What Is a Salicylate Allergy?

Salicylate is one of the commonly used drugs in the clinic. For long-term use in large doses, ototoxic side effects can occur when the salicylic acid serum concentration exceeds 1.45m mol / L. Salicylate is mainly excreted by the kidney. After oral administration, those with normal renal function can be seen in the urine within a few minutes. It can excrete about -half of the poisoning amount in 24 hours. If the urine is alkaline (pH 7.5 or higher), excretion is accelerated 3 Times, 6h can reduce the salicylate in the blood-half. Salicylate poisoning is mostly caused by excessive doses or long-term large-scale application. Salicylates can pass through the placental barrier. Pregnant women take too much and often cause fetal or neonatal poisoning. Sick children may have symptoms such as sweating, high fever, dehydration, respiratory alkalosis or metabolic acidosis, and may have hematuria, proteinuria, uremia, etc .; or cause transaminase increase and jaundice; or nosebleeds, retinal bleeding , Vomiting blood, blood in the stool, and bleeding in other parts of the body, and even cerebrospinal fluid is yellow.

Chinese name: Salicylate

English name: salicylic acid

Salicylate I. Basic content

Chinese name: Salicylic acid

Foreign name: salicylicacid

Alias: o-hydroxybenzoic acid

Molecular formula: C7H6O3

Relative molecular mass: 138

Chemical Category: Organic Matter--Organic Acid

Salicylate 2. Common Salicylic Acids

1. Sodium salicylate, also called sodium salicylate, is commonly used in clinical tablets, with antipyretic and analgesic effects. Clinically used to treat negative damp heat. The dosage is: 0.6-0.9g / time for adults, 3-4 times / day, 0.1-0.15g for children. Take 4 oral doses. Because oral administration is more irritating to the stomach, it is often taken with sodium bicarbonate.
2. Aspirin, also known as acetylsalicylic acid, vinegar acid. Aspirin has antipyretic, analgesic, and anti-rheumatic effects. It is often used for colds, headaches, neuralgia, joint pain, and active rheumatism. It is often made into tablets for clinical application. -General antipyretic dose: 0.3-0.6g / time for adults, 4 times a day, 0.66g / year / time for children; anti-rheumatic dose; 0.6-0.9g / time, 3-4 times / day for adults, children 0.1-0.15g / day, orally in 4 times.
3. Aspirin, phenacetin and caffeine are made into tablets, which is compound aspirin (compound acetylsalicylic acid), which is often used to treat colds and headaches.
4. Phenyl salicylate, also known as salo, can be used as a urethral elimination agent.
5. Methyl salicylate is a volatile oil in holly leaves, so it is also called winter green oil, which has a strong stimulating effect on the kidneys. It is used to treat arthritis and rheumatism.

Clinical manifestations of salicylate three and salicylate ototoxicity

1. Tinnitus is often the first symptom and is more pronounced;

2. Mild to moderate hearing loss;

3. After stopping the drug, tinnitus and hearing loss are reversible;

4. The vestibule is not affected;

The animal model of tinnitus induced by salicylate is the most commonly used and effective method to explore the mechanism of tinnitus. The effects of salicylate on auditory electrophysiology, inner ear morphology, and the possible sites and mechanisms are summarized.

Effects of salicylate IV and salicylate on auditory electrophysiology

Effect on Cochlear Compound Action Potential-A fixed dose of salicylate can cause an increase in the CAP threshold. The artificial extralymphatic solution containing 10 mM sodium salicylate was infused into the guinea pig drum stage, and it was found that the 2-24kHZ CAP threshold increased rapidly by an average of 44dB, and the threshold increased around 7Z11 after perfusion. ; The study also found that the effect of salicylate on the increase of the CAP threshold was dose-dependent. The average increase of the CAP threshold after perfusion with artificial extralymphatic fluid containing SinM and ZmM sodium salicylate was 44 dB and 17 dB, respectively.

Salicylate five, salicylate poisoning

Causes of Salicylate (1)

Salicylate poisoning is mostly caused by excessive doses or long-term large-scale application. External salicylic acid ointment or powder can be absorbed and poisoned through the skin on large areas of skin damage. Patients with dehydration, liver and kidney dysfunction, and hypothrombinemia are more prone to severe toxic reactions. Salicylates can pass through the placental barrier. Pregnant women take too much and often cause fetal or neonatal poisoning ^[1] .

Ingestion of aspirin or sodium salicylate in children 2 to 4 times the amount can cause symptoms of poisoning. The minimum lethal dose of aspirin is 0.3 to 0.4 g / kg. The minimum lethal dose of sodium salicylate is about 0.15g / kg, and the lethal dose of pediatric wintergreen oil is about 4ml.

