Tetracycline derivatives

The tetracyclines are a group of antibiotics having an identical 4-ring carbocycHc structure as a basic skeleton and differing from each other chemically only by substituent variation. Figure 1 shows the principal tetracycline derivatives now used commercially. 

Alcohol, amiodarone, didanosine, 1-asparaginase, piroxicam, stavudine, tamoxifen, tetracycline derivatives, valproic acid, and zidovudine... 

Exposure after this point may result in growth retardation, CNS or other abnormalities, or death (e.g., nonsteroidal antiinflammatory drugs [NSAIDs], angiotensin-converting enzyme inhibitors [ACEIs], and tetracycline derivatives). 

Garcia-Ruiz, C., Crego, A. L., Lavandera, J. L., and Marina, M. L. (2001). Rapid separation of tetracycline derivatives and their main degradation products by capillary zone electrophoresis. Electrophoresis 22, 2775—2781. 

Doxycycline (6-deoxy-5-hydroxytetracycline, Vibramycin, III) is, chemically, the most stable tetracycline in current use but its outstanding property is its high lipid solubility these features combine to make it the most reliably and completely absorbed tetracycline derivative, with the longest half-life. 

Impairment of mitochondrial jj-oxidation leads to accumulation of fat, resulting in steatosis. Examples are various tetracycline derivatives, valproic acid (used to treat seizures) and overdoses of aspirin [64—66]. Certain NSAIDs such as ibuprofen, ketoprofen and naproxen also have the ability to inhibit jj-oxidation [67-69]. 

Labbe, G. et al. (1991) Effects of various tetracycline derivatives on in vitro and in vivo beta-oxidation of fatty acids, egress of triglycerides from the liver, accumulation of hepatic triglycerides, and mortality in mice. Biochemical Pharmacology, 41 (4), 638-641. 

Brand Name(s) Adoxa.Atridox, Doryx, Doxy-100, Doxy Caps, Doxychel Hyclate, Mono-dox, Periostat, Vibramycin, Vibra-Tabs Chemical Class Tetracycline derivative... 

Chemical Class Tetracycline derivative I Clinical Pharmacology ... 

Bromine has also been suggested for an indirect detection process for the determination of tetracyclines in pharmaceutical formulations [155]. A bromine/hydrogen peroxide-based electrogenerated chemiluminescence reaction is shown to be enhanced by tetracycline derivatives and detection levels down to the pg dm level are reported on the basis of this enhancement effect. 

This system is advantageous since tetR has high specificity for both its operator sequences and tetracycline (Hillen and Wissmann, 1989 Takahashi et al., 1986). This allows the system to function at tetracycline concentrations well below toxic levels in mammalian cells (Gossen et al., 1995). Tetracycline-derivatives, such as doxycycline, have been shown to be even better inducers than tetracycline. This is due to their increased affinity for tetR and high functional stability (Gossen et al., 1995 Gossen and Bujard, 1993). This system is commonly referred to as Tet-off since the gene is turned off in the presence of tetracycline. 

Tetracycline and tetracycline derivatives (see Table 33-3) inhibit protein synthesis by binding to several components of the ribosomal apparatus in susceptible bacteria.3,12 Hence, these drugs may cause misreading of the mRNA code, as well as impair the formation of peptide bonds at the bacterial ribosome. Thus, tetracyclines are very effective in preventing bacterial protein synthesis. 

Some of the newer tetracycline derivatives such as doxycycline may be used to overcome bacterial strains that are resistant to the traditional drugs.16 Currently, tetracyclines are used to treat specific infections relating to such bacilli as Chlamydia, Rickettsia, and certain spirochetes (see Table 33-5). Tetracyclines may also be used as alternative agents in treating bacterial strains... 

Sanchez AR, Rogers RS, 3rd, Sheridan PJ. Tetracycline and other tetracycline-derivative staining of the teeth and oral cavity, lnt J Dermatol. 2004 43 709-715. 

A series of tetracycline derivatives has recently been isolated from species of Dactylosporangium. These compounds, the dactylocyclines (Figure 3.55), are glycosides and have the opposite configuration at C-6 to the natural tetracyclines. Importantly, these compounds are active towards tetracycline-resistant bacteria. 

A variety of medical conditions cause water retention as the result of ADH excess. Unfortunately, specific ADH antagonists are available only for investigational purposes. Two nonselective agents, lithium and demeclocycline (a tetracycline derivative), are of limited use in some situations. 

The name tetracycline derives from the naph-thacene nucleus that it possesses. The rings are lettered A through D from right to left and the numbers start at the bottom of ring A. The enolized form as illustrated on next page has been selected arbitrarily and is used most exclusively in the literature. It is further defined as hydrochloride of 4 3-di-methylamino-l,4,4a,5,5a,6,ll,12a-octahydro-3,6 10,12, 12aB-pentahydroxy-6-methyl-1,11-dioxonaphtnacene-2-carboxamide. 

