Tetracycline development

Tetracyclines are classified as broad-spectrum antibiotics obtained from soil acti-nomycetes. All tetracyclines are slightly bitter solids and are weakly soluble in water. Although tetracyclines develop organism resistance, they are the drugs of first choice in venereal disease, atypical pneumonia, cholera, brucellosis, and plague. Tetracyclines also are used in urinary tract infections, amebiasis, acne, and as prophylaxis against meningitis. 

I 7. A culture of bacteria not resistant to tetracycline develops an infection from a virus that is derived from the lysis of tetracycline-resistant bacteria. Most ol the bacterial progeny of the original culture is found to have become resistant to tetracycline. What phenomenon has occurred ... 

An on-line concentration, isolation, and Hquid chromatographic separation method for the analysis of trace organics in natural waters has been described (63). Concentration and isolation are accompHshed with two precolumns connected in series the first acts as a filter for removal of interferences the second actually concentrates target solutes. The technique is appHcable even if no selective sorbent is available for the specific analyte of interest. Detection limits of less than 0.1 ppb were achieved for polar herbicides (qv) in the chlorotriazine and phenylurea classes. A novel method for deterrnination of tetracyclines in animal tissues and fluids was developed with sample extraction and cleanup based on tendency of tetracyclines to chelate with divalent metal ions (64). The metal chelate affinity precolumn was connected on-line to reversed-phase hplc column, and detection limits for several different tetracyclines in a variety of matrices were in the 10—50 ppb range. 

The total U.S. antibiotic market for 1990 was about 4.73 biUion, 233 million of that was tetracyclines. The development of the semisynthetic P-lactam antibiotics (see Antibiotics, P-LACTAMs) and emergence of resistance to the tetracyclines has steadily diminished the clinical usefulness of tetracyclines. 

Tetracyclines are used as alternative dnigs in a variety of circumstances when the patient is unable to take the dnig of choice, eg, in patients allergic to penicillin (88,89). Tetracyclines are widely known to cause staining of teeth (and are therefore contra-indicated in children developing permanent teeth), photosensitivity, and, in the case of minocycline, vestibular toxicity. Details of these adverse effects and others associated with administration of tetracyclines have been comprehensively reviewed (96—101). 

Resistance to Tetracyclines. The tetracyclines stiU provide inexpensive and effective treatment for several microbial infections, but the emergence of acquired resistance to this class of antibiotic has limited their clinical usehilness. Studies to define the molecular basis of resistance are underway so that derivatives having improved antibacterial spectra and less susceptibiUty to bacterial resistance may be developed. Tetracyclines are antibiotics of choice for relatively few human infections encountered in daily clinical practice (104), largely as a result of the emergence of acquired tetracycline-resistance among clinically important bacteria (88,105,106). Acquired resistance occurs when resistant strains emerge from previously sensitive bacterial populations by acquisition of resistance genes which usually reside in plasmids and/or transposons (88,106,107). Furthermore, resistance deterrninants contained in transposons spread to, and become estabUshed in, diverse bacterial species (106). 

Tetracycline antibiotics have found wide application in animal industries for treatment, preventive maintenance and stimulation of growth of large horned livestock owing to what their residue amounts can be present at milk and meat of animals. Residue amounts of antibiotics are not toxic, however, capable to cause allergic reactions and to promote development of tolerance of the some people pathogenic bacterias. According with the legislative requirements of a number of the European countries it is forbidden to deliver to the population production polluted residual contents of tetracyclines. 

A practical process had earlier been developed for the transformation of chlortetracycline (2) into tetracycline (1) by catalytic hydrogenolysis of the aromatic chloro group. Application of the reaction under suitable conditions to demethylchlortetra-... 

Glycylcyclines are a new generation of tetracyclines (e.g. tigilcycline), which have been developed to overcome problems of resistance to common tetracyclines. 

The tetracyclines are contraindicated if the patient is known to be hypersensitive to any of the tetracyclines. Tetracyclines also are contraindicated during pregnancy because of die possibility of toxic effects to the developing fetus. The tetracyclines are classified Pregnancy Category D drag. These drug also are contraindicated... 

Thiatetracyclines contain a sulphur atom at position 6 in the molecule. One derivative, thiacycline, is more active than minocycline against tetracycline-resistant bacteria. Despite toxicity problems affecting its possible clinical use, thiacycline could be the starting point in the development of a new range of important tetracycline-type antibiotics. 

