Sulfonamides Sulfamethoxazole

The results showed that the compounds studied with more frequency in the aquatic environment, and of which, logically, there is more information, are the antibiotics, analgesics and anti-inflammatories (like diclofenac, ibuprofen, naproxen, acetylsalicylic acid, and paracetamol), as well as the p-blocker atenolol. In the category of antibiotics, several families are included, like the macrolides (erythromycin), the fluoroquinolones (ofloxacin and ciprofloxacin), sulfonamides (sulfamethoxazole), penicillins (amoxicillin), the metronidazol, and trimethoprim. Other therapeutic groups also widely studied and frequently found in the environmental waters are the lipid regulators (gemfibrozil and bezafibrat), antiepileptic carbamaze-pine, and antidepressants (diazepam, fluoxetine, paroxetine) (see Table 3). 

The chlorination of the antibacterial sulfonamide sulfamethoxazole was initiated by N-chlorination of the primary amine. Further reaction of the A,A-dichlorinated compound resulted in the final production of 3-amino-5-methyloxazole and 1,4-benzoquinone-imine (Dodd and Huang 2004). 

Macrolide antibiotics (clarithromycin, dehydroerythromycin, etc.) and sulfonamides (sulfamethoxazole, sulfadimethoxine, sulfamethazine, and sulfathi-azole) are the most prevalent antibiotics found in the environment with levels around a few micrograms per liter, whereas fluoroquinolones, tetracyclines, and penicillins have been detected in fewer cases and usually at low concentrations (nanograms per liter) [3,20,23,72]. This result is not surprising, since penicillins are easily hydrolyzed and tetracyclines readily precipitate with cations such as calcium and are accumulated in sewage sludge or sediments. Several reviews have reported the environmental occurrence of different antibiotics in aquatic and soil compartments. Some of these data are detailed in Table 1. 

Inhibition of metabolic pathway Sulfonamides Sulfamethoxazole Efflux Altered target... 

Co-trimoxazole is a combination of trimethoprim and the sulfonamide sulfamethoxazole. Since THF synthesis is inhibited at two successive steps, the antibacterial effect of co-trimoxazole is better than that of the individual components. Resistant pathogens are infrequent a bactericidal effect may occur. Adverse effects correspond to those of the components. 

The combination of the antifolate trimethoprim and the sulfonamide sulfamethoxazole constitutes the treatment of choice for PCP. Other effective drugs include pentamidine, alovaquonc. and a new antifolate, trimetrexate. 

Trimethoprim is often given in conjunction with the sulfonamide sulfamethoxazole (Fig. 10.17). The latter inhibits the incorporation of PABA into folic acid, while the former inhibits dihydrofolate reductase. Therefore, two enzymes in the one biosynthetic route are inhibited. This is a very effective method of inhibiting a biosynthetic route and has the advantage that the doses of both drugs can be kept down to safe levels. To get the same level of inhibition using a single drug, the dose level of that... 

Co-trimoxazole (Septrin) is a well-known combination of a sulfonamide (sulfamethoxazole) with trimethoprim. This combination inhibits enzymes at two points of folic acid (32.2) utilisation - the sulfonamide inhibits incorporation of p-aminobenzoic acid during bacterial folic acid synthesis, and trimethoprim inhibits its conversion into tetrahydrofolate. The overall result is synergistic, i.e. there is a greater activity than the sum of the two components. 

Among the isoxazoles, many biologically active compounds are found. Some of them are important as drugs or biocides, e.g. the long-acting sulfonamide sulfamethoxazole 10, the anti-inflammatory isoxi-cam 11, the antiarthritic and antirheumatic leflunomide 12 and the fungicide 3-hydroxy-5-methylisoxazole. 

Trimethoprim frequently is used as a single agent clinically for the oral treatment of uncomplicated urinary tract infections caused by susceptible bacteria (predominantly community acquired Escherichia coli and other Gram-negative rods). It is, however, most commonly used in a 1 5 fixed concentration ratio with the sulfonamide sulfamethoxazole (Bactrim, Septra). This combination is not only synergistic in vitro but also is less likely to induce bacterial resistance than either agent alone. It is rationalized that microorganisms not... 

A monograph (1) covers the pioneering period of sulfa dmg development and describes over 5000 sulfanilamide derivatives, their preparation, properties, trade names, and biological testing. This review is remarkably complete through 1944. Several thousand additional derivatives have been made since, but no comparable coverage is available. A definitive account of medical appHcations up to 1960 has been pubHshed (2), and a review of experimental antibacterial aspects has been made (3). Chapters on general aspects of sulfonamides and sulfones have appeared (4,5). A review of the clinical efficacy of trimethoprim—sulfamethoxazole has been pubHshed (6). 

