Home About us Contact
|
Home About us Contact | ||
|
|
||
Anhydrase Inhibitors (anhydrase + inhibitor)
Kinds of Anhydrase Inhibitors Selected AbstractsEFFECT OF CARBONIC ANHYDRASE INHIBITORS ON THE INORGANIC CARBON UPTAKE BY PHYTOPLANKTON NATURAL ASSEMBLAGES,JOURNAL OF PHYCOLOGY, Issue 1 2009Jesús M. Mercado The role of carbonic anhydrase (CA) in inorganic carbon acquisition (dissolved inorganic carbon, DIC) was examined in Alboran Sea phytoplankton assemblages. The study area was characterized by a relatively high variability in nutrient concentration and in abundance and taxonomic composition of phytoplankton. Therefore, the relationship between environmental variability and capacity for using HCO3, via external CA (eCA) was examined. Acetazolamide (AZ, an inhibitor of eCA) inhibited the primary productivity (PP) in 50% of the samples, with inhibition percentages ranging from 13% to 60%. The AZ effect was more prominent in the samples that exhibited PP >1 mg C · m,3 · h,1, indicating that the contribution of eCA to the DIC photosynthetic flux was irrelevant at low PP. The inhibition of primary productivity by AZ was significantly correlated to the abundance of diatoms. However, there was no a relationship between AZ effect and CO2 partial pressure (pCO2) or nutrient concentration, indicating that the variability in the PP percentage supported by eCA was mainly due to differences in taxonomic composition of the phytoplankton assemblages. Ethoxyzolamide (EZ, an inhibitor of both external and internal CA) affected 13 of 14 analyzed samples, with PP inhibition percentages varying from 50% to 95%. The effects of AZ and EZ were partially reversed by doubling DIC concentration. These results imply that CA activity (external and/or internal) was involved in inorganic carbon acquisition in most the samples. However, EZ effect was not correlated with pCO2 or taxonomic composition of the phytoplankton. [source] Carbonic Anhydrase Inhibitors: Inhibition of Human Erythrocyte Isozymes I and II with a Series of Phenolic AcidsCHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2010S. Beyza Öztürk Sar, kaya The inhibitory effects of some phenolic acids on the cytosolic human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes hCA I and hCA II were investigated. Ellagic acid, gallic acid, ferulic acid, caffeic acid, quercetin, p -coumaric acid, p -hydroxybenzoic acid, and syringic acid showed KI values in the range of 99,1061 ,m for hCA I and of 105,758 ,m against hCA II, respectively. Quercetin (for hCA I), p -coumaric acid (for hCA II), and gallic acid (for hCA II) exhibited competitive inhibitory effects with 4-nitrophenyl acetate as substrate. All of the other phenolic acids were found as non-competitive inhibitors with 4-nitrophenylacetate as substrate for hCA I and hCA II. The phenolic acids investigated here showed thus interesting hCA I and hCA II inhibitory effects and might be used as leads for generating enzyme inhibitors possibly targeting other CA isoforms which have not been yet assayed for their interactions with such agents. [source] Carbonic Anhydrase Inhibitors: Inhibition of Cytosolic Carbonic Anhydrase Isozymes II and VII with Simple Aromatic Sulfonamides and Some Azo DyesCHEMICAL BIOLOGY & DRUG DESIGN, Issue 2 2009Fabrizio Carta Several substituted benzenesulfonamides were synthesized by various pathways starting from sulfanilamide. The sulfanilamide diazonium salt was reacted with copper (I) halides, potassium iodide and/or aromatic derivatives, leading to 4-halogeno-, and 4-hydroxy-benzenesulfonamides as well as diazo dyes incorporating sulfamoyl moieties. These sulfonamides were assayed as inhibitors of two physiologically relevant isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), i.e., the cytosolic CA II (ubiquitous), and CA VII (brain-specific enzyme). Good CA inhibitory activity was detected for some of these derivatives, with inhibition constants (Ki) in the range of 17.5,863 nm against CA II; and 30,4200 nm against CA VII. [source] Carbonic Anhydrase Inhibitors: Synthesis and Inhibition of Cytosolic/Tumor-Associated Carbonic Anhydrase Isozymes I, II, IX, and XII with N-Hydroxysulfamides , A New Zinc-Binding Function in the Design of Inhibitors.CHEMINFORM, Issue 36 2005Jean-Yves Winum Abstract For Abstract see ChemInform Abstract in Full Text. [source] Tubular reabsorption and diabetes-induced glomerular hyperfiltrationACTA PHYSIOLOGICA, Issue 1 2010P. Persson Abstract Elevated glomerular filtration rate (GFR) is a common observation in early diabetes mellitus and closely correlates with the progression of diabetic nephropathy. Hyperfiltration has been explained to be the result of a reduced load of sodium and chloride passing macula densa, secondarily to an increased proximal reabsorption of glucose and sodium by the sodium-glucose co-transporters. This results in an inactivation of