Although tetracycline, doxycycline, and minocycline are the most commonly prescribed oral antibiotics for acne, erythromycin and clindamycin are appropriate second-line agents for use when patients cannot tolerate or have developed resistance to tetracycline or its derivatives.3 See Table 62-3 for antibiotic dosing guidelines. 

Although their effectiveness is similar to the tetracyclines, the use of erythromycin and clindamycin is often limited due to their potential adverse outcomes. Erythromycin has treatment failure due to resistance and a high incidence of gastrointestinal intolerance, while clindamycin causes diarrhea and carries a risk of developing pseudomembranous colitis with long-term use.3,8... 

Still among the most frequently prescribed drugs, the antibiotic tetracyclines have decreased in popularity recently due to development of bacterial resistance in the clinic. The search for improved agents goes on. 

Implications for treatment. It has recently been shown that tetracycline inhibits the development of filarial nematodes from L3 to L4 in vitro (Smith and Rajan, 2000, Experimental Parasitology 95, 265-270). However, chloramphenicol, erythromycin and ciprofloxacin failed to inhibit the... 

UV detection, diode-array detector (DAD) and fluorescence have been the detection techniques used, coupled to HPLC for the analysis of OTC. UV detection is set at 355 nm [49-51], 350 nm [40], or at 353 nm [52], Using the diode array detector [49] offers advantages that the target peak can be identified by its retention time and absorption spectrum. Compared to UV detection, fluorescence detection is generally more specific and is less interfered by other compounds in the sample matrix [51]. A HPLC method with electrochemical detection has also been suggested recently. Zhao et al. [53] described HPLC with a coulometric electrode array system for the analysis of OTC, TC, CTC, DC, and methacycline (MC) in ovine milk. An amper-ometric detection coupled with HPLC was developed by Kazemifard and Moore [54] for the determination of tetracyclines in pharmaceutical formulations. 

For confirmatory assay, liquid chromatography-tandem mass spectrometry (LC-MS/MS) is becoming more frequently used in the analysis of OTC owing to its high sensitivity and ability. Electrospray ionization (ESI) [55-57] and atmospheric pressure chemical ionization (APCI) [41] methods combined with tandem mass spectrometry are favored because of their higher sensitivity and better reproducibility. Hamscher et al. [58] developed a method for the determination of persistent TC residues in soil fertilized with manure by HPLC tandem mass spectrometry, MS-MS, and confirmation by MS-MS-MS. Zhu et al. [59] developed an LC-tandem mass spectrometry for the analysis of common tetracyclines in water. The detection limit for oxytetracycline was 0.21 pg/L. Lykkeberg et al. [60] used LC-MS/MS for determination of oxytetracycline and its impurities EOTC, TC, ETC, ADOTC, oc-AOTC, and /i-AOTC. 

The medical success of these drugs gave new emphasis to the pharmaceutical industry, which was boosted further by the commencement of industrial-scale penicillin manufacture in the early 1940s. Around this time, many of the current leading pharmaceutical companies (or their forerunners) were founded. Examples include Ciba Geigy, Eli Lilly, Wellcome, Glaxo and Roche. Over the next two to three decades, these companies developed drugs such as tetracyclines, corticosteroids, oral contraceptives, antidepressants and many more. Most of these pharmaceutical substances are manufactured by direct chemical synthesis. 

Tetracyclines inhibit P. acnes, reduce the amount of keratin in sebaceous follicles, and have antiinflammatory properties (inhibiting chemotaxis, phagocytosis, complement activation, and cell-mediated immunity). Drawbacks to tetracyclines include hepatotoxicity and predisposition to infections (e.g., vaginal candidiasis). Other adverse effects include GI disturbances, photosensitivity, tooth discoloration in children, and inhibition of skeletal growth in the developing fetus. Tetracyclines must not be combined with systemic retinoids because of an increased risk of intracranial hypertension. / Tetracycline is the least expensive agent in this class and is often... 

Tetracyclines should be avoided because of teratogenic effects, and sulfonamides should not be administered during the third trimester because of the possible development ofkernicterus and hyperbilirubinemia. Also, the fluoroquinolones should not be given because of their potential to inhibit cartilage and bone development in the newborn. 

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