The biotransformation of olaquindox has been investigated only in the pig. The majority of an oral dose of olaquindox (70%) was excreted in the urine unchanged. The major metabolites appeared to be the reduced compounds, the 1- or 4-mono-N-oxides (16%). Three other compounds thought to be carboxylic acid derivatives made up the remainder. Later work led to the elucidation of the structures of these metabolites in the pig. Again the major urinary component after oral dosing was olaquindox with about 7% present as the 4-mono-N-oxide. Omega oxidation produced the 2-carboxymethylaminocarbonyl compound and its 4-mono-N-oxide derivative (6%). Some of the corresponding 1-mono-N-oxide moiety of the 2-carboxymethylaminocarbonyl was also noted (1%). The remaining metabolite was the di-desoxy derivative of 2-carboxymethylaminocarbonyl compound, 2-carboxymethylaminocarbonyl-3- methyl quinoxaline (>1%).
IDENTIFICATION AND USE: Olaquindox, an antibiotic belonging to the quinoxaline group, is a growth promoter used in pig breeding. HUMAN EXPOSURE AND TOXICITY: There has been reports of both allergic contact dermatitis and photocontact dermatitis following occupational exposure to olaquindox. A farmer developed a photoallergic contact eczema to olaquindox, which progressed to a persistent light reaction. In another case, olaquindox caused a photoallergic contact eczema and subsequently a chronic photosensitive dermatitis with increased UV-A- and UV-B-sensitivity in a breeder of small pigs. ANIMAL STUDIES: Male mice were given oral doses of 2500-5000 mg/kg bw olaquindox. Only 1/10 mice died at the lowest dose used while 100% lethality was noted at the highest dose. Signs of toxicity included decreased activity, lowering of the eyelids, and irregular breathing. Animals died 2-14 days after olaquindox administration. Discolored livers and yellowish-green intestinal contents were noted on gross examination. Similar findings were made when groups of male rats were given olaquindox in a similar manner at doses of 1400-2000 mg/kg bw. Male and female mice were fed diets containing 0, 300, 600, 1200, 2400 and 4800 ppm olaquindox. Signs of toxicity included shaggy fur, dyspnea and reduced motility. A marked reduction in body weight occurred at the highest dietary level in both sexes, and in males given 1200 and 2400 ppm. During the study 1/20 females died at the 600 ppm level as did 18/20 and 5/20 males and females, respectively, at the 1200 ppm level. All the mice given the two highest doses died. No deaths occurred in other groups. At necropsy, hemorrhagic lungs were the main findings. Male and female mice were given diets containing 0, 40, 120 or 360 ppm olaquindox for life. No increased tumor incidence was found in animals given 40 or 120 ppm dietary olaquindox but at 360 ppm there was an increase in the total number of tumors and in the number of animals with benign tumors (pulmonary adenoma and adrenal cortical adenoma in males and in pulmonary adenoma and ovarian granulosa cell tumors in females). There were no increases in the incidence of any malignant tumor types. Female pregnant FB rats were given oral doses of 0, 20, 60 or 180 mg/kg b.w./day olaquindox by gavage from day 6 to day 15 of gestation. Fetuses were delivered by Caesarean section on day 20 of gestation. The pregnant rats given the highest daily dose showed reductions in body weights or rate of weight gain. These animals also showed a higher incidence of resorptions and lower numbers of live fetuses. Fetal weights were lower in the high dose animals. These indices were similar to controls and to rats given 20 or 60 mg/kg bw/day olaquindox. The incidence of malformations in fetuses from dams given 20 or 60 mg/kg bw/day olaquindox was similar to controls but at the highest dose level there was an elevated incidence of malformed fetuses, with 5 malformations reported at a dose level of 180 mg/kg bw/day. In this study, therefore, there was a teratogenic effect at the highest dose level given to pregnant rats (180 mg/kg bw/day) on days 6-15 of gestation. Olaquindox has produced positive results in a number of studies designed to test for reverse mutations in bacteria, including the Ames test with Salmonella typhimurium strains. A positive result has been noted in a forward mutation assay with Escherichia coli. In vivo assays with mouse bone marrow or Chinese hamster spermatogonia as the target tissues have demonstrated the clastogenic activity of olaquindox. Olaquindox was positive in several micronucleus tests in the mouse following oral or inhalation exposure, and in the rat after intraperitoneal injection. Olaquindox has been tested in two dominant lethal assays in the male mouse but a weak positive result was observed in only when a high dose 1 g/kg bw was employed. Positive lethal mutations also occurred when female mice were treated orally with olaquindox despite the use in one study of doses lower than that which effected a positive result in the male mouse (200 and 500 mg/kg bw). Positive results have been obtained in a sister chromatid exchange test using Chinese hamster V79 cells indicating that olaquindox may induce DNA damage. Positive results in bacterial assays including the SOS chromotest confirm this possibility. However, there is no evidence that olaquindox covalently binds to DNA in the rat in vivo. ECOTOXICITY STUDIES: Toxicity of olaquindox was investigated on the freshwater Daphnia magna with a No Observed Effect Concentration of 1000 mg/L.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
副作用
职业性肝毒素 - 第二性肝毒素：在职业环境中的毒性效应潜力是基于人类摄入或动物实验的中毒案例。
Occupational hepatotoxin - Secondary hepatotoxins: the potential for toxic effect in the occupational setting is based on cases of poisoning by human ingestion or animal experimentation.
