Ro 11-2465 (cyan-imipramine), citalopram and their N-desmethyl metabolites: Effects on the uptake of 5-hydroxytryptamine and noradrenaline in vivo and related pharmacological activities

Ro 11-2465 (cianopramine, cyan-imipramine) and citalopram (CIT), putative antidepressant drugs, are very potent and selective 5-hydroxytryptamine (5-HT) uptake inhibitors in vitro. This study investigated the effects of these drugs and their desmethyl metabolites, Ro 12-5419 (desmethylcianopramine, cyan-desipramine) and desmethylcitalopram (DCIT), respectively, on the uptake of 5-HT and noradrenaline (NA) in vivo [protection against H 77/77 (4, alpha-dimethyl-metatyramine)-induced displacement of 5-HT and NA] and on related pharmacological activities. All the investigated drugs antagonized H 77/77-induced displacement of 5-HT in the rat brain, though the effects of the metabolites were considerably weaker than those of the parent compounds. The H 77/77-induced displacement of brain NA in rats and mice was antagonized only by Ro 12-5419 and Ro 11-2465. All the drugs potentiated the pressor response to 5-HT in pithed rats; however, Ro 12-5419 and particularly Ro 11-2465 could also block the response when used in higher doses (0.1 mg/kg). Only Ro 12-5419 and Ro 11-2465 were able to potentiate the pressor response to NA. Ro 12-5419 also potentiated thyrotropin releasing hormone (TRH) hyperthermia and antagonized reserpine hypothermia in mice; Ro 11-2465 potentiated the TRH hyperthermia only. CIT and DCIT were inactive in both these tests. Of all the four drugs only CIT and Ro 12-5419 considerably stimulated the hind limb flexor reflex in spinal rats. However, whereas the stimulatory effect of CIT was inhibited by the 5-HT antagonists metergoline and cyproheptadine, that of Ro 12-5419 was counteracted by the NA antagonist phenoxybenzamine only. Ro 11-2465, when used in low doses (ca. 1 mg/kg), slightly potentiated the flexor reflex, whereas in higher doses (4–16 mg/kg) it had no effect itself but antagonized the stimulatory action of the 5-HT agonists fenfluramine, quipazine and LSD. The results obtained indicate that Ro 11-2465 and CIT, as well as their desmethyl metabolites, are also potent 5-HT uptake inhibitors in vivo. However, only CIT and DCIT are concurrently devoid of effect on uptake of NA. In contrast, Ro 11-2465 and particularly Ro 12-5419 appear to also inhibit the uptake of NA. Moreover, Ro 11-2465 appears to block central and peripheral 5-HT receptors.The results were presented at the 14th CINP Congress, Florence, June 19–23, 1984     

Intravenous and intramuscular pharmacokinetics of recombinant leukocyte a interferon

Summary Interferon is currently being evaluated for the treatment of disseminated cancer and viral diseases. Alpha interferons have shown to be effective in the treatment of a number of malignancies. Recombinant leukocyte A interferon (rIFN-A) is an alpha interferon produced by recombinant DNA techniques. A kinetic evaluation of rIFN-A following intravenous and intramuscular administration has not been adequately defined. The present study was designed to evaluate the kinetics of rIFN-A following intravenous and intramuscular administration of 3, 9 or 18×10⁶ units to patients with disseminated cancer.A preliminary report of this study was presented at the meeting of the American Society for Clinical Pharmacology and Therapeutics in San Diego, March 1983 (1).     

An in vitro Study on the Effect of Momordica charantia on Glucose Uptake and Glucose Metabolism in Rats

The effect of extracts of MOMORDICA CHARANTIA L. fruits on glucose metabolism and glucose uptake was investigated. The fruit of momordica, at all ripening stages, was found to contain two inhibitory compounds: one against hexokinase activity and the other against glucose uptake by rat intestinal fragments. Both inhibitions exhibit competitive profiles VERSUS glucose. The inhibitory factors are extractable in hot water, hot alcohol and hot acetone. A partial purification procedure by TLC for both inhibitors is described.     

"Balanced" thoracic drainage is the method of choice to control intrathoracic pressure following repair of diaphragmatic hernia

Respiratory failure from pulmonary hypoplasia continues to be the major cause of death in newborn infants with diaphragmatic hernia. Recent investigations have suggested that postnatally induced pulmonary injury can result from excessive positive or negative intrathoracic pressure and contribute to the respiratory deterioration. Therefore, the method of thoracic drainage on the side of the diaphragmatic hernia is critical in controlling and maintaining normal intrathoracic pressure in both intrathoracic spaces. No chest tube or an ipsilateral chest tube connected to water seal, can result in either excessive negative or positive intrathoracic pressure and, therefore, both methods should be avoided. Recently, we employed a "balanced" intrathoracic drainage system which maintains the ipsilateral intrathoracic pressure within the normal physiologic range of +2 to -8 cm H2O regardless of the degree of pulmonary hypoplasia, presence of an ipsilateral pulmonary air leak, straining by the infant, or mechanical ventilation. This system is simple, requires no suction apparatus, and is easily assembled with equipment readily available within the hospital. This technique has been utilized in 18 newborn infants with diaphragmatic hernia and pulmonary hypoplasia. There have been no complications which specifically could be related to the balanced drainage system.     

