F Fernandes

A thermodynamic approach to problems of drug antagonism. Measurements of the parameters of affinity (pA2) of antihistaminics and Aβ-haloalkylamine under varying experimental conditions☆

Two measurements of pA2 (in equilibrium and at the receptor site) are described for both diphenhydramine (Benadryl) and phenoxybenzamine (Dibenzyline). For diphenhydramine, after washing out the preparation, there is a spontaneous recovery with a rapid decrease of pA2 (at the receptor site) to 0, though for phenoxybenzamine the preparation remains at a high level of inhibition for several hours, provided the temperature is kept at 37°C. Such a conditioned allowed a measurement of the affinity parameter (pA2 = −log Ki) at different temperatures, from 40°C down to 2–4°C. By using a classical Arrhenius plot it was possible to calculate enthalpies (−ΔH) and entropies (ΔS) of formation of the alleged bindings of phenoxybenzamine with the histamine H1-receptor which was found to depend strongly upon temperature. Above 20°C the enthalpy ΔH = −21,494.8 cal/°K was significant and large enough to suggest a covalent or ionic binding, with a negative entropy of formation. Below 20°CΔH = −3,461.04 e.u. was low and non-significant, with a positive entropy of formation. The conclusion was drawn that at low temperature the binding is probably entropy driven and depends more upon hydrophobic interactions of the antagonist with the receptor site.

Influence of temperature on recovery of inhibition by antihistaminics and β-haloalkylamines toward histamine☆

Abstract The idea that potent antihistaminics are held in the ‘annex’ part of the receptor through hydrophobic bonds allowing mass law competition of the agonist toward the ‘specific’ part of the receptor (charniere effect) suggested that at low temperatures (∼ 5°C) such bonds might be weakened and the recovery curve from inhibition by diphenhydramine accelerated. This was fully confirmed by allowing the complex antagonist-receptor to be formed at 37°C and further exposed to cold (2–4°C). With phenoxybenzamine a more striking result was obtained since the complex antagonist - receptor could be stabilized at the level of the pA2 4 for at least 3 hr when the temperature was kept at 37°C. Exposure to cold (2–4°C) induced an almost complete recovery to the level of pA2, indicating that the receptors were not affected by interaction with the β-haloalkylamine. At any moment after exposure to phenoxybenzamine, 0.2 μg/ml or 0.66 μM/l, a maximal effect could be obtained by addition of the proper concentration of the agonist (histamine). The question of the existence of ‘spare receptors’ is discussed, as well as the thermodynamic implications of the above findings.

Facial emotion recognition in euthymic patients with bipolar disorder and their unaffected first-degree relatives

BACKGROUND Facial emotion recognition (FER) is an important task associated with social cognition because facial expression is a significant source of non-verbal information that guides interpersonal relationships. Increasing evidence suggests that bipolar disorder (BD) patients present deficits in FER and these deficits may be present in individuals at high genetic risk for BD. The aim of this study was to evaluate the occurrence of FER deficits in euthymic BD patients, their first-degree relatives, and healthy controls (HC) and to consider if these deficits might be regarded as an endophenotype candidate for BD. METHODS We studied 23 patients with DSM-IV BD type I, 22 first-degree relatives of these patients, and 27 HC. We used the Penn Emotion Recognition Tests to evaluate tasks of FER, emotion discrimination, and emotional acuity. Patients were recruited from outpatient facilities at the Institute of Psychiatry of the University of Sao Paulo Medical School, or from the community through media advertisements, had to be euthymic, with age above 18years old and a diagnosis of DSM-IV BD type I. RESULTS Euthymic BD patients presented significantly fewer correct responses for fear, and significantly increased time to response to recognize happy faces when compared with HC, but not when compared with first-degree relatives. First-degree relatives did not significantly differ from HC on any of the emotion recognition tasks. CONCLUSION Our results suggest that deficits in FER are present in euthymic patients, but not in subjects at high genetic risk for BD. Thus, we have not found evidence to consider FER as an endophenotype candidate for BD.

Pharmacological analysis of the mediators involved in the acute pulmonary edema produced in rats by adrenaline

The intravenous injection of 40 ~g/kg of adrenaline in the rat produces pulmonary edema and increased histamine content of the lung; hemorrhagic spots are also seen, even macroscopically. Pre-treatment of the animals with diphenhydramine (1 mg/kg) partially inhibits the edema and bleeding and completely blocks the rise in histamine content. With higher doses of the antihistaminic, the pulmonary alterations induced by adrenaline were similar to those of the control experiments. Other antihistaminics, administered in doses of 5 and 25 mg/kg did not inhibit the adrenalineinduced pulmonary alterations. Cyproheptadine, a potent anti-histamine and anti-serotonin agent, potentiated these alterations, while a previous treatment with reserpine accelerated the development of the edema, increased bleeding and the rise in histamine content. Phenoxybenzamine (dibenzyline) and phentolamine (regitine) blocked the edema and hemorrhage but did not interfere with the increased histamine content induced by adrenaline. The previous treatment of rats with cellulose sulfate, which depletes plasma bradykininogen-I and with hexadimethrine bromide, which blocks activation of the kinin system inhibited the development of the pulmonary alterations induced by adrenaline.

