Amikacin's structure has been altered to reduce the possible route of enzymatic deactivation, thus reducing bacterial resistance. Many strains of Gram-negative organisms resistant to gentamicin and tobramycin have shown to be sensitive to amikacin in vitro.
IDENTIFICATION AND USE: Amikacin is an aminoglycoside anti-bacterial agent. Amikacin is used for the short-term treatment of serious infections caused by susceptible gram-negative bacteria. HUMAN EXPOSURE AND TOXICITY: Elevation of serum creatinine, albuminuria, presence of red and white cells, casts, azotemia, and oliguria have been reported. Renal function changes are usually reversible when the drug is discontinued. Reports of toxic nephropathy and acute renal failure have been received during postmarketing surveillance. Toxic effects on the eighth cranial nerve can result in hearing loss, loss of balance, or both. Amikacin primarily affects auditory function. Cochlear damage includes high frequency deafness and usually occurs before clinical hearing loss can be detected. Acute muscular paralysis and apnea can occur following treatment with aminoglycoside drugs. Aminoglycosides can cause fetal harm when administered to a pregnant woman. ANIMAL STUDIES: The cochleotoxic effects of aminoglycosides, such as amikacin, are well-established. Reduced cochlear activity compared to the pre-treatment state was described in rabbits treated with i.m. amikacin. Long term studies in animals to evaluate carcinogenic potential have not been performed, and mutagenicity has not been studied. In zebrafish, amikacin induced embryonic toxicity and reduced survival rate. Amikacin administered subcutaneously to rats did not impair male or female fertility.
Intravenous and intramuscular therapy with amikacin has not been linked to serum alkaline phosphatase or aminotransferase elevations, and no convincing cases of symptomatic or icteric hepatotoxicity due to amikacin have been published. Other aminoglycosides have been linked to very rare cases of cholestatic hepatitis, that typically arise within 1 to 3 weeks of starting therapy, often associated with skin rash, fever and sometimes eosinophilia. Recovery typically occurs within 1 to 2 months and chronic injury has not been described. Amikacin as well as other aminoglycosides are not mentioned in large case series of drug induced liver disease and acute liver failure; thus, hepatic injury due to amikacin is very rare if it occurs at all.
Rapidly absorbed after intramuscular administration. Rapid absorption occurs from the peritoneum and pleura. Poor oral and topical absorption. Poorly absorbed from bladder irrigations and intrathecal administration. The bioavailability of this drug is expected to vary primarily from individual differences in nebulizer efficiency and airway pathology. Following IM administration of a single dose of amikacin of 7.5 mg/kg in adults with normal renal function, peak plasma amikacin concentrations of 17-25 micrograms/mL are attained within 45 minutes to 2 hours. Following IV infusion of the same dose given over 1 hour peak plasma concentrations of the drug average 38 micrograms/mL immediately following the infusion, 5.5 micrograms/mL at 4 hours, and 1.3 micrograms/mL at 8 hours.
This drug is eliminated by the kidneys. In adults with normal renal function, 94-98% of a single IM or IV dose of amikacin is excreted unchanged by glomerular filtration in the kidney within 24 hours. Amikacin can be completely recovered within approximately 10-20 days in patients with normal, healthy renal function. In patients with impaired renal function, the clearance of amikacin is found to be decreased; the more severe the impairment, the slower the clearance. The interval between doses of amikacin should be adjusted according to the level of renal impairment. Endogenous creatinine clearance rate and serum creatinine which have a high correlation with serum half-life of amikacin, may be used as a guide for dosing.
24 L (28% of body weight healthy adult subjects). Following administration of usual dosages of amikacin, amikacin has been found in bone, heart, gallbladder, and lung tissue. Amikacin is also distributed into bile, sputum, bronchial secretions, and interstitial, pleural, and synovial fluids.
