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Demeclocycline

Demeclocycline (marketed as Declomycin, Declostatin, and Ledermycin) is a tetracycline antibiotic derived from a strain of Streptomyces aureofaciens.

Therapeutic use

Demeclocycline is a tetracycline antibiotic active against the following microorganisms: Rickettsiae (Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsial pox, tick fevers), Mycoplasma pneumoniae (PPLO, Eaton agent), agents of psittacosis and ornithosis, agents of lymphogranulomavenereum and granuloma inguinale, the spirochetal agent of relapsing fever (Borrelia recurrentis), Haemophilus ducreyi (chancroid), Yersinia pestis, Pasteurella pestis and Pasteurella tularensis, Bartonella bacilliformis, Bacteroides species, Vibrio comma and Vibrio fetus, and Brucella species (in conjunction with streptomycin).

Used primarily to treat Lyme disease, acne, and bronchitis. Also indicated (but rarely used) to treat urinary tract infections, gum disease, malaria, and other bacterial infections such as gonorrhea and chlamydia. One of its other registered uses is the treatment of hyponatremia (low blood sodium concentration) due to the syndrome of inappropriate antidiuretic hormone (SIADH) where fluid restriction alone has been ineffective. Resistance, though, is gradually becoming more common, and demeclocycline is now rarely used for infections.

Demeclocycline is indicated in the following treatments:

Respiratory Tract Infections

Treatment of respiratory tract infections caused by Mycoplasma pneumoniae. Treatment of respiratory tract infections caused by Haemophilus influenzae, Streptococcus pneumoniae, or Klebsiella. Should only be used for treatment of infections caused by these bacteria when in vitro susceptibility tests indicate the organism is susceptible.

Acinetobacter Infections

Treatment of infections caused by Acinetobacter; minocycline may be the preferred tetracycline for use as an alternative to imipenem or meropenem.

Acne

Adjunctive treatment of moderate to severe inflammatory acne. Not indicated for treatment of noninflammatory acne.

Actinomycosis

Treatment of actinomycosis caused by Actinomyces israelii; oral tetracyclines used as follow-up after initial parenteral treatment with penicillin G.

Amebiasis

Adjunct to amebicides for treatment of acute intestinal amebiasis. Tetracyclines generally not recommended for treatment of amebiasis caused by Entamoeba.

Anthrax

Alternative to doxycycline for treatment of inhalational anthrax when a parenteral regimen is not available. A multiple-drug parenteral regimen (ciprofloxacin or doxycycline and 1 or 2 other anti-infectives predicted to be effective) is preferred for treatment of inhalational anthrax that occurs as the result of exposure to anthrax spores in the context of biologic warfare or bioterrorism.

Bartonella Infections

Treatment of infections caused by Bartonella bacilliformis.

Brucellosis

Treatment of brucellosis; tetracyclines considered drugs of choice. Used in conjunction with other anti-infectives (e.g., streptomycin or gentamicin and/or rifampin), especially for severe infections or when there are complications (e.g., endocarditis, meningitis, osteomyelitis).

Campylobacter Infections

Treatment of infections caused by Campylobacter. Tetracyclines are alternatives, not drugs of choice.

Chancroid

Treatment of chancroid caused by Haemophilus ducreyi. Not included in CDC recommendations for treatment of chancroid.

Chlamydial Infections

Treatment of uncomplicated urethral, endocervical, or rectal infections caused by Chlamydia trachomatis. Doxycycline is the preferred tetracycline for treatment of these infections, including presumptive treatment of chlamydial infections in patients with gonorrhea.

Treatment of trachoma and inclusion conjunctivitis caused by C. trachomatis. Consider that anti-infectives may not eliminate C. trachomatis in all cases of chronic trachoma.

Treatment of lymphogranuloma venereum (genital, inguinal, or anorectal infections) caused by C. trachomatis. Doxycycline is the preferred tetracycline for these infections.

Treatment of psittacosis (ornithosis) caused by C. psittaci. Doxycycline and tetracycline are drugs of choice. For initial treatment of severely ill patients, use IV doxycycline.

Clostridium Infections

Alternative for treatment of infections caused by Clostridium. Tetracyclines are alternatives to metronidazole or penicillin G for adjunctive treatment of C. tetani infections.

