103-90-2 Usage
Antipyretic analgesic
The chemiacal name of Acetaminophen is N-(4-hydroxy phenyl) acetamide and the trade name is paracetamol belonging to acetanilide antipyretic analgesics. It was first synthesized by Morse in 1878 and first used in clinic by VonMering in 1893. It has become an over the counter drug in the USA since 1955 and our country started production at the end of the 1950’s. Acetaminophen is a white crystalline or a crystalline powder in appearance with melting point from 168℃ to 172℃, odorless, slightly bitter taste, freely soluble in hot water or ethanol, dissolved in acetone, practically insoluble in cold water and petroleum ether. It is stable below 45℃ but will be hydrolyzed into p-aminophenol when exposed to humid air, then oxidized further. The color grades gradually from pink to brown then to black, so it should be sealed and stored in a cool and dry place.Acetaminophen?has the antipyretic activity by inhibiting the synthesis of hypothalamic thermoregulation prostaglandins and its strength of antipyretic effect is similar to aspirin. On the other hand, Acetaminophen?can produce analgesic effect by inhibiting the synthesis of prostaglandins in the central nervous system and blocking impulses of nociceptive nerve endings, but weaker than aspirin. Compared with aspirin, Acetaminophen?has minor irritation, few allergic reactions and other advantages. Its antipyretic and analgesic effect is similar to phenacetin, and ??the use of Acetaminophen increases due to limiting or banning using phenacetin in many countries.In clinical, it is mainly used for fever and headache caused by cold and relieving mild to moderate pain such as joint pain, muscle pain, neuralgia, migraine, dysmenorrhea, cancer pain, postoperative analgesia and so on. It can be used for patients who are allergic to aspirin, intolerant of aspirin, or unsuited for aspirin, such as patients with varicella, hemophilia and other hemorrhagic disease (patients having anticoagulant therapy included), as well as patients with slight peptic ulcer and gastritis. In addition, it also can be used for the synthesis of benorylate and used as asymmetric synthetic intermediates, photographic chemicals and stabilizer of hydrogen peroxide.
Chemical property
Obtain prism crystallization from ethanol. Melting point 169-171℃, relative density 1.293(21/4℃). Soluble in ethanol, acetone and hot water, difficult to dissolve in water, insoluble in petroleum ether and benzene. Odorless, bitter. The pH value of saturated aqueous solution is 5.5-6.5.
Pharmacological Actions
Acetaminophen is used as antipyretic analgesics. It has the antipyretic activity by means of mediated peripheral vasodilation and perspiration caused by inhibiting the cyclooxygenase which selectively inhibiting the synthesis of hypothalamic thermoregulation prostaglandins, and its strength of antipyretic effect is similar to aspirin. As a peripheral analgesic, it can produce analgesic effect by inhibiting the synthesis and release of prostaglandins and increasing pain threshold. However, its action is weaker than aspirin and it is only effective for mild to moderate pain. There is no obvious anti-inflammation effect.
Pharmacokinetics
Different sources of media describe the Pharmacokinetics of 103-90-2 differently. You can refer to the following data:
1. The oral absorption is rapid and complete, and the peak time occurs 0.5～2h later. The plasma protein binding rate is 25%～50%. This product is equally distributed in the body, 90%～95% is metabolized in the liver and mainly excreted from the kidney combining with glucuronic acid? and about 3% exits the body unchanged in the urine within 24h. Its half-life (t1/2) is 1～4h (average 2h). In case of renal insufficiency t1/2 is not affected, but t1/2 of patients with hepatic insufficiency, newborns or elderly patients may increase and t1/2 of children may decrease. It can be secreted by milk.
2. Paracetamol is absorbed rapidly from the small intestine after oral
administration; peak plasma concentrations are reached after 30–60min. It
may also be given rectally and intravenously (either as paracetamol or the
prodrug propacetamol). It has good oral bioavailability (70%–90%); rectal absorption is more variable (bioavailability ~50%–80%) with a longer time to
reach peak plasma concentration. The plasma half-life is approximately 2–3 h.
Paracetamol is metabolised by hepatic microsomal enzymes mainly to the
glucuronide, sulphate and cysteine conjugates. None of these metabolites is
pharmacologically active. Aminimal amount of the metabolite N-acetyl-pamino-
benzoquinone imine is normally produced by cytochrome P450–
mediated hydroxylation. This reactive toxic metabolite is rendered harmless
by conjugation with liver glutathione, then excreted renally as mercapturic
derivatives. With larger doses of paracetamol, the rate of formation of the
reactive metabolite exceeds that of glutathione conjugation, and the reactive
metabolite combines with hepatocellular macromolecules, resulting in cell
death and potentially fatal hepatic failure. The formation of this metabolite is
increased by drugs inducing cytochrome P450 enzymes, such as barbiturates
or carbamazepine.
