti ◽  
János Prorok ◽  
...  
Keyword(s):  
Side Effects ◽  
Action Potentials ◽  
Oral Intake ◽  
Potassium Currents ◽  
Delayed Rectifier ◽  
Cardiac Repolarization ◽  
Cardiovascular Side Effects ◽  
Channel Inhibition ◽  
Repolarization Reserve ◽  
Electrophysiological Effects

AbstractCannabis use is associated with known cardiovascular side effects such as cardiac arrhythmias or even sudden cardiac death. The mechanisms behind these adverse effects are unknown. The aim of the present work was to study the cellular cardiac electrophysiological effects of cannabidiol (CBD) on action potentials and several transmembrane potassium currents, such as the rapid (IKr) and slow (IKs) delayed rectifier, the transient outward (Ito) and inward rectifier (IK1) potassium currents in rabbit and dog cardiac preparations. CBD increased action potential duration (APD) significantly in both rabbit (from 211.7 ± 11.2. to 224.6 ± 11.4 ms, n = 8) and dog (from 215.2 ± 9.0 to 231.7 ± 4.7 ms, n = 6) ventricular papillary muscle at 5 µM concentration. CBD decreased IKr, IKs and Ito (only in dog) significantly with corresponding estimated EC50 values of 4.9, 3.1 and 5 µM, respectively, without changing IK1. Although the EC50 value of CBD was found to be higher than literary Cmax values after CBD smoking and oral intake, our results raise the possibility that potassium channel inhibition by lengthening cardiac repolarization might have a role in the possible proarrhythmic side effects of cannabinoids in situations where CBD metabolism and/or the repolarization reserve is impaired.

The effect of dry needling of myofascial trigger points on muscle stiffness and motoneuron excitability in healthy subjects

2021 ◽  
pp. 096452842110275
Author(s):  
Carolina Jiménez-Sánchez ◽  
Julio Gómez-Soriano ◽  
Elisabeth Bravo-Esteban ◽  
Orlando Mayoral-del Moral ◽  
Pablo Herrero-Gállego ◽  
...  
Keyword(s):  
Muscle Tone ◽  
Intervention Group ◽  
Trigger Points ◽  
Muscle Stiffness ◽  
Invasive Technique ◽  
Control Group ◽  
Dry Needling ◽  
Myofascial Trigger Points ◽  
Motoneuron Excitability

Background: Myofascial trigger points (MTrPs) are hypersensitive nodules in a taut band (TB) of skeletal muscle. Dry needling (DN) is an invasive technique recommended for the treatment of MTrPs. However, to our knowledge, no studies have investigated the influence of the DN technique on modification of muscle stiffness and neurophysiological properties of MTrPs. Objective: The objective was to examine the effect of DN on muscle stiffness and motoneuron excitability of a latent medial MTrP (nodule and TB) of the soleus muscle in non-injured subjects. Methods: A double-blinded randomised controlled trial of 46 subjects with latent medial MTrPs of the soleus was conducted, in which all received one session of DN. The intervention group (n = 23) were subjected to DN into the MTrP (the nodule), while the control group (n = 23) were subjected to DN into the TB. Assessment was carried out at baseline (pre-test), after the intervention (post-test) and 1 week after the intervention (follow-up). Biomechanical variables (muscle resistive force at 10°/s and 180°/s, muscle extensibility and strength), as measured with an isokinetic dynamometer, and neurophysiological variables (H-reflex), were recorded. Results: There were no statistically significant differences in biomechanical or neurophysiological assessments between groups. Considering the intra-group analysis, subjects in the intervention group exhibited increased maximal isometric voluntary force to ankle plantarflexion (MIVFp) at both post-intervention and follow-up assessment (p < 0.0125; 0.2 < d < 0.5), while no changes were found in the control group. Conclusion: One session of DN targeting latent MTrPs did not change muscle stiffness, muscle extensibility or motoneuron excitability. Further research on subjects with muscle tone disorders should be considered to better address the impact of DN on muscle tone. Trial registration number: NCT02575586 (ClinicalTrials.gov).

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