Enterobacteriaceae Infections

Treatment of infections caused by susceptible Escherichia coli, Enterobacter aerogenes, Klebsiella, or Shigella. Should only be used for treatment of infections caused by these common gram-negative bacteria when other appropriate anti-infectives are contraindicated or ineffective and when in vitro susceptibility tests indicate the organism is susceptible.

Fusobacterium Infections

Alternative to penicillin G for the treatment of infections caused by Fusobacterium fusiforme (Vincents infection).

Gonorrhea and Associated Infections

Alternative for treatment of uncomplicated gonorrhea (including urethritis) caused by susceptible Neisseria gonorrhoeae. However, tetracyclines are considered inadequate therapy and are not recommended by CDC for treatment of gonorrhea.

Granuloma Inguinale (Donovanosis)

Treatment of granuloma inguinale (donovanosis) caused by Calymmatobacterium granulomatis. Doxycycline is the tetracycline recommended as drug of choice by CDC.

Listeria Infections

Alternative for treatment of listeriosis caused by Listeria monocytogenes. Not usually considered a drug of choice or alternative for these infections.

Nongonococcal Urethritis

Treatment of nongonococcal urethritis (NGU) caused by Ureaplasma urealyticum, C. trachomatis, or Mycoplasma. Doxycycline usually is the tetracycline of choice for NGU. Consider that some cases of recurrent urethritis following treatment may be caused by tetracycline-resistant U. urealyticum.

Plague

Treatment of plague caused by Yersinia pestis. Regimen of choice is streptomycin or gentamicin (with or without doxycycline).

Relapsing Fever

Treatment of relapsing fever caused by Borrelia recurrentis. Tetracyclines are drugs of choice.

Rickettsial Infections

Treatment of rickettsial infections including Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. Tetracyclines are drugs of choice for treatment of most rickettsial infections; doxycycline usually is the preferred tetracycline.

Syndrome of Inappropriate Antidiuretic Hormone Secretion

Treatment of syndrome of inappropriate antidiuretic hormone secretion (SIADH). Only limited value in patients with acute water intoxication caused by excess ADH secretion, but may be effective in inhibiting the action of ADH in patients with chronic form of the disease.

Syphilis

Alternative to penicillin G for treatment of primary, secondary, latent, or tertiary syphilis (not neurosyphilis) in nonpregnant adults and adolescents hypersensitive to penicillins. Doxycycline and tetracycline are the preferred tetracyclines in patients hypersensitive to penicillins. Use tetracyclines only if compliance and follow-up can be ensured since efficacy not well documented.

Tularemia

Treatment of tularemia caused by Francisella tularensis. Tetracyclines considered alternatives to streptomycin (or gentamicin); risk of relapse and primary treatment failure may be higher than with aminoglycosides.

Vibrio Infections

Treatment of cholera caused by Vibrio cholerae. Doxycycline and tetracycline are drugs of choice; used as an adjunct to fluid and electrolyte replacement in moderate to severe disease.

Yaws

Alternative to penicillin G for treatment of yaws caused by Treponema pertenue.

Dosage and Administration

Oral Administration

Administer orally 1 hour before or 2 hours after meals and/or milk. Administer with adequate amounts of fluid to reduce the risk of esophageal irritation and ulceration.

General Pediatric Dosage
Oral: Children >8 years of age: 713 mg/kg daily given in 24 divided doses.c
General Adult Dosage
Oral: 150 mg 4 times daily or 300 mg 2 times daily

Special Populations

Hepatic Impairment: Adjust dosage by decreasing doses or increasing dosing interval. Use with caution.

Renal Impairment: Adjust dosage by decreasing doses or increasing dosing interval. Use with caution.

 

Toxicology

Like other tetracyclines, demeclocycline is contraindicated in children and pregnant or nursing women. All members of this class interfere with bone development and may discolour teeth [1]. Skin reactions with sunlight have been reported.[2] Demeclocycline is unique in that it is the only tetracycline known to cause nephrogenic diabetes insipidus.

Tetracyclines bind to cations, such as calcium, iron (when given orally), and magnesium, rendering them insoluble and inabsorbable for the gastrointestinal tract. Demeclocycline should not be taken with food (particularly milk and other dairy products) or antacids [1].

Common Adverse Effects: GI effects (anorexia, nausea, vomiting, diarrhea); maculopapular and erythematous rash; dose-related BUN increase; hypersensitivity reactions.