the tubuloglomerular feedback (TGF), leading to a reduced afferent arteriolar vasoconstriction and subsequently an increase in GFR. This hypothesis has recently been questioned due to the observation that adenosine A1 -receptor knockout mice, previously shown to lack a functional TGF mechanism, still display a pronounced hyperfiltration when diabetes is induced. Leyssac demonstrated in the 1960s (Acta Physiol Scand58, 1963:236) that GFR and proximal reabsorption can work independently of each other. Furthermore, by the use of micropuncture technique a reduced hydrostatic pressure in Bowman's space or in the proximal tubule of diabetic rats has been observed. A reduced pressure in Bowman's space will increase the pressure gradient over the filtration barrier and can contribute to the development of diabetic hyperfiltration. When inhibiting proximal reabsorption with a carbonic anhydrase inhibitor, GFR decreases and proximal tubular pressure increases. Measuring intratubular pressure allows a sufficient time resolution to reveal that net filtration pressure decreases before TGF is activated which highlights the importance of intratubular pressure as a regulator of GFR. Taken together, these results imply that the reduced intratubular pressure observed in diabetes might be crucial for the development of glomerular hyperfiltration. [source] Effects of (,)-carveol and HPMC on the in vitro ocular transport and the in vivo intraocular pressure lowering effects of dorzolamide formulations in normotensive New Zealand rabbitsDRUG DEVELOPMENT RESEARCH, Issue 3 2009Mohsen I. Afouna Abstract The objective of the current study was to maximize the ocular bioavailability of the carbonic anhydrase inhibitor, dorzolamide hydrochloride (DZD) via (a) enhancement of DZD corneal transport using terpene enhancers, (b) reducing pre-corneal loss of the installed dose via increased formulation viscosity, and (c) assessment of the in vivo intraocular pressure (IOP) lowering effects of test formulations using rabbit. DZD was formulated as a 2% ophthalmic solution containing different concentrations of HPMC as a viscosity improving agent (VIA), and (,)-carveol as a corneal penetration enhancer. The transport of DZD from test formulations was quantitatively determined using in vitro diffusion experiments, the permeability parameters were mathematically calculated, and the in vivo IOP lowering effects were assessed using a Tono-Pen XL® tonometer. The results revealed a good correlation between the in vitro permeability parameters and the in vivo ,IOP. The magnitude of the DZD-IOP lowering effects and durations of actions for DZD formulations were dependent on (a) the concentration of (,)-carveol, and (b) the contact period with ocular tissue which was found to be a single-valued function of the HPMC as VIA. Drug Dev Res 70, 2009. © 2009 Wiley-Liss, Inc. [source] Sulthiame in childhood epilepsyPEDIATRICS INTERNATIONAL, Issue 5 2004Bruria Ben-Zeev AbstractBackground:,Sulthiame is a central carbonic anhydrase inhibitor found to be effective for both partial and generalized seizures. It has been in use in some European countries and in Israel for over 30 years. The aim of the present study was to evaluate the efficacy and tolerability of sulthiame in childhood epilepsy by conducting a multicenter, retrospective study of patients who received this drug. Methods:,The charts of 125 consecutive epilepsy patients treated with sulthiame as monotherapy or add-on therapy were reviewed. Results:,Twenty-nine out of 39 patients with benign focal epilepsy of childhood became seizure-free. Total seizure control was also achieved in 17 of 42 patients with symptomatic, non-refractory localization-related epilepsy, and in all 10 cases with juvenile myoclonic epilepsy. Complete normalization of the EEG occurred in 13 of 20 patients with benign partial epilepy of childhood. Side-effects were minimal and caused discontinuation of treatment in only seven children. Conclusion:,The high tolerability, efficacy, convenience of use and low cost suggest that sulthiame should become a first line drug in the benign partial epilepsies of childhood and juvenile myoclonic epilepsy. It also has a role as add-on treatment in other partial and myoclonic epilepsies. [source] Bimatoprost: A Novel Antiglaucoma AgentCARDIOVASCULAR THERAPEUTICS, Issue 2 2004D. F. Woodward ABSTRACT The aim of glaucoma therapy is to preserve vision by reducing intraocular pressure (IOP). Following recent National Eye Institute sponsored studies, it is becoming increasingly apparent that every mmHg of extra IOP lowering counts. Bimatoprost is the newest and most effective addition to the physician's armamentarium of ocular hypotensive drugs. Direct clinical comparisons have demonstrated that it is more efficacious than the prostaglandin (PG) FP receptor agonist prodrugs, latanoprost and travoprost, as