Preparation method
1. Using nitrobenzene as raw material
In the presence of concentrated sulfuric acid and sixteen alkyl methyl ammonium chloride, nitrobenzene is transformed into p-Aminophenol by catalytic hydrogenation with Pd/C as catalyst. P-acetaminophen is synthesized acetylation by one-step acylation without separation and the yield is 64.3%. The reaction is as followed:
2. Using paranitrophenol as raw material
With paracetamol as raw material and Pd/C as catalyst, paracetamol is synthesized by hydroacylation on one-step method. The optimum solvent is acetic acid of which the dosage is 2 to 5 times of paranitrophenol and the yield of paracetamol is up to 95%. When Pd-La/C is used as catalyst instead, the yield can reach 97%. The reaction is as followed:
?
3. Using p-aminophenol as raw material
Under these conditions of using p-aminophenol and acetic anhydride as raw materials, zinc powder as the antioxidant, activated carbon as the decolorizing agent and dilute acetic acid as the reaction medium, paracetamol is synthesized by microwave irradiation technology and the yield is up to81.2%. The reaction is as followed:
4. Using p-Hydroxyacetophenone as raw material
First oximate p-Hydroxyacetophenone and then rearrange it to obtain paracetamol by means of Beckmann. Under this method, the yield of 4-hydroxyacetophenone oxime obtained by oximating p-Hydroxyacetophenone is 93.5%. Then we use Hβ molecular sieve as catalyst and acetone as the solvent to obtain acetaminophen by rearrangement and the yield is 81.2 %. In the rearrangement reaction, acetone is used as the solvent and Al-MCM-41 molecular sieve is used as the catalyst. The yield is the highest when the content of phosphoric acid in the catalyst is 30%. The reaction is as followed:
?
5. Using? phenol as raw material
Phenol is used as the raw material and synthesizes paracetamol after acetylation, Fries rearrangement, oxime and Beckmann rearrangement. The yields are 82%, 68.6%, 50.5%,
respectively. The reaction is as followed:
Usage and Dosage
Usage
This product is antipyretic and analgesic whose international nonproprietary name is Paracetamol. It is the most common non anti-inflammatory analgesia-antipyretic drugs without anti inflammatory and anti rheumatism action. Its antipyretic effect is similar to aspirin, but analgesic effect is weak. It is the best of breed of acetanilid drugs. The product is especially suitable for patients who cannot use carboxylic acids drugs. It is used for cold and toothache. Acetaminophen is also used as organic synthesis intermediates, stabilizer of hydrogen peroxide, photographic chemicals.
Dosage???
1. Oral (1) Paracetamol tablets or paracetamol capsules: adults take 300～600mg at a time and 3～4 times a day according to the need. The daily dosage should not be greater than 2g. Defervescence treatment is generally less than 3 days and the administration of pain relief lasts less than 10 days. Children take 10～15mg/kg every 4～ 6 hours. The dosage of children under the age of 12 does not exceed 5 times a day, a five-day course at most. This product should not be taken for a long time.
2. Dispersible tablets: When take tablets, disperse them in warm water dispersion. The commonly used amount of children is 10～15mg/kg every 4～ 6 hours. The dosage of children under the age of 12 does not exceed 5 times a day, a five-day course at most. Children under 3 years old cut back on the amount.
Application in Particular Diseases
In Osteoarthritis：
Acetaminophen is recommended by the ACR as first-line drug therapy for pain management of OA. The dose is 325 to 650 mg every 4 to 6 hours on a scheduled basis (maximum dose 4 g/day; maximum 2 g/day if chronic alcohol intake or underlying liver disease). Comparable relief of mild to moderate OA pain has been demonstrated for acetaminophen (2.6 to 4 g/ day) compared with aspirin (650 mg four times daily), ibuprofen (1,200 or 2,400 mg daily), and naproxen (750 mg daily). However, some patients respond better to NSAIDs.
Acetaminophen is usually well tolerated, but potentially fatal hepatotoxicity with overdose is well documented. It should be used with caution in patients with liver disease and those who chronically abuse alcohol. Chronic alcohol users (three or more drinks daily) should be warned about an increased risk of liver damage or GI bleeding with acetaminophen. Other individuals do not appear to be at increased risk for GI bleeding. Renal toxicity occurs less frequently than with NSAIDs.
