Nonresponse

This form of myositis stands apart from the classical PM/DM syndromes on account of its distinctive clinical and histopathological features. There is no clear difference in incidence between males and females and the disorder is typically one of middle or old age. In the majority of cases, progression is slow and skin involvement is not seen, so that the main question of differential diagnosis is its distinction from chronic PM. Unlike classic PM, weakness involves distal muscles as frequently as proximal muscles. CK levels are usually only moderately raised. A common finding which leads to the correct diagnosis of this condition is its nonresponsiveness to steroid treatment or other forms of immunosuppression. 

To date, clozapine remains the only drug with proven and superior efficacy in treatment-resistant patients, and it is currently the only drug approved for the treatment-resistant schizophrenic. Studies have shown a response of approximately 30% to 50% in these well-defined treatment-resistant patients. Clinical trials have consistently found clozapine to be superior to traditional antipsychotics for treatment-refractory patients, and it is efficacious even after nonresponse to other SGAs and in partially responsive patients. It is often rapidly effective even in those who have had a poor response to other medication for years. Recent studies have demonstrated that it has a beneficial effect for aggression and suicidality, which led to the Food and Drug Administration (FDA) approval for the treatment of suicidal behavior in people with psychosis.41... 

Chemotherapy for patients with endocrine-nonresponsive disease. 

Bender S, Eap CB. Very high cytochrome P4501A2 activity and nonresponse to clozapine. Arch Gen Psychiatry 1998 55(11) 1048-1050. 

About half of individuals who do not respond to pyridoxine will sustain ectopia lentisbj age 5-10 years. Indeed, the diagnosis commonly is made by an ophthalmologist. The median IQ score for B6 responsive and nonresponsive patients is 78 and 56 respectively. Some children present at 1-2 years with psychomotor retardation, convulsions (=20% of cases) and psychiatric difficulties such as depression and personality disorders (=50% of cases). 

Management of the pyridoxine nonresponsive patient is difficult. Dietary restriction of methionine would seem logical, but this often is unpalatable, especially to an adult patient who has adapted to a diet that has not been purposefully restricted in protein. 

Several criteria determine whether a steroid-hormone-binding site is a putative receptor. First, the steroid-hormone-binding site must be present in hormone-responsive tissues or brain regions, and absent from nonresponsive ones. Second, it should bind steroids that are either active agonists or effective antagonists of the hormone effect, and should not bind steroids that are inactive in either sense. 

Humans given zinc supplements should be aware of possible complications (Fosmire 1990). Low intakes of 100 to 300 mg of zinc daily in excess of the recommended dietary allowance of 15 mg Zn daily may produce induced copper deficiency, impaired immune function, and disrupted blood lipid profiles. Patients treated with zinc supplements (150 mg daily) to control sickle cell anemia and nonresponsive celiac disease developed a severe copper deficiency in 13 to 23 months normal copper status was restored by cessation of zinc supplements and increased dietary copper (Fosmire 1990). 

Ah-responsive and Ah-nonresponsive strains females, age 10 weeks given single ip injection of 50 mg/kg BW killed after 7 days Both groups had increased body weight, increased blood EROD activity, decreased plasma retinol levels, and increased plasma total thyroid hormone levels. The Ah-responsive group also had increased hepatic pentoxyresorufin-O-deethylase activity, increased livercytochrome P-450 activity, and increased liver weight 12... 

Murk, A.J., J.H. J van den Berg, J.H. Koeman, and A. Brouwer. 1991. The toxicity of tetrachlorobenzyltoluenes (Ugilec 141) and polychlorinated biphenyls (Aroclor 1254 and PCB-77) compared in Ah-responsive and Ah-nonresponsive mice. Environ. Pollut. 72 57-67. 

When adequate doses of a BZ, phenytoin, and phenobarbital have failed, the condition is termed refractory. Failure to aggressively treat early increases the likelihood of nonresponse. Doses of agents used to treat refractory GCSE are given in Table 56-3. 

Medication adherence (missing doses of medications is a primary reason for nonresponse and... 

Patients who have a partial response or nonresponse to therapy should be reassessed for an accurate diagnosis, concomitant medical or psychiatric conditions, and medications or substances that exacerbate mood symptoms. 

Nonresponse to codeine (PMs of CYP2D6 fail to O-demethylate to morphine)... 

Dudley, A.C., et al., An aryl hydrocarbon receptor independent mechanism of JP-8 jet fuel immunotoxicity in AH-responsive and AH-nonresponsive mice, Toxicol. Sci., 59 251, 2001. 

Rao et al.20 demonstrated a fluorescence polarization immunoassay for evaluating serum concentrations of tricyclic antidepressants (amitriptyline, imipramine, clomipramine, and doxepin) with respect to nonresponse, compliance, therapeutic window, and influences of age, sex, substance abuse, and toxicity. Abbott Laboratories TDx/TDxFLx Toxicology Tricyclic Assay FPIA (fluorescence polarization immunoassay) was used. This assay of 50 /uL samples contained tricyclic antidepressant antibodies raised in rabbits and fluorescein-labeled tricyclic antidepressant as a tracer. The assay was calibrated with imipramine in the range of 75 to 1000 fig/L (268 to 3571 nmol/L). Intra-assay and inter-assay coefficients of variation for internal quality control samples from the manufacturer were 4.2 and 4.7%, respectively. The limits of detection were 72,71,64, and 72 nmol/L for amitriptyline, imipramine, clomipramine, and doxepin, respectively. This high-throughput immunoassay was easy to use although amitriptyline, dosulepine, desipramine, and nortriptyline showed cross-reactivities ranging from 74 to 100%. 

Pharmacologically Predictable Adverse Events or Nonresponse Obtained in Early-Phase Development Affect the Risk/Benefit Assessment and Product Labeling . 213... 

Some believe subjects potentially at risk for adverse events or nonresponse based on prior pharmacogenetic and pharmacogenomic studies could be excluded from future studies. Others believe that because these at-risk patients may receive the drug in the real-world setting, they should be included but possibly studied in a closely monitored setting. 

Many antipsychotics show great interindividual variation in plasma levels and so analysis of therapeutic levels can be important clinically as well as in the research laboratory. In addition, nonresponse to the drugs may actually be due to excessive levels of neuroleptics, a paradoxical situation that requires analysis to identify (Rockland, 1986). Several methods using FID were cited in the previous edition of the Handbook of Neurochemistry but ECD and NPD have both shown utility for the typically low therapeutic levels (Cooper, 1988). GC-FID has been used to analyze levels of clozapine in blood, gastric, and urine samples in fatal cases of overdose with this drug (Ferslew et al., 1998), and olanzapine has been measured in blood and urine samples by GC-NPD in overdoses (Stephens et al., 1998). 4-(4-Chlorophenyl)-4-hydroxypiperidine, a metabolite of haloperidol, was analyzed in urine, plasma, brain, and liver from haloperidol-treated rats by GC-ECD, after derivatization with PFBC under aqueous conditions (Fang et al., 1996). 

Many studies have shown associations of SNPs in such genes as the serotonin 5-HT and 5-HT receptors, genes and the histamine receptor gene, not to the phenotype of disease severity, but to phenotypes such as drug response or nonresponse (97). For example, the S-HT receptor gene variants and the variant that encodes the Cys22Ser receptor have been associated with altered responses to clozapine (97). 

Studies of GPCRs in asthma can be differentiated on the basis of whether they measure the contribution of candidate genes to atopy, bronchial hyperreactivity (BHR), drug response/nonresponse, or another phenotype. The contribution of selected GPCR variants to the risk for developing asthma or altered drug response is reviewed. 

---