Effect of phenylephrine on histamine-induced bronchoconstriction in dogs

Purpose Although an α-adrenoceptor has been suggested to be involved in the mechanism of asthma, the effect of α₁-agonist on the airway is still unclear. In this study we evaluated the effect of phenylephrine on the airway with a direct visualization method using a superfine fiberoptic bronchoscope (SFB). Methods Seven mongrel dogs were anesthetized with pentobarbital (30 mg·kg⁻¹ IV) and paralyzed by pancuronium (0.2mg·kg⁻¹·h⁻¹). The trachea was intubated with an endotracheal tube (ID 7 mm) that has a second lumen for insertion of a SFB (OD 2.2 mm) to monitor the bronchial cross-sectional area (BCA) continuously. The tip of a SFB was placed at the level between the second and third bronchial bifurcation. To assess hemodynamics, the direct arterial blood pressure (ABP) and pulmonary arterial pressure (PAP) were monitored via a femoral arterial catheter and Swan-Granz catheter. Bronchoconstriction was elicited by histamine (10 μg·kg⁻¹+ 500 μg·kg⁻¹·h⁻¹_. At 30 min after the histamine was started, saline or phenylephrine (1, 10, and 100μg·kg⁻¹) was given intravenously. The BCA and hemodynamic variables were assessed before (basal) and 30 min after the histamine was started and 5 min after saline and each phenylephrine dose. Results Histamine reduced BCA by 40.3±6.3%. Phenylephrine at 10 and 100 μg·kg⁻¹ significantly increased the ABP and PAP; and it significantly decreased the BCA, by 6.5±6.9% and 14.2±7.9%, respectively. Plasma epinephrine and norepinephrine were also significantly reduced following phenylephrine 100 μg·kg⁻¹ IV. Conclusion The dose of phenylephrine that produced vasopressive actions worsened the histamine-induced bronchoconstriction slightly but significantly. Therefore, phenylephrine should be used with caution in asthmatic patients.     

Significant differences of brain blood flow in patients with chronic low back pain and acute low back pain detected by brain SPECT

Background

The aim of this study was to examine and compare the areas of brain blood flow in patients with chronic low back pain (CLBP) without structural abnormality and acute low back pain (ALBP) with lumber disc herniation (LDH). Functional neuroimaging studies provide evidence of abnormalities in the regional cerebral blood flow during low back pain. Recent studies have shown that CLBP is associated with plastic, pathophysiological changes in the brain. However, there has been no report yet statistically or by neuro-images on the compared brain single photon-emission computed tomography (SPECT) findings between CLBP and ALBP patients.

Methods

The subjects comprised 14 patients, 7 CLBP and 7 ALBP patients. The CLBP group included the patients who had no or minor structural abnormality in the lumbar spine on magnetic resonance imaging (MRI) and met the criteria for a classification of “pain disorder” (chronic) according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. The ALBP group included the patients who had symptoms within 3 months of onset and LDH revealed by MRI. All patients were assessed using brain SPECT. We then performed a two-tailed view analysis using the easy Z score imaging system, determined the mean Z scores, and performed vBSEE software (Fujifilm RI Pharma, Tokyo, Japan) for both CLBP and ALBP patients.

Results

The CLBP group showed significantly reduced blood flow in the bilateral prefrontal cortex of the frontal lobe and increased blood flow in the bilateral posterior lobe of the cerebellum.

Conclusions

SPECT images and statistical analyses revealed the brain blood flow alterations in the patients with ALBP and CLBP. These results may suggest that the dysfunction of the prefrontal cortex could lead to the appearance of unconscious pain behavior controlled by the cerebellum in the patients with CLBP.     

Involvement of thromboxane A2 (TXA2) in the early stages of oleic acid-induced lung injury and the preventive effect of ozagrel, a TXA2 synthase inhibitor, in guinea-pigs

An intravenous injection of oleic acid into animals can produce a lung injury with hypoxaemia and pulmonary vascular hyper-permeability. Although oleic acid lung injury is used as a model of acute respiratory distress syndrome (ARDS), the precise mechanisms of the lung injury are still unclear. We have investigated whether thromboxane A(2) (TXA(2)) participated in the lung injury and have evaluated the efficacy of ozagrel, a TXA(2) synthase inhibitor, on the lung injury in guinea-pigs. Oleic acid injection increased the plasma level of TXB(2), a stable metabolite of TXA(2), and the time-course of plasma TXB(2) was similar to that of the decreased partial oxygen pressure of arterial blood (Pao(2)) induced with oleic acid. Ozagrel administered intravenously 30 min before oleic acid injection prevented the decrease in Pao(2) and pulmonary vascular hyper-permeability. It also prevented increases in lactate dehydrogenase activity, a measure of lung cell injury, TXB(2 )and its weight ratio to 6-keto prostaglandin F(1alpha) in bronchoalveolar lavage fluid. Although ozagrel administered simultaneously with oleic acid ameliorated the decrease in Pao(2), post treatment showed little effect. We suggest that TXA(2) participated in the oleic acid lung injury, as an "early phase" mediator, and rapidly-acting TXA(2) synthase inhibitors were effective in the prevention of acute lung injury.     

