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Journal of Neuromuscular Diseases 2024The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1...
BACKGROUND
The nondystrophic myotonias are rare muscle hyperexcitability disorders caused by gain-of-function mutations in the SCN4A gene or loss-of-function mutations in the CLCN1 gene. Clinically, they are characterized by myotonia, defined as delayed muscle relaxation after voluntary contraction, which leads to symptoms of muscle stiffness, pain, fatigue, and weakness. Diagnosis is based on history and examination findings, the presence of electrical myotonia on electromyography, and genetic confirmation.
METHODS
Next-generation sequencing including the CLCN1 and SCN4A genes was performed in patients with clinical neuromuscular disorders. Electromyography, Short Exercise Test, in vivo and in vitro electrophysiology, site-directed mutagenesis and heterologous expression were collected.
RESULTS
A heterozygous point mutation (c.1775C > T, p.Thr592Ile) of muscle voltage-gated sodium channel α subunit gene (SCN4A) has been identified in five female patients over three generations, in a family with non-dystrophic myotonia. The muscle stiffness and myotonia involve mainly the face and hands, but also affect walking and running, appearing early after birth and presenting a clear cold sensitivity. Very hot temperatures, menstruation and pregnancy also exacerbate the symptoms; muscle pain and a warm-up phenomenon are variable features. Neither paralytic attacks nor post-exercise weakness has been reported. Muscle hypertrophy with cramp-like pain and increased stiffness developed during pregnancy. The symptoms were controlled with both mexiletine and acetazolamide. The Short Exercise Test after muscle cooling revealed two different patterns, with moderate absolute changes of compound muscle action potential amplitude.
CONCLUSIONS
The p.Thr592Ile mutation in the SCN4A gene identified in this Sardinian family was responsible of clinical phenotype of myotonia.
Topics: Adult; Female; Humans; Middle Aged; Electromyography; Italy; Myotonia; Myotonia Congenita; NAV1.4 Voltage-Gated Sodium Channel; Pedigree; Point Mutation
PubMed: 38427496
DOI: 10.3233/JND-230134 -
World Neurosurgery May 2024Ischemic stroke significantly contributes to high mortality and disability rates. Cerebral edema is a common consequence of ischemic stroke and can lead to aggravation... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Ischemic stroke significantly contributes to high mortality and disability rates. Cerebral edema is a common consequence of ischemic stroke and can lead to aggravation or even death. Current treatment strategies are limited to decompressive craniectomy and the intravascular administration of hypertonic drugs, which have significant side effects. Acetazolamide (ACZ) plays a therapeutic role in cerebral edema by inhibiting aquaporin-4 (AQP-4) and improving collateral circulation. This study aimed to perform a meta-analysis and systematic review of ACZ therapy for ischemic stroke and evaluate its efficacy in animal models.
METHODS
We searched Embase, Cochrane Library, PubMed, Web of Science, Chinese National Knowledge Infrastructure, Wanfang Database, and Chinese Biomedical Literature Database until April 2023 for studies on ACZ in ischemic animal models. The quality of the animal trials was assessed using the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Stroke.
RESULTS
After screening 376 articles, only 5 studies were included. We found that ACZ reduced brain edema in cerebral ischemia 24 hours after onset (standard mean difference, -2.00; 95% confidence interval, -3.57 to -0.43, P = 0.01). ACZ also inhibited AQP-4 expression 24 hours after onset (standard mean difference-1.46; 95% confidence interval, -2.01 to -0.91, P < 0.001). Brain edema and AQP-4 expression also showed a declining trend on the third day after onset, although there were not enough data to support this. The effect of ACZ on brain ischemia in animals' neurological function is uncertain because of the limited research data.
CONCLUSIONS
ACZ inhibited AQP-4 and alleviated brain edema after ischemic stroke in the early stages but seemingly could not improve the neurological function.
Topics: Acetazolamide; Ischemic Stroke; Animals; Brain Edema; Humans; Treatment Outcome; Aquaporin 4; Carbonic Anhydrase Inhibitors; Disease Models, Animal
PubMed: 38423457
DOI: 10.1016/j.wneu.2024.02.123 -
Neuro-oncology Advances 2024A significant unmet need exists for the treatment of glioblastoma, wildtype (GBM). Preclinical work shows that acetazolamide sensitizes GBM to temozolomide (TMZ) by...
