(99m)Tc-labeled murine ior C5 monoclonal antibody in colorectal carcinoma patients: pharmacokinetics, biodistribution, absorbed radiation doses to normal organs and tissues and tumor localization.

Monoclonal Antibody (mAb) ior C5 is a murine IgG(1) that recognizes the tumor associated antigen (TAA) ior C2, a cell surface O-linked glycoprotein carbohydrate chain not present in most normal tissues and homogeneously expressed in the cytoplasm of normal colon epithelium and heterogeneously expressed in more than 83% of primary colorectal carcinomas. This study was designed to investigate the pharmacokinetics, biodistribution and the absorbed radiation doses of (99m)Tc-labeled mAb ior C5 antibody in colorectal tumor patients. Ten patients were administered 3 mg of anti-O-linked glycoprotein carbohydrate chain TAA ior C2 murine monoclonal antibody ior C5 radiolabeled with (99m)Tc activity of 1435.0 +/- 123 MBq by intravenous (i.v.) bolus infusion. Blood and urine samples were collected from 4 out of 10 patients at timed intervals from 10 min and up to 24 h after injection of the (99m)Tc-labeled mAb ior C5 for pharmacokinetic studies. Whole body images were taken in 5 out of 10 patients for quantitative normal organ biodistribution and dosimetry studies and planar anterior and posterior and SPECT images were taken in 5 out of 10 patients for tumor localization. Mean absorbed doses were estimated using the methods developed by the Medical Internal Radiation Dose (MIRD) committee. The effective dose equivalent (EDE) and effective dose (ED) were calculated as prescribed in International Commission on Radiological Protection (ICRP) publications 30 and 60. Plasma disappearance curves of (99m)Tc-labeled murine antibody ior C5 were best fit by a two-compartment model in all patients with (t(1/2alpha)) of 4.32 +/- 2.18 h and (t(1/2beta) of 32.6 +/- 3.82 h. Among the main target organs, accumulation of the radiolabeled antibody was found in liver (9.38 +/- 0.80%), heart (8.92 +/- 0.94%) and spleen (1.37 +/- 0.30%) at 5 min post-administration. These values were reduced at 24 h to (5.91 +/- 0.73%) and (0.62 +/- 0.22%), respectively, for the heart and spleen and increased to (9.78 +/- 1.99%) for liver. Estimates of radiation absorbed dose to normal organs in rad/mCi administered were: whole body, 0.0181 +/- 0.0017; heart wall, 0.0768 +/- 0.0090; kidneys, 0.0530 +/- 0.0260; liver, 0.0565 +/- 0.0109 and spleen, 0.0540 +/- 0.0128. The effective dose equivalent and effective dose estimates for adults were 0.0314 +/- 0.0031 and 0.0249 +/- 0.0027 rem/mCi administered. This feasibility study indicates that the O-linked glycoprotein carbohydrate chain TAA ior C2 is expressed in primary and metastatic colorectal carcinomas and shows very limited expression in normal adult tissues. The very good pattern of biodistribution of (99m)Tc-labeled mAb ior C5 in patients will allow imaging of colorectal carcinoma lesions.

Technetium-99m-antiepidermal growth factor-receptor antibody in patients with tumors of epithelial origin: part II. Pharmacokinetics and clearances.

