Chemistry:Toldimfos

Toldimfos (Toldimphos) sodium is the sodium salt of 4-dimethylamino-2-methyl-phenyl-phosphinous acid, a derivative of phosphoric acid. It is indicated for the treatment and prophylaxis of diseases which arise in connection with parturition and the peripartum period, developmental and nutritional disorders in young animals, disorders of bone growth and tetany or paresis caused by disorders of calcium, magnesium and phosphorus metabolism. The recommended therapeutic dose is 10 mg/kg bw given by intravenous, intramuscular or subcutaneous injection. Injections are normally repeated to clinical effect, up to a maximum of 10 injections. Toldimfos is indicated for use in the following food producing species: horses, cattle, sheep, pigs and goats.

Pharmacodynamics

Phosphorus is one of the fundamentally important elements of the body which is involved in many vital processes. Foston contains the aromatic phosphorus compound Toldimphos which falls between phosphorus and phosphoric acid in the stages of oxidation in the body. Toldimphos does not replace deficient phosphorus but stimulates metabolism and:

• increases calcium concentration in blood without simultaneous administration of calcium preparations.
• normalises Aspartate Transaminase (AST) or Serum Glutamic Oxaloacetic Transaminase (SGOT) values.
• has a beneficial effect on serum cholesterol.

Pharmacokinetics

The intramuscular administration of toldimfos to cattle at a dosage level of 10 mg/kg bw led to a peak blood concentration within 10 to 20 minutes after administration. Pharmacokinetic studies in calves showed the mean half life of toldimfos in serum was 1.07 hours, whilst the corresponding value for dairy cows was 1.15 hours. The pharmacokinetic profile corresponded to a one compartment model of distribution. The mean residence time for toldimfos in blood in calves was 3.6 hours, with a value of 3.1 hours being recorded for dairy cows. These studies were not radiolabelled. Urinary excretion studies revealed a rapid elimination of toldimfos following dosing. The major fraction of the administered dose was eliminated within 6 hours, whilst at the 24 hour time-point, only concentrations in the range of the limit of detection (limit of detection:0.5 μg/kg) were observed. Twelve to twenty four hours following a second injection of toldimfos, similar low concentrations were recorded in urine. Toldimfos was eliminated as parent compound. Elimination of the compound in milk was extremely low, with levels below the limit of quantification of the analytical technique (limit of quantification for milk 0.15 μg/kg) at most time points. Repeated dosing in the pharmacokinetic study did not lead to bio-accumulation of the test compound.

Previous Human Use

Toldimfos has been historically used in human medicine since 1920. However, it is not currently indicated for human use. In humans, the product was used as an injectable or an oral preparation for states of debility, following major operations and infectious diseases, the treatment of chronic stress and as treatment for physical and mental overexertion. The recommended dosage rate was 10 to 20 mg of toldimfos per person per day by subcutaneous administration or 300 mg of toldimfos per person per day by oral administration. Toldimfos was well tolerated after both parenteral and oral administration. Although a significant amount of human data was available,the quality of such data was poor, making meaningful interpretation difficult.

A toxicological ADI of 0.1 mg/kg bw (i.e. 6 mg/person for a 60 kg person) was established based on the NOEL of 10 mg/kg bw/day from the 90-day rat study, and applying a safety factor of 100.