Administration Of Ep Research Articles

Influence of the prehospital administered dosage of epinephrine on the plasma levels of catecholamines in patients with out-of-hospital cardiac arrest

AimThis study evaluated whether the prehospital administered dosage of epinephrine (Ep) influences the plasma levels of catecholamines in patients with out-of-hospital cardiac arrest (OHCA). MethodsThis was a prospective, observational clinical study. Patients with OHCA transferred to our hospital between July 2014 and July 2017 were analyzed. The plasma levels of catecholamines were measured using blood samples obtained immediately upon arrival at the hospital and before the administration of Ep. Patients were divided into three groups based on the prehospital administered dosage of Ep: no prehospital administration (group Z); 1 mg of Ep (group O); and 2 mg of Ep (group T). The levels of catecholamines, as well as the conditions of resuscitation prior to and after arrival at the hospital were compared between the three groups. ResultsWe analyzed 145 patients with OHCA (96, 38, and 11 patients in groups Z, O, and T, respectively). Group T exhibited the highest plasma levels of Ep with a statistically significant difference, however, there were no significant differences in the plasma levels of norepinephrine (Nep), dopamine (DOA) and vasopressin (ADH) among the three groups. ConclusionThe prehospital administered dosage of Ep influences the plasma levels of Ep; however, it does not contribute to the plasma levels of Nep, DOA and ADH in patients with OHCA.

Relationship between the Plasma Levels of Catecholamines and Return of Spontaneous Circulation in Patients with Out-of-Hospital Cardiac Arrest.

Purpose The dynamic state of epinephrine (Ep) in the plasma of patients with out-of-hospital cardiac arrest (OHCA) remains unclear. The purpose of this study was to evaluate the relationship between the plasma levels of catecholamines (such as epinephrine (Ep), norepinephrine (Nep), and dopamine) and vasopressin (antidiuretic hormone (ADH)) and the acquisition of return of spontaneous circulation (ROSC) in OHCA patients. Methods This was a prospective, observational clinical study. Patients with OHCA transferred to our hospital between July 2014 and July 2017 were enrolled. The levels of catecholamines and ADH in the plasma were measured using blood samples immediately obtained on arrival at our hospital and before the administration of Ep. Patients in whom Ep was already administered prior to obtaining blood samples were excluded. Patients were divided into two groups: with and without ROSC, that is, ROSC (+) and ROSC (−) groups, respectively. The plasma levels of these agents and the conditions of resuscitation were compared between the two groups. Results A total of 96 patients with OHCA were analyzed. The ROSC (+) and ROSC (−) groups included 34 and 62 patients, respectively. There were no significant differences observed between the two groups in age, cause of cardiopulmonary arrest, and prehospital resuscitation time. The plasma levels of Ep and Nep were significantly lower in the ROSC (+) group than in the ROSC (−) group. However, there were no significant differences in the plasma levels of dopamine and ADH between the two groups. Conclusion Increased levels of Ep in the plasma may not be associated with the acquisition of ROSC in patients with OHCA.

Role of high mobility group box 1 in intestinal mucosal barrier injury in rat with sepsis induced by endotoxin