BACKGROUND
A significant unmet need exists for the treatment of glioblastoma, wildtype (GBM). Preclinical work shows that acetazolamide sensitizes GBM to temozolomide (TMZ) by overcoming TMZ resistance due to BCL-3-dependent upregulation of carbonic anhydrase. Acetazolamide is Food and Drug Administration-approved for the treatment of altitude sickness. Drug repurposing enables the application of drugs to diseases beyond initial indications. This multi-institutional, open-label, phase I trial examined a combination of acetazolamide and TMZ in patients with promoter-methylated high-grade glioma.
METHODS
A total of 24 patients (GBM, -wildtype = 22; Grade 4 astrocytoma, -mutant = 1; Grade 3 astrocytoma, -mutant = 1) were accrued over 17 months. All patients received oral acetazolamide (250 mg BID for 7 days increased to 500 mg BID for Days 8-21 of each 28-day cycle) during the adjuvant phase of TMZ for up to 6 cycles.
RESULTS
No patient had a dose-limiting toxicity. Adverse events were consistent with known sequelae of acetazolamide and TMZ. In the 23 WHO Grade 4 patients, the median overall survival (OS) was 30.1 months and the median progression-free survival was 16.0 months. The 2-year OS was 60.9%. In total 37% of the study population had high BCL-3 staining and trended toward shorter OS (17.2 months vs N.R., = .06).
CONCLUSIONS
The addition of acetazolamide is safe and tolerable in GBM patients receiving standard TMZ. Survival results compare favorably to historical data from randomized trials in patients with promotermethylated GBM and support examination of acetazolamide in a randomized trial. BCL-3 expression is a potential biomarker for prognosis in GBM or for patients more likely to benefit from TMZ.
PubMed: 38420615
DOI: 10.1093/noajnl/vdae014 -
Neurologia I Neurochirurgia Polska 2024Spontaneous CSF leak is a known complication of idiopathic intracranial hypertension (IIH). Patients with CSF rhinorrhea present a unique challenge within the IIH... (Review)
Review
INTRODUCTION
Spontaneous CSF leak is a known complication of idiopathic intracranial hypertension (IIH). Patients with CSF rhinorrhea present a unique challenge within the IIH population, as the occurrence of a leak can mask the typical IIH symptoms and signs, complicating the diagnosis. Treatment of leaks in this population can also be challenging, with the risk of rhinorrhea recurrence if intracranial hypertension is not adequately treated.
OBJECTIVE
The aim of this narrative review was to examine current literature on the association between spontaneous CSF rhinorrhea leaks and IIH, focusing on key clinical features, diagnostic approaches, management strategies, and outcomes.
MATERIAL AND METHODS
A literature search was executed using the PubMed and Scopus databases. The search was confined to articles published between January 1985 and August 2023; extracted data was then analysed to form the foundation of the narrative review.
RESULTS
This search yielded 26 articles, comprising 943 patients. Average age was 46.8 ± 6.5 years, and average body mass index was 35.8 ± 4.8. Most of the patients were female (74.33%). Presenting symptoms were rhinorrhea, headaches and meningitis. The most common imaging findings were empty sella and encephalocele. The standard treatment approach was endoscopic endonasal approach for correction of CSF rhinorrhea leak, and shunt placement was also performed in 128 (13%) patients. Recurrences were observed in 10% of cases.
CONCLUSIONS
The complex relationship between spontaneous CSF leaks and IIH is a challenge that benefits from multidisciplinary evaluation and management for successful treatment. Treatments such as endoscopic repair, acetazolamide, and VP/ /LP shunts reduce complications and recurrence. Personalised plans addressing elevated intracranial pressure are crucial for successful outcomes.
Topics: Humans; Female; Adult; Middle Aged; Male; Pseudotumor Cerebri; Cerebrospinal Fluid Rhinorrhea; Intracranial Hypertension; Acetazolamide; Endoscopy; Cerebrospinal Fluid Leak; Retrospective Studies
PubMed: 38393958
DOI: 10.5603/pjnns.98054 -
Annals of Medicine and Surgery (2012) Feb 2024Sodium channel myotonia (SCM) belongs to the group of sodium channelopathies with mutations involving gene. The main feature of sodium channel myotonia is pure myotonia...