Adverse reaction
1. Allergic reactions: This product has less and slight side effects a dose treatment except for occasional rashes, hives and other allergic reactions. Methemoglobinemia may occur in a few cases.
2. Hepatorenal damage: A large number of long-term use,? hepatorenal damages and thrombocytopenia may occur, even jaundice, oliguria, acute severe hepatitis, which could lead to coma, and death. Using at high dosage may cause nausea, vomiting, stomach pain, stomach cramps, diarrhea, anorexia, sweating, etc.
3. For children under the age of 3, the development of liver and kidney function is not mature with poor detoxification and excretory function, so they should try to avoid using this product. In addition, patients with liver and kidney insufficiency and pregnant women should use cautiously. The long-term drug users should regularly check renal function and hemogram.
Taboo
It is contraindicated in patients allergic to the product and patients with severe liver and kidney function deficiency.
Notes
Allergies are disabled. Patients who are allergic to aspirin do not have allergic reactions generally. However, it has been reported that a small number of patients with asthma caused by aspirin-sensitivity can have an episode of bronchospasm after taking drugs.
This product may increase the risk of liver toxicity when patients suffer from alcohol poisoning, liver disease or viral hepatitis, so it should be used with caution. Patients with renal insufficiency take a lot of products regularly, leading to increasing risk of renal toxicity, so they should be careful. It is contraindicated in patients with severe liver and kidney function deficiency.
When taking the drug for pain, it is not allowed to take for more than 40 consecutive days. Antipyretic treatments shall not exceed 3 days, unless doctors tell you otherwise. After taking this product, patients should immediately stop taking medicine when symptoms of erythema or edema occur. This product is only a drug for symptomatic treatment, it is necessary to take other treatments to relieve reasons of pain or fever at the same time when taken.
This product can be passed through the placenta and secreted in milk, so pregnant women and lactating women are not recommended to use. For children under the age of 3, the development of liver and kidney function is not mature with poor detoxification and excretory function, so they should try to avoid using this product. Because the development of liver and kidney function declines, t1/2 of elderly patients may increase leading to adverse reactions easily. Patients should take with caution or take a smaller amount of use appropriately.
The interferences of diagnosis: ① Glucose measurement, falsely low values are measured by glucose oxidase/peroxidase methods, but no effect occurs when measured by hexokinase /6-dehydrogenase methods; ② Assays for uric acid of serum, falsely high values are measured by phosphotungstic acid method; ③ Determination of urinary 5-hydroxyindoleacetic acid (5-HIAA), falsely positive results are obtained in a screening test with nitroso naphthol reagent, but quantitative test is not affected; ④Liver function tests, prothrombin time, serum bilirubin, lactic dehydrogenase and serum aminotransferase can be increased due to high doses or long-term use.
In case of large dosage, promote vomiting timely and give antagonists named N-acetylcysteine (140mg/kg orally given at the beginning, then 70mg/kg, take 1 times every 4h, 17 times; it can be given intravenously when serious, the drug can be dissolved in 5% 200 ml glucose injection and used through intravenous drip) or take methionine orally, which has a protective effect on the liver. Do not give activated carbon, because it can affect the absorption of drugs. The antagonist should be applied as soon as possible because the effect is satisfactory in 12 h but the effect is worse over 24 h. In the treatment, it is best to monitor the blood concentration and give other therapies, such as hemodialysis or hemofiltration.
Drug interactions
Different sources of media describe the Drug interactions of 103-90-2 differently. You can refer to the following data:
1. For patients with chronic alcohol ingestion or other liver enzyme inducers, especially barbiturates or anticonvulsants, when taking long-term or a large-scale use of this product, they may have a higher risk of liver toxicity.When combined with chloramphenicol, this product can prolong the latter t1/2 and enhance its toxicity.When combined with anticoagulant drugs, this product can increase the anti-blood-clotting effect. So it is necessary to adjust the dosage of anticoagulant drugs.When combining long-term large quantities of Acetaminophen with aspirin or other non-steroidal anti-inflammatory drugs, it will increase the risk of renal toxicity.When combined with the antiviral drug, zidovudine, it can increase the toxicity. We ought to avoid using at the same time.
2. Potentially hazardous interactions with other drugs
None known
Administration nursing care point
Nurse according to the general principles of analgesia-antipyretic drugs.
The caregiver should exhort the patient to pay attention to the following things during medication period: ①No drinking, drinking may aggravate the liver toxicity of this product; ②Drink plenty of water to reduce the concentration of drug in renal tubules and reduce the occurrence of “analgesic nephropathy”; ③When taking chewing chips, chew them up; ④No unauthorized use other NSAIDS or compound preparation containing NSAIDS at the same time to avoid increasing the renal toxicity.