To investigate the role and mechanism of the high mobility group box 1 (HMGB1) in intestinal mucosal barrier injury in rat with sepsis induced by endotoxin lipopolysaccharide (LPS). The rats were given intraperitoneal injection of LPS to reproduce a model of sepsis. The effect of HMGB1 inhibitor EP solution (40 mg/kg) on sepsis was observed, and phosphate buffer (PBS) control group was set up. Seventy-two hours after modeling, abdominal aortic blood was obtained, and enzyme-linked immunosorbent assay (ELISA) was used to measure the plasma levels of D-lactic acid and diamine oxidase (DAO) of mucosal barrier permeability. The pathological changes of the intestinal mucosal were observed with light microscope and the Chiu score was recorded. The intestinal mucosal ultrastructural changes were observed with electron microscopy. Real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and Western Blot were used to measure the mRNA and protein expressions of Occludin, inflammatory factor HMGB1 and its downstream signal molecule nuclear transcription factor-κB p65 (NF-κB p65) in the rat small intestine. The results of histopathology and ultrastructure of the small intestine showed that in the LPS group, the intestinal mucosa tissue swelled obviously, part of the glands were incomplete, the infiltration of neutrophils increased, themicrovillus cells were absent, arranged indisorder, and the number of tight connections significantly reduced compared with the PBS control group. The levels of D-lactic acid and DAO indicating mucosal barrier permeability, the levels of inflammatory factor HMGB1 and its downstream signaling molecule NF-κB p65 mRNA and protein expressions in the LPS group were significantly higher than those in the PBS control group, and the mRNA and protein expression of Occludin in the small intestine was significantly lower than that in the PBS control group, suggesting that the intestinal mucosal barrier function in septic rats was damaged, permeability increased, and the structure was damaged. After the administration of the HMGB1 inhibitor EP, the intestinal mucosal barrier damage was significantly improved. The performance was as follows: the Chiu score of the small intestine tissue and the plasma D-lactic acid and DAO levels in the EP intervene group were significantly lower than those in the LPS group [Chiu score: 1.60±0.48 vs. 3.40±0.48, D-lactic acid (mmol/L): 3.30±0.22 vs. 5.30±0.16, DAO (U/L): 23.66±0.97 vs. 30.47±1.11, all P < 0.05]. Occludin mRNA and protein expression levels were significantly higher than those in the LPS group [Occludin mRNA (2-ΔΔCt): 0.82±0.05 vs. 0.37±0.08, Occludin protein (Occludin/β-actin): 1.04±0.09 vs. 0.75±0.11, both P < 0.05], while the mRNA and protein expression levels of HMGB1 and NF-κB p65 were significantly lower than those in the LPS group [HMGB1 mRNA (2-ΔΔCt): 1.63±0.10 vs. 3.57±0.10, HMGB1 protein (HMGB1/β-actin): 1.40±0.07 vs. 1.87±0.07; NF-κB p65 mRNA (2-ΔΔCt): 1.47±0.09 vs. 2.62±0.13, NF-ΚB p65 protein (NF-κB p65/β-actin): 1.24±0.14 vs. 1.60±0.13, all P < 0.05]. Intestinal mucosal barrier function of septic rats was damaged, permeability increased, and structure was damaged. The mechanism may be that the expression of inflammatory factor HMGB1 was up-regulated and promoted the activation of its downstream signaling molecule NF-κB, thereby mediated the inflammatory cascade reaction and caused damage to the intestinal mucosa.

Levels of Catecholamines in the Plasma of Patients with Cardiopulmonary Arrest.

So far, there remains a controversy regarding the efficacy of epinephrine (Ep) in patients with cardiopulmonary arrest (CPA). In this study, we evaluated the importance of the plasma levels of catecholamines prior to the administration of Ep in patients with CPA. Patients with out-of-hospital cardiac arrest (OHCA) who were transferred to Gunma University Hospital were enrolled prospectively between July 2014 and July 2017. The levels of catecholamines [Ep, norepinephrine (NEp), and dopamine] and vasopressin (antidiuretic hormone) in the plasma were measured using blood samples of cardiogenic patients with OHCA not treated with Ep. Patients were divided into two groups: the return of spontaneous circulation [ROSC (+) ] group and the no return of spontaneous circulation [ROSC (-) ] group. The plasma levels of these agents and the conditions of resuscitation were compared between these two groups. 48 patients with cardiogenic CPA had not been treated with Ep prior to obtaining the blood samples. The ROSC (+) and ROSC (-) groups included 14 and 34 patients, respectively. The frequency of prehospital defibrillation was significantly higher in the ROSC (+) group. However, the prehospital resuscitation time was significantly shorter in the ROSC (+) group. Moreover, the levels of Ep and NEp in the plasma were significantly lower in the ROSC (+) group. The increased levels of Ep in the plasma may not be associated with the acquisition of ROSC in patients with cardiogenic CPA.