来源:DrugBank
吸收、分配和排泄
清除
在肾功能正常的研究对象中，平均血清清除率约为100毫升/分钟，而肾清除率为94毫升/分钟。
The mean serum clearance rate is about 100 mL/min and the renal clearance rate is 94 mL/min in subjects with normal renal function.
Emergence of a multiply drug resistant Enterobacter cloacae during a seven-week period in 1980 caused amikacin to become the aminoglycoside of choice in the initial management of suspected sepsis in a neonatal intensive care unit. Recommended doses (7.5-10 mg/kg loading; 15 mg/kg in two divided doses IV) were given to 5 infants < or = 1,000 gm and to 13 larger babies. Trough levels 11.5 hours after a dose were 16.6 +/- 11.9 ug/mL in infants < or = 1,000 gm and 6.5 +/- 4.3 ug/mL in the larger infants (P < 0.02). Peak levels one hour postinfusion exceeded 40 ug/mL in 3 of 5 < or = 1,000-gm babies and 4 of 12 > 1,000-gm infants (P = NS). Overall, 7 of 10 peak and/or trough levels in < or = 1,000-gm infants were in the range considered toxic in adults, versus 7 of 24 in larger babies (P = 0.03). These data show that ... excessive blood levels of amikacin are likely in infants < or = 1,000 gm and may also occur in larger infants using currently recommended dosage schedules. These ... findings emphasize the need to monitor drug levels and individualize therapy in very low birthweight infants.
Section 1. Chemical Product and Company Identification Amikacin Common Name/ Trade Name Amikacin Section 4. First Aid Measures Eye Contact Check for and remove any contact lenses. In case of contact, immediately flush eyes with plenty of water for at least 15 minutes. Get medical attention if irritation occurs. Skin Contact Wash with soap and water. Cover the irritated skin with an emollient. Get medical attention if irritation develops. Serious Skin Contact Not available. Inhalation If inhaled, remove to fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical attention. Serious Inhalation Not available. Ingestion Do NOT induce vomiting unless directed to do so by medical personnel. Never give anything by mouth to an unconscious person. Loosen tight clothing such as a collar, tie, belt or waistband. Get medical attention if symptoms appear. Serious Ingestion Not available. Section 5. Fire and Explosion Data Flammability of the Product May be combustible at high temperature. Auto-Ignition Temperature Not available. Flash Points Not available. Flammable Limits Not available. Products of Combustion These products are carbon oxides (CO, CO2). Fire Hazards in Presence of Slightly flammable to flammable in presence of heat. Various Substances Non-flammable in presence of shocks. Explosion Hazards in Presence Slightly explosive in presence of open flames and sparks. Non-explosive in presence of shocks. of Various Substances SMALL FIRE: Use DRY chemical powder. Fire Fighting Media and Instructions LARGE FIRE: Use water spray, fog or foam. Do not use water jet. As with most organic solids, fire is possible at elevated temperatures Special Remarks on Fire Hazards Special Remarks on Explosion Fine dust dispersed in air in sufficient concentrations, and in the presences of an ignition source is a potential dust Hazards explosion hazard. Section 6. Accidental Release Measures Small Spill Use appropriate tools to put the spilled solid in a convenient waste disposal container. Finish cleaning by spreading water on the contaminated surface and dispose of according to local and regional authority requirements. Large Spill Use a shovel to put the material into a convenient waste disposal container. Finish cleaning by spreading water on the contaminated surface and allow to evacuate through the sanitary system. Amikacin Section 7. Handling and Storage Precautions Keep away from heat. Keep away from sources of ignition. Do not ingest. Do not breathe dust. If ingested, seek medical advice immediately and show the container or the label. Storage Keep container tightly closed. Keep container in a cool, well-ventilated area. Section 8. Exposure Controls/Personal Protection Engineering Controls Use process enclosures, local exhaust ventilation, or other engineering controls to keep airborne levels below recommended exposure limits. If user operations generate dust, fume or mist, use ventilation to keep exposure to airborne contaminants below the exposure limit. Personal Protection Safety glasses. Lab coat. Dust respirator. Be sure to use an approved/certified respirator or equivalent. Gloves. Personal Protection in Case of Splash goggles. Full suit. Dust respirator. Boots. Gloves. A self contained breathing apparatus should