IDENTIFICATION: Acetazolamide is of synthetic origin. Acetazolamide exists as a white to faintly yellowish-white, odorless crystalline powder. Acetazolamide is very slightly soluble in water and only slightly soluble in ethanol (approx 750 g/l); it is practically insoluble in ether and chloroform. Uses: Preoperative management of closed-angle glaucoma, or as an adjunct in the treatment of open-angle glaucoma. Abnormal retention of fluid: drug-induced edema, obesity, and congestive cardiac failure. Epilepsy Metabolic alkalemia. Periodic paralysis HUMAN EXPOSURE: Patients with either acute or chronic overdosage with acetazolamide may show signs of dehydration with thirst, lethargy, confusion, poor skin turgor, and prolonged capillary refill time, but may have a paradoxical continued diuresis. Electrolyte abnormalities include hyponatremia, hypokalemia, and a non-anion gap hyperchloremic metabolic acidosis in the more than mild ingestion which may lead to further deterioration in mental status, production of seizures, electrocardiographic abnormalities, and arrhythmias. Prior renal insufficiency will lead to increased toxicity at a given dose. There are idiosyncratic reactions producing bone marrow suppression with hepatic and renal insufficiency. Acetazolamide may also precipitate in the renal tubules producing calculi with renal colic. Hypokalemia may lead to muscular weakness, hyporeflexia, and hypochloremic metabolic alkalosis. In geriatric patients, a chronic metabolic acidosis may lead to a chronic compensatory hyperventilation which increases pulmonary vascular resistance and decreases left ventricular function. This can be especially significant in patients on concurrent beta-blocker or calcium channel blocker therapy. The ventricular fibrillation threshold may then be reduced. Cardiac arrhythmias may occur due to potassium deficiency. Abuse or overdose may result in pancreatitis. Hyperglycemia, hyperuricemia, and hyperlipidemia may occur with acute overdose or in chronic use or abuse. Hypersensitivity reactions such as rash, photosensitivity, thrombocytopenia, and pancreatitis are rare. Contraindications: Renal hyperchloremic acidosis. Addison's disease and all types of suprarenal gland failure. Conditions where there is known depletion of sodium and potassium (at least until this is treated). Long-term administration is contraindicated in patients with chronic closed angle-closure glaucoma. Known sensitivity to sulfonamides. Acetazolamide should not be used to alkalinize urine following salicylate overdose since it may worsen metabolic acidosis. Acetazolamide is well absorbed from the gastrointestinal tract. Acetazolamide is distributed throughout body tissues; it concentrates principally in erythrocytes, plasma and kidneys and to a lesser extent in liver, muscles, eyes and the central nervous system. Acetazolamide does not accumulate in tissues. The drug crosses the placenta in unknown quantities. Acetazolamide is tightly bound to carbonic anhydrase and high concentrations are present in tissues containing this enzyme such as erythrocytes and the renal cortex. There is a small amount of irreversible binding to red cells. It is 70 to 90% bound to plasma protein. Acetazolamide is not metabolized. Acetazolamide is excreted unchanged by the kidneys via tubular secretion and passive reabsorption. There is no evidence of enterohepatic circulation although small amounts of unchanged drug are eliminated in the bile. Acetazolamide is a carbonic anhydrase inhibitor. Acetazolamide reduces the formation of hydrogen and bicarbonate ions from carbon dioxide and water by noncompetitive, reversible inhibition of the enzyme carbonic anhydrase, thereby reducing the availability of these ions for active transport into secretions. One patient died of cholestatic jaundice after taking 13 g of acetazolamide in 26 days. In one patient, fatal bone marrow depression with leukopenia, thrombocytopenia, and anemia occurred after therapy with 500 mg of acetazolamide twice daily for 14 weeks. One case of renal failure (anuria) occurred in a patient after taking 500 mg of acetazolamide twice daily for 2 weeks. There have been no reports of congenital defects despite past widespread use though one women on 750 mg per day for glaucoma during the 1st and 2nd trimester had a baby with a sacrococcygeal teratoma but no causal link could be made. Teratogenicity tests in rats and mice showed the