Methazolamide

Essential vocal tremor (EVT) is an uncommon but challenging condition to manage. Several medical and interventional treatment options have been reported but efficacy remains unclear. We performed a scoping review of high-quality clinical trials to identify effective evidence-based treatments for EVT.

Scoping review.

Relevant studies were identified using the databases MedLine, Cochrane Central Register of Controlled Trials, and Embase. Subjective and objective outcomes for each modality were analyzed and the effect sizes were quantified using Hedges' g measure to allow comparison between studies.

We identified 421 studies eligible for screening with 11 included in the final analysis. Evidence supporting effective EVT treatments was found for bilateral versus unilateral deep brain stimulation (DBS) (Hedges' g 0.65, 95% CI = 0.10-1.20) and octanoic acid (Hedges' g 1.15, 95% CI = 0.40-1.90). Evidence to support the use of methazolamide was not sufficient (Hedges' g 0.51, 95% CI = -0.64 to 1.66). Botulinum toxin (BT) injections were equivalent when comparing unilateral versus bilateral (Hedges' g -0.18, 95% CI = -1.06 to 0.70); BT did not display any advantage over propranolol (Hedges' g -0.47, 95% CI = -1.73 to 0.78) or injection augmentation (Hedges' g 0.068, 95% CI = -0.98 to 1.12).

Our review finds very little high-quality evidence supporting any treatment for EVT. Octanoic acid reduced fluctuations in EVT but did not affect the perception of the tremor. In refractory cases, bilateral DBS was superior to unilateral DBS in improving subjective voice outcomes. Unilateral and bilateral BT injections were equivalent, and BT injection was not more effective than injection augmentation. Further direct comparison in well-designed prospective studies may help clarify optimal treatment for EVT patients.

Human carbonic anhydrases (hCAs) play a central role in various physiological processes in the human body. HCAs catalyze the reversible hydration of CO₂ into HCO₃^-, and hence maintains the fluid and pH balance. Overexpression of CA II is associated with diseases, such as glaucoma, and epilepsy. Therefore, CAs are important clinical targets and inhibition of different isoforms, especially hCA II is used in treatment of glaucoma, altitude sickness, and epilepsy. Therapeutically used CA inhibitors (CAI) are sulfonamide-based, such as acetazolamide, dichlorphenamide, methazolamide, ethoxzolamide, etc. However, they exhibit several undesirable effects such as numbness, tingling of extremities, malaise, metallic taste, fatigue, renal calculi, and metabolic acidosis. Therefore, there is an urgent need to identify safe and effective inhibitors of the hCAs. In this study, different phenyl boronic acids 1-5 were evaluated against bovine (bCA II) and hCA II. Among all, compound 1 (4-acetylphenyl boronic acid) was found to be active against bCAII and hCA II with IC₅₀ values of 246 ± 0.48 and 281.40 ± 2.8 μM, respectively, while the remaining compounds were found in-active. Compound 1 was identified as competitive inhibitor of hCA II enzyme (K_i = 283.7 ± 0.002 μM). Additionally, compound 1 was found to be non-toxic against BJ Human fibroblast cell line. The X-ray crystal structure for hCA II in-complex with compound 1 was evaluated to a resolution of 2.6 Å. In fact, this the first structural analysis of a phenyl boron-based inhibitor bound to hCA II, allowing an additional structure-activity analysis of the compounds. Compound 1 was found to be directly bound in the active site of hCA II by interacting with His94, His119, and Thr199 residues. In addition, a bond of 3.11 Å between the zinc ion and coordinated boron atom of the boronic acid moiety of compound 1 was also observed, contributing to binding affinity of compound 1 for hCA II. PDB ID: 8IGF.