UNLABELLED: Detection of myocyte cell damage with 111In-antimyosin and impairment of adrenergic neuron function with [123I]MIBG during doxorubicin administration may provide easy identification of patients at risk of significant functional impairment. METHODS: We studied 36 cancer patients who underwent chemotherapy, including doxorubicin, to assess [123I]MIBG and 111In-antimyosin uptake in the course of doxorubicin administration. MIBG scans, antimyosin scans and ejection fraction measurements were performed before chemotherapy, at intermediate cumulative doses and at maximal cumulative doses of doxorubicin. MIBG uptake was quantified by a heart-to-mediastinum ratio and antimyosin uptake was quantified by a heart-to-lung ratio. RESULTS: All patients had absent antimyosin uptake (mean ratio 1.40 +/- 0.06) with normal MIBG uptake (ratio 1.85 +/- 0.29) before chemotherapy; ejection fraction was 61% +/- 8%. With a 240-300 mg/m2 dose of doxorubicin, an increase in antimyosin uptake was observed with a ratio of 1.85 +/- 0.2 (p < 0.01), whereas a similar degree of MIBG uptake was observed (mean ratio of 1.80 +/- 0.2, p = ns); ejection fraction was 59% +/- 5% (p = ns). At 420-600 mg/m2, increased antimyosin uptake was observed with a ratio of 2.02 +/- 0.3 (p < 0.01), and a decrease in MIBG uptake was also observed (mean ratio of 1.76 +/- 0.2, p < 0.05); ejection fraction was 52% +/- 8% (p < 0.05). Patients with more intense antimyosin uptake at intermediate doses tended to be those with more severe functional impairment at maximal cumulative doses. CONCLUSION: At cumulative doses of 420-600 mg/m2, antimyosin and MIBG studies detect cell damage and impaired adrenergic neuron activity in patients with maintained or slightly decreased ejection fraction.

3-Iodobenzylguanidine↗

PubMed1994

A ketamine mixture anesthetic inhibits neuroendocrine and behavioral consequences of cocaine administration.

Cocaine is known to affect different brain systems, particularly those associated with arousal, motor and motivational functions. In order to identify a possible neurochemical link among these systems, we investigated the effects of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and dissociative anesthetic, ketamine (as a mixture with the sedatives acepromazine and xylazine) on the secretion of pituitary adrenocorticotropin hormone (ACTH) and on the development of behavioral sensitization induced by cocaine. Pretreatment with the ketamine anesthetic mixture (1.6 ml/kg; s.c.) completely blocked the stimulation of ACTH by cocaine (5 mg/kg, i.v.; administered 30 min after the ketamine mixture) without interfering with ACTH secretion induced by exogenous corticotropin-releasing factor (CRF; 5 micrograms/kg; i.v.) or interleukin-1 beta (IL-1 beta; 100 ng/kg; i.v.). Administration of the ketamine mixture prior to each of five repeated cocaine injections (15 mg/kg; i.p.) also completely reversed the behavioral sensitization observed in saline-treated control animals. Administration of the anesthetic mixture did not appear to impair the dopamine (DA) re-uptake blocking properties of cocaine in the nucleus accumbens since substantial increases in extracellular DA were observed in the presence of the ketamine mixture. In addition to the present results, no behavioral sensitization was also observed in rats anesthetized with a different general anesthetic (pentobarbital, 50 mg/kg) under similar conditions to that of the ketamine mixture. Taken together, these results are in accordance with the hypothesis that stimulation of excitatory amino acid receptor function may be just one of the mechanisms whereby cocaine exerts its effects on neuroendocrine and behavioral activating systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1994

Induction of c-fos in rat brain by acute cocaine and fenfluramine exposure: a comparison study.