be used a Large Spill to avoid inhalation of the product. Suggested protective clothing might not be sufficient; consult a specialist BEFORE handling this product. Exposure Limits Not available. Section 9. Physical and Chemical Properties Physical state and appearance Solid. (Powdered solid.) Odor Not available. Taste Not available. Molecular Weight 585.6 g/mole Color White. pH (1% soln/water) Not available. Boiling Point Not available. Melting Point 214°C (417.2°F) Critical Temperature Not available. Not available. Specific Gravity Vapor Pressure Not applicable. Vapor Density Not available. Volatility Not available. Odor Threshold Not available. Not available. Water/Oil Dist. Coeff. Ionicity (in Water) Not available. Not available. Dispersion Properties Solubility Not available. Section 10. Stability and Reactivity Data Stability The product is stable. Not available. Instability Temperature Conditions of Instability Excess heat, dust generation, incompatible materials Incompatibility with various Reactive with oxidizing agents. substances Corrosivity Not available. Amikacin Special Remarks on Not available. Reactivity Special Remarks on Not available. Corrosivity Polymerization Will not occur. Section 11. Toxicological Information Routes of Entry Inhalation. Ingestion. Toxicity to Animals Acute oral toxicity (LD50): >6000 mg/kg [Mouse]. Chronic Effects on Humans May cause damage to the following organs: kidneys, ears. Other Toxic Effects on Slightly hazardous in case of skin contact (irritant), of ingestion, of inhalation. Humans Special Remarks on Not available. Toxicity to Animals Special Remarks on May cause adverse reproductive effects and birth defects (teratogenic) Chronic Effects on Humans Special Remarks on other Acute Potential Health Effects: Toxic Effects on Humans Skin: May cause skin irritation. Eyes: May cause eye irritation. Inhalation: May cause respiratory tract irritation. Ingestion: May cause irritation of the digestive tract. May affect the nervous system (flaccid paralysis without anesthesia). Chronic Potential Health Effects: Ingestion: Prologned or repeated ingestion may cause kidney damage, and may affect the blood, and metabolism (weight loss), hearing (nerve deafness, change in cochlear structure or function). Aminoglycosides are associated with significant nephrotoxicity and/or ototoxicity. Section 12. Ecological Information Ecotoxicity Not available. Not available. BOD5 and COD Possibly hazardous short term degradation products are not likely. However, long term degradation products may Products of Biodegradation arise. Toxicity of the Products The product itself and its products of degradation are not toxic. of Biodegradation Special Remarks on the Not available. Products of Biodegradation Section 13. Disposal Considerations Waste Disposal Waste must be disposed of in accordance with federal, state and local environmental control regulations. Amikacin Section 14. Transport Information DOT Classification Not a DOT controlled material (United States). Identification Not applicable. Not applicable. Special Provisions for Transport DOT (Pictograms) Section 15. Other Regulatory Information and Pictograms No products were found. Federal and State Regulations California California prop. 65: This product contains the following ingredients for which the State of California has found to cause cancer which would require a warning under the statute: No products were found. Proposition 65 Warnings California prop. 65: This product contains the following ingredients for which the State of California has found to cause birth defects which would require a warning under the statute: No products were found. Other Regulations OSHA: Hazardous by definition of Hazard Communication Standard (29 CFR 1910.1200). EINECS: This product is on the European Inventory of Existing Commercial Chemical Substances. WHMIS (Canada) Not controlled under WHMIS (Canada). Other Classifications DSCL (EEC) This product is not classified according S24/25- Avoid contact with skin and eyes. to the EU regulations. S36/37/39- Wear suitable protective clothing, gloves and eye/face protection. Health Hazard HMIS (U.S.A.) 1 National Fire Protection 1 Flammability 1 Association (U.S.A.) Fire Hazard 1 0 Reactivity Health Reactivity 0 Specific hazard Personal Protection E WHMIS (Canada) (Pictograms) DSCL (Europe) (Pictograms) TDG (Canada) (Pictograms) ADR (Europe) (Pictograms) Amikacin Protective Equipment Gloves. Lab coat. Dust respirator. Be sure to use an approved/certified respirator or equivalent.