SAFETY PROFILE A poison by intravenous route. Moderately toxic by ingestion, subcutaneous, and intraperitoneal routes. Human systemic effects by ingestion hemorrhage, dermatitis, and unspecified effects on teeth and supporting strucmres. Human reproductive effects by an unspecified route abnormal postnatal measures or effects. Experimental teratogenic and reproductive effects. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx. See also TETRACYCLINE and various tetracycline derivatives. 

J. Yrjanheikki, T. Tikka, R. Keinanen, G. Goldsteins, P. H. Chan, and J. Koistinaho, A Tetracycline Derivative, Minocycline, Reduces Inflammation and Protects Against Focal Cerebral Ischemia with a Wide Therapeutic Window, Proceedings of National Academy of Sciences, USA, 96(23) (1999) 13496-13500. 

Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J (2001) Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting and proliferation of microglia. J Neurosci 21 2580-2588. 

The presence of food in the GI tract reduces the absorption of many antiinfective agents. Although there are some exceptions (e.g., penicillin V, amoxicillin, and doxycycline), it is generally recommended that penicillin and tetracycline derivatives, as well as certain other antiinfective agents, be given at least 1 h before meals or 2 h after meals to achieve optimum absorption. 

This general model has been extended to the log P of disubstituted aromatic compounds and the solubilities of tetracycline derivatives. 

Adverse effects of minocycline are reported far more often than adverse effects of other tetracycline derivatives. Whatever the mechanisms underlying this larger number of reports might be, they continue to appear. With increasing use of minocycline in acne and other conditions, adverse reactions may become increasingly common early recognition is important to prevent further deterioration, to hasten recovery, and to avoid invasive investigations and treatment (2). The authors of this review recommended that safer alternatives be considered in the treatment of acne. 

The most serious adverse effect of talc is a possible association between talc pleurodesis and the development of acute respiratory failure (usually in the form of ARDS) over 30 cases have been described (13) after intrapleural talc either as a slurry (8) or insufflated (18,19). The literature on acute respiratory failure after intrapleural talc has been reviewed, with recommendations on whether talc should continue to be used to produce pleurodesis (20). Some believe that intrapleural talc should not be used to produce a pleurodesis, since there are effective alternatives for producing pleurodesis (mechanical abrasion if thoracoscopy is performed, tetracycline derivatives or bleomycin if chest tubes are used). 

Sideroblastic anemia is characterized by the accumulation of iron in the mitochondria of erythroblasts. In a Phase I study in 35 patients with refractory tumors, eight taking CMT-3 developed anemia without leukopenia or thrombocytopenia (54). Three of these patients underwent bone-marrow examination and each had ringed side-roblasts. The authors referred to several cases of aplastic anemia, megaloblastic anemia, and hemolytic anemia in which members of the tetracycline family have been implicated. However, they stated that there has been no previous reports of sideroblastic anemia associated with any tetracycline derivative and that the molecular mechanisms by which CMT-3 might cause sideroblastic anemia are unclear. 

Stezowski, J. J. Chemical structural properties of tetracycline derivatives. 1. Molecular structure and conformation of the free base derivatives. J. Amer. Chem. Soc. 98, 6012-6018 (1976). 

Table 10.4 Relative calcium-binding capacities of tetracycline derivatives and decreases in serum levels after 200 mg ferrous sulfate ...

Tetracycline was discovered after a team of workers examined 100000 soil samples from around the world. Tetracycline derivatives include chlor-tetracycline, oxytetracycline, doxycycline and minocycline. The tetracyclines have a broad spectrum of activity they are effective against Grampositive and Gram-negative bacteria, some anaerobes. Chlamydia, Mycoplasma, Ehrlichia and Rickettsia spp. and some protozoa. Their activity against staphylococci is usually limited and they are not active against enterococci. E. coli, Klebsiella, Proteus and Pseudomonas spp. are usually resistant. Doxycycline and minocycline are usually more active in vitro than the other tetracyclines. Differences in the clinical efficacy of the tetracyclines can be attributed to differences in the absorption, distribution and excretion of the individual drugs rather than to differences in bacterial susceptibility. 

A number of the tetracycline derivatives are phototoxic. In one study, chlortetracycline, doxycycline, and dimethylchlortetracycline treatment of normal human skin fibroblasts resulted in total cell death within 14 days when co-administered with UVA. A dimethylchlortetracycline and UVA cotreatment also showed a strong photosensitizing effect in a 7-day exposure study. These results, too, are consistent with clinically reported reactions in humans J15l... 

Bjellerup M, Ljunggren B. Double blind cross over studies on phototoxicity to three tetracycline derivatives in human volunteers. Photodermatology 1987 4(6) 281—7. 

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