Chemical tests and reagents. Related item. Electronic books. Internet Resources. A Metabolism in Crops study should be submitted for each type of crop group. Five categories for crop metabolism studies can be considered: root vegetables, leafy crops, fruits, pulses and oilseeds, and cereals. It should be labelled, to allow for quantification; the preferred radioisotope is 14C, although 32P, 35S can be used.
The study should be performed using a sandy loam soil treated with the radiolabelled test substance.
- Prostaglandins, thromboxanes and leukotrienes in clinical medicine.!
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It may be performed either in a greenhouse or in an outdoor test plot or plant growth chambers. Back to results. University of Bath Library. City, University of London. University of Glasgow Library. University of Hull.
Leukotriene - Wikipedia
Imperial College London Library. LSE Library. University of Leeds Library. Nevertheless, taking into consideration the higher cost involved and the potential for adverse cardiovascular effects, they should be employed only in accordance with strict criteria. Key words: Nonsteroidal antinflammatories, COX 2 inhibitors, indications, adverse effects. Nonsteroidal anti-inflammatory drugs NSAID comprise a heterogeneous group of medications, the majority of which are organic acids with analgesic, antipyretic and anti-inflammatory actions. These drugs are widely used to control fever and acute or chronic pain.
When there is damage to the cell membrane, which is basically made up of phospholipids, the enzyme phospholipase A2, which is present in leukocytes and platelets, is activated by proinflammatory cytokines, such as interleukin IL This enzyme leads to the degradation of phospholipids, resulting in production of arachidonic acid. This, when metabolized, forms leukotrienes through the action of the enzyme lipoxygenase, and prostaglandins, prostacyclins and thromboxanes, through the action of the cyclooxygenase enzyme COX.
COX is the first enzyme involved in producing prostaglandins from arachidonic acid. These prostaglandins are later transformed by isomerases into prostacyclin, thromboxane A2, and prostaglandins D2, E2 and F2 a. Prostaglandin E2 is important because of its pyrogenic action and in increasing sensitivity to pain.
Arachidonic acid also leads to production of leukotrienes, via lipoxygenase enzyme Figure 1. Whereas COX 1 has 17 amino acids at the terminal amino section, COX 2 has 18 amino acids at the terminal carboxyl section.
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Although they are very similar in terms of their protein structure, these enzymes are coded by different genes. COX 1 is present in almost all tissues blood vessels, platelets, stomach, intestine, kidneys and, for this reason, is defined as a constitutive enzyme. Cyclooxygenase 1 is associated with prostaglandin production and results in a variety of physiological effects, such as gastric protection, platelet aggregation, vascular homeostasis and maintenance of renal blood flow.
In contrast, COX 2 is present at the site of inflammation, and because of this is defined as an inducible enzyme.
It is primarily expressed by cells that are involved in the inflammatory process, such as macrophages, monocytes and synoviocytes. Nevertheless, it is known that COX 2 can also be found in other tissues and organs, such as kidneys, brain, ovaries, uterus, cartilage, bones and vascular endothelium. It is probably also expressed in the central nervous system and plays a role in central mediation of pain and fever.
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Prostaglandins are involved in several physiological and pathological processes, including vasodilation or vasoconstriction, contraction and relaxation of bronchial or uterine musculature, hypotension, ovulation, bone metabolism, increase in renal blood flow resulting in diuresis, natriuresis, caliuresis and stimulation of renin secretion , suppression of gastric acid secretion, immunoresponse, hyperalgesia, regulation of chemotactile cellular activity, endocrine response and angiogenesis, among others.
In the gastrointestinal tract, prostaglandins I2 and E2 are cytoprotective of the gastric mucosa - because they suppress acid secretion, increase local blood flow, provoke mucus production and increase synthesis of glutathione and consequently the capacity to eliminate free radicals and because they increase bicarbonate synthesis and blood flow to the surface layers of the gastric mucosa.
In the kidneys they increase glomerular filtration because of their vasodilator effect. Finally, within the cardiovascular system, they can cause several hemodynamic effects, such as vasodilation.
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They also provoke smooth muscle relaxation. Thromboxane A2 a substance that promotes coagulation is produced from platelet COX, and acts as a potent aggregant agent. Prostaglandins also have pathophysiologic effects such as erythema and increased local blood flow, hyperalgesia, probably due to sensitization of pain receptors, and increased body temperature at the hypothalamus through cytokine stimulation. When prostaglandin production is increased, there is increased sensitivity to pain and fever and increased inflammatory response.
Nevertheless, prostaglandins are also capable of anti-inflammatory action due to suppression of IL-1 and TNF synthesis. The mechanism of action of NSAIDs consists in suppression of COX enzymes, resulting in reduction of the production of prostaglandins, thus controlling inflammation, pain and fever.
COX 1 inhibition is associated with increased risk of gastrointestinal bleeding and damage. Selective and specific COX 2 inhibitors were developed in an attempt to reduce the incidence of adverse effects of COX 1 inhibition. The NSAID dose necessary to reduce inflammation is larger than that needed to inhibit prostaglandin formation, suggesting that other mechanisms mediate the anti-inflammatory effects.
In addition to suppressing prostaglandin production, current anti-inflammatories inhibit specific proteases involved in breaking down proteoglycans and collagens in cartilage, and inhibit the generation of oxygen free radicals, particularly superoxide. A study of 11 children with neoplasias assessed the pharmacokinetics of celecoxib. They also observed that absorption of the medication is optimized when taken with a fat-rich meal. In a study undertaken with 18 patients with juvenile rheumatoid arthritis, the pharmacokinetics of meloxicam suspension was evaluated, with greater elimination of the medication being observed in the younger children, although with a similar half-life to other age groups.
