- The Effects of Acetazolamide on Exercise Performance at Sea Level and in Hypoxic Environments: A Review. [Review]
- WEWilderness Environ Med 2018 Oct 09
- Lowlanders rapidly ascending to high altitude (>2500 m) often develop acute mountain sickness (AMS). While acclimatization is the most effective method of reducing symptoms of AMS (ie, headache, fati...
Lowlanders rapidly ascending to high altitude (>2500 m) often develop acute mountain sickness (AMS). While acclimatization is the most effective method of reducing symptoms of AMS (ie, headache, fatigue, nausea, gastrointestinal distress, etc.), it may take several days to become fully acclimated. Prophylactic use of acetazolamide (AZ), a carbonic anhydrase inhibitor, has become a popular alternative to staged acclimatization because it can be a less time-consuming method of reducing symptoms of AMS. While numerous studies have shown the effectiveness of AZ in mitigating the symptoms of AMS, a review of the existing literature regarding the effects of AZ on submaximal and maximal exercise performance at sea level and at altitude has not been performed.Literature search identified 17 peer reviewed articles examining the effects of AZ on exercise performance both at sea level and at altitude, as well as the associated side effects of prophylactic AZ use for the attenuation of AMS. This review finds that AZ treated cohorts experience a reduction in time to exhaustion during both submaximal and maximal exercise performance at sea level. At altitude, AZ treated cohorts' recorded widely variable submaximal and maximal exercise performance. At sea level, AZ impairs submaximal and maximal exercise performance. Due to the wide variation of findings of previously published studies, the effects of AZ on submaximal and maximal exercise performance at altitude remain unknown.
- Whole-Exome Sequencing Implicates SCN2A in Episodic Ataxia, but Multiple Ion Channel Variants May Contribute to Phenotypic Complexity. [Case Reports]
- IJInt J Mol Sci 2018 Oct 11; 19(10)
- Although the clinical use of targeted gene sequencing-based diagnostics is valuable, whole-exome sequencing has also emerged as a successful diagnostic tool in molecular genetics laboratories worldwi...
Although the clinical use of targeted gene sequencing-based diagnostics is valuable, whole-exome sequencing has also emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. Molecular genetic tests for episodic ataxia type 2 (EA2) usually target only the specific calcium channel gene (CACNA1A) that is known to cause EA2. In cases where no mutations are identified in the CACNA1A gene, it is important to identify the causal gene so that more effective treatment can be prioritized for patients. Here we present a case of a proband with a complex episodic ataxias (EA)/seizure phenotype with an EA-affected father; and an unaffected mother, all negative for CACNA1A gene mutations. The trio was studied by whole-exome sequencing to identify candidate genes responsible for causing the complex EA/seizure phenotype. Three rare or novel variants in Sodium channel α2-subunit; SCN2A (c.3973G>T: p.Val1325Phe), Potassium channel, Kv3.2; KCNC2 (c.1006T>C: p.Ser336Pro) and Sodium channel Nav1.6; SCN8A (c.3421C>A: p.Pro1141Thr) genes were found in the proband. While the SCN2A variant is likely to be causal for episodic ataxia, each variant may potentially contribute to the phenotypes observed in this family. This study highlights that a major challenge of using whole-exome/genome sequencing is the identification of the unique causative mutation that is associated with complex disease.
- 1,2,4-Trisubstituted imidazolinones with dual carbonic anhydrase and p38 mitogen-activated protein kinase inhibitory activity. [Journal Article]
- BCBioorg Chem 2018 Oct 01; 82:109-116
- Various 1,2,4 trisubstituted imidazolin-5-one derivatives were synthesized and evaluated for their inhibitory activity against p38 mitogen-activated protein kinase (p38MAPK) and carbonic anhydrase (C...
Various 1,2,4 trisubstituted imidazolin-5-one derivatives were synthesized and evaluated for their inhibitory activity against p38 mitogen-activated protein kinase (p38MAPK) and carbonic anhydrase (CA) enzymes aiming to explore potential dual inhibitors. Results revealed that compounds 3c, 3g, 3h, 4a, 6c and 6d were the most effective derivatives against p38αMAPK (IC50 = 0.14, 0.14, 0.056, 0.14, 0.13 and 0.14 μM, respectively) compared to sorafenib (IC50 = 1.58 μM) as standard drug. On the other hand, compound 4a revealed the best inhibitory activity against all the tested carbonic anhydrase isoforms CA I, II, IV and IX with Ki values of 95.0, 0.83, 6.90 and 12.4 nM, respectively compared to acetazolamide with Ki values 250, 12.1, 74 and 12.8 nM, respectively. Therefore, compound 4a can be considered as a potent dual p38αMAPK/CA inhibitor.