INTRODUCTION AND IMPORTANCE
Sodium channel myotonia (SCM) belongs to the group of sodium channelopathies with mutations involving gene. The main feature of sodium channel myotonia is pure myotonia without episodes of weakness or paralysis. One of the sodium channel myotonia has been classified as acetazolamide-responsive myotonia because of the effectiveness of acetazolamide as an antimyotonic drug.
CASE PRESENTATION
The child presented with generalized muscle hypertrophy and stiffness involving arms, thighs, calves, chest, and back muscles with unusually prominent trapezius muscle. The parents described the warm-up phenomenon as an improvement in stiffness as the day passes and with repetitive action. Percussion myotonia was illustrated in the thenar eminence and trapezius muscle. Characteristic 'dive-bomber' sound was present in electromyography, and whole-exome sequencing revealed a novel Ile239Thr mutation in the gene. Acetazolamide was prescribed for the condition, and regular follow-up shows an excellent clinical response.
CLINICAL DISCUSSION
This case presents a pure myotonic phenotype without episodes of weakness or paralysis. Generalized myotonia with muscle hypertrophy and demonstrating warm-up phenomenon resembles myotonia congenita (a chloride channelopathy). However, genetic analysis revealed a novel Ile239Thr mutation involving gene indicating this case to be a sodium channelopathy.
CONCLUSION
This case limelight sodium channel myotonia with a novel Ile239Thr mutation in gene that phenotypically resembles myotonia congenita but genetically belongs to sodium channelopathy highlighting the poor correlation between genotypes and phenotypes in non-dystrophic myotonia. Acetazolamide can be a safe and cost-effective antimyotonic drug in sodium channel myotonia.
PubMed: 38333241
DOI: 10.1097/MS9.0000000000001673 -
Saudi Pharmaceutical Journal : SPJ :... Mar 2024In order to obtain topical and non-irritating anti-glaucoma drugs, novel semicarbazide-containing sulfonamide derivatives were designed and synthetized by sugar tail...
In order to obtain topical and non-irritating anti-glaucoma drugs, novel semicarbazide-containing sulfonamide derivatives were designed and synthetized by sugar tail method in this study. The hydrophilic monosaccharides were expected to form interaction with the hydrophilic site of hCA II meanwhile the linker semicarbazides are used to further enhance water solubility, and more importantly, regulate the pH values of the target compounds in aqueous solution. First, all target compounds were synthesized and evaluated for their CA inhibitory activities. The results showed our target compounds demonstrated comparable activity to the positive control drug acetazolamide. The best derivative exhibits an IC value of 14 nM for hCA II and 2086-fold selectivity over CA I. Subsequently, physicochemical properties study showed that the target compounds displayed very good water solubility (up to 3 %) and neutral pH value in solutions. Meanwhile, the artificial membrane permeability assay was performed to verify that the target compound could also pass through the membrane structure despite their strong water solubility. In the glaucomatous rabbit eye model, the applied topically representative compounds showed strongly lowered intraocular pressure (IOP), as 1 % or 2 % water solutions. Subsequent drug-like evaluation showed our target compounds possessed low hemolysis effect and low cytotoxicity toward human corneal epithelial cell line. Also, it was not found that these target compounds had significant inhibition of hERG and CYP. In addition, these novel analogs also displayed good liver microsomal metabolic stability and plasma stability. Finally, docking studies provided the rational binding modes of representative compounds in complex with hCA II. Taken together, these results suggested that compound may be a promising hCA II inhibitor deserving further development.
PubMed: 38328793
DOI: 10.1016/j.jsps.2024.101969 -
Steroids May 2024This investigation delves into the inhibitory capabilities of a specific set of triterpenoic acids on diverse isoforms of human carbonic anhydrase (hCA). Oleanolic acid...
