Demeclocycline

464.856

464.85

204-834-8

5R5W9ICI6O

DTXSID1022893

C47980

YELLOW CRYSTALLINE POWDER

D - Dermatologicals|J - Antiinfectives for systemic use

182

0.2

1.3118 (rough estimate)

174-178 °C (decomp)

787.1±60.0 °C(Predicted)

367.8±31.5 °C

1.6000 (estimate)

In water, 1.52X10+3 mg/l @ 21 deg C

1.02E-26mmHg at 25°C

ODORLESS

BITTER

ABOUT 4.8 (1 IN 100 SOLN)

MP: 174-178 (decomposes). Specific optical rotation = -258 °C for D (sodium) line (c = 0.5 in 0.1N H2SO4) /Sesquihydrate/|When heated to decomposition it emits very toxic fumes of Cl+ and NOx.

The photodegradation of demeclocycline hydrochloride in buffer solutions was studied in the absence and presence of some potential photostabilizers under the influence of fluorescent light. Photolysis of drug solutions followed first order kinetics. The drug was more stable in acidic pH. Ionic strength of the buffer did not affect photolysis. Reduced glutathione was the most effective photostabilizer. An increase in glutathione concentration decreased the photodegradation rate, but this decrease

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392).

Oral, rat: LD50 = 2372 mg/kg

No reports of liver injury due to demeclocycline have been published. However, demeclocycline is a tetracycline derivative and is likely to cause liver injury similar to other oral tetracyclines. Both hepatitis and liver failure are mentioned in the product label for demeclocycline, but details of the liver injury are not provided. Finally, demeclocycline causes worsening of kidney function in patients with cirrhosis and should not be used for hyponatremia associated with chronic liver disease.

PRERENAL AZOTEMIA & DRUG TOXICITY MAY ARISE WHEN TETRACYCLINES ARE ADMIN TO PT WITH DECR RENAL FUNCTION. METHOXYFLURANE IS ASSOC WITH DOSE-RELATED IMPAIRMENT OF RENAL FUNCTION, SO POTENTIAL FOR TETRACYCLINE TOXICITY MAY BE INCR FOLLOWING...ANESTHESIA. ... ALL TETRACYCLINES EXCEPT DOXYCYCLINE MAY EXHIBIT SAME...TOXICITY.|SIMULTANEOUS ADMIN OF ALUMINUM, CALCIUM, OR MAGNESIUM IONS SIGNIFICANTLY DECR GI ABSORPTION OF TETRACYCLINE. ... /DEMECLOCYLINE HAS/ BEEN REPORTED TO INTERACT WITH ALUMINUM IONS & DAIRY PRODUCTS CONTAINING CALCIUM (EG, COTTAGE CHEESE & MILK).|BECAUSE METHOTREXATE BINDS TO PLASMA PROTEINS, IT CAN BE DISPLACED FROM ITS BINDING SITES & MADE AVAIL TO REACT WITH DIHYDROFOLATE REDUCTASE. THOSE COMPD THAT HAVE BEEN REPORTED TO DISPLACE METHOTREXATE INCL...TETRACYCLINES.|TETRACYCLINE MAY ANTAGONIZE BACTERICIDAL EFFECT OF PENICILLIN, BUT CLINICALLY SIGNIFICANT INTERACTION OCCURS ONLY IN SITUATIONS WHERE RAPID BACTERICIDAL EFFECT IS NECESSARY (EG, PNEUMOCOCCAL MENINGITIS). ... ALL TETRACYCLINES MAY BE EXPECTED TO INTERACT IN SIMILAR MANNER...|For more Interactions (Complete) data for DEMECLOCYCLINE (7 total), please visit the HSDB record page.

LD50 Rat ip 358 mg/kg|LD50 Mouse ip 454 mg/kg|LD50 Mouse iv 79 mg/kg

41-50%

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.

Demeclocycline is a semisynthetic tetracycline derived from Streptococcus aureofaciens that is used as an antibiotic, but perhaps more frequently as an inhibitor of arginine vasopressin in the therapy of hyponatremia and the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). While demeclocycline has not been linked specifically to liver injury in the published literature, it is an orally available semisynthetic tetracycline and is likely to cause injury similar to that described for tetracycline, oxytetracycline, and doxycycline. Because it is not commonly used, its potential for causing liver injury may not have been fully defined.

