2-{3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-4-methyl-1,3-thiazol-3-ium-5-yl}ethyl hydrogen phosphate

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Preliminary findings of high-dose Thiamine in Dementia of Alzheimer´s Type

Author:

Meador K. et al.

Year:

1993

Bibliographic source:

J Geriatr Psychiatry Neurol. 6(4):222-229

Materials and methods

Endpoint addressed:

repeated dose toxicity: oral

Principles of method if other than guideline:

The test substance was administered orally at 3 g/day and at 4 - 8 g/day, respectively, in patients diagnosed Alzheimer´s disease, which is a type of dementia.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Thiamine hydrochloride

EC Number:

200-641-8

EC Name:

Thiamine hydrochloride

Cas Number:

67-03-8

Molecular formula:

C12H17N4OS.ClH.Cl

IUPAC Name:

3-[(4-amino-2-methylpyrimidin-5-yl)methyl]-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride hydrochloride

Method

Ethical approval:

other: Informed consent was obtained from the patients and their next of kin

Details on study design:

A double-blind, placebo-controlled, randomized, crossover design was performed with patients diagnosed with probable Alzheimer´s disease according to the standard criteria.

Details on exposure:

TYPE OF EXPOSURE: Orally, the test substance was administered in 250 mg and 500 mg tablets, which were obtained from Rugby Laboratories (West Hempstead, NY).

EXPOSURE LEVELS:
First experiment: 3 g/day
Second experiment: 4 - 8 g/day

EXPOSURE PERIOD:
First experiment: 1 month
Second experiment: In the first phase, the first two subjects were initially administered at 3 g/day, and daily dosage incrementally increased 0.5 g/day every 2 weeks, up to 6 g/day. These patients underwent physical examination every 2 weeks. Because the first two patients tolerated dosages up to 6 g/day well without any side effects, the remaining patients were initially administered at 4 g/day, and daily dosage was increased by 1 g/day every month, up to 6 g/day. In the third phase, daily thiamine dosage was incrementally increased by 0.5 g/day each month, up to a maximum of 8 g/day. Subjects were examined and tested every 4 weeks through month 9 in phases 2 and 3 and then every 8 weeks thereafter.

DESCRIPTION / DELINEATION OF EXPOSURE GROUPS / CATEGORIES:
First experiment: 18 patients (including five men and 13 women) with a mean age of 71 years (ranged from 61 to 86 years).
Second experiment: 17 patients; Of these, 6 were included from the first experiment and 11 additional subjects meeting the same diagnostic and experimental criteria were recruited. The subjects included nine men and eight women with mean age of 69 years (ranged from 54 to 93 years).

Results and discussion

Results:

First experiment: all patients tolerated the thiamine dose well, and no side effects were noted.
Second experiment: Most subjects tolerated the dosages well without weakness or side effects. Two subjects developed nausea and indigestion at dosages of 7.0 and 7.5 g/day, respectively. These two subjects were subsequently treated at their highest tolerated dose without side effects in the latter months (i.e., 6.5 and 7.0 g/day).