Safe equivalent dose

Inhaled corticosteroids are not equivalent on a milligram basis however, equivalent doses have been approximated (Table 11-3). Low to moderate doses have been shown to be safe and effective in all age groups. Although some effect is seen from inhaled corticosteroids within 12 hours, 2 weeks of therapy is necessary to see significant clinical effects, and longer treatment periods maybe necessary to see the full effect of these agents on airway inflammation and remodeling. 

Application of a Safety Factor Following the conversion of the NOAEL, MABEL (or PAD), or NOEL to a human equivalent dose (HED), the resulting dose is usually divided by a safety factor in order to calculate the proposed starting dose in humans. This safety factor provides a safety margin between a safe dose in preclinical species and the hrst humans receiving the therapeutic. The default safety factor for most hrst-in-human studies is 10-fold, however, the assignment of this factor should be science-driven. 

The tumor incidence model is then used to estimate a safe ED defined as that equivalent dose which yields a negligible increase in risk for the tumor over the background risk. For the purposes of risk estimation, it is assumed that this safe ED represents the safe ED in humans. It remains only to convert this safe ED in humans into a safe human exposure level. As before, a model relationship is assumed between the ED and exposure dose in humans (usually the same conceptual model as was used in the animal species) and parameter estimates are obtained. In addition to obtaining parameter estimates from the fields previously mentioned, a considerable number of parameters are estimated as simple allometric formulae of parameters which are easily obtained in animals, such as body weight. The complexity of these models, the number of parameters and the number of experiments used to estimate the parameters contribute to the overall uncertainty in the safe dose estimates. 

Mycophenolate mofetil is available in 250 mg capsules and 500 mg tablets, an oral suspension (100 mg/mlL, in cherry syrup), and an injectable.11 Usual doses of mycophenolate mofetil range from 1000 to 3000 mg/day in two to four divided doses. The conversion between oral and IV mycophenolate mofetil is 1 1. Enteric-coated mycophenolic acid is available in 180 and 360 mg tablets. For conversion between mycophenolate mofetil and enteric-coated MPA, 1000 mg mycophenolate mofetil is equivalent to 720 mg enteric-coated MPA.26,29 The recommended starting dose of enteric-coated mycophenolic acid is 720 mg given twice daily.11 It appears that conversion of mycophenolate mofetil to enteric-coated mycophenolic acid is safe, but more studies are needed to determine the exact role of enteric-coated MPA in the immunosuppressive armamentarium. Mycophenolic acid trough concentrations can be monitored, but they are not recommended routinely. 

Immediate vs extended release Patients receiving immediate-release glipizide may be switched safely to the extended-release tablets once a day at the nearest equivalent total daily dose. Patients receiving immediate-release tablets also may be titrated to the appropriate dose of the extended-release tablets starting with 5 mg once daily. 

Tablets, extended-release Intended for once daily administration. Patients treated with diltiazem alone or in combination with other medications may be switched safely to once daily extended-release diltiazem tablets at the nearest equivalent total daily dose. Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted.

The procedure involves converting oxon to thion toxicity equivalents by multiplying the oxon value by its relative toxicity (ED of thion r ED,.q of oxon) in Table I. The ED. value is the aermal dose in ug/cnr of total body surface which produces 50% inhibition of red cell ChE activity 72 hours after application. The total thion and oxon level is then divided by the thion toxicity equivalents and the factor is multiplied by the safe level established for thion in Table I. This procedure was conducted for the dislodgeable residues of parathion-paraoxon, methidathion-methidathion oxon, and azinphosmethyl-azinphosmethyl oxon. The safe levels for the total disloggeable residues were determined to be 0.06, 0.2 and 1.6 ug/cm, respectively, for... 

L 1 and 0.6 jag L, respectively. Due to photolysis, nitrate present in the water at a concentration of 55 mg L 1 was reduced to nitrite generating an additional problem (see section II.D.l). This is because nitrite is thought to be involved in the formation of nitrosamines. Experimental conditions in this plant have been investigated to provide the optimum operating conditions for the removal of herbicides and to minimize the impact of nitrate photolysis. The results obtained in this plant led to concentrations of atrazine and nitrite in the effluent lower than 0.1 and 100 pg L 1, respectively. It must be said, for safe operation of the plant, that an equivalent ozone dose higher than 3 kW energy and a radiant power for the UV lamp between 20 and 35 kW were needed. 