Antiinfective Agents

Antibiotics, Tetracycline|Tetracyclines are especially useful in diseases caused by rickettsiae, mycoplasmas, & chlamydiae. /Tetracyclines/|...THEY ARE OF PROVEN VALUE.../AGAINST/ ROCKY MOUNTAIN SPOTTED FEVER, MURINE TYPHUS, RECRUDESCENT EPIDEMIC TYPHUS, SCRUB TYPHUS, Q FEVER, LYMPHOGRANULOMA VENEREUM, PSITTACOSIS, TULAREMIA, BRUCELLOSIS, GONORRHEA, CERTAIN URINARY TRACT INFECTIONS, OCULAR INFECTIONS, GRANULOMA INGUINALE, CHANCROID, SYPHILIS... /TETRACYCLINES/|...THEY ARE OF PROVEN VALUE.../AGAINST/ DISEASE DUE TO BACTEROIDES & CLOSTRIDIUM. /TETRACYCLINES/|For more Therapeutic Uses (Complete) data for DEMECLOCYCLINE (8 total), please visit the HSDB record page.

... /Tetracyclines/ should not be given to pregnant patients; they should not be employed for treatment of common infections in children under the age of 8 yr; & unused supplies of these antibiotics should be discarded. /Tetracyclines/|Tetracyclines may aggravate uremia in patients with renal disease by inhibiting protein synthesis & provoking a catabolic effect. /Tetracyclines/|Tetracyclines are incompletely absorbed from the GI tract, such that high concns are reached in the bowel, & therefore the enteric flora is markedly altered. Many aerobic & anaerobic coliform microorganisms & gram-positive spore-forming bacteria are sensitive & may be suppressed markedly during long-term tetracycline regimens before resistant strains reappear. /Tetracyclines/|Because of the emergence of resistance, the tetracyclines are no longer indicated for infections caused by staphylococci, streptococci, or meningococci. /Tetracyclines/|For more Drug Warnings (Complete) data for DEMECLOCYCLINE (19 total), please visit the HSDB record page.

2 TO 3. 2= SLIGHTLY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 5-15 G/KG, BETWEEN 1 PINT & 1 QT FOR 70 KG PERSON (150 LB). 3= MODERATELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 0.5-5 G/KG, BETWEEN 1 OZ & 1 PINT FOR 70 KG PERSON (150 LB).

Because of the emergence of resistance, the tetracyclines are no longer indicated for infections caused by staphylococci, streptococci, or meningococci. /Tetracyclines/|Problems of resistance & the availability of superior antimicrobial agents limit the use of tetracyclines for treatment of infections caused by many gram-positive bacteria. /Tetracyclines/

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). Demeclocycline inhibits cell growth by inhibiting translation. Demeclocycline is lipophilic and can easily pass through the cell membrane or passively diffuses through porin channels in the bacterial membrane. Demeclocycline is not a direct bactericidal agent; rather, it is a bacteriostatic drug that impairs bacterial growth. Because it is excreted more slowly than tetracycline, it maintains effective blood levels for longer periods of time.

Substances that inhibit the growth or reproduction of BACTERIA. (See all compounds classified as Anti-Bacterial Agents.)

Tetracyclines are readily absorbed.|Demeclocycline hydrochloride, like other tetracyclines, 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.|Renal cl=35 mL/min/1.73 m2|Tetracyclines are deposited in the skeleton during gestation & throughout childhood. /Tetracyclines/|Tetracyclines distribute widely throughout the body & into tissues & secretions, including the urine & prostate. They accumlate in the reticuloendothelial cells of the liver, spleen, & bone marrow, & in bone, dentine, & the enamel of unerupted teeth. /Tetracyclines/|Tetracyclines cross the placenta & enter the fetal circulation & amniotic fluid. Concn of tetracycline in umbilical-cord plasma reach 60%, & in amniotic fluid 20%, of those in the circulation of the mother. Relatively high concns of these drugs also are found in breast milk. /Tetracyclines/|AFTER ORAL ADMIN OF DEMETHYLCHLORTETRACYCLINE (FREE BASE & HCL SALT) TO RATS, PLASMA LEVELS FROM EACH WERE ESSENTIALLY IDENTICAL.|The newer tetracyclines are defined as those tetracyclines available in the United States but not approved for veterinary use. These include demeclocycline, methacycline, doxycycline, & minocycline. Of these, doxycycline & minocycline appear to offer advantages that would render them useful in certain situations in veterinary medicine. Their major advantage lies in their greater lipid solubility relative to other tetracyclines. This characteristic probably accounts for their enhanced antimicrobial effectiveness for some organisms, more efficient absorption after oral admin, & enhanced distribution in the body. The principal excretory organ for doxycycline is the intestine, where the drug diffuses through the intestinal mucosa into the intestinal tract. This unique characteristic makes this drug useful in cases of preexisting renal dysfunction & may render this drug superior to other tetracyclines in the treatment of intestinal infections. Doxycycline is used in other countries for respiratory tract & intestinal tract diseases of poultry. The usefulness of doxycycline & minocycline in food-producing animals may be limited because of persistent drug residues. Minocycline has, in large doses, been used with streptomycin in the elimination of the carrier state of canine brucellosis. The superiority of doxycycline & minocycline, relative to other tetracyclines, in their distribution to areas of the body such as the eye, brain, cerebrospinal fluid, & prostate gland suggests that trials of their efficacy in tetracycline-sensitive infections of these areas are indicated. Pharmacokinetic studies designed to determine optimal dosage schedules have not been made for domestic animals. These determinations are necessary to evaluate most effectively the usefulness of the newer tetracyclines in veterinary medicine.

