- "To Be or Not to Be" Protonated: Atomic Details of Human Carbonic Anhydrase-Clinical Drug Complexes by Neutron Crystallography and Simulation. [Journal Article]
- SStructure 2018 Jan 29
- Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug targets for decades. Sequence similarities of hCA isoforms necessitate designing specific inhibitors, which requires d...
Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug targets for decades. Sequence similarities of hCA isoforms necessitate designing specific inhibitors, which requires detailed structural information for hCA-inhibitor complexes. We present room temperature neutron structures of hCA II in complex with three clinical drugs that provide in-depth analysis of drug binding, including protonation states of the inhibitors, hydration water structure, and direct visualization of hydrogen-bonding networks in the enzyme's active site. All sulfonamide inhibitors studied bind to the Zn metal center in the deprotonated, anionic, form. Other chemical groups of the drugs can remain neutral or be protonated when bound to hCA II. MD simulations have shown that flexible functional groups of the inhibitors may alter their conformations at room temperature and occupy different sub-sites. This study offers insights into the design of specific drugs to target cancer-related hCA isoform IX.
- Sulfonamide inhibition studies of two β-carbonic anhydrases from the ascomycete fungus Sordaria macrospora, CAS1 and CAS2. [Journal Article]
- JEJ Enzyme Inhib Med Chem 2018; 33(1):390-396
- The two β-carbonic anhydrases (CAs, EC 220.127.116.11) recently cloned and purified from the ascomycete fungus Sordaria macrospora, CAS1 and CAS2, were investigated for their inhibition with a panel of 39 a...
The two β-carbonic anhydrases (CAs, EC 18.104.22.168) recently cloned and purified from the ascomycete fungus Sordaria macrospora, CAS1 and CAS2, were investigated for their inhibition with a panel of 39 aromatic, heterocyclic, and aliphatic sulfonamides and one sulfamate, many of which are clinically used agents. CAS1 was efficiently inhibited by tosylamide, 3-fluorosulfanilamide, and 3-chlorosulfanilamide (KIs in the range of 43.2-79.6 nM), whereas acetazolamide, methazolamide, topiramate, ethoxzolamide, dorzolamide, and brinzolamide were medium potency inhibitors (KIs in the range of 360-445 nM). CAS2 was less sensitive to sulfonamide inhibitors. The best CAS2 inhibitors were 5-amino-1,3,4-thiadiazole-2-sulfonamide (the deacetylated acetazolamide precursor) and 4-hydroxymethyl-benzenesulfonamide, with KIs in the range of 48.1-92.5 nM. Acetazolamide, dorzolamide, ethoxzolamide, topiramate, sulpiride, indisulam, celecoxib, and sulthiame were medium potency CAS2 inhibitors (KIs of 143-857 nM). Many other sulfonamides showed affinities in the high micromolar range or were ineffective as CAS1/2 inhibitors. Small changes in the structure of the inhibitor led to important differences of the activity. As these enzymes may show applications for the removal of anthropically generated polluting gases, finding modulators of their activity may be crucial for designing environmental-friendly CO2capture processes.
- Evolution of pH buffers and water homeostasis in eukaryotes: homology between humans and Acanthamoeba proteins. [Journal Article]
- FMFuture Microbiol 2018; 13:195-207
- This study intended to trace the evolution of acid-base buffers and water homeostasis in eukaryotes. Acanthamoeba castellanii was selected as a model unicellular eukaryote for this purpose. Homologi...
This study intended to trace the evolution of acid-base buffers and water homeostasis in eukaryotes. Acanthamoeba castellanii was selected as a model unicellular eukaryote for this purpose. Homologies of proteins involved in pH and water regulatory mechanisms at cellular levels were compared between humans and A. castellanii.
- The Efficacy and Safety of the Fixed Combination of Brinzolamide 1% and Brimonidine 0.2% in Normal Tension Glaucoma: An 18-Month Retrospective Study. [Journal Article]
- JOJ Ocul Pharmacol Ther 2018 Jan 03
- CONCLUSIONS: BBFC provides a significant IOP reduction and is a safe antiglaucoma medication for NTG patients.
- Formulation Development and Evaluation of the Therapeutic Efficacy of Brinzolamide Containing Nanoemulsions. [Journal Article]
- IJIran J Pharm Res 2017; 16(3):847-857
- Brinzolamide (BZ) is an intraocular pressure reducing agent with low bioavailability. The purpose of the present study was to overcome this issue by development of BZ containing nanoemulsions (NEs) a...
