"subject":

Twenty ml of the fluid under test is placed in a 46 ml type 317 stainless steel chamber containing one each of 12,5 mm (nominal) diameter balls of M-10 tool steel, 52100 steel and naval bronze (60% Cu, 39% Zn, 0,75% Sn);

Test substance preparation

the trial subject or, when the person is not able to give informed consent, his legal representative has given his written consent after being informed of the nature, significance, implications and risks of the clinical trial;

concentration of test substance,

the subject may without any resulting detriment withdraw from the clinical trial at any time by revoking his informed consent;

if the individual is unable to write, oral consent in the presence of at least one witness may be given in exceptional cases, as provided for in national legislation;

details of the administration of the test substance,

details of test substance preparation,

volume of vehicle and test substance added,

Test substances are generally administered as a single treatment.

Test substances are preferably administered as a single treatment.

solubility and stability of the test substance in solvent/vehicle, if known.

Test substances are preferably administered once or twice (i.e. as a single treatment or as two treatments).

Liquid test substances may be dosed directly or diluted prior to dosing.

the trial subject or, when the person is not able to give informed consent, his legal representative has had the opportunity, in a prior interview with the investigator or a member of the investigating team, to understand the objectives, risks and inconveniences of the trial, and the conditions under which it is to be conducted and has also been informed of his right to withdraw from the trial at any time;

The condition of a metabolic activation system may depend upon the class of chemical being tested.

Liquid test substances may be added directly to the test systems and/or diluted prior to treatment.

The number of cells, cultures and concentrations of test substance used should reflect these defined parameters (14).

The choice and condition of a metabolic activation system may depend upon the class of chemical being tested.

For example, any suspected selective toxicity by the test substance for mutant and non-mutant cells should be investigated.

Fresh preparations should be employed unless stability data demonstrate the acceptability of storage.

Fresh preparations of the test substance should be employed unless stability data demonstrate the acceptability of storage.

12 Elderly Population In a multivariate analysis, age was not found to be an independent factor of any of the pharmacokinetic parameters studied.

The titre of such a reagent is determined by making successive twofold dilutions of the reagent under study in 10 % inactivated AB serum in Veronal buffer.

The choice of the cell lines used should be scientifically justified (e.g. by the relevance of the cytochrome P450 isoenzyme for the metabolism of the test substance).

amount of test substance per plate (mg/plate or µl/plate) with rationale for selection of dose and number of plates per concentration,

Negative results indicate that, under the test conditions, the test substance does not induce chromosome aberrations in the bone marrow of the species tested.

conversion from diet/drinking water test substance concentration (ppm) to the actual dose (mg/kg body weight/day), if applicable,

Usually 0,05 or 0,1 ml of test substance/test solution, 0,1 ml of bacteria and 0,5 ml of S9-mix or sterile buffer are mixed with 2,0 ml of overlay agar.

Solid test substances should be dissolved or suspended in appropriate solvents or vehicles and diluted if appropriate prior to treatment of the cells.

Solid test substances should be dissolved or suspended in appropriate solvents or vehicles and diluted if appropriate prior to treatment of the bacteria.

Solid test substance should be dissolved or suspended in appropriate solvents or vehicles and diluted, if appropriate, prior to dosing of the animals.

Solid test substances should be dissolved or suspended in appropriate solvents or vehicles and diluted, if appropriate, prior to dosing of the animals.

Positive results from the in vivo chromosome aberration test indicate that a substance induces chromosome aberrations in the bone marrow of the species tested.

Negative controls, consisting of solvent or vehicle alone, without test substance, and otherwise treated in the same way as the treatment groups, should be included.

Test substances that are cytotoxic already below 5 mg/plate or 5 µl/plate should be tested up to a cytotoxic concentration.

Amongst the criteria to be taken into consideration when determining the highest amount of the test substance to be used are the cytotoxicity and the solubility in the final treatment mixture.

Test substances may also be administered as a split dose, i.e. two treatments on the same day separated by no more than a few hours, to facilitate administering a large volume of material.

Although most studies will give clearly positive or negative results, in rare cases the data set will preclude making a definite judgement about the activity of the test substance.

Although most experiments will give clearly positive or negative results, in rare cases the data set will preclude making a definite judgement about the activity of the test substance.

In patients with Alzheimer’ s disease, inhibition of AChE in CSF by rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested.

The properties of the test substance should be considered carefully if a base analogue or a compound related to the selective agent is tested in any of the mammalian cell gene mutation tests.

At least five different analysable concentrations of the test substance should be used with approximately half log (i.e. 10) intervals between test points for an initial experiment.

In patients with Alzheimer’ s disease, inhibition of AChE in CSF by oral rivastigmine was dose-dependent up to 6 mg given twice daily, the highest dose tested.

The purpose of the unscheduled DNA synthesis (UDS) test with mammalian liver cells in vivo is to identify test substances that induce DNA repair in liver cells of treated animals (1), (2), (3), (4).

Since the time required for uptake and metabolism of the test substance as well as its effect on cell cycle kinetics can affect the optimum time for chromosome aberration detection, a later sample collection 24 hours after the first sample time is recommended.

In the case of a positive response in the L5178Y TK+/- test, colonies are scored using the criteria of small and large colonies on at least one concentration of the test substance (highest positive concentration) and on the negative and positive control.

For the plate incorporation method (1) (2) (3) (4), without metabolic activation, usually 0,05 ml or 0,1 ml of the test solutions, 0,1 ml of fresh bacterial culture (containing approximately 108 viable cells) and 0,5 ml of sterile buffer are mixed with 2,0 ml of overlay agar.

In a clinical study, where subjects were exposed to higher doses of efalizumab (up to 10 mg/ kg intravenous), one subject receiving 3 mg/ kg intravenous dose experienced hypertension, chills, and fever on the day of study drug dosing, which required hospitalization.