Current state of training for simulated patients and standardized patients and problem-based learning/tutorial education in pharmacy education at National University Corporation

Simulated/standardized patient-based (SP) education and problem-based learning (PBL) tutorial education become a powerful tool to heighten the pharmacy students' will to learn in order to cultivate the responsibility to contribute to public health and welfare as a clinical professional and to facilitate students' competences to solve problems by themselves. What this program is trying to do is: 1) to establish the system to train, educate and supply SP who are effective in the training and education of pharmacy students in close cooperation with the medical schools and their affiliated hospitals; 2) to improve the quality of the current PBL tutorial education and thereby establish it as an advanced education program in the education of senior students. We carried out the questionnaire to National University Corporation which establishes a school of pharmacy, as to the training and education of SP. The analysis of the answers to the questionnaire revealed the present status of SP in the Pharmaceutical Objective Structured Clinical Examination (OSCE) in the Pharmaceutical Common Achievement Test, and the existence of the problems on how to standardize SP as well as how to cover such expenses. Furthermore, the activity of the first year consisted of the exchange and sharing of information regarding the existing method of training and education of SP and PBL tutorial education and the identification of the problems to be solved in order to improve the quality of the educational program.     

A CASE OF NONTRAUMATIC CLOSTRIDIAL GAS GANGRENE OCCURRING IN A PATIENT WITH COLON ADENOCARCINOMA, LIVER CIRRHOSIS, AND DIABETES MELLITUS

An autopsy case of clostridial gas gangrene occurring in a 54-year-old man with colon adenocarcinoma, liver cirrhosis, and diabetes mellitus is reported. The patient died 4 days after the onset of symptoms with episodes of vomiting and abdominal pain. Gangrene of both hips and perineum, hemolysis, renal failure, and disseminated intravascular coagulation were the dominant clinical features. Clostridium septicum was isolated from the subcutaneous tissue fluid. Adenocarcinoma of the ascending colon with ulceration found at autopsy was supposed to be an entry of the organism. Histologically, lesions of subcutaneous tissue and muscles were characterized by the absence of inflammatory infiltrates in spite of extensive necrosis. A summary of 35 cases of gas gangrene hospitalized to the Osaka University Hospital for the past 16 years indicates that clostridial gas gangrene patients with underlying diseases such as malignant neoplasm, diabetes, liver cirrhosis or immunodeficiency have a relatively poor prognosis.     

Factors affecting membrane-controlled drug release for an osmotic pump tablet (OPT) utilizing (SBE)(7m)-beta-CD as both a solubilizer and osmotic agent.

Purpose: The purpose of this study was to define membrane controlling factors responsible for drug release from a controlled-porosity osmotic pump tablet (OPT) that utilizes a sulfobutyl ether-β-cyclodextrin, (SBE)_7m-β-CD, as both a solubilizing and osmotic agent. Method: The OPT was spray coated with cellulose acetate solutions varying the amount and size of micronized lactose, the amount of triethyl citrate (TEC) and the composition ratio of dichlormethane to ethanol. Chlorpromazine (CLP) was used as a model drug. The release of CLP from the OPTs was studied using the Japanese Pharmacopoeia dissolution method. The membrane surface area of the OPTs were measured with multi-point analysis by the gas absorption method. Results: The release rate of CLP from OPTs containing (SBE)_7m-β-CD increased with increasing amounts of micronized lactose and decreasing amounts of TEC and lactose particle size in the membrane. Also, the CLP release rates from the spray-coated OPTs using mixtures of varying ratios of dichlormethane to ethanol were almost identical. The membrane surface area of the OPTs following release of membrane components had a linear relationship to CLP release rates from the OPTs. Conclusion: The present results confirmed that the membrane controlling factors responsible for the drug release were the amount and size of micronized lactose and the amount of TEC in the membrane.     