Brinzolamide (BZ) is an intraocular pressure reducing agent with low bioavailability. The purpose of the present study was to overcome this issue by development of BZ containing nanoemulsions (NEs) as an ocular drug delivery system with desirable therapeutic efficacy. Brinzolamide NEs were prepared by the spontaneous emulsification method. Based on initial release studies, twelve formulations with the slowest release characteristics were subjected to further physicochemical investigations such as particle size, polydispersity index, pH, refractive index, osmolality and viscosity. The therapeutic efficacy of these formulations was assessed by measuring the intraocular pressure after instillation of the prepared NEs in normotensive albino rabbit eyes. Nanoemulsions with suitable physicochemical properties exhibited high formulation stability under different conditions. more over biological evaluations indicated that using lower drug concentrations in NE formulations (0.4%) had a similar or even better pharmacodynamic effect compared to the commercial suspension with a higher drug concentration (1%). Our findings suggest that NEs could be effectively used as carriers for enhancing the bioavailability of topically applied ophthalmic drugs.
- Fabrication And Characterization Of Timolol Maleate And Brinzolamide Loaded Nanostructured Lipid Carrier System For Ocular Drug Delivery. [Journal Article]
- CDCurr Drug Deliv 2017 Nov 29
- CONCLUSIONS: With dextrous optimization of dose and excipients concentration, the dual drugs with different characteristic properties can be successfully loaded in NLC formulation.
- Glaucoma Medication Preferences among Glaucoma Specialists in Mexico. [Journal Article]
- JCJ Curr Glaucoma Pract 2017 Sep-Dec; 11(3):97-100
- CONCLUSIONS: Medication cost and accessibility, as well as posology, remain the main factors influencing brand preferences among glaucoma doctors. In our professional opinion, the therapeutic effect must be the leading factor when prescribing topical medications in the daily practice, so that patients receive the best treatment option.
- Changes in Ocular Hemodynamics after Carotid Artery Angioplasty and Stenting (CAAS) in Patients with Different Severity of Ocular Ischemic Syndrome. [Journal Article]
- CECurr Eye Res 2018; 43(2):266-272
- CONCLUSIONS: CAAS can greatly improve ocular blood in OIS patients with and without iris neovascularization. However, CAAS improved BCVA only in patients without iris neovascularization.
- Iridoplasty of fixed-dilated pupil (Urrets-Zavalia syndrome) after deep anterior lamellar keratoplasty. [Journal Article]
- OJOman J Ophthalmol 2017 Sep-Dec; 10(3):225-227
- A 38-year-old woman with advanced keratoconus initially developed Urrets-Zavalia Syndrome (UZS) in the left eye after deep anterior lamellar keratoplasty. During the uneventful surgery, a 7-mm-wide p...
A 38-year-old woman with advanced keratoconus initially developed Urrets-Zavalia Syndrome (UZS) in the left eye after deep anterior lamellar keratoplasty. During the uneventful surgery, a 7-mm-wide pupil unresponsive to light was noticed. On the first postoperative day, intraocular pressure (IOP) was elevated up to 45 mmHg with shallow anterior chamber (AC). A peripheral iridotomy in 2 o'clock position was conducted and a fixed combination of brinzolamide 1% and timolol 0.5% was administered topically. In the subsequent postoperative period, IOP was successfully reduced, but the patient reported severe photophobia, glare, and decreased vision. Twelve months after surgery, her best-corrected visual acuity (BCVA) was 20/200, the fixed-dilated pupil persisted, iris was atrophic, and lens opacities were detected. She was submitted for phacoemulsification cataract surgery combined with iridoplasty using the closed chamber slipping suture technique. Three months after surgery, her BCVA was 20/25, pupil diameter remained stable at 4 mm, and glare symptoms were significantly reduced. A very adequate cosmetic outcome was also achieved. Iridoplasty in postkeratoplasty patient with unilateral UZS was effective in improving patient's visual function disability and restoring residual anisocoria. This technique can be applied as a single procedure or combined with another one for the management of UZS.
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- The Effect of a Decrease in Intraocular Pressure on Optic Nerve Function in Patients with Optic Nerve Drusen. [Journal Article]
- OROphthalmic Res 2017 Oct 31
- CONCLUSIONS: A decrease in IOP in eyes with ODD results in improvement of retinal ganglion cell function and delays the progression of optic neuropathy. PERG should be performed in patients with ODD as it is a sensitive test for monitoring optic neuropathy.