Abstract 124: Levels of Catecholamines in the Plasma of Patients With Cardiopulmonary Arrest

Purpose: The efficacy of epinephrine (Ep) administration to patients with cardiopulmonary arrest (CPA) remains controversial, and correlation between plasma levels of catecholamines and prognosis in CPA patients is unclear. The purpose of this study is to evaluate the importance of the plasma levels of catecholamines at the time of admission to the hospital prior to the administration of Ep in CPA patients. Methods: This was a prospective, observational clinical study, approved by the ethics committee of Gunma University Hospital. Patients with CPA transferred to our hospital were enrolled prospectively between July 2014 and July 2017. The levels of catecholamines (Ep, norepinephrine [NEp], and dopamine [DOA]) and vasopressin (antidiuretic hormone [ADH]) in the plasma were measured using blood samples obtained at the time of admission to our hospital (prior to the administration of Ep). Patients were divided into two groups: the return of spontaneous circulation (ROSC)(+) group and the ROSC(-) group. The levels of these agents in the plasma and the conditions of resuscitation were compared between these two groups. Results: Blood samples were obtained from 170 patients. In 48 patients, the cause of CPA was cardiogenic and Ep was not administered prior to admission to the hospital. The ROSC(+) and ROSC(-) groups included 14 and 34 patients, respectively. The frequency of prehospital defibrillation was significantly higher in the ROSC(+) group, whereas prehospital resuscitation time was significantly shorter in the ROSC(+) group. Moreover, the levels of Ep and NEp in the plasma were significantly lower in the ROSC(+) group. Conclusions: Increased levels of Ep in the plasma may not be associated with the acquisition of ROSC in patients with cardiogenic CPA.

HMGB1 promotes neurovascular remodeling via Rage in the late phase of subarachnoid hemorrhage

High-mobility group box1 (HMGB1) is a nuclear protein widely expressed in the central nervous system. Extracellular HMGB1 serves as a proinflammatory cytokine and contributes to brain injury during the acute stage post-stroke. Recently, increasing evidence has demonstrated beneficial effects of HMGB1 in some types of brain injury, but little is known about its effects during the late phase of subarachnoid hemorrhage (SAH). This study was designed to explore the potential roles and mechanisms of HMGB1 and its receptor, receptor for advanced glycation end-products (Rage), on brain recovery in the late stage of experimental SAH. Two inhibitors of HMGB1, ethyl pyruvate and glycyrrhizin (EP and GA), and Rage antagonist FPS-ZM1 were used to determine whether HMGB1 promotes brain recovery after SAH. The administration of EP, GA, and FPS-ZM1 effectively reduced HMGB1 and Rage expression. Correspondingly, protein levels of beneficial growth factors (NGF, BDNF, and VEGF) and numbers of BrdU and DCX positive neurons in the cortex were also decreased. The biphasic roles of HMGB1 may be based on the different redox modifications of cysteine residues. In this research, rats injected with two different redox status HMGB1 showed different prognosises at 7–14day after SAH. Recombinant HMGB1 can promote cytokine stimulating activity and aggravate brain injury. However, oxidized HMGB1 was unable to stimulate TNF production but can promote brain recovery by promoting neurotrophin expression. In conclusion, our investigation identified that HMGB1 promotes neurovascular recovery via Rage and may act in the oxidized state in the late stage of SAH.

Ethyl pyruvate protects against sepsis by regulating energy metabolism.