Hepatic

10-17 hours|IN PLASMA, IT IS PROTEIN-BOUND 41 TO 90%. ITS T/2 IS ABOUT 12 HR. /HCL/

Demeclocycline inhibits cell growth by inhibiting translation. It binds (reversibly) to the 30S and 50S ribosomal subunit and prevents the amino-acyl tRNA from binding to the A site of the ribosome, which impairs protein synthesis by bacteria. The binding is reversible in nature. The use in SIADH actually relies on a side-effect of tetracycline antibiotics; many may cause diabetes insipidus (dehydration due to the inability to concentrate urine). It is not completely understood why demeclocycline impairs the action of antidiuretic hormone, but it is thought that it blocks the binding of the hormone to its receptor.|Tetracyclines inhibit bacterial protein synthesis by binding to the 30 S bacterial ribosome & preventing access of aminoacyl tRNA to the acceptor (A) site on the mRNA-ribosome complex. They enter gram-negative bacteria by passive diffusion through the hydrophilic channels, formed by the porin proteins of the outer cell membrane, & active transport by an energy-dependent system that pumps all tetracyclines across cytoplasmic membrane. Although permeation of these drugs into gram-positive bacteria is less well understood it also is energy requiring. /Tetracyclines/|...INHIBITORY EFFECTS OF TETRACYCLINES CAN BE REVERSED BY WASHING. THEREFORE, IT IS PROBABLE THAT REVERSIBLY BOUND ANTIBIOTIC IS RESPONSIBLE FOR ANTIBACTERIAL ACTION. /TETRACYCLINES/|... Drugs to antagonize /antidiuretic hormone/, ADH, action can be used /to treat the syndrome of inappropriate antidiuretic hormone secretion/. These include a loop diuretic, demeclocycline ... . ... Demeclocycline & lithium directly impair the response to ADH at the collecting tubule, inducing nephrogenic diabetes insipidus. Demeclocycline usually is better tolerated than lithium.

/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

A double blind cross-over phototoxicity study using demethylchlortetracycline (DMCT) 0.3 g x 2, doxycycline 0.1 g x 2, lymecycline 0.6 g x 2 & placebo was performed on 8 healthy human volunteers. Drugs were given for 3 consecutive days, & on the third day the volunteers were tested with different modalities of artificial long-wave ultraviolet radiation (UVA) & assessed 24 hr later for objective as well as subjective abnormal photoreactions. All 4 substances were tested in each individual at weekly intervals & serum concns of tetracycline were determined. It was found most convenient to irradiate relatively large skin areas using fluorescent tubes emitting mainly UVA but also a small proportion of UVB. Using this type of irradiation, weak erythemal reactions were obtained with all 3 derivatives. Taking only stronger reactions & stinging sensations into account, 0/8 reacted to lymecycline, 0/8 to DMCT & 4/8 to doxycycline. There was no significant difference in serum concn among the 3 derivatives. It is concluded that doxycycline is the most potent photosensitizer at the dosage tested.|Hemolysis induced by ultraviolet radiation as well as demethylchloretetracycline (DMCT) phototoxicity have been investigated in a model using human red blood cells. Total hemolysis for UV-B and UV-C was obtained with 8.3 & 1.9 J/cm2 respectively. DMCT was shown to have pronounced hemolytic properties causing 88% hemolysis at 50 micrograms/ml & 72 J/cm2 of UV-A. No increased hemolysis rate was seen in combination with UV-B. Several factors influencing the results were studied such as incubation time, UV-A dose, drug concn & different methods for hemoglobin detection. Photohemolysis is an accurate tool for demonstrating DMCT phototoxicity.|Hyponatremia has been reported to occur in approx 5% of carbamazepine-treated patients who otherwise do well on that agent. Demeclocycline has been used in the treatment of hyponatremia of various etiologies including one case of carbamazepine-induced hyponatremia. We extended these observations by studying the effects of demeclocycline on carbamazepine-induced hyponatremia in 6 psychiatric inpatients. RESULTS: Once serum sodium concns had normalized after carbamazepine discontinuation, demeclocycline prevented further decreases in sodium levels upon rechallenge with carbamazepine in 5 of 6 patients. Gender, smoking, & neurologic compromise may have played a role in the development of carbamazepine-induced hyponatremia as well as response to this strategy, although our sample size is too small to make firm conclusions.|Hepatic fatty change is a common lesion. Two forms are recognized: micro- & macrovesicular steatosis, the former being much less frequent & more serious than the latter. The case of an alcoholic woman under anticonvulsivant therapy & with medications for a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) who presented with rapidly progressive cholestasis & hepatocellular failure is reported. Massive macro- & micro-vesicular hepatic steatosis was diagnosed at autopsy. The authors review the clinico-pathological features associated with this condition, & causal factors possibly implicated in this case are discussed in regard with currently considered pathophysiological mechanisms.|For more Human Toxicity Excerpts (Complete) data for DEMECLOCYCLINE (7 total), please visit the HSDB record page.