LD50 = 2372 mg/kg (rat, oral)

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
human TDLo oral 10mg/kg (10mg/kg)   British Medical Journal. Vol. 2, Pg. 96, 1977.
human TDLo oral 10mg/kg (10mg/kg) SKIN AND APPENDAGES (SKIN): NAILS: OTHER

SKIN AND APPENDAGES (SKIN): "DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE"
British Medical Journal. Vol. 2, Pg. 96, 1977.
human TDLo oral 68mg/kg/8D (68mg/kg) KIDNEY, URETER, AND BLADDER: URINE VOLUME INCREASED

KIDNEY, URETER, AND BLADDER: OTHER CHANGES IN URINE COMPOSITION
Current Therapeutic Research, Clinical & Experimental. Vol. 15, Pg. 734, 1973.
human TDLo oral 420mg/kg/6W (420mg/kg)   Annals of Internal Medicine. Vol. 79, Pg. 679, 1973.
Link to PubMed
human TDLo oral 420mg/kg/6W (420mg/kg) ENDOCRINE: DIABETES INSIPIDUS (NEPHROGENIC OR CNS) Annals of Internal Medicine. Vol. 79, Pg. 679, 1973.
Link to PubMed
mouse LD50 intraperitoneal 454mg/kg (454mg/kg)   Drugs in Japan Vol. 6, Pg. 497, 1982.
mouse LD50 intravenous 79mg/kg (79mg/kg)   Research Progress in Organic-Biological and Medicinal Chemistry. Vol. 2, Pg. 281, 1970.
mouse LDLo oral 4gm/kg (4000mg/kg)   Journal of Pharmacology and Experimental Therapeutics. Vol. 129, Pg. 350, 1960.
Link to PubMed
mouse LDLo subcutaneous 2500mg/kg (2500mg/kg)   Journal of Pharmacology and Experimental Therapeutics. Vol. 129, Pg. 350, 1960.
Link to PubMed
rat LD50 intraperitoneal 358mg/kg (358mg/kg)   Drugs in Japan Vol. 6, Pg. 497, 1982.
rat LD50 intravenous 146mg/kg (146mg/kg)   Gekkan Yakuji. Pharmaceuticals Monthly. Vol. 9, Pg. 759, 1967.
rat LD50 oral > 6750mg/kg (6750mg/kg)   Drugs in Japan Vol. 6, Pg. 497, 1982.
rat LD50 subcutaneous > 2gm/kg (2000mg/kg)   Drugs in Japan Vol. 6, Pg. 497, 1982

Warnings

Adverse Dental and Bone Effects

Use during tooth development (e.g., pregnancy, children <8 years of age) may cause permanent yellow-gray to brown discoloration of teeth and enamel hypoplasia Effects are most common following long-term use, but may occur following repeated short-term use.

Tetracyclines form a stable calcium complex in any bone-forming tissue. Reversible decrease in fibula growth rate has occurred in prematures receiving tetracycline.

Use not recommended in children <8 years of age unless other appropriate drugs are ineffective or are contraindicated or unless the benefits in certain indications (e.g., anthrax) outweigh the risks. (See Pediatric Use under Cautions.)

Fetal/Neonatal Morbidity

Animal studies indicate possible fetal toxicity (e.g., retardation of skeletal development) and embryotoxicity. If used during pregnancy or if patient becomes pregnant while receiving demeclocycline, patient should be apprised of the potential hazard to the fetus.

Nervous System Effects

Possibility of adverse CNS effects (light-headedness, dizziness, vertigo) that may impair ability to drive vehicles or operate hazardous machinery.

Benign intracranial hypertension (pseudotumor cerebri) in adults reported with tetracyclines; usually manifested as headache and blurred vision. Bulging fontanels reported in infants. Effects usually resolve when drug discontinued, but possibility for permanent sequelae exists.

Renal Effects

Tetracyclines have antianabolic effects and may increase BUN.

In patients with impaired renal function, high serum demeclocycline concentrations may result in azotemia, hyperphosphatemia, and acidosis. Excessive drug accumulation and possible liver toxicity may occur if usual dosage is used patients with renal impairment.

Diabetes Insipidus Syndrome

Diabetes insipidus syndrome (polyuria, polydipsia and weakness) reported with long-term demeclocycline therapy. Syndrome is nephrogenic, dose-dependent, and reversible when drug discontinued.

Laboratory Monitoring

Periodically assess organ system function, including renal, hepatic and hematopoietic, during long-term therapy.

