Aspirin cases

Among the classic cases in this group are the aspirin cases where a particular degree of purification resulted in effectively a new product because as so purified the material had medicinal uses not previously known. The claim of the Hoffman patent (23) is ... 

This review of some cases based on the aspirin cases is not comprehensive. A complete report on Shepard s Citations 45) on this series alone is very long. 

Aside from the statutory requirements of utility, the other important test of patentability is novelty or unobviousness—whether the substance actually existed in nature and whether or not its isolation was obvious from the prior art. Reverting to the tungsten and aspirin cases, tungsten did exist as such in nature whereas aspirin existed previously only as part of a medically unusable crude composite. 

Esters of the phenohc hydroxyl are obtained easily by the Schotten-Baumaim reaction. The reaction ia many cases iavolves an acid chloride as the acylating agent. However, acylation is achieved more commonly by reaction with an acid anhydride. The single most important commercial reaction of this type is the acetylation of sahcyhc acid with acetic anhydride to produce acetylsahcyhc acid [50-78-2] (aspirin). 

Some of these indazoles showed analgesic activity greater than that of aspirin and several possessed significant antiinflammatory action. Both properties were the most striking and characteristic ones of the series. In a few cases the authors isolated the corresponding indazolones (705) which were less active than (704) in terms of analgesic and antiinflammatory properties. 

The case of intramolecular participation in ester hydrolysis has been extensively studied using acetylsalicylic acid (aspirin) and its derivatives. The kinetic data show that the anion is hydrolyzed more rapidly than the neutral species, indicating that the carboxylate group becomes involved in the reaction in some way. Three mechanisms can be considered ... 

In die case of arthritis, do not change from aspirin to acetaminophen without consulting die primary health care provider. Acetaminophen lacks the antiinflammatory properties of aspirin. 

Three years after introduction of aspirin into therapy, Hirschberg in Poznan, now in Poland, described the first case of a transient, acute angioedema/urticaria, occurring shortly after ingestion of aspirin. Reports of anaphylactic reactions to aspirin soon followed. The other major type of adverse reaction, acute bronchospasm, was described in the second decade of the 20th century. In 1920, Van der Veer reported the first death due to aspirin. The association of aspirin sensitivity, asthma and nasal polyps was first recorded by Widal in 1922. This clinical entity, later named the aspirin triad was popularized in 1968 by Samter and Beers [3], who presented a... 

Cross-reactions with aspirin and NSAIDs are of practical importance. Typically, AIA patients are sensitive to all NSAIDs that preferentially inhibit COX-1 (table 2). Acetaminophen (paracetamol), a weak inhibitor of COX-1, is regarded as a relatively safe therapeutic alternative for almost all patients with AIA. High doses of the drug (>1,000 mg) have been reported to provoke mild, easily reversed bronchos-pasm in some AIA patients [13]. Some rare, well-documented cases of coexistence of aspirin and paracetamol sensitivity have been described. However, according to a recent meta-analysis, less that 2% of asthmatics are sensitive to both aspirin and paracetamol [14]. 

Some patients with chronic idiopathic urticaria develop wheals and even angioedema after aspirin or NSAIDs. In others, aspirin causes an obvious increase in the underlying urticaria. The reaction may occur in just 15 min or up to 24 h following aspirin ingestion, but on average it develops within 1-4 h. Most cases resolve within a few hours, but in severe reactions bouts of multiform skin eruptions, covering most of the body, may continue for 10 days after aspirin intake [8,16,17]. 

Patients with chronic idiopathic urticaria, who develop cutaneous reactions in response to aspirin, display certain similarities in eicosanoid profile with AIA. The mechanism of the reactions is often related to COX-1 inhibition [18]. Therefore, aspirin and all drugs that inhibit COX-1 should be avoided in patients who already have had cutaneous reactions to NSAID. Coxibs are usually well tolerated, although occasional adverse reactions have been reported [19, 20]. For treatment of the reactions, antihistamines are usually sufficient, but in more severe cases adrenaline and corticosteroids may be warranted. 

The GP Ilb-IIIa complex inhibitor Tirofiban has been used as an adjunct to thrombolysis in a number of small case series reports." A small transcranial Doppler (TCD) study suggests that it reduces microembolization from unstable carotid plaque." In an open pilot smdy, Tirohban administered within 9 hours after stroke onset blocked the conversion of ischemic penumbra to mature infarction." A phase III study (SETIS) has started recruiting patients to investigate its efficacy versus aspirin within the 6-hour window. 

Some drugs can cause hyperuricemia and gout, such as thiazide diuretics, niacin, pyrazinamide, cyclosporine, and occasionally, low-dose aspirin. In most cases, these drugs block uric acid secretion in the kidney. Long-term consequences of gout and hyperuricemia include joint destruction, tophi, and nephrolithiasis. 

Pharmaceuticals) Ethinyl oestradiol, paracetamol, aspirin, dextropropoxyphene, clofibrate and oxytetracycline Aire river (UK), Lambro river (Italy) and Rur river (Germany) Surface water - Product consumption - Worst-case influent - Excreted post-metabolism - WWTP removal - River water die-away [50]... 

The solution to this problem is to compare the rate constant for the intramolecular reaction with that for the corresponding intermolecular process. In the case of aspirin hydrolysis [3] this would be general base catalysis of the hydrolysis [5] of aspirin by an external carboxylate group, RCOO-, of the same basicity as the carboxylate group of aspirin. The necessary data are... 

Intramolecular general base catalysed reactions (Section II, Tables E-G) present less difficulty. A classification similar to that of Table I is used, but since the electrophilic centre of interest is always a proton substantial differences between different general bases are not expected. This section (unlike Section I, which contains exclusively unimolecular reactions) contains mostly bimolecular reactions (e.g. the hydrolysis of aspirin [4]). Where these are hydrolysis reactions, calculation of the EM still involves comparison of a first order with a second order rate constant, because the order with respect to solvent is not measurable. The intermolecular processes involved are in fact termolecular reactions (e.g. [5]), and in those cases where solvent is not involved directly in the reaction, as in the general base catalysed aminolysis of esters, the calculation of the EM requires the comparison of second and third order rate constants. 

The case of aspirin in Table 8.3 is of special interest. Indeed, its acetyl ester group is particularly labile to enzymatic and nonenzymatic hydrolysis (see Sect. 7.4), and the reaction is even faster when the carboxy group is neutralized by esterification. A true ester prodrug of acetylsalicylic acid must fulfill the condition that its hydrolysis liberates aspirin rather than a prodrug of salicylic acid. An investigation of several aspirin prodrugs confirmed the interest of carbamoylmethyl esters and showed the (ATV-diethylcarbamoyl)methyl ester (Table 8.3) to liberate the highest proportion (ca. 60%) of aspirin [37], In... 

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