BackgroundEthyl pyruvate (EP) is a derivative of pyruvic acid that has been demonstrated to be a potential scavenger of reactive oxygen species as well as an anti-inflammatory agent. In this study, we investigated the protective effects of EP and its role in regulating the energy metabolism in the livers of cecal-ligation-and-puncture-induced septic mice.MethodsThe animals were treated intraperitoneally with 0.2 mL of Ringer’s lactate solution or an equivalent volume of Ringer’s lactate solution containing EP immediately after cecal ligation and puncture. Each mouse in the Sham group was only subjected to a laparotomy. At 30-, 60-, 180-, and 360-minute time points, we measured the histopathological alterations of the intestines, and the plasma levels of interleukin (IL)-1β, IL-6, IL-10, and tumor necrosis factor-α, and the total antioxidative capacity, malondialdehyde content, and lactate and lactate/pyruvate levels in livers. Furthermore, we detected the levels of adenosine triphosphate, total adenylate, and energy charge in the livers.ResultsOur results demonstrated that the administration of EP significantly improved the survival rate and reduced intestinal histological alterations. EP inhibited the plasma levels of IL-1β, IL-6, and tumor necrosis factor-α and increased the IL-10 level. EP significantly inhibited the elevation of the malondialdehyde, lactate, and lactate/pyruvate levels and enhanced the total antioxidative capacity levels in the liver tissues. The downregulation of the adenosine triphosphate, total adenylate, and energy charge levels in the liver tissues was reversed in the septic mice treated with EP.ConclusionThe results suggest that EP administration effectively modulates the energy metabolism, which may be an important component in treatment of sepsis.

EP 80317, a selective CD36 ligand, shows cardioprotective effects against post-ischaemic myocardial damage in mice

The CD36 receptor plays an important role in facilitating fatty acid transport to the heart. The present study aimed to assess whether EP 80317, a selective synthetic peptide ligand of CD36, is cardioprotective in a murine model of myocardial ischaemia and reperfusion (MI/R) injury. Mice were pretreated with daily subcutaneous injections of EP 80317 for 14 days before being subjected to a 30 min ligation of the left anterior descending coronary artery. The treatment reduced the infarct area and improved myocardial haemodynamics and function, as shown by an increase in cardiac output, ejection fraction and stroke work, and a reduced total peripheral resistance. In contrast, administration of EP 51389, a tripeptide analogue devoid of binding affinity to CD36, did not protect against myocardial injury. Six hours after myocardial reperfusion, EP 80317-treated mice showed reduced myocardial fatty acid uptake, as assessed by micro-positron emission tomography, in agreement with reduced levels of circulating non-esterified fatty acids. Studies using [(14)C]-palmitate infusion revealed reduced lipolysis, although no significant change in insulin or catecholamine plasma levels were observed. Increased expression levels of adipogenic and anti-lipolytic genes further supported an effect of EP 80317 in preventing fatty acid mobilization from adipose tissue. No effect of the treatment was observed in CD36(-/-) mice. Our results show that pretreatment with EP 80317 protected the heart against damage and dysfunction elicited by MI/R, along with a transient reduction in peripheral lipolysis. Our findings support CD36 as a novel target for the treatment of ischaemic cardiopathy.

Improvement of cognitive function in Alzheimer’s disease model mice by genetic and pharmacological inhibition of the EP4 receptor

Amyloid-β peptide (Aβ), which is generated by the β- and γ-secretase-mediated proteolysis of β-amyloid precursor protein (APP), plays an important role in the pathogenesis of Alzheimer's disease (AD). We recently reported that prostaglandin E(2) (PGE(2) ) stimulates the production of Aβ through both EP(2) and EP(4) receptors and that activation of the EP(4) receptor stimulates Aβ production through endocytosis and activation of γ-secretase. We here found that transgenic mice expressing mutant APP (APP23) mice showed a greater or lesser apparent cognitive deficit when they were crossed with mice lacking EP(2) or EP(4) receptors, respectively. Mice lacking the EP(4) receptor also displayed lower levels of Aβ plaque deposition and less neuronal and synaptic loss than control mice. Oral administration of a specific EP(4) receptor antagonist, AE3-208 to APP23 mice, improved their cognitive performance, as well as decreasing brain levels of Aβ and suppressing endocytosis and activation of γ-secretase. Taken together, these results suggest that inhibition of the EP(4) receptor improves the cognitive function of APP23 mice by suppressing Aβ production and reducing neuronal and synaptic loss. We therefore propose that EP(4) receptor antagonists, such as AE3-208, could be therapeutically beneficial for the prevention and treatment of AD.