The most common indications for NSAIDs in childhood and adolescence are control of fever, acute and chronic pains and inflammation. Acetylsalicylic acid, naproxen, ibuprofen and tolmetin are the only ones approved for pediatric use by the Food and Drug Administration FDA. Despite not being licensed for the pediatric age group, indomethacin is used to control fever and pain in children and adolescents with juvenile idiopathic arthritis JIA.
Selective COX 2 inhibitors are indicated for patients who exhibit adverse effects that are confirmed to be related to nonselective NSAID use, such as gastric intolerance that cannot be controlled by combination with gastroprotective medication. In the pediatric age group, the use of COX 2 is limited since a majority of these medicines are contraindicated before 18 years of age. Nonsteroidal anti-inflammatories are routinely employed by many specialties. Pediatricians, otorhinolaryngologists, rheumatologists, gynecologists and orthopedists prescribe these medicines the most often.
We should be cautious when prescribing NSAIDs for atopic patients with sensitivity to acetylsalicylic acid ASA , since there is a possibility of exacerbating the allergic condition. It is important to point out that this recommendation is based on the results of few studies involving small numbers of patients, and there are reports of sporadic cases with significant worsening of asthma with the use of selective COX 2 inhibitors.
Martin-Garcia et al. Only the subset given rofecoxib did not exhibit any exacerbation of preexisting asthma. Etoricoxib, another selective COX 2 inhibitor, was also shown to be safe when used on patients with urticaria and angioedema. Urticaria exacerbation related to nonselective COX inhibitors has been known for a long time. Nonselective anti-inflammatories are COX inhibitors and the theoretical explanation for this mechanism may be based on the fact that these enzymes are responsible for synthesis of proinflammatory PGD 2 and anti-inflammatory prostaglandins PGE 2.
PGE 2 inhibits synthesis of leukotrienes LTB 4 ; therefore blocking production of PGE 2 could increase production of leukotrienes, with deterioration of clinical symptoms. There is no overwhelming evidence that demonstrates the superiority of one NSAID over another in terms of effectiveness and, very often, the choice is based on lower frequency and intensity of side effects and on the cost of the medication. Although age over 60 years, previous history of gastrointestinal complications and concurrent corticosteroid use are the principal risk factors for severe gastrointestinal complications from NSAID use, we must not forget that chronic use of these medicines can result in esophagitis, gastritis or duodenitis, gastric or duodenal ulcers, even if subclinical, in children and adolescents.
Although in general children complain less than adults, especially about gastropathy secondary to NSAID use, this does not mean that they are free from endoscopic lesions, as has been demonstrated. The major debate and the greatest uncertainties perhaps reside in sporadic or short-term a few days use of NSAIDs.
What are the true risks? There are no studies in the literature that prove the safety of these medications under these treatment regimes. This does not rule out the possibility of erosive damage and even bleeding from gastro-duodenal mucosa after three or four doses. Advanced age, previous peptic ulcer, previous bleeding and concurrent use of another NSAID or corticosteroids are risk factors for gastric complications such as mucosal ulceration, reflux esophagitis, esophageal thinning and peptic ulcers.
Nevertheless, although some studies have reported lower frequencies of gastrointestinal complications with COX 2 inhibitors than with traditional NSAIDs, recent concerns regarding cardiovascular safety have limited the use of these medications. Conditions such as congestive heart failure, cirrhosis, diabetes, hypertensive nephropathy, advanced age and volume depletion constitute risk factors that can predispose patients to renal complications. Salt retention, acute reversible renal insufficiency and tubulointerstitial nephritis are some of the undesirable effects.
While selective specific COX 2 inhibitors may cause less renal alterations, they are not free from inducing some of these alterations. One study with adults who exhibited "pseudoallergic" reactions to NSAIDs showed that nimesulide and meloxicam were well-tolerated. Hepatic events: liver toxicity with elevated transaminases, cholestasis and necrosis may occur, especially with COX 1 inhibitors.
Central nervous system events: headaches, tingling sensations and dizziness, although possible, are rarely reported by children and adolescents. The most probable hypothesis involves an imbalance between prostacyclin and thromboxane A2. Prostacyclin is a vasodilator and inhibits platelet aggregation and vascular proliferation, while thromboxane A2 causes platelet aggregation, vasoconstriction and proliferation of smooth muscle.
Platelets, which only express COX 1, are the primary products of thromboxane A2, and endothelial cells produce prostacyclin in response to COX 2. In contrast, selective COX 2 inhibitors predominantly suppress prostacyclin, upsetting the balance in favor of thromboxane. In a recent study with 33, patients who presented myocardial infarction, it was observed that any NSAID used at habitual doses can increase the risk of this complication, especially in older patients.
Nonsteroidal anti-inflammatory drugs are contraindicated for children and adolescents in the following situations: dyspeptic syndromes, viral diseases, compromised renal function, cardiac disease, especially congestive heart failure , liver failure, systemic arterial hypertension, coagulation disorders, history of allergic reaction to NSAIDs and the use of oral anticoagulants and hypoglycemic. Nonsteroidal anti-inflammatories bind strongly to plasma proteins and as a result they may displace other medications from their binding sites, which can occurs with methotrexate, phenytoin and sulfonylureas, increasing their activity and toxicity.
Summing up, in general NSAIDs should only be used when there is a precise indication, since they can cause adverse effects even when used for short periods.