In the diagnosis of dysphonia, assessing the patient's voice quality is personal and subjective. The diagnosis of voice abnormalities is based on history, physical examination, and supporting examinations. In determining the degree of Dysphonia disorder, we can use the voice handicap index. Voice Handicap Index (VHI) is one of the most widely used tools to measure the physical, functional, and emotional aspects of Dysphonia disorder.
Abstract: A‐331440 {4′‐[3‐(3( R )‐(dimethylamino)‐pyrrolidin‐1‐yl)‐propoxy]‐biphenyl‐4‐carbonitrile}, a potent and selective antagonist of histamine H 3 receptors, yielded positive results in an in vitro micronucleus assay, predictive of genotoxicity in vivo . Because this compound has highly favourable properties and potential as an antiobesity agent, new compounds of this general chemical class were sought that would retain or improve upon the high potency and selectivity of A‐331440 for H 3 receptors, but would lack the potential for genotoxicity obtained with that compound. Our working hypothesis was that the biphenyl rings in A‐331440 might contribute to interactions with DNA and thereby predispose toward genotoxicity. Toward this end, several analogues were prepared, with substituents introduced onto the biaryl ring to alter the orientation, electronegativity, and polarity of this moiety, and were tested for their radioligand binding potency and selectivity and their propensity to induce genotoxicity in the in vitro micronucleus assay. Using this strategy, novel compounds were discovered that retained or improved upon the potency and selectivity of A‐331440 for H 3 receptors and were devoid of genotoxicity in vitro. Of these, the simple mono‐ and di‐fluorinated analogues (A‐417022 [4′‐{3‐[(3 R )‐3‐(dimethylamino)‐1‐pyrrolidinyl]propoxy}‐3′‐fluoro‐1,1′‐biphenyl‐4‐carbonitrile] and A‐423579 [4′‐{3‐[(3 R )‐3‐(dimethylamino)‐1‐pyrrolidinyl]‐propoxy}‐3′,5′‐difluoro‐1,1′‐biphenyl‐4‐carbonitrile], respectively) were found to bind to H 3 receptors at least as potently as A‐331440, while lacking genotoxicity in the micronucleus assay. The reason of the lack of genotoxicity of the fluorinated analogues is unclear, but is especially noteworthy in light of the general principle that fluorine and hydrogen are very similar in size. Therefore, these fluorinated analogues of A‐331440 represented the most potent and potentially safest compounds for further evaluation as antiobesity leads. Preliminary findings with one of these examples, A‐417022, in a mouse model of obesity are presented.
In this article, an integrated in vivo genotoxicity testing philosophy and a practical approach, as applied to pharmaceuticals, are described. Recently, there has been an effort to integrate the rodent (primarily rat) micronucleus assay with routine 2-4-week toxicokinetic studies. This approach has several advantages: 1) it utilizes the general principles of toxicology that govern the overall toxicity profile of a test substance; 2) factors such as the dose and/or route of drug administration, drug metabolism, principles of toxicokinetics, and saturation of defense mechanisms are considered in evaluating genotoxicity; 3) it uses the concept of administering multiple tolerable doses aiding in achieving steady state plasma drug levels, which is more relevant for risk assessment compared to high acute doses; and 4) it helps minimize the amount of drug, number of animals used, and other resources. This integration approach can be extended to other toxicology studies and other relevant genotoxicity endpoints may be assessed. Based on the experience in our laboratory, integrating micronucleus assessment in routine toxicology testing is promising and should be utilized when practical.
Abstract Mouse and Chinese hamster models have been extensively used for assessing the cytogenetic effects of environmental carcinogens and mutagens. However, there is little information on comparative analysis of chromosomal damage in these species under in vivo and in vivo/in vitro (culturing of cells from animals exposed to the test compound) systems. To obtain such information, mice and Chinese hamsters were injected with varying concentrations (0.5–6.0 mg/kg) of mitomycin C, an antineoplastic drug. The bone marrow and spleen cells were analyzed for the number of sister chromatid exchanges (SCEs) under in vivo and in vivo/in vitro conditions. The results indicated a dose‐related SCE response that varied with species, tissues, and assay conditions. The mouse cells appeared more sensitive to the effects of mitomycin C than did Chinese hamster cells. In general, the SCE frequencies were relatively higher under in vivo conditions than under in vivo/in vitro conditions in both species. The spleen cells had higher SCE values than bone marrow cells under in vivo/in vitro conditions in both species. These differences may be related to the pharmacokinetic properties of the drug in different species and tissues, to treatment conditions, or to the repair capabilities of the cells. This study also indicates the usefulness of recently established bone marow and spleen in vivo/in vitro cell cultures for comparative cytogenetic analysis.