well as a ,-adrenoceptor antagonist, timolol, alone or in fixed combination with the carbonic anhydrase inhibitor, dorzolamide. Moreover, patients that are refractory to latanoprost therapy may be successfully treated with bimatoprost. Such evidence provides support, at the clinical level, for the contention that bimatoprost is pharmacologically distinct from PG FP receptor agonist prodrugs. Bimatoprost is a structural analog of PGF2, -ethanolamide (prostamide F2,), which is formed from the endocannabinoid anandamide by a biosynthetic pathway involving cyclooxygenase-2 (COX-2). Their pharmacology is remarkably similar, such that bimatoprost may be regarded as a prostamide mimetic. The target receptor for bimatoprost and the prostamides appears unique and unrelated to PG- and endocannabinoid-sensitive receptors. Extensive ocular distribution/metabolism studies in non-human primates demonstrate that bimatoprost is not a prodrug, it remains essentially intact. Its profound ocular hypotensive effects may, therefore, be attributed to its prostamide-mimetic properties. [source] 3122: Regulation of retinal tissue oxygenationACTA OPHTHALMOLOGICA, Issue 2010CJ POURNARAS Purpose To evaluate the changes in the retinal oxygen partial pressure (PO2) following physiological stimuli. Methods Evaluation of either the preretinal and intraretina partial pressure of oxygen (PO2) distribution, using oxygen sensitive microelectrodes, in various animal models. Measurements were obtained during changes of the perfusion pressure, systemic hyperoxia, hypoxia, hypercapnia, carbogen breathing and following carbonic anydrase inhibitors use. Results The oxygen tension (PO2) in the inner half of the retina remains largely unaffected by moderate changes in perfusion pressure. The increase of the systemic PaO2 through breathing of 100% O2 (hyperoxia) induces endothelin (ET) mediated marked vasoconstriction of the inner retinal arterioles in both anesthetized animals and normal human subjects. The regulatory vasoconstriction maintains the PO2 in retinal tissue constant. A decrease in PaO2 (hypoxia) induces a vasodilation of the retinal arterioles through endothelium-derived NO release. As a result, trans-retinal PO2 profiles made during steps of systemic hypoxia have shown that the values measured in the inner retina up to half of its thickness, remain rather stable. By contrast, the PO2 values, measured close to the choroid and in the outer retina, decrease in a linear manner with the decrease of the PaO2. An increase in the PaCO2 (hypercapnia) of arteriolar blood, produces an increase in retinal blood flow and retinal tissue PO2. Intravenous injection of acetazolamide (carbonic anhydrase inhibitor) produces an increase in preretinal PO2 due to dilation of the retinal vessels Conclusion Thanks to the autoregulatory capability of the retinal circulation, the oxygen tension (PO2) in the inner half of the retina, remains largely unaffected during physiological stimuli. [source] New Glaucoma Medications in the Geriatric Population: Efficacy and SafetyJOURNAL OF AMERICAN GERIATRICS SOCIETY, Issue 5 2002Gary D. Novack PhD Glaucoma can be considered a disease of the aging eye. Most medications used to treat glaucoma are in topical eyedrop form and may cause numerous untoward systemic effects in older persons. In recent years, several new ocular hypotensive medications have become available. These medications are being used more commonly because there is a growing trend by ophthalmologists to aggressively lower intraocular pressure. Therefore, geriatricians require a comprehensive knowledge of medications used to treat glaucoma, in addition to an understanding of their mechanism of action profiles of untoward effects and possible interactions with other diseases or medications. Therefore, we performed a review of the medications recently introduced into clinical practice. We selected drugs approved by the U.S. Food and Drug Administration between 1996 and September 2001. The safety profiles of these agents and their untoward side effects were reviewed by class: topical carbonic anhydrase inhibitors (brinzolamide: ocular tolerance, taste perversion), ,-adrenoceptor antagonists (timolol: bradycardia and bronchospasm), ,-adrenergic agonists (brimonidine: oral dryness, headache, and fatigue), and prostaglandin analogs (latanoprost, bimatoprost, travoprost, and unoprostone isopropyl: ocular hyperemia, iris color changes). The function of this review is to make geriatricians more aware of the efficacy and untoward effects of medications recently introduced into clinical practice. We recommend that geriatricians perform a medication review on all medications their patients use, including eye drops. [source] Cyclodextrin complexes of sulfonamide carbonic anhydrase inhibitors as long-lasting topically acting antiglaucoma agentsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2002Francesca Maestrelli Abstract Complexes of several 1,3,4-thiadiazole-2-sulfonamide derivatives possessing strong carbonic anhydrase (CA) inhibitory properties with ,-cyclodextrin and hydroxypropyl-,-cyclodextrin were obtained and characterized. Although the investigated CA inhibitors possessed very powerful inhibitory properties against the two CA isozymes involved in aqueous humor production within the eye, i.e., CA II and CA IV, these compounds were topically ineffective as intraocular pressure (IOP) lowering agents in normotensive/hypertensive rabbits, due to their very low water solubility. On the contrary, the cyclodextrin,sulfonamide complexes proved to be effective and long-lasting IOP lowering agents in the two animal models of glaucoma mentioned above. © 2002 Wiley-Liss Inc. and the American Pharmaceutical Association J Pharm Sci 91:2211,2219, 2002 [source] Therapeutic applications of glycosidic carbonic anhydrase inhibitorsMEDICINAL RESEARCH REVIEWS, Issue 3 2009Jean-Yves Winum Abstract The zinc enzymes carbonic anhydrases (CAs, EC 4.2.1.1) are very efficient catalysts for the reversible hydration of carbon dioxide to bicarbonate and hence play an important physiological role. In humans, 16 different isozymes have been described, some of them being involved in various pathological disorders. Several of these isozymes are considered as drug targets, and the design of selective inhibitors is a long-standing goal that has captured the attention of researchers for 40 years and has lead to clinical applications against different pathologies such as glaucoma, epilepsy, and cancer. Among the different strategies developed for designing selective CA inhibitors (CAIs), the "sugar approach" has recently emerged as a new attractive and versatile tool. Incorporation of glycosyl moieties in different aromatic/heterocyclic sulfonamide/sulfamides/sulfamates scaffolds has led to the development of numerous and very effective inhibitors of potential clinical value. The clinical use of a highly active carbohydrate-based CA inhibitor, i.e., topiramate, constitutes an interesting demonstration of the validity of this approach. Other carbohydrate-based compounds also demonstrate promising potential for the treatment of ophthalmologic diseases. This review will focus on the development of this emerging sugar-based approach for the development of CAIs. © 2008 Wiley Periodicals, Inc. Med Res Rev, 29, No. 3, 419-435, 2009 [source] Dorzolamide hydrochloride: an antiglaucoma agentACTA CRYSTALLOGRAPHICA SECTION C, Issue 2 2007Balasubramanian Sridhar Dorzolamide hydrochloride [systematic name: (4S)- trans -4-ethylammonio-6-methyl-5,6-dihydro-4H -thieno[2,3- b]thiopyran-2-sulfonamide 7,7-dioxide chloride], C10H17N2O4S2+·Cl,, belongs to a class of drugs called carbonic anhydrase inhibitors. The ethylammonio side chain is in an extended conformation and is protonated at the N atom, which is hydrogen bonded to the Cl, anion. The dihedral angle between the planes of the thiophene ring and the sulfonamide group is 80.7,(1)°. A comparison is made with the dorzolamide bound in human carbonic anhydrase in the solid state. Hydrogen bonding is mediated by Cl, anions, resulting in indirect connectivity between the molecules. [source] 2224: Oxygenation of the human retinaACTA OPHTHALMOLOGICA, Issue 2010E STEFANSSON Purpose Partial pressure of oxygen in the optic nerve and retina is regulated by the intraocular pressure and systemic blood pressure, the resistance in the blood vessels and oxygen consumption of the tissue. The PO2 is autoregulated and moderate changes in intraocular pressure, blood pressure or tissue oxygen consumption do not affect the retinal and optic nerve oxygen tension. Methods If the intraocular pressure is increased above 40 mmHg or the ocular perfusion pressure decreased below 50 mmHg the autoregulation is overwhelmed and the optic nerve becomes hypoxic. The levels of perfusion pressure that lead to optic nerve hypoxia in the laboratory correspond remarkably well to the levels that increase the risk of glaucomatous optic nerve atrophy in human glaucoma patients. Medical intervention can affect optic nerve PO2. Lowering the intraocular pressure tends to increase the optic nerve PO2, even though this effect may be masked by the autoregulation when the optic nerve PO2 and perfusion pressure is in the normal range. Results Carbonic anhydrase inhibitors increase retinal PO2 through a mechanism of vasodilatation and lowering of the intraocular pressure. Carbonic anhydrase inhibition reduces the removal of CO2 from the tissue and the CO2 accumulation induces vasodilatation resulting in increased blood flow and improved oxygen supply. This effect is inhibited by indomethacin but not other cyclo-oxygenase inhibitors. Conclusion Carbonic anhydrase inhibitors increase retinal blood flow and increase