UNLABELLED: Radiolabeled antitumor antibodies hold promise for diagnostic imaging and therapy in oncology. The purpose of this study was to investigate the pharmacokinetics, clearances and possible differences of two dosage administrations of the 99mTc-labeled antiepidermal growth factor (EGF)-receptor antibody and to predict the best dose and schedule for future clinical evaluations of this radiopharmaceutical. METHODS: Nine patients (4 women, 5 men; mean age 46.4 +/- 14.0 yr) were administered 1-3 mg 99mTc-labeled anti-EGF-receptor antibody (a murine IgG2a isotype) by intravenous bolus infusion. After administration, blood samples were collected from 7 patients from an antecubital vein opposite to the injection side at intervals from 2 min to 24 hr after injection, and plasma samples were obtained for pharmacokinetic analysis. Appropriate plasma samples were examined for isotope clearance (i.e., microCi/ml at various intervals) and 99mTc complexation to plasma proteins by fast protein liquid chromatography (FPLC) analysis. Urine was collected from each patient at 3 hr intervals up to 24 hr after monoclonal antibody administration to monitor 99mTc clearance. Plasma time-activity curves were fitted to a two-compartment model using nonlinear least-squares regression analysis by the method of flexible polyhedrals. RESULTS: Plasma disappearance curves of 99mTc-labeled anti-EGF-receptor antibody were best fit by biexponential equation with a distribution half-life (t(1/2alpha)) of 0.137 +/- 0.076 hr (n = 7) and elimination half-life (t(1/2beta)) of 20.3 +/- 8.0 hr. Analysis of urine showed that activity clearance by this route amounted to 4.9% +/- 0.6% of the injected dose in 24 hr, and FPLC analysis showed no evidence of decomposition, only 6%-7% of 99mTc was in a low molecular weight species. CONCLUSION: Plasma pharmacokinetics and urine clearance indicate comparability in both doses. The pharmacokinetic properties of the 99mTc-labeled anti-EGF-receptor antibody were found to be dose-independent. These findings provide an initial characterization of the radiopharmaceutical disposition in patients and may be used as the basis for calculating a better estimate of biodistribution and dosimetry for patients who will receive 188Re-labeled anti-EGF-receptor antibody (MAb ior egf/r3) injection for radioimmunotherapy and warrants further controlled clinical trials to define the efficacy of the radiopharmaceutical.

Plasma neurotransmitters, blood pressure and heart rate during supine resting, orthostasis and moderate exercise in severely ill patients: a model of failing to cope with stress.

BACKGROUND: Previous clinical research has shown that severely ill (somatic) as well as many psychosomatic patients show raised noradrenaline (NA), adrenaline (AD), cortisol, free serotonin (f5HT) and platelet aggregability. Conversely, they show reduced NA/AD plasma ratio and platelet serotonin (p5HT). They also show adrenal hyperresponsiveness to an oral glucose load. These findings are opposed to those observed in depressed patients who show adrenal gland sympathetic hyporesponsiveness and neural sympathetic hyperactivity. OBJECTIVE: To investigate adrenal gland and neural sympathetic systems as well as the other parameters in nondrepressed severely ill patients through the orthostasis exercise stress test which in normals triggers NA but no AD rise. METHODS: We investigated 35 severely ill patients and their age- and sex-paired controls. Systolic, diastolic pulse pressure (PP), heart rate and neuroendocrine parameters were measured supine (0 min), at orthostasis (1 min) and exercise (5 min). A second test was performed 2 weeks later, after atropine injection. Multivariate analysis of variance, paired t test and Pearson product-moment test were employed. RESULTS: The normal PP orthostasis fall was not observed in patients. At this period, an abnormal AD peak substituted the normal NA peak. The normal p5HT-f5HT orthostasis-exercise peaks were absent in patients. Cortisol and platelet aggregability were raised in patients. CONCLUSIONS: Severely ill (somatic) patients responded to the orthostasis-exercise stress test with adrenal and corticosuprarenal but not neural sympathetic activity. They did not show the normal parasympathetic activity at orthostasis. This adrenal gland sympathetic hyperactivity registered in somatic patients is similar to that observed in mammals which fail to cope with stress and contrary to the profile registered in depressed subjects who show NA but not AD rise.

Plasma neurotransmitters, blood pressure, and heart rate during supine-resting, orthostasis, and moderate exercise conditions in major depressed patients.

Major depressed patients showed greater heart rate, noradrenaline, and free-serotonin values than normal. Conversely, platelet-serotonin values in major depressed patients were significantly lower than normal. Patients registered the normal differential blood pressure reduction during orthostasis. They also revealed progressive and significantly higher heart rate rises during orthostasis and exercise periods, when compared to normals. Whereas noradrenaline showed maximal rises during the two last periods, adrenaline only showed small but significant increase during exercise. The analysis of correlations, together with the above data, suggests that major depressed patients register maximal neural sympathetic activity as well as adrenal glands sympathetic hypoactivity. In addition, these patients show hyperparasympathetic activity, as reflected by the free-serotonin profile. Finally, the fact that both the Hamilton Depression Rating Scale and the self-rating Beck Depression Inventory correlated positively with noradrenaline/adrenaline ratio and free-serotonin values strongly suggests that both neural sympathetic and cholinergic mechanisms are involved in major depression.