absence of fourth and fifth digits from the right forelimb in the offspring of rats and mice. There were no apparent lessions in the newborn of rabbits and monkeys. The drug crosses the placenta in unknown quantities. Potentially hazardous interactions: The effects of folic acid antagonists, oral hypoglycaemic agents and oral anticoagulants may be increased by acetazolamide. The urinary antiseptic effect of methenamine may be prevented by acetazolamide by keeping the urine alkaline. The alkalinization of the urine by acetazolamide can reduce the urinary excretion of many weak bases (including amphetamine, quinine, quinidine, and diethylcarbamazine) and thus enhance their pharmacological effects. In one patient taking phenytoin and acetazolamide drug-induced osteomalacia was reported. The more serious effects include blood disorders, skin toxicity and renal stone formation. Stevens-Johnson syndrome has not been reported. Symptomatic adverse effects: Flushing, thirst, headache, drowsiness, dizziness, fatigue, irritability, excitement, paresthesias, ataxia, hyperpnoa and gastrointestinal disturbances have all been reported (Dollery). Oral ingestion is the usual means of exposure. There is no appreciable dermal absorption. There is no significant absorption or local irritation. ANIMAL/PLANT STUDIES: Numerous animal studies have demonstrated that the toxicity of acetazolamide was very low in the species studied (mouse, dog, rat, monkey).
Carbonic anhydrase inhibitors are avidly bound by carbonic anhydrase and, accordingly, tissues rich in this enzyme will have higher concentrations of carbonic anhydrase inhibitors following systemic administration. /Carbonic Anhydrase Inhibitors/
ACETAZOLAMIDE RELATED TO RESPONSE IN RABBIT; KIDNEY RESPONSE, MEASURED BY MONITORING URINE FLOW & NA ELIMINATION, URINE FLOW & NA ELIMINATION OCCUR IMMEDIATELY AFTER INJECTION CORRELATED WITH LOG DOSE.
IV BOLUS INJECTIONS OF (14)C-LABELED, ACETAZOLAMIDE WERE MADE IN RABBITS. PLASMA, URINE, & WASHED RED BLOOD CELL CONCN WERE MEASURED, THE LATTER INDICATING BOUND DRUG.
SECTION 1: Identification of the substance/mixture and of the company/undertaking Product identifiers Product name : Acetazolamide REACH No. : A registration number is not available for this substance as the substance or its uses are exempted from registration, the annual tonnage does not require a registration or the registration is envisaged for a later registration deadline. CAS-No. : 59-66-5 Relevant identified uses of the substance or mixture and uses advised against Identified uses : Laboratory chemicals, Manufacture of substances SECTION 2: Hazards identification Classification of the substance or mixture Classification according to Regulation (EC) No 1272/2008 Skin irritation (Category 2), H315 Eye irritation (Category 2), H319 For the full text of the H-Statements mentioned in this Section, see Section 16. Classification according to EU Directives 67/548/EEC or 1999/45/EC Xi Irritant R36/38 For the full text of the R-phrases mentioned in this Section, see Section 16. Label elements Labelling according Regulation (EC) No 1272/2008 Pictogram Signal word Warning Hazard statement(s) H315 Causes skin irritation. H319 Causes serious eye irritation. Precautionary statement(s) P305 + P351 + P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. Supplemental Hazard none Statements Other hazards - none SECTION 3: Composition/information on ingredients Substances Chemical characterization : Natural product Synonyms : N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide Formula : C4H6N4O3S2 Molecular Weight : 222,25 g/mol CAS-No. : 59-66-5 EC-No. : 200-440-5 Hazardous ingredients according to Regulation (EC) No 1272/2008 Component Classification Concentration Acetazolamide CAS-No. 59-66-5 Skin Irrit. 2; Eye Irrit. 