雄烯二酮 在
α-MEM 、 normal cultured human breast epithelial cells from early lactation milk 、 阿米卡星 、 hydrocortisone sodium succinate 、 fetal calf serum 、 insulin 作用下，
反应 8.0h，
以1.0%的产率得到雌酚酮
参考文献：
名称：
Androstenedione metabolism in epithelial cells derived from early-lactation human milk
摘要：
Epithelial cells derived from duct epithelium were cultured from early lactation human milk in medium supplemented with 15% fetal calf serum, insulin (0.3 u/ml), cortisol 21-sodium succinate (6 micrograms/ml) and amikacin (50 micrograms/ml). The capacity of these cells to metabolize androstenedione to estrone, estradiol and C19 metabolites was studied during continuous culture. After extraction of the medium, the products were subjected to phenolic partition and separated by thin-layer and paper chromatography, followed by recrystallization to constant specific activity. The study demonstrated a progressive increase in the formation of estrone and testosterone over the first 24 h in culture, while estradiol formation showed an initial 2-4 h lag, then increased slowly. The C19 compounds identified were androsterone, 5 alpha-androstanedione, epiandrosterone, dihydrotestosterone and etiocholanolone. 5 alpha-Androstanedione and androsterone were the major 5 alpha-reduced metabolites. Since these cells are derived from normal duct epithelium, their metabolic characteristics may be more representative of normal breast tissue than those of tissue removed from patients with pathological breast disorders.
Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
申请人：Vertex Pharmaceuticals Incorporated
公开号：US20150231142A1
公开（公告）日：2015-08-20
The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
[EN] ANTIBACTERIAL 8-PHENYLAMINO-3-(PYRAZOL-4-YL)IMIDAZO[1,2-A]PYRAZINE DERIVATIVES<br/>[FR] DÉRIVÉS ANTIBACTÉRIENS DE 8-PHÉNYLAMINO-3-(PYRAZOL-4-YL)IMIDAZO[1,2-A]PYRAZINE
申请人：HOFFMANN LA ROCHE
公开号：WO2021219578A1
公开（公告）日：2021-11-04
The invention provides novel imidazopyrazine derivatives having the general formula (I), wherein X and R3 to R9 are as described herein or pharmaceutically acceptable salts thereof, wherein X and R3 to R9 are as defined herein. Further provided are pharmaceutical compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds as medicaments, in particular methods of using the compounds as antibiotics for the treatment or prevention of bacterial infections and resulting diseases.
[EN] OXAZOLIDINONE COMPOUNDS AND METHODS OF USE THEREOF AS ANTIBACTERIAL AGENTS<br/>[FR] COMPOSÉS OXAZOLIDINONE ET PROCÉDÉS D'UTILISATION DE CES DERNIERS EN TANT QU'AGENTS ANTIBACTÉRIENS
申请人：MERCK SHARP & DOHME
公开号：WO2017066964A1
公开（公告）日：2017-04-27
The present invention relates to oxazolidinone compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, E, and R1 are as defined herein. The present invention also relates to compositions which comprise at least one oxazolidinone compound of the invention. The invention also provides methods for inhibiting growth of mycobacterial cells as well as a method of treating mycobacterial infections by Mycobacterium tuberculosiscomprising administering a therapeutically effective amount of an oxazolidinone of the invention and/or apharmaceutically acceptable salt thereof, or a composition comprising such compound and/or salt.
