Antidepressant-like effect of centrally acting non-narcotic antitussive caramiphen in a forced swimming test

Recently, we reported that a centrally acting non-narcotic antitussive (cough suppressant drug), tipepidine produces an antidepressant-like effect in the forced swimming test in rats. Because pharmacological properties of tipepidine apparently differ from those of typical antidepressants developed to date, we speculated that caramiphen, another centrally acting antitussive, has an antidepressant-like effect. That effect of caramiphen was studied in rats using the forced swimming test. Caramiphen at 20 and 40 mg/kg i.p. significantly reduced immobility. At 40 mg/kg i.p., it increased climbing behavior. Even at 40 mg/kg, this drug had no effect on locomotor activity. Results suggest that a centrally acting antitussive possessing inhibition of GIRK channels has an antidepressant-like effect.     

Hemodynamic and neuroendocrine adaptations of the preterm lamb left ventricle to acutely increased afterload

The birth process is associated with dramatic alterations of left ventricular (LV) volume loading, pressure loading, and contractile state. The preterm LV has considerable volume loading reserve. We have assessed neuroendocrine and related hemodynamic responses of the preterm lamb LV at 0.8 gestation during acute pressure loading within the first 2-4 h after birth. We measured plasma catecholamines and hemodynamic and cineangiocardiographic parameters of LV pump performance and contractility at basal levels and during rapid LV pressure loading by partial balloon obstruction of the ascending aorta before and after propranolol. A relatively high level of propranolol (3 mg/kg) was required to produce beta-adrenoceptor blockade associated with reduction of heart rate and blood pressure, but after atrial pacing there was no detectable difference of basal LV pump performance or contractility at comparable heart rate, preload, and afterload. The LV pump performance was maintained and plasma catecholamines and LV contractility were increased when aortic systolic pressure was augmented 60% over baseline. The increased contractile state at greater afterload was minimally blunted by propranolol. Thus the preterm LV is relatively hypercontractile soon after birth and is capable of an integrated augmentation of pump performance and contractile state during pressure loading. These findings are relevant to the maintenance of adequate LV performance and successful adaptation to the acute alterations of afterload associated with the transitional circulation at birth.     

Dose response of thyrotropin-releasing hormone on pulmonary maturation in corticosteroid-treated preterm rabbits

The dose-response effect of thyrotropin-releasing hormone in enhancing pulmonary maturation was investigated with six dosing regimens. Pregnant does received thyrotropin-releasing hormone (5, 10, or 50 micrograms/kg every 12 hours for four doses or one dose of 20 micrograms/kg) in conjunction with betamethasone beginning on day 25 of gestation, with betamethasone alone or saline solution used as comparison treatment groups. Half of the newborn rabbits received supplemental surfactant therapy after delivery on day 27, and all were ventilated on a ventilator plethysmography system for 30 minutes. There were no differences among the four thyrotropin-releasing hormone doses in surfactant pool sizes, compliances, or proteins leak into or out of the air spaces. The groups that received multiple doses of thyrotropin-releasing hormone had significantly higher perinatal loss rates than the single-dose group. The lungs of the group treated with thyrotropin-releasing hormone plus steroid and the rabbits treated only with steroid were more compliant than the controls without surfactant therapy, and showed significant improvements in protein leak. The addition of thyrotropin-releasing hormone to betamethasone improved several of the protein leak measurements compared with use of betamethasone alone. These results question the necessity of multiple doses of thyrotropin-releasing hormone to induce pulmonary maturation, especially when the higher perinatal mortality and the theoretical long-term effects of fetal hyperthyroidism on thyroid axis function are considered.     

Comparison of four surfactants: in vitro surface properties and responses of preterm lambs to treatment at birth