The sulfa dmgs are stiH important as antimicrobials, although they have been replaced in many systemic infections by the natural and semisynthetic antibiotics. They are of great value in third world countries where problems of storage and lack of medical personnel make appropriate use of antibiotics difficult. They are especially useful in urinary tract infections, particularly the combination of sulfamethoxazole with trimethoprim. Their effectiveness has been enhanced by co-adniinistration with dihydrofolate reductase inhibitors, and the combination of sulfamethoxazole with trimethoprim is of value in treatment of a number of specific microbial infections. The introduction of this combination (cotrimoxazole) in the late 1960s (1973 in the United States) resulted in increased use of sulfonamides. 

Trimethoprim (Trimpex) interferes with the ability of bacteria to metabolize folinic acid, thereby exerting bacteriostatic activity. Trimethoprim is used for UTIs that are caused by susceptible microorganisms. Trimethoprim administration may result in rash, pruritus, epigastric distress, nausea, and vomiting. When trimethoprim is combined with sulfamethoxazole (Septra), the adverse effects associated with a sulfonamide may also occur. The adverse reactions seen with other anti-infectives, such as ampicillin, the sulfonamides, and cephalosporins, are given in their appropriate chapters. 

The answers are 484-k 485-j. (tlardman, pp 1061-1062, 1682-1685.) Sulfonamides can cause acute hemolytic anemia. In some patients it mayr be related to a sensitization phenomenon, and in other patients the hemolysis is due to a glucose-6-phosphate dehydrogenase deficiency Sulfamethoxazole alone or in combination with trimethoprim is used to treat UTls. The sulfonamide sulfasalazine is employed in the treatment of ulcerative colitis. Daps one, a drug that is used in the treatment of leprosy, and primaquine, an anti mala rial agent, can produce hemolysis, particularly in patients with a glucose-6-phosphate dehydrogenase deficiency. 

The antibacterial agent sulfamethoxazole produced chlorinated and nonchlorinated DBFs when reacted with chlorine [91]. A ring-chlorinated product was formed via halogenation of the aniline moiety at sub-stoichiometiic concentrations of chlorine. 3-Amino-5-methylisoxazole, sulfate, and A-chloro-p-benzoquinone imine were formed via rupture of the sulfamethoxazole sulfonamide moiety at stoichiometric excess of chlorine. 

Currently, the most widely used are sulfisoxazole, sulfamethoxazole, sulfadiazine, sul-famethizole, and trisulfapyrimidine (a mixture of sulfamerazine, sulfamethazine, and sulfadiazine). The first two drugs mentioned are the most widely used. The long-lasting sulfonamide (sulfadioxin) is used only in combination with pyrimethamine (an antagonist of folic acid) for prevention and treatment of tropical fever. 

Trimethoprim has a broad spectrum of antimicrobial activity. It is 20-100 times more active than sulfamethoxazole with respect to most bacterial forms. Trimethoprim is active with respect to Gram-positive, aerobic bacteria such as Staphylococcus aureus, Staphylococcus epidermidis, and various types of Streptococcus and Listeria monocytogenes. Trimethoprim is inferior to sulfonamides against forms of Nocardia. It is active... 

Intermediate-acting sulfonamides include sulfadiazine and sulfamethoxazole. Sulfamethoxazole is combined with trimethoprim in co-trimoxazole. Sulfadiazine shows good penetration into the cerebrospinal fluid and is effective for cerebral Toxoplasmosis. It has an elimination half-life 10-17 hours which prolonged in renal impairment. 

Note that in addition to the adverse events due to trimethoprim the combination trimethoprim-sulfamethoxazole may cause all of the untoward reactions associated with sulfonamides. In HIV positive patients the incidence of rashes can increase to 50%. Desensibilisation with increasing doses of co-trimoxazole has been successful. 

Serious adverse effects are rare except in AIDS patients. TMP-SMX can cause the same adverse effects as those associated with sulfonamide administration, including skin rashes, central nervous system (CNS) disturbances, and blood dyscrasias. Blood dyscrasias, hepatotoxicity, and skin rashes are particularly common in patients with AIDS. Most of the adverse effects of this combination are due to the sulfamethoxazole component. Trimethoprim may increase the hematological toxicity of sulfamethoxazole. Long-term use of trimethoprim in persons with borderline foUc acid deficiency, such as alcoholics and the malnourished, may result in megaloblastic anemia, thrombocytopenia, and granulocytopenia. 

As indicated earher, sulfonamides are effective in both gram-positive and gramnegative bacteria. Mostly prescribed for humans in the United States, in this class is sulfamethoxazole, mostly in combination with trimethoprim (SMZ-TMP) in a 5 1 ratio. Trimethoprim inhibits dihydropholic acid reductase and this, just like sulfonamides, also interferes with the synthesis of folic acid (Fig. 1.8). As a matter of fact, use of the combined SMZ-TMP has been steadily increasing recently as is displayed by the number of prescriptions (Fig. 1.7). Oral doses of sulfonamides are absorbed well and eliminated by the liver and kidney with 20-60% excreted as the parent compound (Queener and Gutierrez, 2003). 

Chemical Class Dihydrofolate reductase inhibitor (trimethoprim) sulfonamide derivative (sulfamethoxazole)... 

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