Effects of a novel selective agonist for prostaglandin receptor subtype EP4 on hyperalgesia and inflammation in monoarthritic model.

Cytokines have crucial role in the development and maintenance of inflammation and pain in arthritis. Activation of prostaglandin receptor subtype EP(4) suppresses cytokine production in immune cells. The purpose of this study was to evaluate whether a novel EP(4) agonist would be able to suppress thermal and mechanical hyperalgesia and paw swelling in acute and chronic phases in rat monoarthritic model. Monoarthritis was induced by an injection of complete Freund's adjuvant (CFA) intracapsularly into the tibiotarsal joint of the rats. Withdrawal latencies to thermal stimulation on the hind paw, withdrawal thresholds to mechanical stimulation, paw volume, and ankle diameter were measured 24 h and 4 weeks after the CFA injection. A novel selective EP(4) receptor agonist, ONO-AE1-329 (10, 25, or 50 microg) or saline was administered intracapsularly into the joint. Withdrawal latencies and withdrawal thresholds were significantly (P < 0.05) shortened and decreased, respectively, on the arthritic side but not on the contralateral side 24 h and 4 weeks after the CFA injection. In addition, significant (P < 0.05) increases in paw volume and ankle diameter on the arthritic side were observed. Intracapsularly administered ONO-AE1-329 showed significant (P < 0.05) inhibition of thermal and mechanical hyperalgesia and significant (P < 0.05) decrease in paw volume and ankle diameter in a dose-dependent manner at 24 h and 4 weeks after CFA. Intracapsular administration of EP(4) receptor agonist effectively inhibited mechanical and thermal hyperalgesia and inflammatory reactions in acute and chronic monoarthritis. An EP(4) agonist would be a potential strategy for inflammatory pain in arthritis.

Growth hormone-independent cardioprotective effects of hexarelin in the rat.

We previously reported that induction of selective GH deficiency in the rat exacerbates cardiac dysfunction induced by experimental ischemia and reperfusion performed on the explanted heart. In the same model, short-term treatment with hexarelin, a GH-releasing peptide, reverted this effect, as did GH. To ascertain whether hexarelin had non-GH-mediated protective effects on the heart, we compared hexarelin and GH treatment in hypophysectomized rats. Hexarelin (80 microg/kg sc), given for 7 days, prevented exacerbation of the ischemia-reperfusion damage induced by hypophysectomy. We also demonstrate that hexarelin prevents increases in left ventricular end diastolic pressure, coronary perfusion pressure, reactivity of the coronary vasculature to angiotensin II, and release of creatine kinase in the heart perfusate. Moreover, hexarelin prevents the fall in prostacyclin release and enhances recovery of contractility. Treatment with GH (400 microg/kg sc) produced similar results, whereas administration of EP 51389 (80 microg/kg sc), another GH-releasing peptide that does not bind to the heart, was ineffective. In conclusion, we demonstrate that hexarelin prevents cardiac damage after ischemia-reperfusion, and that its action is not mediated by GH but likely occurs through activation of specific cardiac receptors.

Growth Hormone-Independent Cardioprotective Effects of Hexarelin in the Rat

We previously reported that induction of selective GH deficiency in the rat exacerbates cardiac dysfunction induced by experimental ischemia and reperfusion performed on the explanted heart. In the same model, short-term treatment with hexarelin, a GH-releasing peptide, reverted this effect, as did GH. To ascertain whether hexarelin had non-GH-mediated protective effects on the heart, we compared hexarelin and GH treatment in hypophysectomized rats. Hexarelin (80 μg/kg sc), given for 7 days, prevented exacerbation of the ischemia-reperfusion damage induced by hypophysectomy. We also demonstrate that hexarelin prevents increases in left ventricular end diastolic pressure, coronary perfusion pressure, reactivity of the coronary vasculature to angiotensin II, and release of creatine kinase in the heart perfusate. Moreover, hexarelin prevents the fall in prostacyclin release and enhances recovery of contractility. Treatment with GH (400 μg/kg sc) produced similar results, whereas administration of EP 51389 (80μ g/kg sc), another GH-releasing peptide that does not bind to the heart, was ineffective. In conclusion, we demonstrate that hexarelin prevents cardiac damage after ischemia-reperfusion, and that its action is not mediated by GH but likely occurs through activation of specific cardiac receptors.