Natural sheep surfactant, rabbit surfactant, human surfactant, and surfactant TA were compared for in vitro surface properties and for responses of preterm lambs to treatment. Equivalent amounts of sheep, rabbit, and human surfactants were needed to lower the surface tension to less than 10 dynes/cm, whereas four times less surfactant TA similarly lowered the surface tension. Surface-spreading rates were similar for the surfactants. The surface adsorption of the batch of human surfactant tested was much slower than was adsorption of the other surfactants. Ventilation was significantly improved in all surfactant-treated lambs relative to the control lambs, indicating the general efficacy of the surfactant treatments. Overall, surfactant TA had the best in vitro characteristics, yet the preterm lambs treated at birth with surfactant TA had lower PO2 values and higher ventilatory requirements than did the sheep surfactant-treated lambs. The in vivo responses to rabbit surfactant were intermediate between the responses to sheep surfactant and to surfactant TA. Human surfactant resulted in the least effective clinical response. More of the phosphatidylcholine associated with human surfactant and surfactant TA was lost from the alveoli and lung tissue after four hours of ventilation than was lost from sheep or rabbit surfactant-treated lambs. More intravascular radiolabeled albumin leaked into the alveoli of the surfactant TA-treated lambs than sheep or rabbit surfactant-treated lambs. The four surfactants also had different sensitivities to the effects on minimum surface tensions of the soluble proteins present in alveolar washes. The study demonstrates that the range of clinical responses was not predictable based on the in vitro surface properties that we measured.(ABSTRACT TRUNCATED AT 250 WORDS)     

Estimating an EQ-5D population value set: the case of Japan

Quality adjustment weights for quality-adjusted life years (QALYs) are available with the EQ-5D Instrument, which are based on a survey that quantified the preferences of the British public. However, the extent to which this British value set is applicable to other, especially non-European, countries is yet unclear. The objectives of this study are (a) to compare the valuations obtained in Japan and Britain, and (b) to explore a local Japanese value set. A diminished study design is employed, where 17 hypothetical EQ-5D health states are evaluated as opposed to 42 in the British study. The official Japanese version of the instrument and the Time Trade-Off method are used to interview 543 members of the public. The results are: firstly, the evaluations obtained in Japan and those from Britain differ by 0.24 on average on a [-1, +1] scale, and mean absolute error (MAE) in predicting the Japanese preferences with the British value set is 0.23. Secondly, comparable regressions suggest that the two peoples have systematically different preference structures (p<0.001 for 8 of 12 coefficients; F-test). Thirdly, using alternative models, the predictions are improved so that the local Japanese value set achieves MAE in the order of 0.01.     

Transgenic expression of the protein-L-isoaspartyl methyltransferase (PIMT) gene in the brain rescues mice from the fatal epilepsy of PIMT deficiency

Protein-L-isoaspartyl methyltransfearase (PIMT) plays a physiological role in the repair of damaged proteins containing isoaspartyl residues. In previous studies, we showed that PIMT-deficient mice developed a fatal epileptic seizure associated with the accumulation of damaged proteins in the brain. The mutant mice also showed a neurodegenerative pathology in hippocampi and impaired spatial memory. Still undefined, however, is how the accumulation of isoaspartates leads to the death of PIMT-deficient mice. In the present study, we generated PIMT transgenic (Tg) mice to investigate whether the exogenous expression of PIMT could improve the symptoms associated with PIMT deficiency. Rescue experiments showed that Tg expression of PIMT driven by a prion promoter effectively cured the PIMT-deficient mice. Biochemically, a higher expression level of transgene led to the effective repair of damaged proteins in vivo. Although a lower level of expression caused an accumulation of damaged proteins in a partially rescued line, the mice survived. Interestingly, synapsin I, which was extensively modified posttranslationally in PIMT-deficient mice, was specifically repaired in a partially rescued, but symptom-improved, Tg line. Our results suggest that an overall accumulation of damaged proteins does not necessarily lead to a fatal epileptic seizure, whereas certain modifications, such as changes in synapsin I, may play a pivotal pathological role in epilepsy.     

Effective weekly paclitaxel administration for gastric cancer with malignant ascites--a case report

We report a case in which weekly paclitaxel (TXL) administration was effective for gastric cancer with malignant ascites. TXL (80 mg/m2) was infused over 1 hour after short premedication on an outpatient basis. Administration was continued for 3 weeks followed by 1 week rest. The patient was a 49-year-old woman who suffered from non-resectable gastric cancer, staged intraoperatively as having severe lymph node metastasis and malignant ascites. As an outpatient treatment, she was first treated with 5-fluorouracil combined with high-dose Leucovorin for 4 cycles. However, she complained of abdominal fullness and ascites, and received weekly TXL administration as the second line treatment. The ascites had completely disappeared 3 months after administration. The toxic events were anemia (grade 1) and alopecia (grade 2). No major adverse effects such as hypersensitivity reaction, leukopenia or peripheral neuropathy were observed.     

