ABSTRACT
An attractive approach to the treatment of inflammatory conditions such as osteo- and rheumatoid arthritis, inflammatory bowel disease, and sepsis is through the selective inhibition of human inducible nitric oxide synthase (hiNOS) since localized excess nitric oxide (NO) release has been implicated in the pathology of these diseases. A series of monosubstituted iminohomopiperidinium salts possessing lipophilic functionality at ring positions 3, 5, 6, and 7 has been synthesized, and series members have demonstrated the ability to inhibit the hiNOS isoform with an IC50 as low as 160 nM (7). Compounds were found that selectively inhibit hiNOS over the human endothelial constitutive enzyme (heNOS) with a heNOS/hiNOS IC50 ratio in excess of 100 and as high as 314 (9). Potencies for inhibition of hiNOS and the human neuronal constitutive enzyme (hnNOS) are comparable. Substitution in the 3 and 7 positions provides compounds that exhibit the greatest degree of selectivity for hiNOS and hnNOS over heNOS. Submicromolar potencies for 6 and 7 in a mouse RAW cell assay demonstrated the ability of these compounds to inhibit iNOS in a cellular environment. These latter compounds were also found to be orally bioavailable and efficacious due to their ability to inhibit the increase in plasma nitrite/nitrate levels in a rat LPS model.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Azepines/pharmacology , Enzyme Inhibitors/pharmacology , Imines/pharmacology , Nitric Oxide Synthase/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Azepines/administration & dosage , Azepines/chemical synthesis , Azepines/pharmacokinetics , Biological Availability , Cell Line , Enzyme Induction/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Imines/administration & dosage , Imines/chemical synthesis , Imines/pharmacokinetics , Inflammation/blood , Inflammation/chemically induced , Lipopolysaccharides/toxicity , Macrophages/drug effects , Macrophages/enzymology , Mice , Nitric Oxide Synthase Type I , Nitric Oxide Synthase Type II , Nitric Oxide Synthase Type III , Rats , Rats, Inbred Lew , Recombinant Proteins/chemical synthesis , Recombinant Proteins/pharmacology , Structure-Activity RelationshipABSTRACT
OBJECTIVE: To determine the effect of spinal manipulation upon the intensity of emotional arousal in phobic subjects exposed to a threat stimulus. DESIGN: Randomized, controlled, double-blind clinical trial. SETTING: Community college campus. SUBJECTS: Eighteen phobic community college student volunteers randomized into treatment and control groups. INTERVENTION: Visual analog scale (VAS) and pulse rates were obtained in response to the subjects' viewing their phobogenic stimulus. Spinal manipulation was performed while the subjects experienced emotional responses. Manual muscle testing was utilized to ascertain the associated spinal segments and involved emotion. RESULTS: Data were analyzed using analysis of variance for a repeated measures experimental design and Least Significant Differences (LSDs) for mean comparisons. Baseline, preintervention and postintervention pulse rates were not statistically different for the control and treatment groups (p = .0807). VAS postintervention mean for the spinal manipulation group was significantly lower than the control means (p = .05) and from its corresponding preintervention mean (p = .001). CONCLUSION: Spinal manipulation significantly decreased the intensity of emotional arousal reported by phobic subjects. The mechanism for this effect is not known.
Subject(s)
Chiropractic , Emotions , Phobic Disorders/psychology , Spine/physiology , Analysis of Variance , Arousal , Double-Blind Method , Humans , Physical StimulationABSTRACT
OBJECTIVE: To determine phobic and nonphobic subject response to a provocative threat stimulus and to determine variables that confound the response. DESIGN: Randomized blind examiner test-retest of randomized phobic and control subjects with qualitative, semistructured, informal postint-ervention interview. SETTING: Private chiropractic clinic. SUBJECTS: Thirteen phobic individuals, as determined by the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R), and 14 control volunteer subjects. INTERVENTION: Manual muscle testing was performed while each subject viewed a threat stimulus (i.e., a cue word on a printed card). The results were recorded as "weak" or "strong." RESULTS: The analysis of data demonstrates poor inter- (K = -0.19) and intraexaminer reliability (K = -0.14(-) +0.29) the test for independence for valid muscle testing was strong for both examiners (p = .462, p = 1.00). When confounding variables were corrected for, the validity of muscle testing increased to 91%. CONCLUSION: This preliminary inquiry demonstrates the need for musculoskeletal, attentional and presensitized subject variables to be controlled to ascertain if muscle testing can be reliably used as a tool to identify emotional arousal.