Plasma neurotransmitters, blood pressure, and heart rate during supine resting, orthostasis, and moderate exercise in dysthymic depressed patients.

Dysthymic depressed patients showed platelet-serotonin (pS) + plasma-free serotonin values greater than normal as well as plasma noradrenaline values lower than normal during supine resting period (0'). Conversely, no significant differences were observed in the 0' values of any other of the measured parameters: systolic, diastolic and differential blood pressure (SBP, DBP, DP), heart rate (HR), adrenaline (Ad), dopamine (DA), cortisol, and platelet aggregability between patients and controls. Although patients showed then normal DP reduction at orthostasis (1'), this was not prevented by atropine as it does in controls. Patients but not normals showed significant rises of DBP at orthostasis and exercise (5') periods, which were positively correlated with NA rises. On the contrary, the abnormally raised resting fS values registered in patients showed progressive and significant reductions throughout the test that were negatively correlated with DBP-NA values. Adrenaline did not show the normal 5'-fS peak. The above findings suggest that dysthymics show hypoactivity of the two branches of the sympathetic system (neural + adrenal) along with hyperparasympathetic activity. Furthermore, their low NA + high pS values contrast with the high NA + low pS registered in major depressed subjects.

Miositis osificante progresiva congénita: A propósito de un caso revisión de la literatura / Congenital progressive myositis osifficant: Apropos of a case and review of literature

La miositis osificante progresiva es una enfermedad rara caracterizada por la formación de áreas de calcificación en el tejido conectivo intersticial de músculos, tendones, ligamentos, fascias y aponeurosis que pueden ser detectadas radiológicamente. Aunque las manifestaciones de la enfermedad pueden no ser evidentes hasta después de los diez años de vida, está asociada a ciertas anomalías congénitas como acortamiento de los pulgares hallux valgus y clinodactilia. El curso de la enfermedad es progresivo causando anquilosis, invalidez e incluso la muerte. El tratamiento es discutido, en la actualidad el etidronato disódico y la prednisona son los medicamentos más utilizados con resultados poco alentadores. Presentamos el caso de una niña de 2 años y 10 meses con manifestaciones clínicas de un año de evolución, nódulos calcificantes en diferentes sitios del cuerpo y limitación severa a la movilización del cuello y cintura escapular, inicialmente diagnosticada como dermatomiositis. Se enfatizan los hallazgos radiológicos y anatomopatológicos, así como la importancia de evitar los traumatismos y procedimientos invasivos como medida preventiva en estos niños

Plasma neurotransmitters throughout an oral glucose tolerance test in non-depressed essential hypertension patients.

The oral glucose tolerance test (OGTT) with plasma neurotransmitter assays and blood pressure measurements were performed on 68 hypertensive (A and B) and 68 paired normal controls (group C). Those patients who failed to show significant or persistent blood pressure reductions throughout OGTT constitute group A (37 subjects); and those who did show significant and persistent reductions constitute group B (31 subjects). The purpose of this study was to assess if there were any significant differences between those patients whose blood pressure levels normalized throughout OGTT and those who didn't and, further, compare them to their controls. In group A, noradrenaline (NA) was high at the 0' (fasting) period, increasing further at 60' and 90'; however, circulating serotonin (p5HT) did not vary throughout OGTT. Group B, although showing high NA at 0', did not show rises afterwards; whereas, significant and sustained p5HT rises registered throughout postprandial periods. In group C, both p5HT and plasma NA showed significant and sustained increases. Therefore, the NA/p5HT ratio is higher in A, than in B and C. Group A patients were awake and alert throughout. Group B patients were mostly drowsy and many slept light and intermittently. Group C subjects slept throughout, dreaming and showing rapid eye movements. Our findings suggest that the hypertensive syndrome is most severe in those patients who do not show a rise in postprandial circulating serotonin (parasympathetic activity), group A, than those who do exhibit such a rise, group B.

Pimozide therapy for trigeminal neuralgia.