() Salicylate (II) Pathogenesis

After oral administration of salicylates, they are quickly absorbed by the stomach and upper small intestine. After 2 hours, the plasma concentration reached a peak. Salicylate is mainly excreted by the kidney. After oral administration, those with normal renal function can be seen in the urine within a few minutes. It can excrete about -half of the poisoning amount in 24 hours. If the urine is alkaline (pH 7.5 or higher), excretion will be accelerated 3 Times, 6h can reduce the salicylate in the blood-half.

The pathophysiological changes caused by poisoning mainly include the following aspects:

1. Respiratory alkalosis The high concentration of salicylate stimulates the respiratory center and hyperventilation occurs. As a result, a large amount of CO2 is expelled in the breath, which causes respiratory alkalosis (blood pH rise), which is more common in children over 5 years old.

2. Metabolic acidosis With the above-mentioned central pathophysiological changes, kidney compensation occurs due to the presence of respiratory alkalosis, and as a result, potassium and sodium are excreted in large quantities with urine; meanwhile, vomiting, water loss, sodium loss, and water Inhibition of salicylate on dehydrogenase and aminotransferase, blocking the tricarboxyl cycle, disturbing the metabolism of carbohydrates, eventually leading to the rise of blood ketones and the formation of metabolic acidosis. Especially in infancy, the pathophysiological process in the second stage develops rapidly, making acidosis a major manifestation.

3. The toxic dose of salicylate in peripheral circulation failure can directly affect the vascular smooth muscle, expand the surrounding blood vessels and lower the blood pressure; and can paralyze the vascular movement center, leading to peripheral circulation failure.

4. Hemorrhage-prone whole blood reduces salicylate and can inhibit liver prothrombin synthesis. Aspirin also affects platelet function. Such as the formation of ATP, are all factors that cause bleeding tendency. Aspirin is a weakly acidic substance that has a stimulating effect on gastric mucosa. Long-term oral administration can induce gastrointestinal ulcers and chronic bleeding. It can also cause severe anemia and even decrease in whole blood due to the suppression of bone marrow hematopoiesis.

5. Kidney damage can cause salicylate poisoning. Kidney damage, severe tubular necrosis can occur, leading to acute renal failure. Long-term high-dose application can cause changes in renal nipples, tubular necrosis, renal degeneration, and atrophy.

6. Hepatitis, encephalopathy and allergic reactions Aspirin can cause hepatitis, encephalopathy and allergic reactions.

In acute poisoning, the pathophysiological changes are mainly 1, 2 and 2.

Symptoms of Salicylate (3)

The most common symptoms are nausea, vomiting, abdominal pain, headache, dizziness, drowsiness, deep breathing, tinnitus, deafness, and visual disturbances. Began to look flushed. Later, the skin becomes pale, lips cyanosis, and body temperature is lower than normal. Sick children may have symptoms such as sweating, high fever, dehydration, respiratory alkalosis or metabolic acidosis, and may have hematuria, proteinuria, uremia, etc .; or cause transaminase increase and jaundice; or nosebleeds, retinal bleeding , Vomiting blood, blood in the stool, and bleeding in other parts of the body, and even cerebrospinal fluid is yellow. Because salicylate can pass through the placenta quickly and its concentration in the newborn's plasma is higher than the plasma concentration of the pregnant woman, pregnant women in labor can cause newborn bleeding after taking aspirin. Children with severe poisoning may have delirium, hallucinations, mental disorders, muscle tremors, and even convulsions, coma, shock, pulmonary edema, and respiratory failure. Children allergic to this product can cause asthma, hemoptysis, hemoptysis, rash, epidermal necrosis, purpura, edema, or glottic edema and throat spasm caused by a small amount of aspirin.

Effects of Salicylate VI, Salicylate on Bacteria

The effects of salicylate preparations and their related compounds on different bacteria are diverse, or even opposite. -On the one hand, it can inhibit the growth of bacteria, reduce the production of bacterial virulence factors, play an antibacterial role, and increase the sensitivity of bacteria to certain antibacterial drugs; on the other hand, it can also induce a variety of bacteria to produce certain antibacterial agents. Drug resistance, thereby reducing the antibacterial activity of antibacterial drugs ^[2] .

1. Effect on bacterial virulence factors and bacterial growth

Bacterial virulence factors are associated with bacterial infection in the host. -In general, bacterial virulence factors include bacterial pili, flagella, capsular polysaccharides, mucus, biofilms, etc., and are related to bacterial adhesion, iron acquisition, and avoidance of host immune mechanisms. Salicylate can reduce the production of bacterial virulence factors.

Fimbriae is very important for E. coli to adhere to the surface of epithelial cells, and the pilus synthesis of E.coli growing in salicylates is reduced. Taking salicylates may prevent certain fimbriae-infected E. coli infections. Salicylates can also prevent E. coli from sticking to silicone catheters. Using salicylate-coated catheters may prevent iatrogenic E. coli infections. Klebsiella pneumoniae has a reduction in capsular polysaccharide synthesis under the action of salicylate, and the ability of Klebsiella pneumoniae to lose host defense mechanism is reduced. Salicylates can reduce the synthesis of extracellular polysaccharides used by P. aeruginosa and S. epidermidis to form biofilms. Abnormal biofilm formation prevents these bacteria from sticking to contact lenses and other medical devices. Biofilms can produce extracellular mucus, which contains polysaccharides, teichoic acid, and proteins. The synthesis of mucus-related proteins and teichoic acid of Staphylococcus epidermidis is inhibited by salicylates. The use of salicylate-coated contact lenses and medical devices can prevent the infection of these microorganisms.

Bacterial chemotaxis is achieved by regulating the rotation of flagella. When the flagella rotates counterclockwise, the bacteria swim along a linear orbit; when they rotate clockwise, the bacteria assume a flipping motion. Salicylate can prolong the flipping motion of E. coli, and finally remove E. coli from salicylate, and can inhibit the group swimming of E. coli in a dose-dependent manner. At the same time, salicylate can also inhibit the production of E. coli by inhibiting the production of flagellin, the monomer that constitutes flagella. It has also been speculated that salicylates inhibit the synthesis and movement of E. coli flagella because it reduces the synthesis of the outer membrane protein OmpF, which is necessary for assembling flagella. In addition, the movement of common proteobacteria and Proteus miekiensis, Providencia reesei, Providencia sclerotii, and Pseudomonas onion grew in varying degrees in salicylate. This effect is reversible and dose-dependent.

Flagella is an important virulence factor for some bacteria. For example, sheathed flagella are one of the virulence factors that Helicobacter pylori mediates to infect infections. Bismuth salicylate can be partially converted to salicylate at the infection site, and has been used to treat Helicobacter pylori infection. The drug's elimination of Helicobacter pylori infection may be due in part to salicylates that can reduce H. pylori viability. In addition to activating the system's acquired resistance pathways, salicylates produced by plants may also reduce the movement of flagellated plant pathogens such as Pseudomonas onion, thereby reducing the pathogenic capacity of these pathogenic microorganisms.

In recent years, studies have found that under the conditions of in vitro culture, sodium salicylate, aspirin, indomethacin and selective cyclooxygenase 2 inhibitor SC-236 not only inhibit the growth of H. pylori in a dose-dependent manner, but also It has bactericidal activity at larger doses. Further research has also shown that aspirin and related compounds can reduce urease and vacuolar toxin activity in a dose-dependent manner, thereby reducing the pathogenicity of H. pylori.

Bacterial iron is essential for the survival of bacteria.Some bacteria, such as Pseudomonas onion, Pseudomonas aeruginosa, and Mycobacterium tuberculosis, can produce certain substances that can bind to iron. Cases survive. Studies have shown that salicylate can participate in the synthesis of cheloflavin from Pseudomonas aeruginosa, which is beneficial to the survival of bacteria.

2. Effects on the development of multiple antimicrobial resistance in bacteria

Some bacteria growing in salicylates have increased resistance to antimicrobials. Generally, bacteria's resistance to antibacterials is derived from the acquisition of foreign genes on the one hand and mutations on their own chromosomal genes on the other. In most cases, salicylate-induced bacterial resistance is caused by altering bacterial membrane protein synthesis, thereby reducing drug accumulation in bacteria.

Salicylates increase the resistance of Gram-negative E. coli to ampicillin, cephalosporins, fluoroquinolones, tetracycline, chloramphenicol, and nalidixic acid. This may be because salicylates can promote the transcription of multi-antibiotic resistance genes (mar) of E. coli, which in turn leads to increased expression of the MarA protein and induces increased expression of proteins with multi-drug outflow pump function (TolC and AcrAB) To reduce the synthesis of the outer membrane protein OmpF associated with the passive diffusion of antibacterials into the bacteria, thereby reducing the accumulation of antibacterials in the bacterial cells.