Although cocaine shares the ability of fenfluramine to inhibit the synaptic reuptake of serotonin, previous observations from our group suggest that the genomic effects of fenfluramine in the rat striatum are primarily mediated by dopaminergic rather than serotonergic mechanisms. To compare and further understand the nerve cell type(s) targeted by psychotropic drugs, we studied, by use of immunocytochemistry and in situ hybridization, changes in c-fos in brain nerve cells of the caudate putamen and hypothalamus following acute cocaine or fenfluramine exposure. Predictably, both drugs (20 mg/kg; i.p.) evoked rapid but transient increases in c-fos in the caudate putamen. In addition, double labeling immunocytochemistry indicated that Fos-like protein was expressed preferentially in striatal neurons containing the protein phosphatase inhibitor, DARPP-32. In contrast, fenfluramine, but not cocaine, elicited c-fos mRNA and Fos-like protein in the neuroendocrine paraventricular nucleus (PVN) of the hypothalamus despite the fact that both drugs are known to be equally capable to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. This difference is discussed in terms of serotonergic, dopaminergic and DARPP-32 input to hypothalamic neurons and tanycytes associated with adrenocorticotropin hormone (ACTH) secretion. To further identify the phenotypes of nerve cells expressing c-fos by fenfluramine in the PVN, it was demonstrated that the immediate-early gene was induced in a subpopulation of neurons constitutively expressing nitric oxide synthase (NOS). Taken together, we identified a number of common and disparate actions of cocaine and fenfluramine in striatal and hypothalamic tissue, thereby suggesting that c-fos induction in these two brain structures is differentially regulated by intrinsic events in addition to neuronal phenotype. We propose that the genomic effects produced by these two drugs represent part of a general dopaminergic and glutamateric mechanism by which monoamine reuptake inhibitor drugs affect specific brain nerve cells.

Animals↗

PubMed1994

Acute administration of alcohol blocks cocaine-induced striatal c-fos immunoreactivity protein in the rat.

Immediate-early genes, such as c-fos, are induced in the brain by cocaine and other psychotropic drugs. This induction is thought to be mediated via the activation of dopamine D1 and glutamate N-methyl-D-aspartate (NMDA) receptor subtypes. Because alcohol selectively blocks NMDA receptor function, we determined the ability of alcohol to block the expression of c-fos normally induced by systemic cocaine exposure in perikarya of the rat striatum. Acute administration of alcohol (2 g/kg; IP) approximately 30 min prior to a single cocaine (20 mg/kg) injection significantly reduced the patchy appearance of intensely immunoreactive gene signal in dorsal-central quadrants of the caudate putamen. Separate administration of three doses of alcohol alone (1, 2, or 3 g/kg) was ineffectual in inducing FOS-like protein in this or other regions of the rat brain. The blockade of the encoded protein by alcohol was partial in magnitude reminiscent of that produced by MK-801 and related NMDA receptor antagonist drugs. Furthermore, the blockade of cocaine-induced FOS-like protein by alcohol occurred at a dose which produced a blood alcohol concentration of approximately 180 mg/dl (40 mM), comparable to that detected in intoxicating humans. Considering the fact that the concomitant use of alcohol and cocaine is the most common substance abuse pattern found in the addictive population, the present results suggest an antagonist effect exerted by these two drugs at the transcriptional level and further support the consensus that NMDA receptors are the plausible surface-target elements mediating some of the effects of alcohol and cocaine.

Animals↗

PubMed1994

Induction of c-fos and CRF mRNA by MK-801 in the parvocellular paraventricular nucleus of the rat hypothalamus.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) stimulates the secretion of adrenocorticotropin hormone (ACTH). As corticotropin-releasing factor (CRF) represents the primary modulator of this secretion, we tested the hypothesis that the ability of MK-801 to activate the hypothalamic-pituitary-adrenal (HPA) axis was modulated through actions at the hypothalamic level that modulate the secretion of CRF. Induction of the immediate-early gene c-fos, as well as of CRF mRNA within the paraventricular nucleus (PVN) of the rat hypothalamus, was examined following the intraperitoneally administration of MK-801 (1 mg/kg). MK-801 markedly increased the expression of Fos-like protein in parvocellular nerve cells of the PVN within 60 min of systemic treatment, and double labeling immunocytochemistry indicated that Fos was primarily localized in CRF-containing neurons of the PVN. MK-801 also significantly increased CRF biosynthesis as detected by in situ hybridization, thus suggesting that c-fos could be involved in the regulation of CRF genes. Taken together, these results suggest that MK-801 stimulates the rat HPA axis probably through the neuronal gene expression of PVN CRF. The significance of these data is discussed in terms of hypothalamic NMDA receptor blockade and subsequent transcriptional regulation of CRF by immediate-early genes.

Animals↗

PubMed1994

Antigranulocyte antibody bone marrow scans in cancer patients with metastatic bone superscan appearance.