2; H315, <= 100 % EC-No. 200-440-5 H319 Hazardous ingredients according to Directive 1999/45/EC Component Classification Concentration Acetazolamide CAS-No. 59-66-5 Xi, R36/38 <= 100 % EC-No. 200-440-5 For the full text of the H-Statements and R-Phrases mentioned in this Section, see Section 16 SECTION 4: First aid measures Description of first aid measures General advice Consult a physician. Show this safety data sheet to the doctor in attendance. If inhaled If breathed in, move person into fresh air. If not breathing, give artificial respiration. Consult a physician. In case of skin contact Wash off with soap and plenty of water. Consult a physician. In case of eye contact Rinse thoroughly with plenty of water for at least 15 minutes and consult a physician. If swallowed Never give anything by mouth to an unconscious person. Rinse mouth with water. Consult a physician. Most important symptoms and effects, both acute and delayed The most important known symptoms and effects are described in the labelling (see section 2.2) and/or in section 11 Indication of any immediate medical attention and special treatment needed no data available SECTION 5: Firefighting measures Extinguishing media Suitable extinguishing media Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. Special hazards arising from the substance or mixture Carbon oxides, nitrogen oxides (NOx), Sulphur oxides Advice for firefighters Wear self contained breathing apparatus for fire fighting if necessary. Further information no data available SECTION 6: Accidental release measures Personal precautions, protective equipment and emergency procedures Use personal protective equipment. Avoid dust formation. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Avoid breathing dust. For personal protection see section 8. Environmental precautions Do not let product enter drains. Methods and materials for containment and cleaning up Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. Reference to other sections For disposal see section 13. SECTION 7: Handling and storage Precautions for safe handling Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.Normal measures for preventive fire protection. For precautions see section 2.2. Conditions for safe storage, including any incompatibilities Store in cool place. Keep container tightly closed in a dry and well-ventilated place. Light sensitive. Specific end use(s) A part from the uses mentioned in section 1.2 no other specific uses are stipulated SECTION 8: Exposure controls/personal protection Control parameters Components with workplace control parameters Exposure controls Appropriate engineering controls Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. Personal protective equipment Eye/face protection Safety glasses with side-shields conforming to EN166 Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). Skin protection Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. The selected protective gloves have to satisfy the specifications of EU Directive 89/686/EEC and the standard EN 374 derived from it. Full contact Material: Nitrile rubber Minimum layer thickness: 0,11 mm Break through time: 480 min Material tested:Dermatril® (KCL 740 / Z677272, Size M) Splash contact Material: Nitrile rubber Minimum layer thickness: 0,11 mm Break through time: 480 min Material tested:Dermatril® (KCL 740 / Z677272, Size M) data source: KCL GmbH, D-36124 Eichenzell, phone +49 (0)6659 87300, test method: EN374 If used in solution, or mixed with other substances, and under conditions which differ from EN 374, contact the supplier of the CE approved gloves. This recommendation is advisory only and must be evaluated by an industrial hygienist and safety officer familiar with the specific situation of anticipated use by our customers. It should not be construed as offering an approval for any specific use scenario. Body Protection impervious clothing, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. Respiratory protection For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). Control of environmental exposure Do not let product enter drains. SECTION 9: Physical and chemical properties Information on basic physical and chemical properties a) Appearance Form: powder b) Odour no data available c) Odour Threshold no data available d) pH no data available e) Melting point/freezing Melting point/range: 258 - 259 °C point f) Initial boiling point and no data available boiling range g) Flash point no data available h) Evapouration rate no data available i) Flammability (solid, gas) no data available j) Upper/lower no data available flammability or explosive limits k) Vapour pressure no data available l) Vapour density no data available m) Relative density no data available n) Water solubility no data available o) Partition coefficient: n- no data available octanol/water p) Auto-ignition no data available temperature q) Decomposition no data available temperature r) Viscosity no data available s) Explosive properties no data available t) Oxidizing properties no data available Other