Dexamethasone suppression test as an aid for selection of specific antidepressant drugs in patients with endogenous depression

The dexamethasone suppression test (DST) and response to two different antidepressant drugs (maprotiline as a specific noradrenergic, and amitriptyline as a predominantly serotoninergic drug) were investigated in 44 endogenously depressed female inpatients. The more anxious and/or agitated patients were mostly treated with amtiriptyline, the non-anxious and retarded patients with maprotiline. It was found that among maprotiline responders (N = 15) there were significantly more abnormal DSTs and postdexamethasone serum cortisol levels were significantly higher than among amitriptyline responders (N = 16). On the other hand, DST abnormalities among amitriptyline non-responders (N = 10) were similar to those among maprotiline responders. The results confirm earlier reports by Brown et al. (1980), Ettigi et al. (1983) and Fraser (1983) and indicate that abnormal DST may identify the "noradrenergic" subtype of endogenous depression and that the DST represents a good way of selecting a specific antidepressant drug for the treatment of endogenously depressed patients.     

Axonal and myelin lesions inβ-mannosidosis: Ultrastructural characteristics

Summary Ultrastructural changes in central nervous system (CNS) white matter of three goats affected with-mannosidosis were analyzed to further define characteristics and pathogenesis of axonal and myelin abnormalities. The variations in myelin association and contents of axonal spheroids were delineated. The occurrence of spheroids in a 96/150-day fetus documented the early development of these axonal lesions. In regions of severe myelin deficits, the presence of apparently normal axons and a reduction in the number of oligodendrocytes were confirmed. Many remaining cells in myelin-deficient regions were characterized by dark, vacuolated cytoplasm. The occurrence of internodes with myelin sheaths adjacent to internodes without myelin sheaths suggested that an axonal defect is not primarily responsible for the absence of myelin sheaths. A mild myelin deficit in the spinal cord was indicated by the presence of unmyelinated axons. Except for occasional mild cytoplasmic vacuolation, the spinal cord glial cells appeared relatively normal. The findings presented here are consistent with the hypothesis that an oligodendrocyte defect, expressed by regional differences, is a major factor in the pathogenesis of myelin deficiency in-mannosidosis.Supported by NIH grant NS-16886 to MZJ and BRSG funds from the College of Osteopathic Medicine, Michigan State University, to KLL     

Third-dimension sweep: new scanning method in diagnostic ultrasound

The inability to image the 3rd dimension has meant a loss of valuable information, e.g., examination of an IUD in the uterine cavity. Whatever plane is examined longitudinal, transverse, or oblique the image always is a 2-dimensional tomograph producing either bars or dots. Even when the transducer lies perpendicular to the long axis of the IUD, the IUD cannot be visualized as a whole because the 1st bar produces an acoustic shadow that covers all the other bars. A technique now exists for obtaining the 3rd dimension by moving a linear array transducer over the area to be examined, which produces an endless number of images on the screen. Since the commonly used real-time scanners are not equipped with storage capacity, these images immediately fade away. This problem can be resolved by using a Polaroid camera as a storage device. The shutter is opened for the longest exposure possible, i.e., 1 second, while the diaphragm is closed. During this 1 second of exposure, the linear array transducer is "swept" over the area for examination using the compound movement technique. A second is a relatively long time, but some training is necessary before the operator can easily perform the "sweep." If the whole movement cannot be carried out in 1 second, an additional second can be used. This will rusult in a slightly overexposed picture, but these are sometimes even easier to interpret. It is important that the area be well lubricated, and the patient stop breathing for the duration of the scan. The equipment used in the study included a Picker 2000 and a Unirad real-time scanner. Both scanners were handled in the same way, and the same technique was used. Different kinds of IUDs were visualized and recorded.     

In vivo measurement of brain tumor pH using [11C]DMO and positron emission tomography

In vivo measurements of regional brain tissue/tumor pH (rpH) have been accomplished in 9 patients with primary or metastatic brain tumors using [11C]dimethyloxazolidinedione [( 11C]DMO) and positron emission tomography. Tumor rpH values ranged from 6.88 to 7.26, whereas gray matter and white matter rpH values ranged from 6.74 to 7.09 and from 6.77 to 7.03, respectively. Our results, which are consistent with reported [14C]DMO autoradiographic measurements of brain and tumor pH, suggest that the pH microenvironment of brain tumors is not more "acidic" than that of normal gray or white matter.     

Diagnosis and taxonomy of periodical psychosis

The concept and taxonomy of periodic psychosis still remains in controversy for the past 100 years. In China, it was first reported by Ji, and thereafter various rinds of terminology and views were given by different authors. In the presentation, clinical investigation and follow up were carried out in 62 cases. In many of these cases, the so-called "periodic psychosis" or "phasophrenia" was early clinical features of schizophrenia or manic-depression. In those cases with apparent symptoms and signs of diencephalic function, differential diagnosis should be carried out from organic brain syndrome. In a small number of cases, their clinical manifestations, conforming to previous diagnostic criteria, might be an uncommon syndrome. It was concluded by the authors that until now periodic could be considered only as a clinical syndrome rather than a disease entity.     

Carbamazepine dosage and its blood serum level in children

Evaluating in 62 children aged from 4 months to 14 years (mean age 3 years 7 months) the correlation between the carbamazepine dosage (carbamazepine was given as the only drug in 21 cases, and as one of several drugs in 41) the authors failed to find a simple correlation. Nevertheless, most children receiving the "proper" doses had therapeutic plasma carbamazepine levels. Moreover, it was found that carbamazepine dose increase over 25 mg/kg daily caused on further rise of its plasma level.