In a poisoning caused by this product, we should give patients oral antagonists, acetylcysteine (Tan Yijing) as soon as possible, not oral activated carbon, because the latter can affect the absorption of antagonists. Initial dose of acetylcysteine is 140 mg/kg, add 70 mg/kg every 4 h, 17 times totally. Intake: configure acetylcysteine into a 5% solution or add in triple drinks and take after shaking well to avoid fetid odors and irritations. For the occurrence of vomiting within 1 h after medication, resupply, if necessary, take nasal or rectal administration. In severe cases, the drug can be dissolved in 5% 200 ml glucose injection and used through intravenous drip. The antagonist should be applied as soon as possible because the effect is satisfactory in 12 h but the effect is worse over 24 h. In the treatment, it is best to monitor the blood concentration and give other therapies, such as hemodialysis or hemofiltration.
Usage
Organic synthesis intermediates, stabilizer of hydrogen peroxide, photographic chemicals, non anti-inflammatory analgesia-antipyretic drugs.
Production
Produced by acetylation of p-aminophenol.
Method 1: add p-aminophenol into dilute acetic acid, then add glacial acetic acid, heat up to 150℃and react for 7h, add acetic anhydride and react for 2h, check the end point and cool to 25℃ after the acceptance, shake it and filter, water until no acetic acid flavor exists, dry to get crude products.
Method 2: distill p-aminophenol, acetic acid and acid industrial containing more than 50% acid together, the speed of distilling dilute acid for is 1/10 of the total distillate in one hour, check the residue of p-aminophenol less than 2.5% aminophenol by sampling inspection when inner temperature rises up to 130℃, add dilute acid (content of more than 50%), cool to get crystallization. After shaking and filter, first use a small amount of dilute acid to wash, and then use a large number of water till filtrate is near colourless to get crude products. The yield of method 1 is 90%, but the yield of method 2 is 90-95%. Refining methods: add the crude product when the water is heated to near boiling. Heat up to the total dissolution, add activated carbon soaked in water, use dilute acetic acid to adjust till pH=4.2-4.6, boil for 10min. Filter press, add a small amount of sodium bisulfite into the filtrate. Cool to below 20℃, separate crystals out. After shaking and filter, wash and dry to get active ingredients, paracetamol finished products.
Other methods of production are as followed:
(1) p-nitrophenol is reduced by zinc in acetic acid, and acetaminophen is obtained by acetylation at the same time;
(2) put the hydrazone generated from p-hydroxyacetophenone in acid solution containing sulfuric acid, and then add sodium nitrite to get acetaminophen by renversement.
Chemical Properties
White Solid
Originator
Trigesic ,Squibb ,US ,1950
Uses
Different sources of media describe the Uses of 103-90-2 differently. You can refer to the following data:
1. Analgesic; antipyretic
2. antiinfectant
3. dispersing agent in liquid scintillation counting
4. manufacture of azo dyes, photographic chemicals.
5. Acetaminophen is widely used as an analgesic and fever-reducing agent. Acetaminophen is
designed for moderate analgesia. It is also effective like aspirin and is used in analgesia for
headaches (from weak to moderate pain), myalgia, arthralgia, chronic pain, for oncological and
post-operational pain, etc.
Indications
Acetaminophen (Tylenol) is an effective antipyretic and
analgesic that is well tolerated at therapeutic doses. It
has only weak antiinflammatory activity; thus, it is not
useful in the treatment of rheumatoid arthritis and
other inflammatory conditions.
Manufacturing Process
About 250 ml of a reaction mixture obtained by the electrolytic reduction of
nitrobenzene in sulfuric acid solution and containing about 23 grams of paminophenol
by assay is neutralized while at a temperature of 60°C to 65°C,
to a pH of 4.5 with calcium carbonate. The calcium sulfate precipitate which
forms is filtered off, the precipitate washed with hot water at about 65°C and
the filtrate and wash water then combined. The solution is then extracted
twice with 25 ml portions of benzene and the aqueous phase is treated with
0.5 part by weight, for each part of p-aminophenol present, of activated
carbon and the latter filtered off. The activated carbon is regenerated by
treatment with hot dilute caustic followed by a hot dilute acid wash, and
reused a minimum of three times.
To the filtrate obtained, there are then added about 0.2 gram of sodium
hydrosulfite or sodium sulfite and 15.0 grams of anhydrous sodium acetate in
about 27 grams of acetic anhydride at 40°C. The reaction mixture formed is
cooled to 8°C to 10°C with stirring and held at this temperature for 60
minutes. A crystalline precipitate of about 27 grams of N-acetyl-paminophenol
is obtained melting at 169-171°C. This is equivalent to a yield of
85%.
