Nonsteroidal anti-inflammatory drugs ibuprofen

Figure 29 Separation of the nonsteroidal anti-inflammatory drugs ibuprofen (peak 1), naproxen (2), ketoprofen (3), and suprofen (4) in anion-exchange CEC mode using a strong anion-exchange monolithic column. Conditions on-column alkylated monolith prepared from mixtures consisting of 8% 2-dimethylaminoethyl methacrylate, 24% 2-hydroxyethyl methacrylate, 8% ethylene dimethacrylate, 20% cyclohexanol, 40% 1-dodecanol UV-initiated polymerization at room temperature for 16 h cfpmode= 1423 nm. Column dimensions inner diameter 0.1 mm, total length 335 mm, effective length 250 mm. Mobile phase 0.4 mol/L acetic acid and 4 mmol/L triethylamine in acetonitrile/methanol (60/40), voltage -25 kV, injection -5 kV for 5 s, temperature 50°C, UV detection at 250 nm. (Reprinted from Ref. 127, with permission.)...

P6-26o A new catalytic pathway for an important intermediate in the production of the nonsteroidal anti-inflammatory drug ibuprofen (e.g., Advil) has been developed/CAer/j. Eng. Set, 51, 10, 1663(1996)]. The pathway involves the hydrogenation of p-isobutyl acetophenone (B) in a solution of methanol containing a HY zeolite catalyst and saturated with hydrogen. The intermediate products are p-isobutylphenyl ithanol (C), p-iscbutylphaiylethylnEtl lether (E) and p-isobutylethyl benzene (F). The reaction scheme is shown below. 

Antidepressants selective serotonin reuptake inhibitors, tricyclic antidepressants Antihypertensives felodipine Antibiotics quinolones, isoniazid Bronchodilators albuterol, theophylline Corticosteroids prednisone Dopa agonists levodopa Herbals ma huang, ginseng, ephedra Nonsteroidal anti-inflammatory drugs ibuprofen Stimulants amphetamines, methylphenidate, caffeine, cocaine Sympathomimetics pseudoephedrine Thyroid hormones levothyroxine Toxicity anticholinergics, antihistamines, digoxin Withdrawal alcohol, sedatives... 

Nonsteroidal anti-inflammatory drugs ibuprofen, ketoprofen, naproxen sodium Alternative mefenamic acid, acupuncture Bloating/fluid retention Sodium reduction/restriction Spironolactone... 

As a model nonsteroidal anti-inflammatory drug ibuprofen was chosen. It is very effective for the systemic treatment of rheumatoid arthritis, osteoarthritis, and ankylosing spondylitis. It is almost insoluble in water (1.74 x IQ- mol L ) [30], while its solubility in IPM is 0.160 + O.OlSg mL [31]. As a weak acid (pK = 4.4) its solubility increases with increasing pH. Ibuprofen shows a considerable surface activity [32] that could contribute to its enhanced permeation through biological membranes [33]. The release profiles of tested ME samples are shown in Figure 10.10a. 

Carboxylic acids can he prepared from nitriles by heating with aqueous acid or base by a mechanism that we ll see in Section 15.7. Since nitriles themselves are easily made by Sn2 reaction of a primary or secondary alkyl halide with CN , the two-step sequence of cyanide displacement followed by nitrile hydrolysis is a good way to make a carboxylic acid from an alkyl halide (RBr RC=N RCO2H). Note that the product acid has one more carbon than the starting alkyl halide. An example occurs in one commercial route for the synthesis of the nonsteroidal anti-inflammatory drug ibuprofen. 

Like aspirin, ibuprofen is a nonsteroidal anti-inflammatory drug. It is a cyclooxygenase inhibitor that interferes with COX-1 and COX-2 forms of that enzyme. Its effects on COX-2 give it fever-reducing (antipyretic), analgesic (pain relief), and anti-inflammatory functions. 

Another vasoactive substance produced by the endothelium is thromboxane A2 (TxA2). Normally, small amounts of TxA2 are released continuously however, increased synthesis appears to be associated with some cardiac diseases. Synthesized from arachidonic acid, a plasma membrane phospholipid, TxA2 is a potent vasoconstrictor. Furthermore, this substance stimulates platelet aggregation, suggesting that it plays a role in thrombotic events such as myocardial infarction (heart attack). Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen block formation of TxA2 and reduce formation of blood clots. 

In addition to their beneficial effects, some medications may actually cause cellular injury and disease. An example of this phenomenon involves nonsteroidal anti-inflammatory drugs (NSAIDS). These drugs include aspirin (a derivative of salicylic acid), ibuprofen (arylpropionic acid, Advil ), and acetaminophen (para-aminophenol derivative, Tylenol ). Because of their beneficial pharmacological effects, consumption of these agents has increased significantly in recent years. NSAIDS have the ability to treat fever, pain, acute inflammation, and chronic inflammatory diseases such as arthritis. They are also used prophylactically to prevent heart disease, stroke, and colon cancer. 

