Dose in man

Codeine (morphine methyl ether) resembles morphine in its general effect, but is less toxic and its depressant action less marked and less prolonged, whilst its stimulating action involves not only the spinal cord, but also the lower parts of the brain. In small doses in man it induces sleep, which is not so deep as that caused by morphine, and in large doses it causes restlessness and increased reflex excitability rather than sleep. The respiration is slowed less than by morphine (cf. table, p. 261). Cases of addiction for codeine can occur but according to Wolff they are rare. The best known ethers of morphine are ethylmorphine and benzyl-morphine [cf., table, p. 261), both used to replace morphine or codeine for special purposes. 

Red P is poisonous on inhalation or ingestion, but slower acting than white P. The lowest published lethal dose in man by oral ingestion is 1.4mg/kg (Ref 7). It should never be allowed to... 

The equation is an approximation, adapted from that for intravenous dosing [81], corrected by addition of a term for absorption. Essentially it assumes instantaneous absorption of the dose, but for compounds with reasonable physico-chemical and PK properties that are expected to be suitable for once-a-day dosing, this approximation makes little difference to the predicted value of Cmin ss. Use of the relationship can provide a simple approach for estimating the required dose in man for a compound in the discovery phase. 

The U.S. FDA has issued a guidance document that assists both the toxicologist and the clinician to propose the first dose in man.12 The starting dose becomes a fraction (often 10%) of the lowest no-adverse-effect level (NOAEL) in the rodent or nonrodent repeated dose studies. This is an oversimplistic statement and the reader is referred to the specifics of the guidance. 

It is difficult to estimate the lethal dose in man due to the many confounding factors that may be present, as well as the selective reporting of deaths following either unusually high or low dosage (both of which probably have more medical news value ). One authority has declared a surely fatal dose to be about 1200 mg. Most pharmacology texts, on the other hand, tend to give estimates at least ten times lower. 

The lethal potential of each of the drugs we studied was always a concern. In general, we had to rely on animal studies when estimating the lethal dose in man. It was necessary to test several species to be sure that they were similarly susceptible. And even if animal studies suggested a large safety margin for humans, additional factors had to be considered. 

NG EA 3580A Estimate of minimal effective dose in man. Edgewood Arsenal, MD. CRDL Technical Memorandum 2-12. 1965... 

Eor the observed dose in an experimental animal study, and the equivalent dose in man,... 

Lund, J., Thayssen, P., Mengel, H., Pedersen, O.L., Kristensen, C.B., and Gram L.F. (1982) Paroxetine pharmacokinetics and cardiovascular effects after oral and intravenous single doses in man. Acta Pharmacol Toxicol (Copenh) 51 351—357. 

Mayol, R.F., Adamson, D.S., Gammans, R.E., and LaBudde, J.A. (1985) Pharmacokinetics and disposition of 14C-buspirone HCl after intravenous and oral dosing in man. Clin Pharmacol Ther... 

Toxicity. The minimum lethal dose in man is about 6 mg although recovery has occurred after much larger doses. 

Two SI units refer to doses of radioactivity and these are used when calculating exposure levels for a particular source. The sievert (Sv) is the amount of radioactivity giving a dose in man equivalent to 1 gray (Gy) of v-rays 1 Gy = an energy absorption of 1 Jkg. The dose received in most biological experiments is a negligible fraction of the maximum permitted exposure limit. Conversion factors from older units are given in Table 35.3. 

It was one of the first glycolates used In relatively high doses in man, so more years have elapsed in which long-range consequences might have occurred. 

Incapacitating Dose in Man. Edgewood Arsenal Technical Memorandum 114-2. 

Bottigllerl, N 1965 EA 3580A Estimate of Minimal Effective Dose In Man. Chemical Research and Development Laboratories Technical Memorandum 2-12. 

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