In lieu of utilizing calcium carbonate as the neutralizing agent, calcium
hydroxide, barium hydroxide, barium chloride or other alkaline earth metal
salt or hydroxide forming an insoluble sulfate may be employed.
Brand name
Acephen (G & W);
Infants’ Feverall (Actavis); Injectapap (Ortho-McNeil);
Neopap (Polymedica); Tylenol (McNeil);Anacin;Crocin.
Therapeutic Function
Analgesic, Antipyretic
World Health Organization (WHO)
Paracetamol, a widely used analgesic and antipyretic is known, in
case of overdose, to cause liver damage, frequently with fatal outcome. In
recommended dosages this risk does not occur. Paracetamol is listed in the WHO
Model List of Essential Drugs.
Synthesis Reference(s)
The Journal of Organic Chemistry, 27, p. 1092, 1962 DOI: 10.1021/jo01050a543Tetrahedron Letters, 22, p. 1257, 1981 DOI: 10.1016/S0040-4039(01)90289-8
General Description
Odorless white crystalline solid. Bitter taste. pH (saturated aqueous solution) about 6.
Air & Water Reactions
Slightly soluble in water.
Reactivity Profile
Acetaminophen is sensitive to light. Incompatible with strong oxidizers.
Fire Hazard
Flash point data for Acetaminophen are not available; however, Acetaminophen is probably combustible.
Flammability and Explosibility
Nonflammable
Biological Activity
Cyclooxygenase inhibitor; may be selective for COX-3 (IC 50 values are 460, > 1000 and > 1000 μ M for canine COX-3, and murine COX-1 and COX-2 respectively). Widely used analgesic and antipyretic agent.
Mechanism of action
The mechanism of action of paracetamol is not well understood, but it may
act in a similar fashion to NSAIDs, with inhibition of cyclo-oxygenase
enzymes COX-1 and COX-2 to reduce the phenoxyl radical
formation required for COX-1 and 2 activity and prostaglandin synthesis. I t
has selectivity for inhibition of prostaglandin synthesis with low
concentrations of peroxidases and arachidonic acid, but limited effect at
higher concentrations and, therefore, has limited anti-inflammatory effects.
Unlike opioids, paracetamol has no well-defined endogenous binding sites.
I n some circumstances, it may exhibit a preferential effect on COX-2
inhibition. There is growing evidence of a central antinociceptive effect of
paracetamol. It has also been found to prevent prostaglandin production at
the cellular transcriptional concentration, independent of COX activity.
Clinical Use
Acetaminophen is weakly acidic (pKa = 9.51) and synthesized by the acetylation of p-aminophenol. It is weakly bound
to plasma proteins (18–25%). Acetaminophen is indicated for use as an antipyretic/analgetic, particularly in those
individuals displaying an allergy or sensitivity to aspirin. It does not possess anti-inflammatory activity, but it will
produce analgesia in a wide variety of arthritic and musculoskeletal disorders. It is available in various formulations,
including suppositories, tablets, capsules, granules, and solutions. The usual adult dose is 325 to 650 mg every 4 to
6 hours. Doses of greater than 2.6 g/day are not recommended for long-term therapy because of potential
hepatotoxicity issues. Acetaminophen, unlike aspirin, is stable in aqueous solution, making liquid formulations readily
available, a particular advantage in pediatric cases.
Synthesis
Acetaminophen, p-acetaminophenol (3.2.80), is synthesized by reacting
p-aminophenol with acetic anhydride [76,77].
Environmental Fate
Although a major part of the ingested dose of acetaminophen is
detoxified, a very small proportion is metabolized via the
cytochrome P450-mixed function oxidase pathway to a highly
reactive n-acetyl-p-benzoquinoneimine (NAPQI). The toxic
intermediate NAPQI is normally detoxified by endogenous
glutathione to cysteine and mercapturic acid conjugates and
excreted in the urine. Recent studies have shown that hepatic
P450s, CYP2E1, and to a lesser extent CYP1A2 are responsible
for conversion of acetaminophen to NAPQI. In acetaminophen
overdose, the amount of NAPQI increases and depletes
endogenous glutathione stores. Time course studies have
shown that covalent binding of reactive NAPQI and subsequent
toxicity occur only after cellular glutathione stores are
reduced by 70% or more of normal. Mitochondrial dysfunction
and damage can be seen as early as 15 min after a toxic dose in
mice, suggesting that this may be a critical to cellular necrosis.
The NAPQI is then thought to covalently bind to critical
cellular macromolecules in hepatocytes and cause cell death.