Many nonsteroidal anti-inflammatory drugs (NSAIDs) are substituted 2-arylpropionic acids. Most NSAIDs also have a chiral carbon next to the carboxylate and are administered as a racemic mixture of the two enantiomers. In general, the (S)-enantiomcr is responsible for most of the antiinflammatory activity of these agents. It was found that the (/ -enantiomer is converted to the (S)-enantiomer but the reverse does not occur (23). As with amino acid conjugation, the pathway involves reaction with ATP to form an AMP ester, which is, in turn, converted to a Co-A ester, and it is the Co-A ester that undergoes chiral inversion (Fig. 7.14). Substrates include ibuprofen, naproxen, and fenoprofen. 

Analysis of non-steroidal anti-inflammatory drugs (ibuprofen, ketoprofen, naproxen, fenoprofen, flurbiproen, and suprofen) Impurity profiling of ketorolac, a chiral nonsteroidal antiinflammatory drug Impurity profiling of a non-steroidal analgesic drug... 

For therapeutical purposes, a likewise frequently used group of drug compounds are the nonsteroidal anti-inflammatory drugs (NSAID). Among the best known representatives of the aryl acetic acid derivatives is diclofenac as well as ibuprofen, an aryl propionic acid derivative. As both have acidic properties, they dissociate while being dissolved and may form salts with amphiphilic properties. Together with appropriate counterions these amphiphilic organic acids may form lyotropic mesophases with water even at room or body temperature, for example, diclofenac diethylamine... 

Lithium toxicity can occur as a result of intentional overdose therefore, care must be taken when administering lithium to potentially suicidal patients with BPAD. Inadvertent lithium toxicity may also occur. For example, diuretics and nonsteroidal anti-inflammatory drugs such as ibuprofen (Advil, Motrin) slow the excretion of lithium and can lead to accidental toxicity. Consequently, the patient should be advised not to take such commonly available medications while treated with lithium. In addition, dehydration resulting from varied causes such as diarrhea, vomiting, and profuse sweating can lead to accidental lithium toxicity. One should advise the patient who takes lithium to be careful to remain well hydrated at all times and to contact his/her physician if any medical condition arises that may cause rapid fluid losses (e.g., stomach virus, high fevers). 

We do not recommend the routine use of selegiline, nonsteroidal anti-inflammatory drugs like ibuprofen, or herbs such as ginkgo biloba for patients with dementia. These all have the potential for problematic side effects that may outweigh their benefit. If they are used, please be sure that a physician closely monitors your patient. 

Most of the nonsteroidal anti-inflammatory drugs (NSAIDs) are carboxylic acids. Aspirin (8.69) (acetylsalicylic acid, ASA) has been used since the turn of the last century to reduce pain and fever, but the parent compound, salicylic acid, has been known and used since antiquity, owing to its common occurrence as a glycoside in willow bark. Acetylation merely decreases its irritating effect. Among the numerous other salicylates known and used, flufenisal (8.70) has a longer duration of activity and fewer side effects than aspirin. Mefenamic acid (8.71) and flufenamic acid (8.72) are derivatives of anthranilic acid, while ibuprofen (8.73) and naproxen (8.74) are derivatives of phenylacetic and naphthylacetic acids, respectively. 

Nonsteroidal anti-inflammatory drugs [P] Inhibition of platelet function, gastric erosions some agents increase hypoprothrombinemic response (unlikely with diclofenac, ibuprofen, or naproxen). 

The enzymatic enantioselective hydrolysis of esters of naproxen and ibuprofen has attracted considerable attention because the (S)-enantiomers of these nonsteroidal anti-inflammatory drugs (NSAIDs) are the pharmacologically active isomers. These reactions have been successfully performed in a range of ionic liquids (Figure 10.10) [60, 65, 121]. 

Despite the resolving power of TLC-MS-MS, few applications in drug residue analysis have been reported. One application concerns the HPTLC-MS-MS analysis of a number of nonsteroidal anti-inflammatory drugs, including salicylic acid and its glycine conjugate salicylhippuric acid, diclofenac, indomethacin, naproxen, phenacetin, and ibuprofen (67). Another application describes the detection and identification of some of these compounds or their metabolites in urine by TLC-MS-MS (67). 

Clinical use Ibuprofen (Busson, 1986) is a nonsteroidal anti-inflammatory drug, commonly used for the treatment of mild to moderate pain. It is used in conditions like rheumatoid arthritis, osteoarthritis, joint and soft tissue pain, dental pain, postoperative pain, dysmenorrhoea and headache, including acute migraine attacks. 

Since most codeine is dispensed as part of a compound preparation, potential side effects of the other drug(s) must also be considered. For instance, someone with stomach ulcers should not take codeine that is combined with a nonsteroidal anti-inflammatory drug (NSAID) such as aspirin or ibuprofen. Another type of risk from a compound preparation relates to codeine abuse. For instance, a person who abuses codeine might routinely take a dose of 100-200 mg of codeine to produce noticeable euphoria. Using Tylenol 3 to obtain this dose would also mean ingesting 1,000-2,000 mg of acetaminophen. Taking that amount of acetaminophen for any extended period presents a risk for liver damage, especially in combination with alcohol. 

The first example of process intensification at DSM is the pilot-scale test of the enzymatic production of S-ibuprofen, a nonsteroidal, anti-inflammatory drug. The molecular scheme is given in Figure 5. More details can be found in Refs. 3 and 4. 

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