Serum levels of clomipramine and desmethylclomipramine and clinical improvement in panic disorder

Several placebo-controlled trials have shown the efficacy of clomipramine (CMI) in panic disorder. However, none has investigated the relationship between CMI, and desmethylclomipramine (DCMI) plasma levels, and outcome. In this trial, 41 patients meeting the DSM-III-R criteria for panic disorder with/without agoraphobia received 50-200 mg of CMI daily in a single-blind, flexible dose regimen for 14 weeks. At the end of treatment, 97% of the patients were free of panic attacks. Patients were classified into two groups of improvement according to the panic symptom items of the 'Patient-Rated Anxiety Scale'. A repeated-measures analysis of variance suggested a significant association between outcome and serum DCMI level/daily dose ratio as well as total serum level/daily dose. Patients with intense improvement showed DCMI and total serum levels lower than those with moderate improvement. The results indicate the importance of monitoring clomipramine and desmethylclomipramine serum levels in this disorder.     

Dizziness predicts initial worsening in panic disorder: an otoneurological investigation

Dizziness is a frequent complaint during the initial worsening of panic patients treated with clomipramine. In order to investigate the relationship between dizziness and initial worsening mechanisms, otoneurological tests were administered to 32 consecutive patients with panic disorder, with or without agoraphobia, before treatment, 36 h after the first dose of 25 mg clomipramine and after treatment and full remission of the panic and agoraphobic symptoms. A pretreatment complaint of 'dizziness during panic attacks' but not the occurrence of otoneurological abnormalities, predicted the occurrence of clinical worsening at the start of treatment. A specific pattern of otoneurological abnormalities was not found, but only three patients had normal results in all three sessions. The inconsistent test results suggest that functional vestibular pathology is frequently associated with panic disorder.     

Involvement of GABA(B) receptors in the motor inhibition produced by agonists of brain cannabinoid receptors

The present study was designed to investigate the possibility of activation of GABA(B) receptors during the motor inhibition caused by cannabimimetics. Adult male rats were injected with an acute dose of arachidonylethanolamide (AEA), Delta(9)- tetrahydrocannabinol (THC), beclofen or vehicle, after pretreatment with CGP 35348, a specific antagonist for GABA(B) receptors, or vehicle, and the behavioral response produced by these compounds tested in an open field. As expected, the administration of either AEA or THC produced a very pronounced motor inhibition, reflected by decreased ambulation and increased time spent in inactivity. The administration of baclofen also produced a marked motor deficit, with similar changes to those observed with both cannabimimetics. Pretreatment with the GABA(B) antagonist, CGP 35348, prevented the motor inhibition induced by baclofen and also attenuated the motor deficit caused by both cannabimimetics, suggesting a role for this receptor. In summary, a GABAergic influence, acting through GABA(B) receptors, seems to be involved in mediating motor effects of cannabimimetics, since the blockade of these receptors attenuates cannabimimetic-induced signs of motor inhibition.     

δ9-Tetrahydrocannabinol affects mesolimbic dopaminergic activity in the female rat brain: interactions with estrogens

Summary In this work, we studied the possible estrogenic modulation of the effects of ⁹-tetrahydrocannabinol (THC) on mesolimbic dopaminergic activity, by examining the effects of an acute dose of this cannabinoid: (i) during the estrous cycle; (ii) after ovariectomy, chronic estrogen-replacement and tamoxifen (TMX)-induced blockade of estrogenic receptors; and (iii) combined with a single and physiological injection of estradiol to ovariectomized rats. THC significantly decreased the density of D1 dopaminergic receptors and non-significantly increased the L-3,4-dihydroxyphenylacetic acid (DOPAC) content in the limbic forebrain of ovariectomized rats chronically replaced with estrogens. The decrease in D1 receptors was also produced by TMX, whereas the coadministration of both THC and TMX did not lead to a major decrease. In addition to the trend of THC increasing DOPAC content, this cannabinoid was also able to increase the ratio between DOPAC and dopamine, although this last effect only occurred after coadministration of THC and TMX, which had been ineffective administered individually. All these effects were not seen when THC was administered to normal cycling rats during each phase of estrous cycle and to ovariectomized rats without chronic estrogen replacement or only submitted to a single and acute dose of estradiol. This observation might be related to the fact that the density of limbic cannabinoid receptors increased in chronic estrogen-replaced ovariectomized ratsversus normal cycling, ovariectomized or acutely estrogen-treated ovariectomized rats. Interestingly, THC administration in ovariectomized rats was followed by a slight, although significant, increase in tyrosine hydroxylase activity, which was also observed after coadministration of THC with a short-time and acute dose of estradiol. In summary, THC stimulated the presynaptic activity of mesolimbic dopaminergic neurons, but accompanied by a decrease in their postsynaptic sensitivity. These effects did not appear in normal cycling rats being only evident after ovariectomy and chronic estrogen replacement, which might be related to changes in binding characteristics of cannabinoid receptors in this area. Moreover, some of them appeared after TMX-induced blockade of estrogenic cytosolic receptors, which likely suggests the existence of a certain estrogenic modulation of the actions of THC on mesolimbic neurons. On the contrary, coadministration of THC with a single and shortly tested dose of estradiol was always ineffective in modifying THC effects.Presented in abstract form to the Third IBRO World Congress of Neuroscience, Montreal (Canada), August 4–9, 1991     

Radiological characteristics of primary intestinal lymphoma of the "Mediterranean" type: observations on twelve cases.