Pimozide was compared with carbamazepine in a double-blind crossover trial in 48 patients with trigeminal neuralgia who were refractory to medical therapy. Pimozide treatment produced greater reduction in trigeminal neuralgia symptoms than carbamazepine treatment. All of the pimozide-treated patients improved, while only 56% of carbamazepine-treated patients were relieved of their pain. Although both drugs provoked some adverse effects, it was not necessary to interrupt the trial in any case. After this 24-week trial, all patients began receiving pimozide and were followed up according to an open-label study design. In all cases, the pimozide dosage was progressively reduced until the minimal effective dose was reached. Central and peripheral mechanisms that may underlie pimozide-induced improvement are discussed.

Recurrent gastroesophageal symptoms and precordial pain in a gastrectomized man improved by amitriptyline. Physiologic, metabolic, endocrine, neurochemical and psychiatric findings.

A 57-year-old white man presenting frequent recurrent chest and precordial pain, heartburn (pyrosis) and post-prandial vomiting for the previous 33 years (one to two years after Bilroth II gastrectomy) was submitted to cardiovascular, endoscopic, radiologic and biochemical studies with negative results. Doctors recommended surgical operation because of an excessively long afferent loop, Several biologic markers were performed at our hospital (intestinal pharmacomanometry, i.m. clonidine test, plasma neurotransmitters plus hormones, oral glucose tolerance test, plasma insulin, etc.), revealing an autonomic nervous system (ANS) imbalance characterized by hyperactivity of the cholinergic plus hypoactivity of the noradrenergic central system. Psychiatric evaluation demonstrated Dysthymic Depression. Treatment with a small daily dose of amitriptyline (a drug which enhances central noradrenergic activity and exerts powerful anticholinergic effects) suppressed symptoms, normalized physiological plus hormonal plus neurochemical parameters and made depressive manifestations disappear. The results suggest that the ANS imbalance was related to depressive syndrome and potentiated by neurohumoral disorders depending on duodenal and jejunal exclusion, and on intestinal post-prandial hyper-osmolarity.

Definite and sustained improvement with pimozide of two patients with severe trigeminal neuralgia. Some neurochemical, neurophysiological and neuroendocrinological findings.

In the present study we report two typical cases of trigeminal neuralgia in whom all conventional drug treatments were attempted without success, and in whom low doses of pimozide, a dopaminergic blocking agent, provoked a definite and sustained improvement. All biological markers used in these cases provided indirect evidence that a central serotonergic hypoactivity is an underlying mechanism in this disease. A low intestinal tone, raised levels of norepinephrine, dopamine, platelet serotonin and non-platelet plasma serotonin were registered during relapses and normalized during improvement periods. Pimozide was not able to improve the depressive state diagnosed in these two cases, nor in 13 other trigeminal neuralgia patients (not reported in this study).

Effects of clonidine on blood pressure, noradrenaline, cortisol, growth hormone, and prolactin plasma levels in high and low intestinal tone depressed patients.

Systolic blood pressure (SBP), diastolic blood pressure (DBP), norepinephrine (NE) plasma levels, cortisol (CRT), growth hormone (GH), and prolactin (PRL) plasma levels were investigated in 26 high intestinal tone (high-IT) and 24 low intestinal tone (low-IT) depressed patients, before and after the intramuscular injection of clonidine (2.5 micrograms/kg). A positive correlation was found between NE, DBP, and Hamilton Depression Rating Scale (HRS) values in low-IT depressed patients, while a negative correlation was found between HRS/IT and NE in high-IT depressed patients. Although clonidine induced significant reduction of SBP in both groups, the drug reduced DBP and NE in the low-IT group, only. CRT mean level was greater in the high-IT than in the low-IT depressed group. However, clonidine was unable to induce changes in CRT, GH, and PRL mean levels in any depressed group. Our results suggest that the clonidine-induced DBP reduction is a reliable index of sympathetic activity in depressed patients and that both parameters (DBP and IT) are useful physiological markers to differentiate two types of depressive syndromes.

Treatment of ulcerative colitis with clonidine.

In the present 30-week, double-blind study of 45 ulcerative colitis (UC) patients treated with prednisone, sulfasalazine, clonidine, or placebo, we found that clonidine (an alpha 2 agonist) and prednisone were effective in treating idiopathic UC. Both drugs were more effective than sulfasalazine. Furthermore, clonidine potentiated prednisone and sulfasalazine effects. Clonidine was chosen because its effect on distal colon motility is similar to thioproperazine, an antipsychotic drug that, despite many adverse effects, possesses powerful anti-UC properties. Rating scales were outlined in order to evaluate clinical, endoscopic, histologic, and radiologic changes. Plasma cortisol levels, sedimentation rate, serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, and other biochemical parameters were determined to assess the efficacy of each drug. Distal colon motility changes were also assessed. All our UC patients showed raised cortisol plasma levels and low sigmoidal tone during relapse periods. These parameters were reversed during remission periods. Peripheral and central mechanisms are discussed.

