Actions of Cos-P in details
Cos-P is a synthetic derivative of the herbal active ingredient vasicine. Preclinically, it has been shown to increase the proportion of serious bronchial secretion. Cos-P enhances mucus transport by reducing mucus viscosity and by activating the ciliated epithelium (mucociliary clearance).
In clinical studies, Cos-P showed a secretolytic and secretomotor effect in the bronchial tract area, which facilitates expectoration and eases cough. Pharmacokinetics: Cos-P is absorbed well by the enteral route, the absorption half-life of a Cos-P solution is 0.4 hrs. Following oral intake of Cos-P tablets, the peak plasma concentration is reached within approximately 1 hr (tmax). Cos-P is subject to a first-pass effect of 75-80%; the absolute bioavailability of oral dosage forms is therefore given as 20-25% (37,40). Food before administration of Cos-P enhances the bioavailability of the compound.
Following pre-oral administration, Cos-P shows dose linearity in the dose range 8-32 mg. At least 10 different Cos-P metabolites have been discovered in the plasma, including the pharmacologically active metabolite ambroxol.
There is a high level of plasma protein-binding at 95-99% and a large distribution volume of 7 L/kg body weight (IV administration). Cos-P accumulates in the lung rather than in the plasma.
The dominant elimination half-life is given as 1 hr, the terminal elimination half-life is 13-40 hrs. Following oral administration of 8 mg, the plasma levels fell after 8-12 hrs to 1.5 ng/mL and 0.2 ng/mL, respectively. For the most part, Cos-P is excreted renally in the form of metabolites that pass through the kidneys while only minor amounts of 0-10% parent compound are found in unchanged form in the urine. After 24 hrs and 5 days, 70% and 88% of the oral dose, respectively is recovered in the urine, 4% is excreted with the feces.
Cos-P does not cumulate as the long terminal elimination half-life is not dominant. Steady-state levels are reached after 3 days at the latest.
In animal studies, Cos-P penetrates the cerebrospinal fluid and the placenta. It is expected that the compound is excreted in breast milk.
Reduced clearance of Cos-P parent substance can be expected in the case of severe liver disease; in the case of severe renal insufficiency, cumulation of metabolites cannot be ruled out; pharmacokinetic studies for these conditions are not available.
Toxicology: Acutely, Cos-P HCl has a very low index of toxicity:
Oral LD
50 values were >5 g/kg in rats, >4 g/kg in rabbits, >10 g/kg in dogs and >1 g/kg in newborn rats. The intraperitoneal LD50 in rats was 2 g/kg. The LD50 values for the syrup formulation were >10 mL/kg in mice and rats. No clinical signs were observed at these acute doses.In repeated oral dose toxicity studies over 5 weeks, mice tolerated 200 mg/kg [no observed adverse effect level (NOAEL)]. At 2000 mg/kg, mortality was high. The few surviving mice showed a reversible increase in liver weight and serum cholesterol. Rats tolerated 25 mg/kg over 26 or 100 weeks, while at 500 mg/kg, convulsions and deaths occurred. The centrilobular hepatocytes were enlarged due to vacuolic change. Another 2-year study confirmed that doses up to 100 mg/kg are well-tolerated, while at 400 mg/kg, convulsions occurred sporadically in a few rats. Dogs tolerated 100 mg/kg (NOAEL) orally over 2 years. Cos-P syrup (0.8 mg/mL) was well-tolerated up to 20 mg/kg in rats, but there was a reversible centrilobular simple fatty change of liver. An IM dose of 8 mg injectable solution was locally and systemically well-tolerated in dogs treated for 6 weeks.
Cos-P was neither embryotoxic nor teratogenic in segment II at oral doses up to 300 mg/kg (rat) and 200 mg/kg (rabbit). Fertility was not impaired in segment II at doses up to 300 mg/kg. The “NOAEL” during the peri- and postnatal development in segment II was 25 mg/kg.
A single intra-articular injection of 4 mg Cos-P was well-tolerated in rabbits and dogs. The lesions after IM injection in rabbits compared well with those after physiological saline solution. In vitro, 1 mL injectable solution showed a hemolytic action when mixed with 0.1 mL human blood.
In 2 studies (Ames and micronucleus tests), Cos-P had no mutagenic potential. Cos-P did not show a tumorigenic potential in the 2-year studies on rats given up to 400 mg/kg and on dogs given up to 100 mg/kg.
Cos-P administration
Should be taken with food.
References
- DailyMed. "TERBUTALINE SULFATE: DailyMed provides trustworthy information about marketed drugs in the United States. DailyMed is the official provider of FDA label information (package inserts).". https://dailymed.nlm.nih.gov/dailyme... (accessed September 17, 2018).
- NCIt. "Terbutaline Sulfate: NCI Thesaurus (NCIt) provides reference terminology for many systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities.". https://ncit.nci.nih.gov/ncitbrowser... (accessed September 17, 2018).
- EPA DSStox. "Terbutaline: DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology.". https://comptox.epa.gov/dashboard/ds... (accessed September 17, 2018).
Reviews
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Information checked by Dr. Sachin Kumar, MD Pharmacology