Radiological findings in 12 cases of "Mediterranean" lymphoma are analyzed, 4 of which are associated with gammapathy. These findings have not permitted differentiation of this type of lymphoma from those classically described, although there are two signs that strongly suggest this diagnosis: extension of the lesions along wide areas of the small intestine, almost always including the duodenum, and spiculation of the mucosal fold edges, representing massive plasmocyte infiltration of the lamina propria. The principal clinical, immunological, and pathological aspects are described, as well as the radiological differential diagnosis.     

Hypoglycemic effect of plants used in Mexico as antidiabetics.

The objective of this work is to investigate the hypoglycemic effect of 12 "antidiabetic" plants used in Mexico. The studies were performed using 27 healthy rabbits with the gastric administration of water, tolbutamide or decoction of the "antidiabetic" plant before the induction of temporary hyperglycemia by subcutaneous injection of 50% dextrose solution (4 ml/kg of weight) at the beginning of the experiment and after 60 min. Blood glucose was determined every 60 min for a period of 5 h. Tolbutamide and eight of the studied plants decreased significantly the hyperglycemia as compared with control test (water) (p < 0.05). The strongest effect was yielded by Guaiacum coulteri, followed by Marrubium vulgare, Crataegus pubescens, Cynodon dactylon, Calea zacatechichi, Buddleia americana, Bauhinia divaricata and Coix lachryma. The decrease of hyperglycemia caused by Physalis phyladelphyca, Pavonia schiedeana and Eucaliptus globulus was not significant (p > 0.05). Urtica dioica increased glycemia slightly.     

Motor neuron diseases in the university hospital of Fortaleza (Northeastern Brazil): a clinico-demographic analysis of 87 cases

In this retrospective (1980-1998) study, we have analyzed clinico-demographically, from the records of the University Hospital of Fortaleza (Brazil), a group of 87 patients showing signs and symptoms of motor neuron diseases (MNDs). Their diagnosis was determined clinically and laboratorially. The WFN criteria were used for amyotrophic lateral sclerosis (ALS) diagnosis. The clinico-demographic analysis of the 87 cases of MNDs showed that 4 were diagnosed as spinal muscular atrophy (SMA), 5 cases as ALS subsets: 2 as progressive bulbar paralysis (PBP), 2 as progressive muscular atrophy (PMA) and 1 as monomelic amyotrophy (MA), and 78 cases of ALS. The latter comprised 51 males and 27 females, with a mean age of 42.02 years. They were sub-divided into 4 groups according to age: from 15 to 29 years (n= 17), 30 to 39 years (n= 18), 40 to 69 years (n= 39) and 70 to 78 years (n= 4). From the 78 ALS patients, 76 were of the classic sporadic form whilst only 2 were of the familial form. The analysis of the 87 patients with MNDs from the University Hospital of Fortaleza showed a predominance of ALS patients, with a high number of cases of juvenile and early onset adult sporadic ALS.     

Differential scanning calorimetry differences in micronized and unmicronized nimesulide uptake processes in biomembrane models.

Nimesulide release from micronized and unmicronized drug particles was tested at pH 7.4 by measuring the transfer to dimyristoylphosphatidylcholine liposomes (multilamellar and unilamellar vesicles), chosen as a biomembrane model. The perturbing effect of increasing molar fractions of pure nimesulide on the thermotropic behaviour of dimyristoylphosphatidylcholine liposomes was investigated by differential scanning calorimetry. In order to study the drug dissolution process by its uptake into void liposomes, measurements were carried out on suspensions of blank liposomes added to weighed amounts of free powdered nimesulide (micronized and unmicronized). The amount of drug transferred was quantified by comparing the effect caused by the dissolved and released drug to that caused by the free drug that had been previously molecularly dissolved in the liposomes. The calorimetric results show that the dissolution rate depends on the nimesulide form (micronized or unmicronized), and that the transfer to the void liposomes is quicker when the drug is in a micronized form. The uptake was faster when unilamellar vesicles were used instead of multilamellar vesicles because of the greater lipid surface. The calorimetric technique could represent an alternative 'in vitro' method that can be applied to the study of the dissolution kinetics directly at the site of drug uptake, mimicking a biological system.     

Use of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy in the treatment of locally advanced head and neck cancer patients.

PURPOSE: To evaluate safety and preliminary efficacy of the humanized anti-epidermal growth factor receptor monoclonal antibody h-R3 in combination with radiotherapy (RT) in unresectable head and neck cancer patients. Secondary end points were the measurement of h-R3 serum levels and the assessment of the potential mechanisms of antitumor effect on patient biopsies. Anti-idiotypic response to h-R3 was assessed. To predict pharmacologic effect, a mathematical model for antibodies recognizing antigens expressed in tumors and normal tissues was built. PATIENTS AND METHODS: Twenty-four patients with advanced carcinomas of the head and neck received six once-weekly infusions of h-R3 at four dose levels in combination with RT. Pretreatment tumor biopsies were obtained to evaluate epidermal growth factor receptor expression as an enrollment criterion. Second biopsies were taken to evaluate the proliferative activity and angiogenesis in comparison with the pretreatment samples. Patient serum samples were collected to measure h-R3 levels and anti-idiotypic response. RESULTS: The combination of h-R3 and RT was well tolerated. Antibody-related adverse events consisted in infusion reactions. No skin or allergic toxicity appeared. Overall survival significantly increased after the use of the higher antibody doses. Immunohistochemistry studies of tumor specimens before and after treatment revealed that antitumor response correlated with antiproliferative and antiangiogenic effect. One patient developed antibodies to h-R3. The mathematical model predicted that the maximum difference between the area under the curve in tumors and normal tissues is reached when the antibody has intermediate affinity. CONCLUSION: h-R3 is a well-tolerated drug that may enhance radiocurability of unresectable head and neck neoplasms.