Salicylate can also increase the resistance of other Gram-negative bacteria to antimicrobials. Studies have shown that salicylates increase the resistance of Salmonella typhimurium to chloramphenicol and enoxacin, and the mechanism is related to the sal regulators inducing the mar regulator of Salmonella typhimurium. Under the influence of salicylates, Klebsiella pneumoniae has increased resistance to B-lactams, clindamycin, tetracycline, norfloxacin, etc., which may be an increase in salicylates- The expression of a RamA homologous to MarA caused a decrease in the synthesis of two porins (porinA and pofinB), and eventually affected the aggregation of antibacterial drugs in bacteria. Pseudomonas aeruginosa growing in salicylates showed increased resistance to B-lactams, phenylureas, and quinolones. Studies have found that this increase in drug resistance is related to the outflow on the outer membrane of the bacteria. The increase in the expression of the pump-functioning outer membrane protein OprN is related to the decrease in the levels of OprD and OprJ that may have porin on the outer membrane of bacteria. Under the action of salicylates, P. sphaeroides increased resistance to chloramphenicol, ciprofloxacin, and trimethoprim, and the expression of 39.68ku (40kDa) OpcS protein on its outer membrane decreased, while This outer membrane protein may be a porin that is selectively permeated by an antibacterial agent on the outer membrane of P. onion, which is related to the entry of the antibacterial agent into the outer membrane of the bacteria. Salicylates can transform Acinetobacter baumannii from imipenem (sensitive strains to resistant strains, and at the same time, lack of resistant strains after treatment with salicylates-species 28.77ku (29kDa) outer membrane Protein expression. Salicylates can also reduce the permeability of cephalosporins of different strains of C. freundii to cephalosporins, which may be related to the outer membrane of the bacteria 44.64ku (45kDa). Protein expression is related to decline; research has also found that salicylates can reduce B-lactamase activity of C. Freundii and increase the resistance of the bacteria to cephalosporins. Under the action of salicylates, OmpC on the outer membrane of the bacteria increases and OmpF decreases. Salicylates can also increase the oxygen consumption of Mycobacterium tuberculosis and produce multiple antimicrobial resistance. Gene chip research found that Salicylates can induce the expression of L protein and efflux pump genes in the outer membrane of Mycobacterium tuberculosis. Salicylates can also down-regulate bacteria's genes related to RNA, protein and ATP synthesis, thereby turning off transcription, translation and energy. produce.

It has been reported in the literature that salicylate or acetylsalicylate does not change ciprofloxacin or melo for gram negative bacteria such as Pseudomonas aeruginosa, Serratia marcescens and common proteus. The minimum inhibitory concentration of cilin. For Gram-positive bacteria such as Staphylococcus aureus, salicylate can increase its resistance to fluoroquinolones and fusidic acid. Salicylates can increase the frequency of fusidic acid-sensitive Staphylococcus aureus to become resistant strains, and can also increase the resistance level of resistant strains. Similarly, salicylate can increase the frequency of staphylococcus aureus sensitive to fluoroquinolones. The mutation that caused S. aureus resistance to fusidic acid and fluoroquinolones was located at an unrelated site of S. aureus chromosomes, and was not related to the multidrug outflow pump NorA.

3. Effect on the sensitivity of certain bacteria to antibacterials

Salicylates may play an auxiliary role in the treatment of certain bacterial infections.For example: salicylates can enhance the antibacterial activity of aminoglycoside antibacterials against E. coli and Klebsiella pneumoniae. As the salicylates dissociate after entering the bacteria, the membrane potential of the outer membrane of the bacteria is increased, thereby increasing the permeability of the outer membrane of the bacteria to the drug, which is beneficial for the drug to enter the bacteria. In a mouse model that treats Klebsiella pneumoniae infection with amikacin, the simultaneous use of salicylate can increase its efficacy. Similarly, in the rabbit model experiment of Staphylococcus aureus infective endocarditis, the combined application of aspirin can improve the efficacy of vancomycin. Staphylococcus aureus growing in salicylic acid has reduced resistance to fluoroquinolones and fusidic acid. When the salicylate or similar compound ibuprofen is added, the antifungal drug fluconazole has enhanced antibacterial activity against Candida albicans in vitro. Metronidazole, amoxicillin and clarithromycin are clinically used in the eradication of Helicobacter pylori. Recent studies have found that aspirin, indomethacin, and SC-236 can reduce the in vitro MIC of these three antibacterial drugs against Helicobacter pylori, thereby increasing the sensitivity of Helicobacter pylori to these three antibacterial drugs, and even making resistant strains Change to a sensitive strain.