Prostaglandin E receptor EP 3 subtype is involved in thermal hyperalgesia through its actions in the preoptic hypothalamus and the diagonal band of Broca in rats

The effects of microinjection of prostaglandin E 2 (PGE 2) (0.5 fg–500 pg/0.2 μl) into the medial part of the preoptic area (MPO) on nociception were studied using a hot-plate test in rats. The intraMPO microinjection of PGE 2 only at non-pyrogenic doses (5–50 fg) reduced the paw-withdrawal latency, suggesting hyperalgesia. Maximal reduction was obtained 15 min after the injection of PGE 2 at 50 fg. Subsequently, to determine which types of prostanoid receptors are involved in the hyperalgesic effect of PGE 2 in the MPO, we administered PGE 2 receptor agonists, i.e., 17-phenyl- ω-trinor PGE 2 (an EP 1 receptor agonist), butaprost (an EP 2 receptor agonist) and M&B28767 (an EP 3 receptor agonist) into the MPO and observed the nociceptive behavior. The intraMPO injection of M&B28767 (0.005 fg–50 pg), like that of PGE 2, exhibited a U-shaped dose response characteristic, i.e., a significant decrease of the paw-withdrawal latency only at 0.05–5 fg with the maximal response at 0.5 fg. However, neither the administration of EP 1 (0.5 fg–50 ng) nor EP 2 (0.5 fg–500 pg) agonists had any effect on nociception. The microinjection of M&B28767 at 0.5 fg into the other parts of preoptic hypothalamus (the lateral part of the preoptic area and the median preoptic nucleus) and the diagonal band of Broca (DBB) produced hyperalgesia similar to the intraMPO-induced hyperalgesia in terms of magnitude and time course. Microinjection of M&B28767 (0.5 fg) into either the paraventricular nucleus, the ventromedial hypothalamus, the lateral hypothalamic area or the septal nucleus had no effect on nociception. These findings suggest that PGE 2 at non-pyrogenic doses in the brain induces hyperalgesia, at least in part, through its actions on EP 3 receptors in the preoptic hypothalamus and the DBB in rats.

Role of polyol pathway in nonenzymatic glycation

In order to confirm the link between nonenzymatic glycation and the polyol pathway, we observed the effect of treatment with epalrestat (Ep), an aldose reductase inhibitor, on the concentration of advanced glycation end-products (AGEs) in erythrocytes from diabetic patients. We also examined the effect of the drug on erythrocyte fructose 3-phosphate (F3P), a novel metabolite that has been reported to relate to the polyol pathway, and ascertained the glycation capability of F3P and its possible breakdown product, 3-deoxyglucosone (3DG), by incubating the metabolites with bovine serum albumin (BSA). Incubation of BSA with F3P or 3DG resulted in a greater production of AGEs in comparison with the incubation with glucose or fructose. F3P was significantly increased in erythrocytes from diabetic patients compared with those from nondiabetic individuals and was lower in patients who had been treated with Ep than in those who were free from the compound. A treatment of patients with Ep for 1 month resulted in a significant decrease in F3P. Erythrocyte AGEs were significantly elevated in diabetic patients compared with nondiabetic individuals and tended to be lower in patients taking Ep than in those without Ep. Administration of Ep for 2 months decreased AGEs. These results show that the polyol pathway is likely to play a substantial role in the nonenzymatic glycation of proteins and the suppression of E3P as well as AGEs by an aldose reductase inhibitor may explain in part the preventive effect of the drug on diabetic complications.

Toxic effects of cholelitholytic solvents on gallbladder and liver. A piglet model study.