Declomycin

Clortetrin, Demetraciclina, Detravis, Meciclin, Mexocine /Hydrochloride/|Main ingredient in the drug Declomycin by Lederle Laboratories (oral tablets). /Hydrochloride/|DOSAGE FORMS--CAPSULES NF: 75, 150, & 300 MG; TABLETS NF: 75, 150, & 300 MG.

Improved fermentation processes: Szumski; Goodman, Matrishin; Goodman, US patents 3,012,946 and 3,019,172; 3,050,446 (1961 and 1962 to Am Cyanamid); French patent 1,344,645 (1963 to Merck & Co); Neidleman, US patent 3,154,476 (1964 to Olin Mathieson).

REVERSE PHASE HIGH SPEED LIQ CHROMATOGRAPHY PRESENTED FOR SEPARATION & DETECTION OF TETRACYCLINES. APPROACH IS SUPERIOR TO ION-EXCHANGE LIQ CHROMATOGRAPHY & SPECTROPHOTOMETRIC, CHEM & MICROBIOLOGICAL PROCEDURES CURRENTLY IN USE.|TLC METHOD DESCRIBED IN WHICH TETRACYCLINES ARE SEPARATED ON CELLULOSE LAYER DEVELOPED WITH AQ SOLN OF CERTAIN SALTS (MG, CA, BA & ZINC CHLORIDE). UV FLUORESCENCE OF SPOTS (WITHOUT FURTHER TREATMENT) USED FOR DIRECT PHOTOMETRIC DETECTION WITH GOOD ACCURACY.|Performance of Tet-Lux, a newly developed microbiological test for the detection of tetracycline residues in raw milk, based on tetracycline-controlled luminescence activation of the test bacteria, was evaluated in bovine milks with variable amounts of somatic cells, bacteria, fat, protein, & natural inhibitory compounds. The sensitivity of Tet-Lux was also compared to a commercially available tetracycline immunoassay (Snap, Idexx Laboratories Inc.) & to a microbial inhibition test (Delvotest SP, Gist-Brogades). There were slight differences in the luminescence signals between different milk samples, but no single factor could be pointed out to be responsible for them. There appeared to be a modest inverse relationship between luminescence & increasing fat & protein content. The amount of somatic cells, bacteria, & the natural inhibitors lysozyme & lactoferrin did not affect the luminescence response. The test fulfilled the sensitivity requirement specified by the European Union (max residue limit 100 ng/ml for tetracyclines). The Tet-Lux test was clearly more sensitive to all tetracyclines tested (oxytetracycline, tetracycline, chlortetracycline, doxycycline, demeclocycline, methacycline, minocycline) than Delvotest SP, & for 5 tetracyclines out of 7 more sensitive than Snap. The test provides a fast, simple, & robust microbial method for the qualitative detection of tetracycline residues in milk.

SIMPLE & INEXPENSIVE FLUORIMETRIC METHOD FOR ANALYSIS OF MIXT OF TETRACYCLINES (INCL DEMETHYLCHLORTETRACYCLINE) IN PLASMA CONSISTS OF CONVERSION TO FLUORESCENT FORM & MEASUREMENT IN SPECTROFLUORIMETER.

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