ABSTRACT
We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI), potentiates serotonin (5-HT) receptor agonist 5-methoxy--dimethyltryptamine (5-MeO-DMT)-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline-induced hypothermia and 5-MeO-DMT-elicited hyperthermia were attributable to the loss of heat through the activation of 5-HTreceptor and thermogenesisthe stimulation of 5-HTreceptor, respectively. Thus serotonergic 5-MeO-DMT-induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects. This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on 5-MeO-DMT and harmaline PK properties, and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects. Furthermore, the modeling results revealed a 4-fold decrease of apparent SCvalue (1.88-0.496 µmol/L) for 5-MeO-DMT when harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-MeO-DMT-induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of harmaline and 5-MeO-DMT were linked to the increased systemic exposure to harmaline rather than 5-MeO-DMT, although the body temperature profiles were mispredicted by the model. The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.
ABSTRACT
To present a unilateral central visual field defect in a patient with psoriatic arthritis treated with Methotrexate and folic acid supplement, probably induced by toxic posterior optic neuropathy. The scotoma incompletely resolved after cessation of Methotrexate [MTX] therapy. Serial fundoscopic, perimetric and electrophysiological examination as well as comprehensive neurological investigation including lumbar puncture, carotid sonography, electroneurography, and MRI of the brain. A female patients with psoriatic arthritis on long-standing Methotrexate [MTX 15 mg IM/once a week] therapy suffered first from an acute attack of central visual field defect in her right eye and later on from two subsequent deteriorations of her scotoma within one year. A demyelinating retrobulbar optic neuritis was excluded through repeated comprehensive neurological investigations and unresponsiveness to systemic corticosteroid therapy. A MTX-induced posterior optic neuropathy was suspected and the patient experienced improvement of her visual field defects only six weeks after discontinuing MTX therapy. Further improvement was observed through follow-up perimetric examinations half a year after cessation. Central scotoma with unremarkable optic disc can occur after long-standing treatment with MTX and despite folic acid supplementary therapy. This is most probably due to posterior optic neuropathy. Early cessation of the drug or change to another antimetabolite therapy can stop the deterioration of the visual field changes and even improve them. The exact pathomechanism is still unclear and the involvement of only one eye requires more investigation. MTX-induced posterior optic neuropathy should be included in the differential diagnosis of toxic optic neuropathy. This is getting more frequent than before because of the nowadays standard use of MTX in treatment of many autoimmune collagen diseases