Sensitivity Reactions

Photosensitivity, manifested by an exaggerated sunburn reaction, reported with tetracyclines.

Photosensitivity reactions may develop within a few minutes to several hours after sun exposure and usually persist 12 days after discontinuance of the drug. Most reactions result from accumulation of tetracyclines in skin and are phototoxic in nature; photoallergic reactions may also occur.Discontinue drug at first evidence of skin erythema.

Pharmacokinetic

Bioavailability 60-80%
Protein binding 7591%
Cmax 1.2-2.5 mg/ml (150 and 500mg dose)
tmax (hrs) 4-6
Metabolism hepatic
Half life 10-17 hrs
Clrenal 35 ml/min/1.73 m2
Distribution volume Vd (l) 121
Excretion renal (40%), faecal (43%)

Patients with severe renal impairment have an half-life 4268 hours.

Absorption

Tetracyclines are readily absorbed. Food and/or milk decrease GI absorption by ≥50%.

Distribution

Demeclocycline is well distributed into body tissues and fluids.

Excretion

Demeclocycline hydrochloride is concentrated in the liver and excreted into the bile where it is found in much higher concentrations than in the blood. Following a single 150 mg dose of demeclocycline hydrochloride in normal volunteers, 44% (n = 8) was excreted in urine and 13% and 46%, respectively, were excreted in feces in two patients within 96 hours as active drug.

Metabolism

Does not appear to be metabolized.

Mechanism of action

As with related tetracycline antibiotics, demeclocycline acts by binding to the 30S and 50S ribosomal subunits, which impairs protein synthesis by bacteria. Demeclocycline is lipophilic and can easily pass through the cell membrane or passively diffuses through porin channels in the bacterial membrane. Demeclocycline is bacteriostatic (it impairs bacterial growth but does not kill bacteria directly). Because it is excreted more slowly than tetracycline, it maintains effective blood levels for longer periods of time.

It is not completely understood why demeclocycline impairs the action of antidiuretic hormone, but is thought to block the binding of the hormone from its receptor [3].

Microbiology

 


Medicinal Chemistry

CAS number: 127-33-3   EINECS: 204-834-8

Molecular Formula: C21H21ClN2O8

Average mass: 464.852997 Da

Monoisotopic mass: 464.098633 Da

Systematic name: (4S,4aS,5aS,6S,12aS)-7-Chloro-4-(dimethylamino)-3,6,10,12,12a-pentahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydro-2-tetracenecarboxamide

SMILES: CN(C)[C@H]1[C@@H]2C[C@@H]3[C@@H](c4c(ccc(c4C(=O)C3=C([C@@]2(C(=O)C(=C1O)C(=O)N)O)O)O)Cl)O
 

Std. InChI: 1S/C21H21ClN2O8/c1-24(2)14-7-5-6-10(16(27)12-9(25)4-3-8(22)11(12)15(6)26)18(29)21(7,32)19(30)13(17(14)28)20(23)31/h3-4,6-7,14-15,25-26,28-29,32H,5H2,1-2H3,(H2,23,31)/t6-,7-,14-,15-,21-/m0/s1

CD/LogP: -1.067 # of Rule of 5 Violations: 2
ACD/LogD (pH 5.5): -3.59 ACD/LogD (pH 7.4): -4.03
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 10 #H bond donors: 7
#Freely Rotating Bonds: 7 Polar Surface Area: 181.62 2
Index of Refraction: 1.761 Molar Refractivity: 109.255 cm3
Molar Volume: 265.184 cm3 Polarizability: 43.312 10-24cm3
Surface Tension: 107.971000671387 dyne/cm Density: 1.753 g/cm3
Flash Point: 429.838 C Enthalpy of Vaporization: 120.098 kJ/mol
Boiling Point: 787.125 C at 760 mmHg Vapour Pressure: 0 mmHg at 25C


Melting point: 220-223 C

Water solubility: 1520 mg/l (at 21 C)

Storage conditions: 2025C


1. Lexi-Comp. "Demeclocycline". The Merck Manual Professional. 2008.

2. Tolstoi LG. "A brief review of drug-induced syndrome of inappropriate secretion of antidiuretic hormone". Medscape Pharmacotherapy 2002, 4, (1).

3. De Troyer A, Demanet JC (1975). "Correction of antidiuresis by demeclocycline". N Engl J Med 1975, 293, (18), 9158. 

 

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