| Identification | More | [Name]
Tetracycline hydrochloride | [CAS]
64-75-5 | [Synonyms]
[4s-(4alpha,4aalpha,5aalpha,6beta,12aalpha)]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrochloride
ACHROMYCIN HCL
ACHROMYCIN HYDROCHLORIDE
DESCHLOROBIOMYCIN
TETRACYCLINE HCL
TETRACYCLINE HYDROCHLORIDE
10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-,monohydrochloride,[4s-(4alpha,4a
12,12a-pentahydroxy-6-methyl-1,11-dioxo-1monohydrochloride
4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-,m2-Naphthacenecarboxamide
5aalpha,6beta,12aalpha)]-alph
alatet
amycin,hydrochloride
artomycin
cancycline-250
cefracyclinetablets
chlorhydratedetetracycline
chlorowodorkutetracykliny
cyclopar
diacycine
dumocyclin | [EINECS(EC#)]
200-593-8 | [Molecular Formula]
C22H25ClN2O8 | [MDL Number]
MFCD00078142 | [Molecular Weight]
480.9 | [MOL File]
64-75-5.mol |
| Chemical Properties | Back Directory | [Appearance]
Yellow crystalline powder | [Melting point ]
220-223 °C(lit.)
| [alpha ]
-252 º (c=0.5, H2O) | [refractive index ]
-253 ° (C=0.5, 0.1mol/L HCl) | [storage temp. ]
2-8°C
| [solubility ]
H2O: 10 mg/mL as a stock solution. Stock solutions should be filtered sterilized and stored at −20°C. Stable at 37°C for 4 days.
| [form ]
powder
| [color ]
faint yellow to yellow | [PH]
pH(10g/l, 25℃) : 1.8～3.0 | [Stability:]
Stable. Incompatible with strong oxidizing agents. | [optical activity]
[α]/D -255 to 240° (Specific rotation ) | [Water Solubility ]
50 g/L | [Sensitive ]
Air & Light Sensitive | [Merck ]
14,9196 | [BRN ]
3844873 | [InChIKey]
XMEVHPAGJVLHIG-FMZCEJRJSA-N | [CAS DataBase Reference]
64-75-5(CAS DataBase Reference) | [EPA Substance Registry System]
64-75-5(EPA Substance) |
| Safety Data | Back Directory | [Hazard Codes ]
Xi,Xn | [Risk Statements ]
R36/37/38:Irritating to eyes, respiratory system and skin .
R20/21/22:Harmful by inhalation, in contact with skin and if swallowed . | [Safety Statements ]
S26:In case of contact with eyes, rinse immediately with plenty of water and seek medical advice .
S36:Wear suitable protective clothing . | [RIDADR ]
UN 3077 9 / PGIII | [WGK Germany ]
2
| [RTECS ]
QI9100000
| [F ]
8-10-23 | [TSCA ]
Yes | [HazardClass ]
3 | [HS Code ]
29413000 | [Safety Profile]
Poison by intraperitoneal and intravenous routes. Moderately toxic by ingestion and subcutaneous routes. Human systemic effects: change in taste function. An experimental teratogen. Experimental reproductive effects. Mutation data reported. When heated to decomposition it emits very toxic fumes of HCl and NOx. See also TETRACYCLINE. | [Toxicity]
LD50 orally in rats: 6443 mg/kg (Goldenthal) |
| Hazard Information | Back Directory | [General Description]
Crystals or fine bright yellow powder. pH of 2% aqueous solution: 2.1-2.3. | [Reactivity Profile]
TETRACYCLINE HYDROCHLORIDE(64-75-5) is acidic. Reacts with strong oxidizing agents . | [Air & Water Reactions]
Water soluble. | [Fire Hazard]
Flash point data concerning this compound are not available, however, TETRACYCLINE HYDROCHLORIDE is probably combustible. | [Description]
Tetracycline is a broad-spectrum antibiotic that prevents bacterial growth by inhibiting protein synthesis. It binds to a single site in the 30S ribosomal subunit which prevents attachment of aminoacyl tRNA to the ribosomal acceptor site.1 It is used in cell biology as a selective agent in cell culture systems. Tetracycline is toxic to prokaryotic and eukaryotic cells and selects for cells harboring the bacterial tetR gene, which are resistant to the antibiotic.2 | [Chemical Properties]
Yellow crystalline powder | [Uses]
Antibiotic substance produced by Streptomyces spp. Antiamebic; antibacterial; antirickettsial. | [Uses]
Tetracycline hydrochloride is a salt prepared from tetracycline taking advantage of the basic dimethylamino group which protonates and readily forms the salt in hydrochloric acid solutions. The hydrochloride is the preferred formulation for pharmaceutical applications. Tetracycline hydrochloride has broad spectrum antibacterial and antiprotozoan activity and acts by binding to the 30S and 50S ribosomal sub-unit,s blocking protein synthesis. | [Biochem/physiol Actions]