Recent proteomic studies have identified at least 20 known
proteins that are covalently modified by the reactive acetaminophen
metabolite. The resulting acetaminophen-cysteine
(APAP-CYS) protein adducts can be quantified via a highpressure
liquid chromatography coupled with electrochemical
detection (HPLC-EC). Hepatic necrosis and inflammation
develop as a consequence of hepatocellular death, which
results in development of clinical and laboratory findings
consistent with liver failure. A similar mechanism is postulated
for the renal damage that occurs in some patients following
acetaminophen toxicity.
Metabolic pathway
Acetaminophen (APAP) is metabolized by mice, and
nine metabolites are identified in the urine. The main
metabolites are APAP-glucuronide and 3-cysteinyl-
APAP. Hydroquinone metabolites of S-(2,5-
dihydroxyphenyl)cysteine and S-(2,5-dihydroxyphenyl)-
N-acetylcysteine result from the benzoquinone
metabolite of APAP.
Metabolism
acetaminophen is undergoes rapid first-pass metabolism in the GI tract primarily by conjugation reactions, with the
O-sulfate conjugate being the primary metabolite in children and the O-glucuronide being the primary metabolite in
adults. A minor, but significant, product of both acetaminophen and phenacetin is the N-hydroxyamide produced by a
CYP2E1 and CYP3A4.
Purification Methods
Recrystallise Paracetamol from water or EtOH. The 3,5-dinitrobenzamide complex gives orange crystals from hot H2O and has m 171.5o. [Beilstein 13 H 460, 13 I 159, 13 II 243, 13 III 1056, 13 IV 1091.]
Check Digit Verification of cas no
The CAS Registry Mumber 103-90-2 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 1,0 and 3 respectively; the second part has 2 digits, 9 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 103-90:
(5*1)+(4*0)+(3*3)+(2*9)+(1*0)=32
32 % 10 = 2
So 103-90-2 is a valid CAS Registry Number.
InChI:InChI=1/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10)/i2D,3D,4D,5D
103-90-2Relevant articles and documents
Enhanced catalytic activity of natural hematite-supported ppm levels of Pd in nitroarenes reduction
Gholinejad, Mohammad,Shojafar, Mohammad,Sansano, José M.
, p. 2033 - 2043 (2020)
In this work, Pd NPs supported on amine-modified natural hematite have been prepared and characterized. Using this simple catalyst, nitroaromatic compounds as a major cause of industrial pollution were reduced to corresponding amines with ppm levels of Pd in the presence of designer surfactant TPGS-750-M and NaBH4 at room temperature in aqueous media. Synergistic effect between hematite and Pd is responsible for the observed enhanced catalytic activity. This catalyst was recycled for at least four times with a small decrease in the activity.
Influence of medium and temperature on the hydrolysis kinetics of propacetamol hydrochloride: Determination using derivative spectrophotometry
Barcia, Emilia,Martin, Alicia,Azuara, Ma. Luz,Negro, Sofia
, p. 277 - 280 (2005)
Propacetamol hydrochloride (PRO) is a water-soluble prodrug of paracetamol (PA) which can be parenterally administered as analgesic for the treatment of postoperative pain, acute trauma, and gastric and/or intestinal disorders where oral administration is not possible. In these circumstances, PRO can be administered in physiologic or glucose solutions since it is rapidly and quantitatively hydrolyzed into PA by plasma estearases. We have studied the degradation kinetics of PRO in 5% glucose and 0.9% saline solutions at 4 °C and 25 °C (storage and room temperatures, respectively). The analytic technique used to determine PRO and PA quantitatively was first-derivative spectrophotometry. The degradation process of PRO can be best fitted to a second-order kinetics with independence of the medium used (saline or glucose solution). The hydrolysis kinetics of PRO conversion into PA depends on the temperature but not on the assay medium (saline or glucose solution). The degradation rate constants obtained for PRO were approximately 4.5 times higher at 25 °C than at 4 °C. The values of t90% for PRO were 3.17 h and 3.61 h at 25 °C, and 13.42 h and 12.36 h at 4 °C when the tests were performed in 5% glucose and 0.9% saline solutions, respectively.
Subphthalocyanines: Addressing water-solubility, nano-encapsulation and activation for optical imaging of B16 melanoma cells
Bernhard, Yann,Winckler, Pascale,Chassagnon, Remi,Richard, Philippe,Gigot, lodie,Perrier-Cornet, Jean-Marie,Decrau, Richard A.