Influence of genetic variants of opioid-related genes on opioid-induced adverse effects in patients with lung cancer: A STROBE-compliant observational study

Despite the dramatic advancement of cancer chemotherapy and immunotherapy, the insufficient progress has been made in basic or translational research on personalization of opioid therapy. Predicting the effectiveness of opioid analgesic therapy and the risk of adverse effects prior to therapy are expected to enable safer and more appropriate opioid therapy for cancer patients. In this study, we compared the incidence of opioid-induced adverse effects between patients with different variants of the genes related to responsiveness to opioid analgesics.Participants were 88 patients with lung cancer who provided general consent for exome sequencing and were treated with morphine or oxycodone at Shizuoka Cancer Center Hospital between April 2014 and August 2018. Incidence rates for 6 adverse effects of opioid therapy (somnolence, nausea, constipation, delirium, urinary retention, and pruritus) were determined and the influence of single nucleotide polymorphisms in coding regions of the opioid μ receptor 1 (OPRM1) (rs1799971), opioid δ receptor 1 (rs2234918), opioid κ receptor 1 (rs1051660), catechol-O-methyltransferase (COMT) (rs4680), dopamine receptor D2 (rs6275), adenosine triphosphate binding cassette B1 (rs1045642), G-protein regulated inward rectifier potassium channel 2 (rs2070995), and fatty acid amide hydrolase (rs324420) genes on those adverse effects were analyzed.Analysis of OPRM1 gene variant status (Asn133Asp A > G) showed that G/G homozygotes were at significantly lower risk of somnolence compared with A allele carriers (0% vs 28.4%; Fisher exact test, P = .005; OR, 0; 95% CI, 0–0.6), and analysis of COMT gene variant status (Val158Met, G > A) showed that G/G homozygotes were at significantly higher risk of somnolence compared with A allele carriers (35.0% vs 10.4%; Fisher exact test, P = .008; OR, 4.5; 95% CI, 1.4–18.1). No relationship between variant status and adverse effects was found for the other genes.These findings demonstrate that OPRM1 and COMT gene variants influence the risk of somnolence as an adverse effect of opioid analgesic therapy.     

Oxidative stress in early stage of acute lung injury induced with oleic acid in guinea pigs

Changes in several biomarkers in bronchoalveolar lavage fluid (BALF) during an early stage of lung injury induced with oleic acid were examined in guinea pigs. In addition, a possible contribution of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and xanthine oxidase to the oxidative changes in the lung injury was investigated. An intravenous injection of oleic acid increased the levels of lipid peroxidation products, lactate dehydrogenase, and total proteins, decreased the ratio of glutathione to glutathione disulfide in the BALF, and also affected the levels of other oxidative biomarkers such as superoxide dismutase and catalase in the BALF in a dose-dependent manner. Diphenyleneiodonium chloride, a NADPH oxidase inhibitor, inhibited the oxidative changes in the BALF and the decrease in partial pressure of oxygen in artery induced with oleic acid, while allopurinol, a xanthine oxidase inhibitor, had no inhibitory effects. The results demonstrate that oxidative stress would be an important mechanism of oleic acid-induced lung injury, and indicate that the NADPH oxidase-dependent pathway contributes significantly to the generation of reactive oxygen species in oleic acid-induced lung injury.     

Protection afforded by a herbal medicine,Sho‐seiryu‐to (TJ‐19), against oleic acid‐induced acute lung injury in guinea‐pigs

Objectives The effect of a herbal medicine, Sho‐seiryu‐to (TJ‐19), on oleic acid‐induced lung injury, an animal model of acute respiratory distress syndrome or acute lung injury (ARDS/ALI), was examined. Methods Acute lung injury was induced by an intravenous injection of 15 μl/kg oleic acid to guinea‐pigs. TJ‐19 was administered by a single oral dose (3 g/kg) or by multiple oral doses (0.75 g/kg). Key findings The decrease in partial oxygen pressure of arterial blood (Pao₂) and the increase in airway vascular permeability induced by the oleic acid injection were attenuated by a single dose of TJ‐19. When TJ‐19 was administered orally twice a day for two weeks and then oleic acid was injected, a potent prophylactic effect of the drug was observed. TJ‐19 also prevented airway vascular hyperpermeability, lung cell injury, oxidative stress and thromboxane A₂ generation, associated with the oleic acid injection. Conclusions TJ‐19 significantly attenuated the oleic acid‐induced lung injury probably through the antioxidative effect and inhibitory effect of thromboxane A₂ generation, although the precise inhibitory mechanisms were not fully elucidated due to the diversity in constituents of the herbal medicine. We suggest that TJ‐19 is a promising drug candidate and a medicinal resource for preventing ARDS/ALI.