A9-tetrahydrocannabinol, the active component in herbal cannabis, is very safe. Laboratory animals (rats, mice, dogs, monkeys) can tolerate doses of up to 1000 mg/kg, equivalent to some 5000 times the human intoxicant dose. Despite the widespread illicit use of cannabis, there are very few, if any, instances of deaths from overdose (9). 

A dose of 1 pg desmopressin acetate has antidiuretic activity that is equivalent to 4U arginine vasopressin. Desmopressin acetate has recently been evaluated in normal horses. The author and coworkers diluted desmopressin acetate (0.1 mg/ml) nasal spray in sterile water and administered 0.05pg/kg i.v. (25 pg, equivalent to 100 U of antidiuretic activity in a 500 kg horse) to horses with polyuria induced by repeated nasogastric intubation of water for 3 days. Urine was collected for 8h after desmopressin acetate administration and there was an increase in urine specific gravity to >1.020 from 2 to 7h after administration (Fig. 10.2). The drug had no effects on heart rate or systemic blood pressure. These preliminary data demonstrate that the i.v. administration of desmopressin acetate appears to be safe and a useful tool for the evaluation of horses with DI. 

In asthmatic human patients, fluticasone propionate improves asthma symptoms and parameters, improves pulmonary function and reduces pulmonary inflammation and airway reactivity (Barnes et al 1998). Regular fluticasone reduces or eliminates the need for rescue 2 agonist therapy and produces progressive improvement in airway reactivity and pulmonary function. In clinical studies, equivalent efficacy is demonstrated with one-quarter of the dose of fluticasone compared with flunisolide and budesonide, and equivalent efficacy is demonstrated with one-half of the dose of fluticasone compared with beclometasone. Adrenal function is less affected by fluticasone propionate at therapeutic doses than with beclometasone, flunisolide or budesonide. Although all aerosolized corticosteroids are considered safe, fluticasone has the least potential for adverse systemic effects and has the most favorable therapeutic index. 

The ACC/AHA guidelines, developed before the Val-HeFT, CHARM, and VALIANT trials were completed, indicate that ARBs should not be considered equivalent or superior to ACE inhibitors and that they should be considered in patients who are intolerant of ACE inhibitors. Collectively, the results of these trials clearly support this recommendation. Eor patients unable to tolerate an ACE inhibitor, usually due to intractable cough or angioedema, an ARB is a safe and effective alternative, although caution stiU should be exercised when it is used in patients with angioedema from ACE inhibitors. ARBs are not an alternative in patients with hypotension, hyperkalemia, or renal insufficiency secondary to ACE inhibitors because they are as likely to cause these adverse effects. The specific drugs and doses proven to be effective in chnical trials should be used. The role of ARBs as an adjunct to ACE inhibitors remains controversial. 

First marketed in the United States in 1996,recombinant factor IX is produced in Chinese hamster ovary cells transfected with the factor IX gene. Blood and plasma products are not used to produce recombinant factor IX nor to stabilize the final product thus recombinant factor IX has an excellent viral safety profile. Clinical trials have shown the product to be safe and efficacious in the treatment of acute bleeding episodes and in the management of bleeding associated with surgical procedures. Although the half-life of recombinant factor IX is similar to that of the plasma-derived products, recovery is approximately 28% lower. As a result, doses of recombinant factor IX concentrate must be higher than those of plasma-derived products to achieve equivalent plasma levels. Because individual pharmacokinetics may vary, recovery and survival studies should be performed to determine optimal treatment. Recombinant factor IX is often considered the treatment of choice for hemophilia B. 

First, the use of AOIs (or their equivalent) tends to give the impression that exposures to chemicals are either "safe" (below the ADI) or "unsafe" (above the ADI). Those who work in the area know that this is a false Interpretation, because risk to a population does not simply "disappear" at a given dose. In fact there may be for some agents a range of doses well above their ADIs that fall well within the low or even zero risk category. On the other hand, risk may sometimes rise rapidly through and above an ADI. The point is that there are no sharp divisions In the continuum of dose-risk relations, at least Insofar as we are concerned with population, not individual, risks(3). 

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