Decreased taurine concentration in skeletal muscles after exercise for various durations

PURPOSE: To examine the changes of taurine concentrations in blood and skeletal muscles after transient exercise. METHODS: Rats were placed on a treadmill set at 25 m.min-1. The animals were divided into four groups: control (no exercise) and exercise groups 1, 2, and 3. The exercise duration for groups 1, 2, and 3 was 30, 60, and 100 +/- 12.5 min (to exhaustion: mean +/- SD), respectively. We examined the plasma concentrations of taurine and lactate, the serum concentrations of sodium and chloride ions, as well as the skeletal muscle taurine content in the soleus (slow-twitch fiber dominant type), gastrocnemius (slow- and fast-twitch fiber mix type), and plantaris and extensor digitorum longus (fast-twitch fiber dominant type) muscles. RESULTS: Although the plasma taurine concentration was not affected by the increased exercise duration, that in skeletal muscles was significantly decreased. The gastrocnemius and plantaris muscles from the exercise group 3 had a significantly lower concentration of taurine than those of the control group. The extensor digitorum longus taurine concentration from the different exercise groups was significantly decreased compared with that from the control group. However, there was no significant difference among the exercise groups. CONCLUSION: Taurine concentration was decreased in all skeletal muscles after exercise, regardless of the duration. Moreover, this decrease was specific to fast-twitch dominant fibers. However, under these conditions, the plasma taurine concentration remained unchanged.     

Memory and learning-enhancing effect of Daikenchuto, a traditional Japanese herbal medicine, in mice

The effect of Daikenchuto (DKT), a traditional Japanese herbal medicine (Kampo medicine), and its constituents (ginger rhizome, ginseng root, rice gluten and Zanthoxylum fruit) on the memory formation process was examined in mice by means of a Morris water maze test. The administration of DKT [300–4000 mg/kg, administered orally (p.o.)] for 3 consecutive days dose-dependently shortened the time required by the mice to find the platform in the water maze test relative to the control. Among the four constituents of DKT, the extract of Zanthoxylum fruit (70 mg/kg, the dose equivalent to 4000 mg/kg DKT) administered p.o. for 3 consecutive days significantly promoted the memory and learning rate. The memory- and learning-enhancing effect was potently elicited by 5 mg/kg (p.o., 2 days) hydroxy-sanshool, the active component of the ethyl acetate fraction of Zanthoxylum fruit. In another series of experiments with the water maze test, the administration of scopolamine [1 mg/kg, intraperitoneally (i.p.)] for 3 consecutive days significantly prolonged the time needed by the mice to find the platform. The subsequent administration of DKT (4000 mg/kg, p.o.) for 3 consecutive days possessed an abatement effect on the scopolamine-induced dementia. The present results indicate that DKT and, more specifically, its constituent Zanthoxylum fruit and the active component of Zanthoxylum fruit, hydroxy-sanshool, all have a memory- and learning-enhancing effect and are probably associated with the release of acetylcholine from neuronal terminals in the brain.     

Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea.

The therapeutic efficacy of irinotecan (CPT-11), a DNA topoisomerase inhibitor, is often limited by the induction of severe late-onset diarrhea. This prodrug and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have a labile alpha-hydroxy-lactone ring that undergoes pH-dependent reversible hydrolysis. At physiological pH and higher, equilibrium favors the less toxic carboxylate form, whereas at acidic pH, the more potent lactone form is favored. We have reported previously that the initial uptake rate of CPT-11 and SN-38 by intestinal cells was significantly different between the respective lactone and carboxylate form. Results from the present study in HT-29 cells further demonstrate the correlation between the CPT-11/SN-38 initial uptake rate and the induced toxicity, cell cycle alteration, apoptosis, and colony-forming efficiency. The exposure of HT-29 cells to SN-38 for a limited period of time (<2 h) was sufficient to induce these events. Because the decreased initial uptake of SN-38 carboxylate resulted in a reduced cellular toxicity, we postulated that the CPT-11-induced diarrhea was preventable by influencing the equilibrium toward the carboxylate form and, thus, reducing its intestinal uptake. In the golden Syrian hamster model, p.o. sodium bicarbonate supplementation (5 mg/ml in drinking water) led to alkalization of the intestinal contents. In addition, this alkalization resulted in the reduction of the histopathological damage to the mucosa of the small and large intestine, as well as a 20% reduction of the intestinal SN-38 lactone concentration of animals receiving CPT-11 (20-50 mg/kg x 7 days). Taken together, these results from in vitro and in vivo studies support intestinal alkalization by sodium bicarbonate supplementation as a preventive mechanism against CPT-11-induced diarrhea. In addition, this provides a strong rationale for the usage of this measure as an adjunct to CPT-11 treatment.