Gray matter volumes in patients with bipolar disorder and their first-degree relatives

Bipolar disorder (BD) is highly heritable. First-degree relatives of BD patient have an increased risk to develop the disease. We investigated abnormalities in gray matter (GM) volumes in healthy first-degree relatives of BD patients to identify possible brain structural endophenotypes for the disorder. 3D T1-weighted magnetic resonance images were obtained from 25 DSM-IV BD type I patients, 23 unaffected relatives, and 27 healthy controls (HC). A voxel-based morphometry protocol was used to compare differences in GM volumes between groups. BD patients presented reduced GM volumes bilaterally in the thalamus compared with HC. Relatives presented no global or regional GM differences compared with HC. Our negative results do not support the role of GM volume abnormalities as endophenotypes for BD. Thalamic volume abnormalities may be associated the pathophysiology of the disease.

Cognitive effects of creatine monohydrate adjunctive therapy in patients with bipolar depression: Results from a randomized, double-blind, placebo-controlled trial

BACKGROUND Depressive episodes and cognitive impairment are major causes of morbidity and dysfunction in individuals suffering from bipolar disorder (BD). Novel treatment approaches that target clinical and cognitive aspects of bipolar depression are needed, and research on pathophysiology suggests that mitochondrial modulators such as the nutraceutical creatine monohydrate might have a therapeutic role for this condition. METHODS Eighteen (N=18) patients with bipolar depression according to DSM-IV criteria who were enrollled in a 6-week, randomized, double-blind, placebo-controlled trial of creatine monohydrate 6g daily as adjunctive therapy were submitted to neuropsychological assessments (Wisconsin Card Sorting Test, Digit Span subtest of the Wechsler Adult Intelligence Scale-Third Edition, Stroop Color-Word Test, Rey-Osterrieth complex figure test, FAS Verbal Fluency Test) at baseline and week 6. RESULTS There was a statistically significant difference between the treatment groups of the change on the total scores after 6 weeks in the verbal fluency test, with improvement in the group receiving adjunctive treatment with creatine. We did not find significant differences between the groups of the changes on other neuropsychological tests. LIMITATIONS Small sample and lack of a control group of healthy subjects. CONCLUSIONS Our trial, which was the first to investigate the cognitive effects of creatine monohydrate on bipolar depression, indicates that supplementation with this nutraceutical for 6 weeks is associated with improvement in verbal fluency tests in patients with this condition.

Serum BDNF levels in unaffected first-degree relatives of patients with bipolar disorder

Objective: Unaffected relatives of bipolar disorder (BD) patients have been investigated for the identification of endophenotypes in an attempt to further elucidate the pathophysiology of the disease. Brain-derived neurotrophic factor (BDNF) is considered to be implicated in the pathophysiology of BD, but its role as an endophenotype has been poorly studied. We investigated abnormal serum BDNF levels in BD patients, in their unaffected relatives, and in healthy controls. Methods: BDNF levels were obtained from 25 DSM-IV bipolar I disorder patients, 23 unaffected relatives, and 27 healthy controls. All BD patients were in remission. The unaffected subjects were first-degree relatives of the proband who had no lifetime DSM-IV diagnosis of axis I disorder. BDNF serum levels were determined by sandwich ELISA using monoclonal BDNF-specific antibodies. Results: There were no statistical differences in BDNF levels among BD patients, relatives, and healthy controls. Conclusion: Serum BDNF levels may not indicate high genetic risk for BD, possibly acting as state markers rather than trait markers of the disease.

The association between social skills deficits and family history of mood disorder in bipolar I disorder

Objective: To compare social skills and related executive functions among bipolar disorder (BD) patients with a family history of mood disorders (FHMD), BD patients with no FHMD and healthy control (HCs). Methods: We evaluated 20 euthymic patients with FHMD, 17 euthymic patients without FHMD, and 31 HCs using the Social Skills Inventory (SSI) and a neuropsychological battery evaluating executive function, inhibitory control, verbal fluency and estimated intelligence. Results: Both BD groups had lower SSI scores than controls. Scores for one subfactor of the social skills questionnaire, conversational skills and social performance, were significantly lower among patients with FHMD than among patients without FHMD (p = 0.019). Both groups of BD patients exhibited significant deficits in initiation/inhibition, but only BD patients with FHMD had deficits in verbal fluency, both compared to HC. There were no associations between social skills questionnaire scores and measures of cognitive function. Conclusion: Euthymic BD patients have lower social skills and executive function performance than HC. The presence of FHMD among BD patients is specifically associated with deficits in conversational and social performance skills, in addition to deficits in verbal fluency. Both characteristics might be associated with a common genetically determined pathophysiological substrate.