Primary Targetbinding of aminoacyl tRNA to the A-site of ribosomes | [Veterinary Drugs and Treatments]
While tetracycline still is used as an antimicrobial, most small animal
clinicians prefer doxycycline and large animal clinicians prefer
oxytetracycline when a tetracycline is indicated to treat susceptible
infections. The most common use of tetracycline HCl today is in
combination with niacinamide for the treatment of certain immune-
mediated skin conditions in dogs, such as pemphigus. | [storage]
Store at -20°C | [Purification Methods]
The hydrochloride is recrystallised from MeOH/n-BuOH or n-BuOH/HCl. It is insoluble in Et2O and pet ether. It has UV max at 270 and 366nm in MeOH. [Gottstein et al. J Am Chem Soc 81 1198 1959, Conover et al. J Am Chem Soc 84 3222 1962, Stephen et al. J Am Chem Soc 78 4155 1956, Beilstein 14 IV 2627.] |
| Material Safety Data Sheet(MSDS) | Back Directory | [msds information]
[4S-(4alpha,4aalpha,5aalpha,6beta,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrochloride(64-75-5).msds |
| Questions and Answers (Q&A) | Back Directory | [Overview]
Tetracycline hydrochloride was discovered in 1948 as natural fermentation products of a soil bacterium, Streptomyces aureofaciens. The first chemically purified tetracycline was chlortetracycline (1954).[1] Currently, 3 groups of tetracyclines are available: tetracycline natural products, tetracycline semisynthetic compounds, and chemically modified tetracyclines (CMTs).[2,3] Perusal of the literature suggests that tetracyclines, besides acting as antibiotics, may also affect inflammation, immunomodulation, cell proliferation, and angiogenesis.[4,5]
Figure 1 the chemical structure of tetracycline hydrochloride
The tetracyclines were the first major group of antimicrobial agents for which the term 'broad-spectrum' was used i.e. they exhibit activity against a wide range of Gram-positive and Gram-negative bacteria, including obligate anaerobes[6, 7]. Chlamydiae, mycoplasmas, rickettsiae, and protozoan parasites are also, in general, susceptible to tetracyclines[7, 8]. The broad spectrum of activity and relative safety of the tetracyclines led to their widespread use in the therapy of infections in man, animals and even certain plants and insects (e.g. see Levy, 1984) and in 1980 the estimated global availability of tetracyclines was 5000 metric tonnes [10]. However, one of the most important limitations to the continued widespread use of tetracyclines has been the emergence of microbial resistance to these agents[6, 9, 11].
| [References]
- Stephens CR, Conover LH, Pasternak R, Hochstein FA, Moreland WT, Regna PP, et al. The structure of aureomycin. J Am Chem Soc 1954;76:3568-75.
- Golub LM, Soummalainen K, Sorsa T. Host modulation with tetracyclines and their chemically modified analogues. Curr Opin Dent 1992;2:80-90.
- Nelson ML. Chemical and biological dynamics of tetracyclines. Adv Dent Res 1998;12:5-11.
- Shapira LL, Soskolne WA, Houri Y, Barak V, Halabi A, Stabholz A. Protection against endotoxic shock and lipopolysaccharideinduced local inflammation by tetracycline: correlation with inhibition of cytokine secretion. Infect Immun 1996;64:825-8.
- Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial mechanisms. Adv Dent Res 1998;12:12-26.
- Chopra, I., Howe, T. G. B., linton, A. H., Linton, K. B., Richmond, M. H. & Speller, D. C. E. (1981). The tetracyclines: prospects at the beginning of the 1980s. Journal of Antimicrobial Chemotherapy 8, 5-21.
- Cunha, B. A. (1985). Clinical uses of the tetracyclines. In The Tetracyclines (Hlavka, J. J. & Boothe, J. H., Eds), pp. 393-404. Springer-Verlag, Berlin.
- Edlind, T. D. (1989). Tetracydines as antiparasitic agents: lipophilic derivatives are highly active against Giardia lamblia in vitro. Antimicrobial Agents and Chemotherapy 33, 2144-5.
- Levy, S. B. (1984). Resistance to the tetracyclines. In Antimicrobial Drug Resistance (Bryan, L. E., Ed.), pp. 191-204. Academic Press, Orlando, FL.