We evaluated the toxic effects of four currently used chemolytic solvents--dimethyl sulfoxide (DMSO, 99%), ethyl propionate (EP, 99%), tetrasodium ethyl-dimethyl tetraacetate (4Na-EDTA, 2%, pH 11), and methyl tert-butyl ether (MTBE, purity = 99.5%) in an animal model. Each solvent was tested in nine farm piglets (Landrace), weighing between 20 and 25 kg. A solvent-resistant catheter was inserted transhepatically into the gallbladder (GB) using sonographic guidance 24 hr prior to each experiment. Seventy-five milliliters of each solvent was infused over 3 hr into the gallbladder. The following day, a laparotomy was performed in order to assess for possible damage to the liver, GB, bile ducts (BD), or intestines. The GB and liver were resected and their histology examined. The following pathologic grades were assigned to GB, BD, and liver specimens to describe the tissue damage: normal (0), mild (1), moderate (2), and severe (3). We found that DMSO had the highest score on gallbladder and bile duct injury (49, 3), followed by EP (36, 2), EDTA (14, 1) and MTBE (16, 0), respectively; the difference in gallbladder damage was statistically significant. Very mild hepatocyte damage was present in the DMSO (2) and MTBE (2) groups. The administration of EP and EDTA resulted in no liver injury at all. Piglets within each treatment group suffered from varying degrees of tissue injury. No deaths were attributed to the administered solvents. We concluded that DMSO, EP, EDTA, and MTBE do not have serious local toxic effect on the GB, BD, and intestine; nor do they lead to severe hepatotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Sequencing and schedule effects of cisplatin plus etoposide in small-cell lung cancer: results of a North Central Cancer Treatment Group randomized clinical trial.

The combination of etoposide (E) and cisplatin (P) is an accepted standard therapy for small-cell lung cancer (SCLC); however, the optimal sequencing and administration schedule has not been defined. This study was designed to evaluate different sequencing and administration schedules of E and P in the treatment of SCLC. Five hundred fifty-two eligible patients with limited-(LD) and extensive-stage (ED) SCLC were randomized to receive one of the following regimens: arm A, P 30 mg/m2 by intravenous (IV) bolus followed by E 130 mg/m2 bolus; arm B, E 130 mg/m2 bolus followed by P 30 mg/m2 bolus; arm C, E 130 mg/m2 by 24-hour infusion and P 30 mg/m2 bolus at the end of each 24-hour infusion of E; arm D, E 130 mg/m2 by 24-hour infusion and P 45 mg/m2 by 24-hour infusion on day 2 and 3 only. Two 3-day induction cycles of IV EP were administered 4 weeks apart. Subsequent therapy was the same for all arms, consisting of four cycles of cyclophosphamide, doxorubicin, and vincristine (CAV) at 4-week intervals. Consolidative thoracic radiation therapy (TRT) and prophylactic cranial irradiation (PCI) were administered to responders. The overall response rate (84%) was similar in all treatment arms. Treatment arm A was associated with the best complete response (CR) rate (52%), the most favorable median survival time (MST) of 15 months, and a 26% 2-year survival rate. Patients with LD on arm A had a MST of 20 months and a 42% 2-year survival rate. Multivariate analysis indicated that extent of disease, performance status, arm of therapy, and sex were significant independent factors influencing survival. Toxicity of the four regimens was similar, except for greater thrombocytopenia on arm D. The bolus administration of EP with E following P for the first two cycles of chemotherapy was the most effective regimen, with especially encouraging survival for LD patients.