- Advances in the available non-biological pharmacotherapy prevention and treatment of acute mountain sickness and high altitude cerebral and pulmonary oedema. [Journal Article]
- EOExpert Opin Pharmacother 2018 Oct 11; :1-12
- The physiological responses on exposure to high altitude are relatively well known, but new discoveries are still being made, and novel prevention and treatment strategies may arise. Basic informatio...
The physiological responses on exposure to high altitude are relatively well known, but new discoveries are still being made, and novel prevention and treatment strategies may arise. Basic information has changed little since our previous review in this journal 10 years ago, but considerable more detail on standard therapies, and promising new approaches are now available. Areas covered: Herein, the authors review the role of pharmacological agents in preventing and treating high-altitude illnesses. The authors have drawn on their own experience and that of international experts in this field. The literature search was concluded in March 2018. Expert opinion: Slow ascent remains the primary prevention strategy, with rapid descent for the management of serious altitude illnesses. Pharmacological agents are particularly helpful when rapid ascent cannot be avoided or when rapid descent is not possible. Acetazolamide remains the drug of choice for prophylaxis of acute mountain sickness. However, evidence indicates that reduced dosage schemes compared to the current recommendations are warranted. Calcium channel blockers and phosphodiesterase inhibitors remain the drugs of choice for the management of high-altitude pulmonary edema. Dexamethasone should be reserved for the treatment of more severe cases of altitude illnesses such as cerebral edema.
- Synthesis, carbonic anhydrase inhibitory activity and antioxidant activity of some 1,3-oxazine derivatives. [Journal Article]
- DDDrug Dev Res 2018 Oct 10
- Hit, Lead & Candidate Discovery A series of 1-(6-methyl-2-substituted phenyl-4-thioxo-4H-1,3-oxazin-5-yl)ethanones (3a-n) were synthesized by the reaction of benzoyl isothiocyanates with active methy...
Hit, Lead & Candidate Discovery A series of 1-(6-methyl-2-substituted phenyl-4-thioxo-4H-1,3-oxazin-5-yl)ethanones (3a-n) were synthesized by the reaction of benzoyl isothiocyanates with active methylene compound acetylacetone in the presence of triethyl amine in a one-pot process. The structures of the products were elucidated by elemental analyses, FT-IR, 1 H NMR, 13 C NMR, and mass spectroscopy. These new 1,3-oxazine derivatives were evaluated for their inhibitory activity against carbonic anhydrase II. Results for in vitro assay revealed that compound 3b having 4-methoxy phenyl moiety was the most potent inhibitor with IC50 value of 0.144 ± 0.008 μM. It exhibited higher enzyme inhibitory activity as compared to the standard acetazolamide (IC50 = 0.997 ± 0.061 μM). The compounds 3c, 3h, and 3n also displayed superior inhibitory activities compared to the rest of the synthesized oxazine derivatives. The radical scavenging activity of oxazine derivatives was also performed and it was found that compounds showed moderate antioxidant activity. Lipinski rule confirmed the therapeutic potential of the synthesized compounds. Molecular docking studies were also performed to further understand the binding affinity of these compounds with PDBID 1V9E which confirmed that the synthesized derivatives bind in the active binding site of the target protein. Based upon our results, it is proposed that compound 3b may serve as a lead structure to design more potent carbonic anhydrase inhibitors.
- New daily persistent headache (NDPH) triggered by a single Valsalva event: A case series. [Journal Article]
- CCephalalgia 2018 Oct 09; :333102418806869
- Objective To describe a new subtype of new daily persistent headache that is triggered by a single Valsalva event. Methods A case series of patients was evaluated in an academic headache clinic over ...
Objective To describe a new subtype of new daily persistent headache that is triggered by a single Valsalva event. Methods A case series of patients was evaluated in an academic headache clinic over a 3-year time period. Results A total of seven patients (four female and three male) were diagnosed with this new subtype of new daily persistent headache. The headaches all began after a single Valsalva event. Average age at time of headache onset was 41 years (males: 39 years; females: 43 years) with an age range of 20-62 years. All patients developed their syndrome during the months of September to February with November and February being the most cited months (5/7 patients). Immediate worsening in the Trendelenburg position occurred in all patients and appeared to be an almost diagnostic test for the syndrome. No patient had papilledema on funduscopic exam. Five out of seven patients had no prior headache history including cough, exercise or migraine. Four of seven patients were of normal weight, while one was overweight and two were obese. A crowded posterior fossa was identified in five of seven patients on brain MRI. On cerebrospinal fluid pressure/volume lowering medication (acetazolamide, indomethacin and/or spironolactone), five out of seven patients achieved 90% plus improvement in headache frequency while three patients became pain free. Three patients were able to taper off medication without headache recurrence. Conclusion New daily persistent headache after a single Valsalva event appears to be a unique subtype of new daily persistent headache that is responsive to cerebrospinal fluid pressure/volume lowering medications. An abnormal reset of cerebrospinal fluid pressure/intracranial pressure to an elevated state is the presumed pathogenesis and may relate to the patient's baseline neuroanatomy of a crowded posterior fossa. There appears to be a circadian periodicity to the onset of the syndrome. Worsening in the Trendelenburg position is a probable diagnostic test. Defining new daily persistent headache subtypes by triggering event appears to be making a positive inroad in the understanding of this condition and helps present new effective therapies.