- Col, N. F. & O'Connor, R. W. (1987). Estimating worldwide current antibiotic usage: report of Task Force 1. Reviews of Infectious Diseases 9, Suppl. 3. S232-4
- Levy, S. B. (1989). Evolution and spread of tetracycline resistance determinants. Journal of Antimicrobial Chemotherapy 24, 1-3.
- Martin RB. Tetracyclines and daunorubicin in metal ions in biological systems. In: Sigel H, editor. Antibiotics and their complexes. New York: Marcel Dekker; 1985. pp. 19-40.
- Tritton, T. R. (1977). Ribosome-tetracycline interactions. Biochemistry 16, 4133-
- Gale, E. F., Cundliffe, E, Reynolds, P. E., Richmond, M. H. & Waring, M. J. (1981). The Molecular Basis of Antibiotic Action. 2nd edn. Wiley, London
- Chopra, I. (1985). Mode of action of the tetracyclines and the nature of bacterial resistance to them. In The Tetracyclines (Hlavka, J. J. & Boothe, J. H., Eds), pp. 317-92. Springer-Verlag, Berlin.
- Rasmussen, B., Noller, H. F., Daubresse, G., OKva, B., Misulovin, Z., Rothstein, D. M., Ellestad, G. A., Gluzman, Y., Tally, F. P. & Chopra, I. (1991). Molecular basis of tetracycline action: identification of analogs whose primary target is not the bacterial ribosome. Antimicrobial Agents and Chemotherapy 35, 2306-11
- Welling PG, Koch PA, Lav CC et al. Bioavailability of tetracycline and doxycycline in fasted and non-fasted subjects. Antimicrob Agents Chemother 1977; 11: 462–9.
- Fabre J, Milek E, Kalpopoulos et al. La Cinetique des tetracyclines chez I’homme. Schweiz med Wschr 1977; 101, 573–8.
- Neuvonen PJ. Interactions with the absorption of tetracyclines. Drugs 1976; 11: 45–54
- Klein NC, Cunha BA. Tetracyclines. Med Clin North Am 1995; 79: 789–801.
- Kunin CM, Rees SB, Merrill JP et al. Persistence of antibiotics in blood of patients with acute renal failure I tetracycline and chlortetracycline. J Clin Invest 1959; 38: 1487–97.
- Vincon G, Albin J, Paccalin J et al. Elimination des antibiotiques dans la bile. Bordeaux Medical 1979; 12: 795–9.
- Russell, A. D. & Chopra, I. (1990). Understanding Antibacterial Action and Resistance. Ellis Horwood, London.
- Chopra, I. (1986). Genetic and biochemical basis of tetracycline resistance. Journal of Antimicrobial Chemotherapy 18, Suppl. C, 51
- Salyers, A. A., Speer, B. S. & Shoemaker, N. B. (1990). New perspectives in tetracycline resistance. Molecular Microbiology 4, 151-6.
- Manavathu, E. K., Fernandez, C. L., Coopennan, B. S. & Taylor, D. E. (1990). Molecular studies on the mechanism of tetracycline resistance mediated by Tet(O). Antimicrobial Agents and Chemotherapy 34, 71-7.
- Walters, B. N. J. & Gubbay, S. S. (1981). Tetracycline and benign intracranial hypertension: report of five cases. British Medical Journal 282, 19-2
|
| Questions And Answer | Back Directory | [Chemistry]
Tetracyclines and analogues with biological effects on bacteria and mammalian targets show a basic chemical structure consisting of a tetracyclic naphthacene carboxamide ring system (Fig 1). Tetracyclines with antibiotic activity have a dimethylamine group at carbon 4 (C4) in ring A. Removal of the dimethylamino group from C4 reduces its antibiotic properties, but enhances non-antibiotic actions[3]. Utilization of this strategy was the basis for the development of several chemically modified tetracyclines[2]. The ring structure of tetracyclines is surrounded by upper and lower peripheral zones. These contain various chemical functional groups and substituents[12]. Synthetic modification of the lower peripheral region reduces both antibiotic and non-antibiotic properties. On the other hand, biological targets may be enhanced by modifying the upper peripheral zone, particularly in positions C7 through C9 of the D ring. This has been accomplished with tetracycline semisynthetic compounds such as minocycline and doxycycline[3].
| [Indication]
Tetracyline hydrochloride is used for the treatment of bacterial infections such as Rocky Mountain spotted fever, typhus fever, tick fevers, Q fever, rickettsia pox and Brill-Zinsser disease. May be used to treat infections caused by Chlamydiae spp., B. burgdorferi (Lyme disease), and upper respiratory infections caused by typical (S. pneumoniae, H. influenzae, and M. catarrhalis) and atypical organisms (C. pneumoniae, M. pneumoniae, L. pneumophila). May also be used to treat acne. Tetracycline may be an alternative drug for people who are allergic to penicillin.