This investigation delves into the inhibitory capabilities of a specific set of triterpenoic acids on diverse isoforms of human carbonic anhydrase (hCA). Oleanolic acid (1), maslinic acid (2), betulinic acid (3), platanic acid (4), and asiatic acid (5) were chosen as representative triterpenoids for evaluation. The synthesis involved acetylation of parent triterpenoic acids 1-5, followed by sequential reactions with oxalyl chloride and benzylamine, de-acetylation of the amides, and subsequent treatment with sodium hydride and sulfamoyl chloride, leading to the formation of final compounds 21-25. Inhibition assays against hCAs I, II, VA, and IX demonstrated noteworthy outcomes. A derivative of betulinic acid, compound 23, exhibited a K value of 88.1 nM for hCA VA, and a derivative of asiatic acid, compound 25, displayed an even lower K value of 36.2 nM for the same isoform. Notably, the latter compound displayed enhanced inhibitory activity against hCA VA when compared to the benchmark compound acetazolamide (AAZ), which had a K value of 63.0 nM. Thus, this compound surpasses the inhibitory potency and isoform selectivity of the standard compound acetazolamide (AAZ). In conclusion, the research offers insights into the inhibitory potential of selected triterpenoic acids across diverse hCA isoforms, emphasizing the pivotal role of structural attributes in determining isoform-specific inhibitory activity. The identification of compound 25 as a robust and selective hCA VA inhibitor prompts further exploration of its therapeutic applications.
Topics: Humans; Acetazolamide; Betulinic Acid; Carbonic Anhydrase I; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Molecular Structure; Oleanolic Acid; Pentacyclic Triterpenes; Protein Isoforms; Structure-Activity Relationship
PubMed: 38325751
DOI: 10.1016/j.steroids.2024.109381 -
Cureus Feb 2024Idiopathic intracranial hypertension (IIH) and multiple sclerosis (MS) are rare neurological disorders that largely affect females within the reproductive age group....
Idiopathic intracranial hypertension (IIH) and multiple sclerosis (MS) are rare neurological disorders that largely affect females within the reproductive age group. The clinical pictures of both diseases can overlap, which therefore places great importance on accurately studying and reporting their concurrence. Therein, we report a case of IIH presenting and progressing simultaneously with MS. This young, previously healthy female presented with the primary complaint of a severe right-sided headache associated with blurred vision and a finding of papilledema. The initial investigations including a lumbar puncture (LP) that revealed high opening pressure (more than 25 mm HO) with normal cerebrospinal fluid (CSF) analysis led to an impression of idiopathic intracranial hypertension, and she was treated accordingly with acetazolamide and scheduled for regular follow-ups with both neurology and neuro-ophthalmology. However, about two months after the initial presentation, she complained of unusual headaches, and a neuro-ophthalmology clinical evaluation revealed complete right homonymous hemianopia, suggesting a lesion in the left temporo-parietal occipital region. The patient was thus admitted as a case of cerebral edema following an urgent brain magnetic resonance imaging (MRI). After obtaining thorough imaging and workup, the patient was given steroids and markedly improved, favoring a diagnosis of tumefactive MS with IIH.
PubMed: 38314385
DOI: 10.7759/cureus.53374 -
Cureus Jan 2024Although ocular complications following COVID-19 vaccination have been reported, particularly retinal vascular occlusion and uveitis, their definitive causal...
Although ocular complications following COVID-19 vaccination have been reported, particularly retinal vascular occlusion and uveitis, their definitive causal relationships remain uncertain. This report presents a case of central retinal artery occlusion (CRAO) with paracentral acute middle maculopathy (PAMM) developed one day after receiving Pfizer COVID-19 vaccine, with a favorable outcome. The patient experienced sudden vision loss in her left eye, and her vision dropped to hand motion the day after vaccination. The initial examination suggested CRAO, but optical coherence tomography (OCT) revealed PAMM. We administered intravenous d-mannitol and acetazolamide and performed ocular massage. Two days later, her corrected visual acuity improved to 0.4, and further improvement to 1.2 occurred after 16 days. To the best of our knowledge, no reports have documented CRAO with PAMM following mRNA COVID-19 vaccination. The relationship between COVID-19 vaccination and retinal vascular occlusion remains unknown, highlighting the need for further research.
PubMed: 38304677
DOI: 10.7759/cureus.51501 -
Current Heart Failure Reports Apr 2024Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in... (Review)
Review
PURPOSE OF REVIEW
Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and current trial evidence for different diuretic strategies and explore potential future directions of research.
RECENT FINDINGS
We will assess recent trials, including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high-dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.
Topics: Humans; Heart Failure; Sodium Potassium Chloride Symporter Inhibitors; Quality of Life; Diuretics; Hospitalization
PubMed: 38300391
DOI: 10.1007/s11897-024-00644-2