In clinical practice, it may be difficult to distinguish a metastatic bone superscan appearance from a normal bone scan. To determine if assessment of bone marrow is helpful in the diagnosis of bone invasion in patients with suspected bone superscans, the authors performed antigranulocyte antibody bone marrow scans in 10 consecutive cancer patients who had a conventional bone scan interpreted as metastatic superscan appearance. All patients presented with bone marrow scans showing marked absence of tracer uptake in the central skeleton suggesting tumour replacement. Laboratory tests showed decreased peripheral blood cells in 9 patients. Bone radiographs showed metastatic involvement with diffuse osteoblastic lesions in 9 patients. Antigranulocyte bone marrow scans show extensive bone marrow invasion in cancer patients with suspected bone superscans. This result reinforces the concept of these patients having extensive bone invasion despite mild abnormalities in the bone scan. Confirmation of extensive bone invasion on patients with suspected bone superscans may contribute to a proper staging of these patients.

Adult↗

PubMed1994

Antigranulocyte bone marrow scans in Paget's disease.

Paget's disease of bone is a disorder of bone remodeling in which excessive production of structurally abnormal bone occurs, with the primary and fundamental abnormality residing in the osteoclast. To evaluate further the jeopardized bone marrow in Paget's disease, the authors studied 29 skeletal lesions by means of conventional bone imaging and antigranulocyte antibody bone marrow imaging in eight consecutive patients affected by Paget's disease. Bone scans showed abnormal tracer uptake in the 29 skeletal sites (11 pelves, 10 vertebrae, 5 extremities, 2 skulls, and 1 rib). Antigranulocyte antibody bone marrow scans showed decreased uptake of radiopharmaceutical in 16 (55%) of those 29 areas (8 pelves, 7 vertebrae, and 1 rib). Lesions appeared to be more extensive on bone scans than on bone marrow scans. It was concluded that antigranulocyte bone marrow scans may show focal defects in hematopoietic bone marrow in patients with Paget's disease. Paget's disease affects the cortical bone more severely than the bone marrow.

Aged↗

PubMed1994

Invasive pulmonary aspergillosis: a rare presentation of non-Hodgkin's lymphoma.

We describe a patient with rapidly progressive pneumonia and a high level of serum lactate dehydrogenase, in whom postmortem study revealed the presence of a diffuse, small and large-cell multicentric non-Hodgkin's lymphoma, together with an invasive pulmonary aspergillosis. Aspergillosis is rare as a presenting feature of a lymphoproliferative disease; only one previous case has been reported to the best of our knowledge. Invasive aspergillosis and lymphoma should be considered in patients presenting with pneumonia and high level of lactate dehydrogenase.

Aged↗

PubMed1994

Effect of alpha-interferon on erythrocyte and hepatocyte plasma membranes derived from cirrhotic rats.

Interferons are recognized to inhibit collagen production. Since fibrosis has been associated with liver dysfunction, we investigated the effects of alpha-interferon on the function and lipid composition of hepatocyte and erythrocyte plasma membranes derived from CCl4-cirrhotic male Wistar rats. In both cell types, CCl4 decreased Na+/K+ and Ca(2+)-ATPase activity and increased the cholesterol to phospholipids (CH/PL) ratio (p < 0.05). Administration of interferon (80,000 IU/kg s.c. for 8 weeks) increased survival from 40 to 90%, and preserved normal ATPase activity and CH/PL ratio. Our results show that administration of alpha-interferon to CCl4-cirrhotic rats improves survival, and liver and erythrocyte membrane function and composition, probably as a result of its antifibrogenic effect.

Animals↗

PubMed1994

Effects of postnatal methylmalonate administration on neurobehavioral development of rats.

Administration of methylmalonic acid in rats has been used as a model for methylmalonicacidemia in humans. Nestling Wistar rats of both sexes received 5 injections daily at 3-h intervals (starting at 7:30 a.m.) of saline or methylmalonic acid (MMA, 10 mg/ml) in a volume of 9 microliters/g body weight per injection subcutaneously in the lumbar region from the 5th to the 9th day of life and 11 microliters/g from day 10 to 14. Growth and neuromotor development were assessed by monitoring the following parameters daily in 54 rats: body weight, ear unfolding, incisor eruption, eye opening, righting, palmar grasp, negative geotaxis, cliff avoidance, free-fall righting and startle reflex. The only statistically significant effects of MMA administration were on the day of appearance of the free-fall righting reflex: MMA, 12.44 +/- 1.55 vs 11.0 +/- 0.39 days for saline control (P < 0.05, by two-way ANOVA) and a significant decrease in weight (P < 0.05, by ANOVA with repeated measures). The results suggest that chronic MMA administration to rats has a selective effect on neuromotor development.

Animals↗