Cystinosis is a rare autosomal recessive disorder, characterized by the abnormal accumulation of cystine in the lysosomes. Cystinosis is mostly caused by mutations in the cystinosin gene (CTNS). The major mutation, which is present in almost 50% of the cystinosis patients, is a 57-kb deletion. This deletion removes the first 9 exons and a part of exon 10 of the CTNS gene. Exon 10 of the CTNS gene is a upstream 5' region that encodes for the CARKL gene and also for the first two noncoding exons of the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1) gene. TRPV1 belongs to the transient receptor potential (TRP) superfamily of cation channels. TRPV1 is primarily expressed in sensory nerves and is activated by heating (\>43°C) and a wide range of chemical stimuli. One of these chemical stimuli is capsaicin, the pungent ingredient in hot chilli peppers. The effect of binding of the exogenous ligand capsaicin with the TRPV1 receptor is well known to provoke the release of a number of bioactive substances including calcitonin gene-related peptide (CGRP). These substances, in turn, act on target cells in the surrounding tissue such as mast cells, immune cells and vascular smooth muscle cells. The resulting response is characterized by redness and warmth (secondary to vasodilatation), swelling (secondary to plasma extravasation) and allodynia (i.e. hypersensitivity to heat and touch secondary to alterations in the excitability of primary sensory neurons). The present study wants to test the following hypotheses: (i) The DBF response to topical applied capsaicin is decreased in cystinosis patients, compared to matched control subjects. (ii) The skin sensitivity response after topical applied capsaicin is decreased in cystinosis patients, compared to matched control subjects. (iii) The temperature sensitivity is decreased in cystinosis patients, compared to matched control subjects.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
NONE
Enrollment
50
During the study period (Day 1), in each subject 3 equally spaced (minimum distance of 4 cm) 10-mm rubber O-rings (8 mm inner diameter) will be placed on the volar surface of the forearm. The most proximal ring (i.e. at least 15 cm proximal of the wrist crease) is referred to as ring number 1; the most distal ring is referred to as ring number 3; in between is ring number 2. In ring number 1 and 2, subjects will receive a topical dose of 1000 µg/20 µL capsaicin (single-blind). Change in dermal blood flow induced by capsaicin will be measured with Laser Doppler Imaging.
During the study period (Day 1), in each subject 3 equally spaced (minimum distance of 4 cm) 10-mm rubber O-rings (8 mm inner diameter) will be placed on the volar surface of the forearm. The most proximal ring (i.e. at least 15 cm proximal of the wrist crease) is referred to as ring number 1; the most distal ring is referred to as ring number 3; in between is ring number 2. In ring number 3, subjects will receive a topical dose of placebo (single-blind).Change in dermal blood flow induced by placebo will be measured with Laser Doppler Imaging.
Von Frey filaments will be used to measured the mechanical detection and pain threshold of the volunteers. The Von Frey filaments will be applied on the upper capsaicin spot in sequential order. The subject will be asked to indicate when he feels the application of the Von Frey filaments and when it hurts.
Temperature sensitivity (detection and pain threshold) will be determined using Advanced Thermal stimulation. A thermode will be attached to the hand of the volunteer with a baseline temperature of 32°C. The thermode will heat up and cool down with a rate of 1°C/second and the volunteer will be asked to click on a computer mouse when he feels the change in temperature and when it hurts.
Centre for Clinical Pharmacology, UZ Leuven
Leuven, Vlaams-Brabant, Belgium
Change from baseline of the dermal blood flow response to topical applied capsaicin at 10, 20, 30, 40, 50 and 60 minutes, measured with Laser Doppler Imaging and expressed in % change to baseline
At baseline and every 10 minutes during 60 minutes after capsaicin application. DBF measurement will be done using a Laser Doppler scanner (PIM III Perimed).
Time frame: Day 1 at baseline and 10, 20, 30, 40, 50 and 60 minutes after capsaicin application
Change from baseline of the skin sensitivity response after topical applied capsaicin at 10, 20, 30, 40, 50 and 60 minutes, measured with the Numerical rating scale and skin sensitivity to mechanical stimulation, measured with Von Frey filaments.
At baseline and every 10 minutes during 60 minutes after capsaicin application, skin sensitivity to capsaicin will be measured using the Numerical rating scale (NRS) -11. Skin sensitivity to mechanical stimulation will be tested using Von Frey filaments after DBF measurements are performed.
Time frame: Day 1 at baseline and 10, 20, 30, 40, 50 and 60 minutes after capsaicin application
Temperature sensitivity (detection and pain threshold), measured with Advanced Thermal stimulation and expressed in degrees Celsius.
Temperature sensitivity will be measured using Advanced Thermal stimulation (ATS) ( Pathway ATS Medoc) after DBF measurements are performed. A thermode will be attached to the hand of the volunteer with a baseline temperature of 32°C. The thermode will heat up and cool down with 1°C/second and the volunteers will be asked to click on a computer mouse when he/she detects the change in temperature and when it hurts.
Time frame: Day 1
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