safety information no data available SECTION 10: Stability and reactivity Reactivity no data available Chemical stability Stable under recommended storage conditions. Possibility of hazardous reactions no data available Conditions to avoid no data available Incompatible materials Strong oxidizing agents Hazardous decomposition products Other decomposition products - no data available In the event of fire: see section 5 SECTION 11: Toxicological information Information on toxicological effects Acute toxicity LD50 Oral - mouse - 4.300 mg/kg Skin corrosion/irritation no data available Serious eye damage/eye irritation no data available Respiratory or skin sensitisation no data available Germ cell mutagenicity no data available Carcinogenicity IARC: No component of this product present at levels greater than or equal to 0.1% is identified as probable, possible or confirmed human carcinogen by IARC. Reproductive toxicity no data available Specific target organ toxicity - single exposure no data available Specific target organ toxicity - repeated exposure no data available Aspiration hazard no data available Additional Information RTECS: AC8225000 Headache, fatigue, Anorexia., Gastrointestinal disturbance, Drowsiness, To the best of our knowledge, the chemical, physical, and toxicological properties have not been thoroughly investigated. SECTION 12: Ecological information Toxicity no data available Persistence and degradability no data available Bioaccumulative potential no data available Mobility in soil no data available Results of PBT and vPvB assessment PBT/vPvB assessment not available as chemical safety assessment not required/not conducted Other adverse effects no data available SECTION 13: Disposal considerations Waste treatment methods Product Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging Dispose of as unused product. SECTION 14: Transport information UN number ADR/RID: - IMDG: - IATA: - UN proper shipping name ADR/RID: Not dangerous goods IMDG: Not dangerous goods IATA: Not dangerous goods Transport hazard class(es) ADR/RID: - IMDG: - IATA: - Packaging group ADR/RID: - IMDG: - IATA: - Environmental hazards ADR/RID: no IMDG Marine pollutant: no IATA: no Special precautions for user no data available SECTION 15 - REGULATORY INFORMATION N/A
Acetazolamide-based [ 18 F]-PET tracer: In vivo validation of carbonic anhydrase IX as a sole target for imaging of CA-IX expressing hypoxic solid tumors
作者：Kunal N. More、Jun Young Lee、Dong-Yeon Kim、Nam-Chul Cho、Ayoung Pyo、Misun Yun、Hyeon Sik Kim、Hangun Kim、Kwangseok Ko、Jeong-Hoon Park、Dong-Jo Chang
DOI：10.1016/j.bmcl.2018.01.060
日期：2018.3
CarbonicanhydraseIX is overexpressed in many solid tumors including hypoxic tumors and is a potential target for cancer therapy and diagnosis. Reported imaging agents targeting CA-IX are successful mostly in clear cell renal carcinoma as SKRC-52 and no candidate was approved yet in clinical trials for imaging of CA-IX. To validate CA-IX as a valid target for imaging of hypoxic tumor, we designed
A series of saccharide-modified thiadiazole sulfonamide derivatives has been designed and synthesized by the “tail approach” and evaluated for inhibitory activity against carbonic anhydrases II, IX, and XII. Most of the compounds showed high topological polar surface area (TPSA) values and excellent enzyme inhibitory activity. The impacts of some compounds on the viability of HT-29, MDA-MB-231, and MG-63 human cancer cell lines were examined under both normoxic and hypoxic conditions, and they showed certain inhibitory effects on cell viability. Moreover, it was found that the series of compounds had the ability to raise the pH of the tumor cell microenvironment. All the results proved that saccharide-modified thiadiazole sulfonamides have important research prospects for the development of CA IX inhibitors.
DUAL-TARGETED CARBONIC ANHYDRASE IX COMPLEX AND CONTRAST AGENT THEREOF
申请人：Institute of Nuclear Energy Research, Atomic Energy Council, Executive Yuan, R.O.C
公开号：US20210154334A1
公开（公告）日：2021-05-27
Disclosed herein are a dual-targeted carbonic anhydrase IX complex, a contrast agent comprising the same, and a synthesizing method thereof. The dual-targeted carbonic anhydrase IX complex includes a carbonic anhydrase IX (CA9) binding peptide, a sulfonamide derivative, and a metal chelating agent. The dual-targeted carbonic anhydrase IX complex has potential for use as a molecular nuclear drug.