, p. 13975 - 13978 (2014)
Water-soluble disulfonato-subphthalocyanines (SubPcs) or hydrophobic nano-encapsulated SubPcs are efficient probes for the fluorescence imaging of cells. 20 nm large liposomes (TEM and DLS) incorporated about 13% SubPc. Moreover, some of these fluorophores were found to be pH activatable.
Regioselective preparation of 5-hydroxypropranolol and 4′-hydroxydiclofenac with a fungal peroxygenase
Kinne, Matthias,Poraj-Kobielska, Marzena,Aranda, Elisabet,Ullrich, Rene,Hammel, Kenneth E.,Scheibner, Katrin,Hofrichter, Martin
, p. 3085 - 3087 (2009)
An extracellular peroxygenase of Agrocybe aegerita catalyzed the H2O2-dependent hydroxylation of the multi-function beta-adrenergic blocker propranolol (1-naphthalen-1-yloxy-3-(propan-2-ylamino)propan-2-ol) and the non-steroidal anti-inflammatory drug diclofenac (2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetic acid) to give the human drug metabolites 5-hydroxypropranolol (5-OHP) and 4′-hydroxydiclofenac (4′-OHD). The reactions proceeded regioselectively with high isomeric purity and gave the desired 5-OHP and 4′-OHD in yields up to 20% and 65%, respectively. 18O-labeling experiments showed that the phenolic hydroxyl groups in 5-OHP and 4′-OHD originated from H2O2, which establishes that the reaction is mechanistically a peroxygenation. Our results raise the possibility that fungal peroxygenases may be useful for versatile, cost-effective, and scalable syntheses of drug metabolites.
Preparation of β-cyclodextrin functionalized reduced graphene oxide: Application for electrochemical determination of paracetamol
Fu, Li,Lai, Guosong,Yu, Aimin
, p. 76973 - 76978 (2015)
β-Cyclodextrin functionalized reduced graphene oxide (β-CD/RGO) was successfully prepared using a simple wet chemical method. The β-CD/RGO nanohybrid was characterized by UV-vis spectroscopy, FTIR, Raman spectroscopy, TEM and SEM. The results confirmed that β-CD had effectively covered the RGO surface. The β-CD/RGO nanohybrid modified glassy carbon electrode was employed for the sensitive electrochemical determination of paracetamol. Cyclic voltammetry measurements indicated that β-CD/RGO could significantly enhance the electrochemical response of paracetamol due to the outstanding electronic properties of RGO sheets and the high supramolecular recognition and enrichment capability of β-CD. The experimental factors were investigated and optimized. Under optimized conditions, the amperometric oxidation currents of paracetamol were linearly proportional to the concentration in the range of 0.01 to 0.8 mM with a detection limit of 2.3 μM (S/N = 3). Furthermore, the proposed sensor exhibited an excellent anti-interference property and acceptable reproducibility.
Spectrophotometric Determination of Aspirin by Transacetylation of 4-Aminophenol
Verma, Krishna K.,Jain, Archana
, p. 821 - 824 (1986)
Aspirin transacetylates 4-aminophenol, yielding acetaminophen (N-acetyl-4-aminophenol), which can be determined by its oxidation to an orange-yellow product either by iodylbenzene in acetone when the absorbance is measured at 430 nm or by photometric titration with 2-iodylbenzoate in acetone-water medium at 444 nm.Salicylic acid, salicylamide, oxyphenbutazone, caffeine, and sodium hydrogen carbonate do not interfere.Drug mixtures of acetaminophen and aspirin have been analyzed by determining acetaminophen alone directly with iodyl reagents and then determining acetaminophen plus aspirin after 4-aminophenol reaction; aspirin is found b y difference
Assessment of cytochrome P450 (1A2, 2B6, 2C9 and 3A4) induction in cryopreserved human hepatocytes cultured in 48-well plates using the cocktail strategy
Gerin, Brigitte,Dell'aiera, Sylvie,Richert, Lysiane,Smith, Steven,Chanteux, Hugues
, p. 320 - 335 (2013)
1. A fast, straightforward and cost-effective assay was validated for the assessment of CYP induction in cryopreserved human hepatocytes cultured in 48-well plates. The cocktail strategy (in situ incubation) was used to assess the induction of CYP1A2, CYP2B6, CYP2C9 and CYP3A4 by using the recommended probe substrate, i.e. phenacetin, bupropion, diclofenac and midazolam, respectively. 2. Cryopreserved human hepatocytes were treated for 72 h with prototypical reference inducers, β-naphthoflavone (25 μM), phenobarbital (500 μM) and rifampicin (10 μM) as positive controls for CYP induction. The use of a cocktail strategy has been validated and compared to the classical approach (single incubation). The need of using phase II inhibitor (salicylamide) in CYP induction assay was also investigated. 3. By using three different batches of cryopreserved human hepatocytes and our conditions of incubations, we showed that there was no relevant drug-drug interaction using the cocktail strategy. The same conclusions were observed when a broad range of enzyme activity has to be assessed (wide range of reference inducers, i.e. EC50-Emax experiment). In addition, the interassay reproducibility assessment showed that the day-to-day variability was minimal. 4. In summary, the study showed that the conditions used (probe substrates, concentration of probe substrate and time of incubation) for the cocktail approach were appropriate for investigations of CYP induction potential of new chemical entities. In addition, it was also clear that the use of salicylamide in the incubation media was not mandatory and could generate drug-drug interactions. For this reason, we recommend to not use salicylamide in CYP induction assay.