oxygen delivery. Glaucoma drugs and glaucoma surgery lower intraocular pressure, increase ocular perfusion pressure and blood flow. Demand of oxygen by retinal cells may be reduced through apoptosis and tissue atrophy, as well as active destruction of tissue by laser photocoagulation. [source] 3121: Oxygen and treatment of ocular ischemic diseasesACTA OPHTHALMOLOGICA, Issue 2010E STEFANSSON Purpose In ischemia, reduced blood flow results in hypoxia. Hypoxic cells make hypoxia inducible factor (HIF), which controls many of the adaptive responses of tissue to ischemia. This includes vasodilatation, production of vascular endothelial factor (VEGF) with neovascularization and leakage, and finally apoptosis and tissue atrophy. Methods If hypoxia is improved this will reduce the production of VEGF and thereby reduce new vessel formation on one hand and vascular leakage and edeam formation on the other. Several methods are available to improve retinal hypoxia, including laser treatment, vitrectomy, vasodilatory drugs such as carbonic anhydrase inhibitors in addition to breathing oxygen. These treatment methods have been studied by many research groups with invasive polarographic electrodes and optical probes as well as noninvasive oxymetry in human patients and animal subjects. Results We will review experimental and clinical studies, which confirm that oxygen tension of the retina is increased following 1. retinal laser treatment 2. Vitrectomy 3. carbonic anhydrase inhibitors Conclusion Oxygen is the natural control of VEGF. VEGF levels in the retina and other ocular tissues are affected by oxygen levels and ischeimc diseases are currently treated with methods that affect oxygen and consequently VEGF. The addition of anti VEGF drugs to oxygen directed treatment such as laser and vitrectomy further influences the oxygen-HIF-VEGF-neovascularization/edema axis in ischemic retinopathies. [source] Impact of medication on ocular blood flowACTA OPHTHALMOLOGICA, Issue 2009L SCHMETTERER Purpose Reduced ocular blood flow appears to play a role in the pathophysiology of glaucoma. Hence, there is considerable interest in drugs that are capable of improving ocular perfusion. Methods A large numer of clinical trials have been performed investigating the ocular hemodynamic effects of topical and systemic medications. Such trials used a variety of different methods to assess ocular blood flow parameters. Results When adminsitered systemically most vasodilators decrease systemic blood pressure thereby reducing ocular perfusion pressure (OPP). Only few classes of drugs have been reported to increase ocular blood flow with no or minimal effect on OPP. Among these carbonic anhydrase inhibitors and endothelin receptor anatgonists show the most prononced ocular vasodilator effects. The ocular hemodynamoic effects of topical medications is generally considered small. Conclusion When drugs are given systemically the effects on OPP have to be considered. In addition, the potentially positive effects on ocular perfusion need to be carefully weighed against the side effects. With topically administered drugs the ocular hemodynamic effects will be generally small, because the drugs reach the posterior pole of the eye in small concentrations only. [source] Glaucoma associated with KProsACTA OPHTHALMOLOGICA, Issue 2009K HILLE Purpose Glaucoma is one of the most serious problems in Keratoprostheses. Already glaucoma is very frequent in patients with severe changes of the ocular surface requiring keratoprosthesis surgery. About 50% of those patients have pre-existing secondary glaucoma. Preoperatively all efforts should be done to detect its presence very early on. In KPro detection of glaucoma with traditional aids is difficult. A rough estimation of the tension by digital palpation will be the only available method. All indirect clues such as the medical history of glaucoma, echographic signs of disc cupping and anterior synechiae and examination of the visual field should be considered. Methods The incidence of postoperative secondary glaucoma vary among the different kinds of prostheses according to the surgery affecting the anterior segment and the long term anatomic results. In Osteo-Odonto-Keratoprostheses (OOKP) the most vision threatening complication is a primary or secondary glaucoma, due to the extended interventions required in the anterior segment. In Boston Keratoprostheses the risk seems to be somehow less. Results As the absorption of topical anti-glaucomatous medication will not reach the inner eye because of the anatomic barrier in KPro the only promising possibilities of treatment are systemic carbonic anhydrase inhibitors, different kinds of aqueous shunts and endo-cyclo-laserphotocoagulation. Conclusion Glaucoma is still a mayor problem in KPro. PS: This lession will be presented at the KPro-Meeting!! [source] | ||||||||||||||||