Erythropoietin Does Not Cross the Placenta into the Fetus

Erythropoiesis in the fetus is controlled by erythropoietin (Ep). To determine the role of maternal Ep in this process, we used catheterized preparations of sheep and monkey fetuses to assess the ability of Ep administered to the mother to cross the placental barrier into the fetus. Ep was injected into pregnant sheep (3,600 IU/sheep) or monkeys (800-2,000 IU/animal) as a single intravenous dose, or into sheep in intravenous doses of 2,000 IU once every 12 h for a total of 4 injections. Maternal and fetal blood samples for Ep and reticulocyte determinations were obtained before and at intervals after Ep injections. The administration of Ep resulted in significant increases in maternal circulating Ep levels in sheep and monkeys. Despite the presence of high levels of maternal Ep, however, no increase in fetal plasma Ep levels was detected. The administration of Ep to the mother caused significant increases in reticulocyte production in the mother but not the fetus; injection of Ep directly to the fetus stimulated fetal erythropoiesis. These results demonstrate that Ep does not cross the placenta into the fetus even under conditions of chronically elevated maternal Ep levels, and suggest that red cell production in the fetus is regulated by Ep produced from sites within the fetus.

Beta-endorphin inhibits hypoglycemia-induced gene expression of corticotropin-releasing factor in the rat hypothalamus.

Endogenous opioid peptides have a role in the regulation of the hypothalamic-pituitary-adrenal axis. Recently, beta-endorphin (EP) has been thought to inhibit CRF release in vivo and in vitro. In the present study we examined the effects of central administration of EP on ACTH secretion and gene expression of both CRF in the hypothalamus and POMC in the anterior pituitary gland (AP) during basal and insulin-induced hypoglycemia in pentobarbital-anesthetized rats. Administration of EP in the lateral ventricle decreased basal CRF levels in the median eminence and inhibited basal and hypoglycemia-induced ACTH secretion in a dose-dependent manner. Hypoglycemia-induced POMC mRNA levels in the AP and CRF mRNA levels in the hypothalamus were also dose-dependently inhibited by the administration of EP. The inhibitory effect of EP was reversed by naloxone. These results suggest that 1) central administration of EP acts through the opioid receptor to inhibit hypoglycemia-induced CRF gene expression in the hypothalamus and CRF release, which results in a decrease in ACTH secretion and POMC mRNA levels in the AP; and 2) the active site of EP is the CRF neuron in the paraventricular nucleus.

Effect of Cu(2+)-ascorbic acid on lipid peroxidation, Mg(2+)-ATPase activity and spectrin of RBC membrane and reversal by erythropoietin.

The effect of erythropoietin (Ep), a glycoprotein hormone, has been studied on lipid peroxidation induced by Cu2+ and ascorbate in vitro, Mg2+ ATPase activity and spectrin of RBC membrane. Our present investigation reveals that Cu2+ and ascorbic acid increases lipid peroxidation of RBC membrane significantly. It has further been observed that under the same experimental condition spectrin, a major cytoskeleton membrane protein, and Mg(2+)-ATPase activity of RBC membrane decrease significantly. However, exogenous administration of Ep completely restores lipid peroxidation and Mg(2+)-ATPase activity and partially recovers spectrin of RBC membrane.

Effects of burst-promoting activity and erythropoietin from human urine on erythroid burst forming units in human peripheral blood.

Erythropoietin (Ep) was isolated from the urine of patients with aplastic anemia [Yanagawa et al, J. Biol. Chem., 259, 2707 (1984)] and burst-promoting activity (BPA) was extensively purified from the residue obtained after removal of Ep. These erythropoietic factors were studied for their effcects on erythroid burst-colony formation of human peripheral blood mononuclear cells in methylcellulose cultures. Reddish bursts were formed with the addition of Ep alone. Addition of BPA not only elevated the number of bursts but also greatly reduced the amount of Ep required for burst formation. The presence of BPA alone in cultures did not permit bursts to form but did permit the growth of small colonies that did not contain hemoglobin (Hb). Addition of Ep to these small colonies led to the formation of erythroid bursts. Administration of Ep to the cultures could be delayed for 6 days without decreasing the number of bursts if the cultures were initiated in the presence of BPA; in the absence of BPA, the erythroid precursors (BUF-E) were rapidly lost if Ep was not provided at the start of the cultures. BPA produced larger bursts than those formed in the presence of Ep alone. Microassays of Hb in the bursts indicated that BPA increased the amonut of Hb per burst. This increase could not be entirely explained by the augumentation in cell number per burst but was partly ascribable to the increased amount of Hb per cell.