| [Mode of action]
The tetracyclines inhibit bacterial growth primarily by inhibiting protein synthesis at the level of the ribosome[13-16]. Inhibition of protein synthesis results from disruption of codon-anticodon interactions between tRNA and mRNA so that binding of aminoacyl-tRNA to the ribosomal acceptor (A) site is prevented[14, 15]. The precise mechanism by which tetracyclines prevent attachment of aminoacyl-tRNA to the A site is not understood. However, inhibition is likely to result from interaction of these antibiotics with the 30S ribosomal subunit since many of the tetracyclines are known to bind strongly to a single site on the 30S subunit[15]. Nevertheless, interaction of these tetracyclines with the 30S ribosomal subunit is reversible since these agents are bacteriostatic.
| [Pharmacodynamic]
Absorption is variable ranging from 0% to almost 90%; however, for most agents it is in the range 25–60%[17]. Serum concentrations rise slowly after oral administration with absorption occurring in the stomach, duodenum and small intestine. Cmax (mg/L) depends on dose, but is generally in the range 1–5 mg/L. Tmax is in the range 2–4 h. All these tetracyclines form insoluble complexes with calcium, magnesium, iron and aluminium, which markedly reduce absorption[18]. the effect of disease on the absorption of these drugs is unknown. Protein, fat and carbohydrate meals reduce the absorption of tetracycline by about 50%[16]. The volume of distribution (V) for these agents is in the order of 1.3–1.7 L/kg or a total volume of distribution of 100–130 L. These data imply some concentration in tissues; however, most data on tissue penetration are of poor quality, making firm conclusions about their relative distribution difficult. Protein binding is variable. None of these agents undergoes metabolism with the exception of tetracycline, 5% of which is excreted as the metabolite D-epitetracycline. Unchanged drugs are excreted by renal and bilary routes. Renal elimination (CLR) is related to glomerular filtration for most agents, the exception being chlortetracycline.[19, 20] The amount of drug excreted in the urine is <50%; rolitetracycline is said to have high renal elimination. Greater than 40% appears in the faeces after biliary elimination and most drugs have some enterohepatic circulation.[18, 22]
| [Resistance issue]
Bacterial resistance to clinically useful tetracyciines is predominantly due to acquired resistance i.e. when resistant strains emerge from previously sensitive bacterial populations by acquisition of resistant genes. In essence, this results from the selective pressure exerted on bacteria during the administration of tetracyciines for chemotherapy in humans and animals. The genes determining resistance to tetracyciines usually reside in plasmids and/or transposons[11, 15]. It is now well recognized that acquisition of resistance determinants on plasmids and transposons is particularly important in the evolution of antibiotic resistant bacteria because it provides the recipient cell with pre-evolved genes refined to express high-level resistance[23].
Three distinct biochemical mechanisms of resistance to tetracyciines have been identified: (a) energy-dependent efflux of antibiotic mediated by resistance proteins that are inserted into the bacterial cytoplasmic membrane[15, 24, 25]; (b) ribosomal protection whereby tetracyciines no longer bind productively to the bacterial ribosome[25, 26], and (c) chemical alteration of the tetracycline molecule by a reaction that requires oxygen and which renders the drug inactive as an inhibitor of protein synthesis[25].
| [Side effects]
The ability of tetracyclines to cause permanent discolouration of teeth is well-known and therefore these antibiotics are not administered to children less than eight years old. Tetracyclines are also contra-indicated in children because they can cause temporary inhibition of bone growth. Tetracyclines can produce Candida! Overgrowth or diarrhoea due to the relatively high proportion of antibiotic reaches the lower gastrointestinal tract. These antibiotics tend to accumulate in patients with renal insufficiency and may cause further impairment of renal function including nephrotoxicity and/or nephrogenic diabetes insipidus. Phototoxic reactions occasionally occur with tetracycline and minocycline, but are less common with doxycycline. Rarely, tetracyclines may cause benign intracranial hypertension, presenting as blurring of vision and headache often in young adults who are being treated for acne[27]. Minocycline can cause vestibular disturbance. Amongst the tetracyclines this effect is apparently unique to minocycline and probably relates to the high lipid solubility of the drug. The lipid-laden cells of the vestibular apparatus are believed to concentrate the drug resulting in vertigo and nausea. However, the effects are reversible upon discontinuation of therapy with the antibiotic.
|
|
|