Distal colon motility and clinical parameters in depression.

Eighty-six patients suffering from nonpsychotic unipolar major depressive disorder, according to Research Diagnostic Criteria, were rated on a modified Hamilton Rating Scale for Depression (HRS). All completed the self-rating Beck Depression Inventory (BDI). Distal colon motility (dcm) studies, performed in all the patients, differentiated two types: low intestinal tone (low-IT) = 40 subjects, and high intestinal tone (high-IT) = 46 subjects. Low-IT depressed patients showed a statistically significant preponderance in the HRS items 'retardation', 'somatization', 'fatigability', 'hypochondriasis' and 'obsessional symptoms'. The high-IT depressed patients, on the other hand, showed preponderance in the items 'guilt', 'suicide', 'insomnia', 'agitation', 'anxiety psychic', 'loss of insight', 'depersonalization' and 'paranoid symptoms'. A positive correlation (r) was found between HRS- and BDI-mean total scores. In addition, a positive correlation (r) was found between HRS scores and distal colon tone in high-IT patients, although the same was not true for low-IT patients. Our results suggest the existence of two subtypes of depressive syndromes, distinguishable on the basis of distal colon motility profiles.

Distal colon motility as a predictor of antidepressant response to fenfluramine, imipramine and clomipramine.

The present study gathers results obtained in the treatment of 86 depressed outpatients. The patients were grouped according to their distal colon tone, low-IT and high-IT. All the patients fulfilled the Research Diagnostic Criteria for nonpsychotic unipolar major depressive disorder and were rated on a slightly modified 18-item Hamilton Rating Scale for Depression (HRS). They also completed the 21-item self-rating Beck Depression Inventory (BDI). The 46 subjects from the high-IT group and the 40 subjects from the low-IT group were divided into three subgroups each for double-blind trials performed with clomipramine (CMI), imipramine (IMI), and fenfluramine (FENF). Normalization of HRS and BDI scores and reduction of IT were obtained with IMI and FENF but not CMI in high-IT patients; whereas normalization of both scores and increase in IT were obtained with CMI but not with IMI or FENF in low-IT patients. FENF was not tolerated in this last group. HRS and BDI scores correlated well during in-treatment periods. Our results suggest that distal colon tone is a guide to determining the pharmacotherapy in the depressive disorders. Furthermore, it was shown that FENF is a useful anti-depressant drug in one type of patient.

On the use of clonidine and thioproperazine in a woman with Gilles de la Tourette's disease.

A 25-year-old woman with Gilles de la Tourette's disease was successfully treated with clonidine (an inhibitor of noradrenaline release). However, the drug was stopped because of side effects. Thioproperazine, a phenothiazine derivative which blocks subcortical dopaminergic receptors, suppressed Gilles de la Tourette's symptoms totally. The patient has tolerated the drug well for over a year since its introduction. The pharmacomanometric investigation performed in this patient showed hyperactivity of her noradrenergic system.

Pharmacomanometric studies of colonic motility as a guide to the chemotherapy of schizophrenia.

Distal colon motility studies performed in 41 psychotic subjects demonstrated that 32 of them had hyperactivity of the noradrenergic system at this peripheral level, while the remaining nine cases showed hyperactivity of the dopaminergic system. The noradrenergic-hyperactive patients fulfilled the Research Diagnostic Criteria of schizophrenia, whereas the dopaminergic-hyperactive patients were diagnosed as having schizoaffective disorders. Noradrenergic-hyperactive subjects were successfully treated with clonidine, a drug which inhibits release of noradrenaline, while dopaminergic-hyperactive subjects were successfully treated with clonazepam, a drug which inhibits release of dopamine. The addition of sulpiride (a postsynaptic dopaminergic blocking agent) and of phentolamine (a postsynaptic noradrenergic blocking agent) to clonidine and clonazepam, respectively, induced further significant improvements in both types of psychotic patients.