Working… Menu

In Vivo Assessment of Histamine Pharmacodynamics

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00809692
Recruitment Status : Withdrawn (Study withdrawn and combined with a new protocol)
First Posted : December 17, 2008
Last Update Posted : January 7, 2021
Information provided by (Responsible Party):
Children's Mercy Hospital Kansas City

Brief Summary:
A critical first step to address the "pharmacodynamic information gap" in pediatrics resides with the development of methods capable of accurately measuring the time dependent effects of xenobiotic exposure in a manner sufficient to enable an integrative analysis of drug action which incorporates both pharmacokinetic and pharmacogenetic determinants. The proposed study will evaluate laser Doppler flowimetry, a necessary initial step in developing an "ideal" pharmacodynamic surrogate endpoint that ultimately could be used in infants, children and adolescents to fully characterize the impact of development on the pharmacokinetic (PK) / pharmacodynamic (PD) / pharmacogenetic (PG) determinants of drug effect for agents capable of modulating the cellular response to histamine.

Condition or disease Intervention/treatment Phase
Histamine Biotransformation Procedure: validated techniques for histamine response Procedure: new technique for histamine response Not Applicable

Detailed Description:

The overall goal of this research is to develop and validate non-invasive approaches suitable for use in pediatrics that are sufficient to directly evaluate genotype-phenotype associations as determinants of the concentration-effect profile of drugs capable of altering microvascular function. The specific goal of this project will be to assess whether microvascular blood flow determined by a previously validated laser Doppler technique can be used as a reliable surrogate endpoint capable of functionally discriminating the effects of polymorphisms in the genes which are quantitatively important for histamine biotransformation. The investigators hypothesize that microvascular blood flow velocity can be used as a valid surrogate marker to discriminate the functional consequences of allelic variants in the enzymes primarily responsible for the biotransformation of histamine.

The project includes two parts:

  1. Validation of histamine iontophoresis (with measurement of microvascular blood flow by laser Doppler flowimetry) in a pediatric cohort as a pharmacologic provocation test capable of reliably characterizing the normal physiologic response of the cutaneous microvasculature to this xenobiotic addressed by a study in 50 children with a diagnosis of allergic disease or other "allergic" conditions where treatment with antihistamines represents the medical "standard of care". Subjects will concomitantly (on contralateral extremities) receive histamine challenges by the "gold standard" cutaneous prick test (time dependent response assessed by serial assessment of wheal and flare reactions) and by a previously described iontophoresis technique (time dependent response by serial assessment of microvascular blood flow using a validated laser Doppler technique).Additionally, DNA will be isolated from these subjects for genotyping as described in part 2).
  2. Assessment of microvascular response to histamine challenge as a surrogate marker capable of functionally discriminating genotype-phenotype associations for polymorphically expressed genes that are quantitatively important in regulating the biotransformation and pharmacologic inactivation of histamine addressed first by genotyping 150 additional subjects who have an established diagnosis of allergic disease where treatment with antihistamines represents the medical "standard of care". Genotype data for candidate genes of primary interest, histamine-N-methyltransferase (HNMT) and diamine oxidase (DAO), will thus be available from a total of 200 subjects. Based upon known genotype-phenotype associations for HNMT (the enzyme primarily responsible for histamine biotransformation), two cohorts of subjects will be selected from those studied using an extreme discordant phenotype approach: subjects predicted, based upon genotype, to have reduced HMNT activity (i.e., those with 1 or 0 functional alleles) and subjects predicted to have normal enzyme activity (i.e., those with two functional alleles). These study participants will then receive a transcutaneous histamine challenge delivered by iontophoresis, followed by repeated assessment of microvascular reactivity reflected by time-averaged measurement of blood flow velocity using an established laser Doppler technique. Statistical analysis of blood flow velocity and other parameters from the laser Doppler assessment will be used as the primary outcome measurement for comparison of the two study cohorts with respect to expression of HNMT and DAO and the functional consequences thereof, using histamine response as the surrogate assessment of phenotype.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: In Vivo Functional Assessment of Histamine Pharmacodynamics in Children
Actual Study Start Date : September 2007
Actual Primary Completion Date : May 2008
Actual Study Completion Date : September 2008

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Health Checkup

Arm Intervention/treatment
Active Comparator: 1
50 subjects with allergic disease receiving histamine challenges by the prick test and iontophoresis technique (serial assessment of blood flow using validated Doppler technique)
Procedure: validated techniques for histamine response
the prick test and iontophoresis technique (serial assessment of blood flow using validated Doppler technique)

Experimental: 2
150 additional subjects with allergic disease; undergo genotyping; laser Dopper assessment
Procedure: new technique for histamine response
laser Dopper technique and genotyping

Primary Outcome Measures :
  1. Statistical analysis of blood flow velocity and other parameters from the laser Doppler assessment [ Time Frame: 0 ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   7 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Male or female between ages of 7 and 18 years
  • Diagnosed with allergic disease (i.e., allergic rhinitis, allergic conjunctivitis, allergic asthma)
  • Informed consent (Parental permission and subject assent)

Exclusion Criteria:

  • Previous history or laboratory evidence of McCune Albright syndrome, immunodeficiency, mastocytosis, receipt of immunomodulatory treatment, chronic conditions associated with abnormalities of the integument, hepatic or renal compromise, neoplastic disease, movement or neurologic disorders and uncontrolled ADHD
  • Evidence of atopic dermatitis within a 2 year period from the time of study
  • History of previous anaphylactic or anaphylactoid episode
  • Evidence of pregnancy (by urinary hCG) or lactation at the time of study
  • Receipt of drugs (within a specified time period) of agents capable of altering the response to histamine provocation (e.g., antihistamines, systemic corticosteroids, tricyclic antidepressants)
  • Presence of any condition that, in the opinion of the investigator, would produce difficulty with adherence to study procedures.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00809692

Layout table for location information
United States, Missouri
Children's Mercy Hospitals and Clinics
Kansas City, Missouri, United States, 64108
Sponsors and Collaborators
Children's Mercy Hospital Kansas City
Layout table for investigator information
Principal Investigator: Bridgette L. Jones, MD Children's Mercy Hospital and Clinics
Layout table for additonal information
Responsible Party: Children's Mercy Hospital Kansas City Identifier: NCT00809692    
Other Study ID Numbers: 10898
First Posted: December 17, 2008    Key Record Dates
Last Update Posted: January 7, 2021
Last Verified: January 2021
Keywords provided by Children's Mercy Hospital Kansas City:
histamine biotransformation
laser Doppler flowimetry
pediatric pharmacology
Additional relevant MeSH terms:
Layout table for MeSH terms
Histamine phosphate
Histamine Agonists
Histamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs