Microbiology: Antibacterial Activity: Miotin dry syrup exerts potent antibacterial activity against gram-positive bacteria and some gram-negative bacteria. (See Table 1.)
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Induction of Resistance: Midecamycin does not induce resistance in Staphylococcus aureus.
Action Mechanism: Miotin shows antibacterial activity due to inhibition of protein synthesis by binding to the 50S subunit of microbial ribosomes.
Enforcement of Antibacterial Activity In Vivo: S. aureus 209 P JC-1: 0.39 mcg/mL; S. epidermidis ATCC 14990: 0.78 mcg/mL; S. pyogenes Cook: 0.39 mcg/mL; S. pneumoniae type 1: 0.05 mcg/mL; H. influenzae 9334: 0.39 mcg/mL; Mycoplasma pneumoniae: 0.0001-0.0625 mcg/mL; Chlamydia pneumoniae: 0.06-0.25 mcg/mL; Peptostreptococcus sp: 0.2-1.56 mcg/mL; Bacteroides sp: 0.2-0.39 mcg/mL; Legionella pneumophila: 0.06-0.5 mcg/mL.
Pharmacokinetics: Absorption: Blood Concentration: When a dose of 600 mg (potency) of Miotin was administered orally to 6 adults on an empty stomach, the mean peak blood concentration reached 2.38 mcg/mL after 0.5 hr and the biological half-life was about 1.3 hrs. When the same dose was administered after a meal, the mean peak blood concentration reached 1.83 mcg/mL after 0.5 hr and the biological half-life was about 1.5 hrs. In infants, when a dose of 10 or 20 mg (potency)/kg of Miotin was administered orally on an empty stomach, the peak blood concentration reached 0.77 mcg/mL after 30 min or 1.14 mcg/mL after 1 hr, respectively. When administered at 10 or 20 mg (potency)/kg after a meal, the peak blood concentration reached 0.63 mcg/mL after 1 hr or 1.3 mcg/mL after 2 hrs, respectively.
Transfer to Body Fluid and Tissues: The drug level in the tonsil is higher than that in the blood, and Miotin is efficiently transferred to the sputum.
Metabolism and Excretion: Midecamycin is excreted after having been metabolized, mainly at the site of absorption or in the liver. The 24-hr urinary excretion rate was 4-5% when 600 mg (potency) of Miotin was orally administered to humans.
Clinical Data: The results of the clinical trials, which involved a total of 1703 cases, are summarized as follows. These trials include 4 double-blind controlled studies on respiratory tract infections (RTI), skin and soft tissue infections, and otitis media.
Clinical Efficacy: Respiratory Tract Infections (RTI).
Upper RTI: An efficacy rate of 80.6% (295/366 cases) was reported for upper RTI eg, tonsillitis and laryngopharyngitis due to S. aureus, S. hemolyticus, etc.
Lower RTI: An efficacy rate of 76.3% (361/473 cases) was reported for lower RTI eg, mycoplasmal pneumonia, primary atypical pneumonia and bronchitis, etc.
Skin and Soft Tissue Infections: An efficacy rate of 73.5% (166/226 cases) was reported for skin and soft tissue infections eg, furuncle, carbuncle, phlegmon and subcutaneous abscess due to S. aureus, S. epidermidis, etc.
Otitis Media: An efficacy rate of 56.9% (99/174 cases) was reported for acute otitis media and acute exacerbation of chronic otitis media due to S. aureus, S. epidermidis, gram-negative bacilli, etc.
Side Effects and Changes in Laboratory Findings: Of a total 3,517 cases, 54 cases (1.5%) were reported to have developed side effects: Gastrointestinal disorders eg, gastric discomfort, diarrhea, vomiting, etc (1.1%); and skin disorders eg, rash, urticaria, etc (0.4%). Changes in laboratory findings were seen in 34 cases (1%): Eosinophilia (0.3%) and elevation of GOT-GPT (0.6%), etc.
Toxicology: Nonclinical Tests: Acute Toxicity: See Table 2.
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Subacute Toxicity: When 1000, 2000 and 4000 mg/kg/day of Miotin were orally administered to rats for 5 weeks, there were no abnormalities in their general condition. However, changes in RBC, LDH, serum creatinine and cholesterol were observed in the 2000- and 4000-mg/kg groups. Histopathological examination revealed necrosis of the renal tubular epithelial cells and slightly increased weights for the kidney and liver in the female 2000- and 4000-mg/kg group. There were no other noteworthy abnormalities.
Chronic Toxicity: When 125-1000 mg/kg/day of Miotin was orally administered to rats for 26 weeks, cholesterol was increased while RBCs and lymphocytes were decreased in the groups receiving ≥500 mg/kg. In the male 1000-mg/kg group, increases in cholesterol, SGOT and calcium, and decreases in serum total protein and albumin were observed. However, the general condition was normal in all groups. Histopathological examination revealed increases in the absolute and relative weights of the kidney, and slight degeneration of the renal tubular epithelial cells in the male groups receiving ≥500 mg/kg. There were no other abnormalities.
When 100-1200 mg/kg/day of Miotin was orally administered to dogs for 26 weeks, there were no remarkable abnormalities in the general condition, hematology, serum biochemistry, urinalysis or histopathology in any of the groups.
Influence on Reproduction: Fertility test before and early pregnancy 125-1000 mg/kg/day of Miotin was orally administered to male rats for 11 weeks and to female rats for 14 days. After copulation, the same doses were orally administered to the pregnant rats for a further 7 days. There were no particular effects on the reproductive function in the groups receiving ≤500 mg/kg/day or on fetuses in any of the groups.
Teratogenicity: Teratology test during period of organogenesis 100-1000 mg/kg/day of Miotin was orally administered during the period of organogenesis to rats for 11 days and to rabbits for 13 days. There were no effects on the organogenesis or growth of the rabbits receiving ≤400 mg/kg. On the other hand, the rats showed no effects at any dosage.
Teratology test during perinatal and lactation periods 125-1000 mg/kg/day of Miotin were orally administered to rats from the 17th day of pregnancy to the 21st day after birth. There were no effects on the growth or physical development of the newborns in any of the groups.
Mutagenicity: An in vitro reverse mutagenicity test using Salmonella typhimurium and a dominant lethal test in vivo confirmed that Miotin shows no mutagenicity.
Antigenicity: Miotin was mixed with Freund's complete adjuvant and used to sensitize rabbits, guinea pigs and mice by SC injection. Miotin did not induce antibody production or active anaphylaxis.
Transfer to Animal Tissues: When Miotin was orally administered to rats and dogs, it was transferred in high concentrations to the lung, liver, kidney, spleen, parotid, submandibular gland, submandibular lymph node, accessory sinus of the nose and oral cavity mucosa, tonsil and adjacent tissue, pharynx and trachea, etc.