- A Case Report of Intravitreal Bevacizumab for Iris Metastasis of Small Cell Lung Carcinoma with Neovascular Glaucoma. [Journal Article]
- CRCase Rep Ophthalmol 2018 May-Aug; 9(2):401-404
- A 79-year-old man who had been diagnosed with small cell lung carcinoma (SCLC) complained of right ocular pain and blurred vision. His right intraocular pressure (IOP) was 30 mm Hg, and anterior cham...
A 79-year-old man who had been diagnosed with small cell lung carcinoma (SCLC) complained of right ocular pain and blurred vision. His right intraocular pressure (IOP) was 30 mm Hg, and anterior chamber cells and multiple grayish white iris masses associated with peripheral anterior synechia (PAS) and neovascularization of the right iris were observed. We presumed that the iris masses were iris metastasis of SCLC. Despite therapy with topical eye drops and oral acetazolamide, the IOP was poorly controlled, so we injected intravitreal bevacizumab into his right eye for neovascular glaucoma. Neovascular glaucoma disappeared rapidly, but the IOP did not improve because of total PAS. To our knowledge, there is only one report of the use of intravitreal bevacizumab for SCLC metastasis in that eye and they reported that intravitreal injection resulted in successful short-term regression of presumed iris metastasis and improved control of secondary neovascular glaucoma, and the case had over one-half PAS. The previous report and our results suggest that secondary neovascular glaucoma with iris metastasis may be controlled by early intravitreal bevacizumab injection.
- Vancomycin associated acute kidney injury in pediatric patients. [Journal Article]
- PlosPLoS One 2018; 13(10):e0202439
- CONCLUSIONS: Moderate to severe acute kidney injury due to vancomycin is infrequent in children and associated with concomitant medication use and total dose of vancomycin. Serum vancomycin concentrations are not useful predictors of vAKI in the pediatric population.
- Treatment of hypochloremia with acetazolamide in an advanced heart failure patient and importance of monitoring urinary electrolytes. [Journal Article]
- JCJ Cardiol Cases 2018; 17(3):80-84
- Chloride was recently recognized to play an important role in the pathophysiology of heart failure (HF). Chloride manipulation, including the use of acetazolamide, may be a requisite therapeutic targ...
Chloride was recently recognized to play an important role in the pathophysiology of heart failure (HF). Chloride manipulation, including the use of acetazolamide, may be a requisite therapeutic target in HF treatment. An 87-year-old male patient with advanced HF and hypertrophic cardiomyopathy was admitted to the hospital due to hypochloremia (94 mEq/L) and hyponatremia (134 mEq/L) under diuretic treatment with azosemide, spironolactone, and tolvaptan. On admission, HF-related signs of overhydration were lacking, but B-type natriuretic peptide was moderately elevated. The etiology of the hypochloremia/natremia state was depletion of both electrolytes based on serum analysis and spot urinary concentrations. Immediately after admission, acetazolamide (500 mg/d) was prescribed to correct the hypochloremia in parallel with cessation of the preceding administration of azosemide and spironolactone, and tapering off of the tolvaptan over 7 days. Under treatment, both serum chloride and sodium concentrations recovered to normal (108 mEq/L and 148 mEq/L, respectively), and the serum potassium concentration decreased from 3.9 mEq/L to 2.4 mEq/L. Urinary concentrations of sodium and potassium increased from 18 mEq/L to 31 mEq/L and from 19 mEq/L to 51.5 mEq/L respectively, in concordance with the changes in serum concentrations, but the chloride concentration decreased from 18 mEq/L to 12 mEq/L, opposite the changes in the serum concentration. <Learning objective: The present case confirms that the classic drug acetazolamide, although rarely used now for HF treatment, is a potent "chloride-regaining" or "chloride-retaining diuretic" with concomitant activity to reduce serum potassium. Additionally, this case study highlights the importance of monitoring both serum and urinary electrolyte concentrations to determine the electrolyte disturbance and efficacy of diuretic treatment through analytic evaluation of changes in the serum electrolytes and their tubular reabsorption in the kidney.>.
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- Resting-state Functional Magnetic Resonance Imaging Identifies Cerebrovascular Reactivity Impairment in Patients With Arterial Occlusive Diseases: A Pilot Study. [Journal Article]
- NNeurosurgery 2018 Sep 20
- CONCLUSIONS: BOLD TS analysis has potential as a noninvasive alternative to current methods based on CVR for identification of tissue at risk of ischemic stroke.