来源:Haz-Map, Information on Hazardous Chemicals and Occupational Diseases
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
来源:Hazardous Substances Data Bank (HSDB)
毒理性
解毒与急救
/SRP:/ 高级治疗：对于昏迷、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W TKO /SRP: "保持开放"，最低流量/。如果出现低血容量的迹象，使用0.9%生理盐水（NS）或乳酸钠林格氏液（LR）。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Experiments with (3-1)4C-olaquindox intraduodenally administered to rats with bile duct fistulas suggested that around 18% of the dose was excreted in the bile. Similar findings were made after intravenous dosing. Distribution occurred in a generalized manner throughout the body after oral dosing and most of the radioactivity had disappeared by 24 hours. Autoradiography revealed the highest amount in the rat kidney at 4 hours, indicative of the extent of urinary excretion already noted. Slightly elevated concentrations were also observed in liver, testes, adrenals and hair follicles.
After pigs were given diets containing up to 45 ppm olaquindox for the duration of the fattening period, the highest levels were found in the liver (0.14 ppm) and kidney (0.28 ppm) 6 hours after withdrawal. By 24 hours the levels were below the limit of detection (0.1 ppm). Similar results were noted when pigs were given diets containing 10 ppm olaquindox.
When pigs were dosed at levels in the range of those recommended in use (up to 100 ppm in the diet) for up to 20 weeks, relatively high levels were found in the kidney (around 2000 ppb) with relatively moderate levels in the liver (300 ppb) when the animals were killed six hours after drug withdrawal. When killed 2 days after withdrawal, levels had fallen to below the limits of detection (50 ppb) in liver, kidney and muscle. Pigs given diets containing olaquindox at levels in excess of those recommended (160 or 250 ppm) for up to 4 weeks also had high initial levels in kidney, liver and muscle but these had fallen to below the limits of detection by day 2 after withdrawal.
Olaquindox was rapidly absorbed when given orally to pigs. Over 90% of an oral dose of 2 mg/kg bw was eliminated in the urine within 24 hours, which is indicative of rapid and extensive absorption. The remainder was excreted in the feces. Maximum plasma levels were attained within 1-2 hours of dosing (1-2 ppm). This was followed by a rapid decline in plasma levels reaching around 0.03 ppm by 24 hours and 0.005-0.01 ppm by 48 hours. Radioactivity was present in all tissues when examined 2 days after dosing, but the levels were extremely low. In the kidney and liver, levels of 110 and 52 ppb were found, while levels in muscle were only 9 ppb. After 8 days, levels in liver and kidney had fallen to 27 and 12 ppb, respectively, while those in muscle were in the range of 2.5 ppb. By 28 days after dosing only low levels were found in kidney and muscle (0.9 and 0.5-0.8 ppb, respectively) with slightly higher concentrations in the liver (2 ppb).
Compounds according to the formula A-B-Z-W, wherein
A is selected from (C
6
-C
10
)aryl-, or (C
1
-C
9
)heteroaryl-, which groups may be optionally substituted;
B is selected from
(a) O, NH, NR
10
, —(CH
2
)
k
—O—, —(CH
2
)
k
—N—, and —(CH
2
)
k
—NR
10
—, where R
10
is (C
1
-C
6
)alkyl and where k is 1 to 6 in each case, or
1
where said group (i) through (iv) is optionally substituted by 1 to 4, preferably 1 to 2, groups selected from (C
1
-C
6
)alkyl, halo, and (C
1
-C
6
)alkyl optionally substituted by 1 to 3 halo atoms wherein one of carbon atoms C
1
, C
2
, C
3
and C
4
of said piperidine or piperazine group is optionally replaced by a carbonyl group;
Z and W are as herein described; and pharmaceutically acceptable salts, solvates or hydrates thereof; pharmaceutical compositions thereof; and methods useful to facilitate secretion of growth hormone(GH) in mammels.
Somatostatin antagonists and agonists that act at the SST subtype 2 receptor
申请人：——
公开号：US20020091125A1
公开（公告）日：2002-07-11
Compounds according to the formula A-Z-W as herein described, wherein A is selected from the groups consisting of: A′—(CH
2
)
n
—, A′—(CH
2
)
n
SO
2
—, and A′—(CH
2
)
n
CO—, where n is
0
to
4;
and A′ is selected from
(a) (C
6
-C
10
)aryl-, or
(b) (C
1
-C
9
)heteroaryl-; which groups may be optionally substituted; and pharmaceutically acceptable salts, solvates or hydrates thereof; pharmaceutical compositions thereof; and methods useful to facilitate secretion of growth hormone(GH) in mammals.
[EN] COMPOUNDS AND METHODS OF TREATING BACTERIAL INFECTIONS<br/>[FR] COMPOSÉS ET MÉTHODES DE TRAITEMENT D'INFECTIONS BACTÉRIENNES
申请人：ULTUPHARMA AB
公开号：WO2017095319A1
公开（公告）日：2017-06-08
The invention relates to compounds of Formula (I), wherein the variables are as defined in the claims, which are useful in the treatment and/or prevention of bacterial infections in a subject. The invention further relates to the use of a compound of Formula (I) in the manufacture of a medicament, and medical devices when used in a method of treating or preventing a bacterial infection in a subject, and related aspects.
Methods and compositions for photo-cross linking photoactive compounds to target tissue
申请人：——
公开号：US20030013696A1
公开（公告）日：2003-01-16
The present invention discloses novel photoactive compounds that may be crosslinked to target substrates. Methods for the preparation and use of the compounds, as well as compositions comprising them, are also disclosed.