Oxidation of human cytochrome P450 1A2 substrates by Bacillus megaterium cytochrome P450 BM3
Kim, Dong-Hyun,Kim, Keon-Hee,Kim, Dooil,Jung, Heung-Chae,Pan, Jae-Gu,Chi, Youn-Tai,Ahn, Taeho,Yun, Chul-Ho
, p. 179 - 187 (2010)
Cytochrome P450 enzymes (P450s or CYPs) are good candidates for biocatalysis in the production of fine chemicals, including pharmaceuticals. Despite the potential use of mammalian P450s in various fields of biotechnology, these enzymes are not suitable as biocatalysts due to their low stability, low catalytic activity, and limited availability. Recently, wild-type and mutant forms of bacterial P450 BM3 (CYP102A1) from Bacillus megaterium have been found to metabolize various. It has therefore been suggested that CYP102A1 may be used to generate the metabolites of drugs and drug candidates. In this report, we show that the oxidation reactions of typical human CYP1A2 substrates (phenacetin, ethoxyresorufin, and methoxyresorufin) are catalyzed by both wild-type and mutant forms of CYP102A1. In the case of phenacetin, CYP102A1 enzymes show only O-deethylation product, even though two major products are produced as a result of O-deethylation and 3-hydroxylation reactions by human CYP1A2. Formation of the metabolites was confirmed by HPLC analysis and LC-MS to compare the metabolites with the actual biological metabolites produced by human CYP1A2. The results demonstrate that CYP102A1 mutants can be used for cost-effective and scalable production of human CYP1A2 drug metabolites. Our computational findings suggest that a conformational change in the cavity size of the active sites of the mutants is dependent on activity change. The modeling results further suggest that the activity change results from the movement of several specific residues in the active sites of the mutants.
Identification of human cytochrome P450s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data
Li, Xue-Qing,Bjoerkman, Anders,Andersson, Tommy B.,Gustafsson, Lars L.,Masimirembwa, Collen
, p. 429 - 442 (2003)
Objective: Knowledge about the metabolism of anti-parasitic drugs (APDs) will be helpful in ongoing efforts to optimise dosage recommendations in clinical practise. This study was performed to further identify the cytochrome P450 (CYP) enzymes that metabolise major APDs and evaluate the possibility of predicting in vivo drug clearances from in vitro data. Methods: In vitro systems, rat and human liver microsomes (RLM, HLM) and recombinant cytochrome P450 (rCYP), were used to determine the intrinsic clearance (CLint) and identify responsible CYPs and their relative contribution in the metabolism of 15 commonly used APDs. Results and discussion: CLint determined in RLM and HLM showed low (r2=0.50) but significant (Pint values were scaled to predict in vivo hepatic clearance (CLH) using the 'venous equilibrium model'. The number of compounds with in vivo human CL data after intravenous administration was low (n=8), and the range of CL values covered by these compounds was not appropriate for a reasonable quantitative in vitro-in vivo correlation analysis. Using the CLH predicted from the in vitro data, the compounds could be classified into three different categories: high-clearance drugs (> 70% liver blood flow; amodiaquine, praziquantel, albendazole, thiabendazole), low-clearance drugs (int drug categories. The identified CYPs for some of the drugs provide a basis for how these drugs are expected to behave pharmacokinetically and help in predicting drug-drug interactions in vivo.
SELECTIVE ACYLATIONS OF AMINOPHENOLS AND HYDROXYALKYLPHENOLS WITH 1-ACETYL-v-TRIAZOLOPYRIDINE.
Paradisi, Mario Paglialunga,Zecchini, Giampiero Pagani,Torrini, Ines
, p. 5029 - 5032 (1986)
The title triazolide serves as a convenient reagent for highly chemoselective acetylations of aminophenols and hydroxyalkylphenols.
