Synthetic smoke with acrolein but not HCl produces pulmonary edema

1988 ◽  
Vol 64 (3) ◽  
pp. 1121-1133 ◽  
Author(s):  
C. A. Hales ◽  
P. W. Barkin ◽  
W. Jung ◽  
E. Trautman ◽  
D. Lamborghini ◽  
...  
Keyword(s):  
Pulmonary Edema ◽  
Low Dose ◽  
Smoke Inhalation ◽  
High Dose ◽  
Lung Water ◽  
Thermodilution Technique ◽  
Carbon Particles ◽  
Delayed Onset ◽  
Dose Dependent Fashion ◽  
Dose Dependent

The chemical toxins in smoke and not the heat are responsible for the pulmonary edema of smoke inhalation. We developed a synthetic smoke composed of carbon particles (mean diameter of 4.3 microns) to which toxins known to be in smoke, such as HCl or acrolein, could be added one at a time. We delivered synthetic smoke to dogs for 10 min and monitored extravascular lung water (EVLW) accumulation thereafter with a double-indicator thermodilution technique. Final EVLW correlated highly with gravimetric values (r = 0.93, P less than 0.01). HCl in concentrations of 0.1-6 N when added to heated carbon (120 degrees C) and cooled to 39 degrees C produced airway damage but no pulmonary edema. Acrolein, in contrast, produced airway damage but also pulmonary edema, whereas capillary wedge pressures remained stable. Low-dose acrolein smoke (less than 200 ppm) produced edema in two of five animals with a 2- to 4-h delay. Intermediate-dose acrolein smoke (200-300 ppm) always produced edema at an average of 147 ± 57 min after smoke, whereas high-dose acrolein (greater than 300 ppm) produced edema at 65 ± 16 min after smoke. Thus acrolein but not HCl, when presented as a synthetic smoke, produced a delayed-onset, noncardiogenic, and peribronchiolar edema in a roughly dose-dependent fashion.

Smoke aldehyde component influences pulmonary edema

1992 ◽  
Vol 72 (2) ◽  
pp. 555-561 ◽  
Author(s):  
C. A. Hales ◽  
S. W. Musto ◽  
S. Janssens ◽  
W. Jung ◽  
D. A. Quinn ◽  
...  
Keyword(s):  
Pulmonary Edema ◽  
Weight Ratio ◽  
Dry Weight ◽  
Leukotriene B4 ◽  
Smoke Inhalation ◽  
High Dose ◽  
Lung Water ◽  
Protein Ratio ◽  
Arterial Blood ◽  
Lung Lymph

The pulmonary edema of smoke inhalation is caused by the toxins of smoke and not the heat. We investigated the potential of smoke consisting of carbon in combination with either acrolein or formaldehyde (both common components of smoke) to cause pulmonary edema in anesthetized sheep. Seven animals received acrolein smoke, seven animals received a low-dose formaldehyde smoke, and five animals received a high-dose formaldehyde smoke. Pulmonary arterial pressure, pulmonary capillary wedge pressure, and cardiac output were not affected by smoke in any group. Peak airway pressure increased after acrolein (14 +/- 1 to 21 +/- 2 mmHg; P less than 0.05) and after low- and high-dose formaldehyde (14 +/- 1 to 21 +/- 1 and 20 +/- 1 mmHg, respectively; both P less than 0.05). The partial pressure of O2 in arterial blood fell sharply after acrolein [219 +/- 29 to 86 +/- 9 (SE) Torr; P less than 0.05] but not after formaldehyde. Only acrolein resulted in a rise in lung lymph flow (6.5 +/- 2.2 to 17.9 +/- 2.6 ml/h; P less than 0.05). Lung lymph-to-plasma protein ratio was unchanged for all three groups, but clearance of lymph protein was increased after acrolein. After acrolein, the blood-free extravascular lung water-to-lung dry weight ratio was elevated (P less than 0.05) compared with both low- and high-dose formaldehyde groups (4.8 +/- 0.4 to 3.3 +/- 0.2 and 3.6 +/- 0.2, respectively). Lymph clearance (ng/h) of thromboxane B2, leukotriene B4, and the sulfidopeptide leukotrienes was elevated after acrolein but not formaldehyde.(ABSTRACT TRUNCATED AT 250 WORDS)

Enlargement of cerebrospinal fluid spaces in long-term benzodiazepine abusers

1987 ◽  
Vol 17 (4) ◽  
pp. 869-873 ◽  
Author(s):  
C. Schmauss ◽  
J.-C. Krieg
Keyword(s):  
Low Dose ◽  
Matched Control ◽  
Control Group ◽  
High Dose ◽  
Withdrawal Therapy ◽  
The Mean ◽  
Dose Dependent ◽  
Dose Dependent Effect ◽  
Age And Sex

SynopsisIn 17 benzodiazepine (BDZ) dependent in-patients a CT scan was performed before initiation of withdrawal therapy. The evaluation of the ventricular to brain ratio (VBR) by standardized and computerized measurements revealed significantly higher mean VBRs for both high-and low-dose BDZ-dependent patients compared to the mean VBR of an age- and sex-matched control group. In addition, the mean VBR of high-dose BDZ-dependent patients (N = 8) was significantly higher than the mean VBR of low-dose BDZ-dependent patients (N = 9). This difference could not be accounted for by the age of the patients or duration of BDZ-dependency and, therefore, suggests a dose-dependent effect of BDZs on the enlargement of internal CSF-spaces. On the other hand, higher values for the width of external CSF-spaces were found to be related to increasing age of the patients and duration of BDZ-dependency.

scholarly journals Major Depressive Disorder (MDD) and Antidepressant Medication Are Overrepresented in High-Dose Statin Treatment

2021 ◽  
Vol 8 ◽  
Author(s):  
Leutner Michael ◽  
Matzhold Caspar ◽  
Kautzky Alexander ◽  
Kaleta Michaela ◽  
Thurner Stefan ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Inpatient Care ◽  
Low Dose ◽  
Antidepressant Medication ◽  
Statin Treatment ◽  
High Dose ◽  
Major Depressive ◽  
Dependent Relationship ◽  
Different Types ◽  
Dose Dependent

Objective: To examine the dose-dependent relationship of different types of statins with the occurrence of major depressive disorder (MDD) and prescription of antidepressant medication.Methods: This cross-sectional study used medical claims data for the general Austrian population (n = 7,481,168) to identify all statin-treated patients. We analyzed all patients with MDD undergoing statin treatment and calculated the average defined daily dose for six different types of statins. In a sub-analysis conducted independently of inpatient care, we investigated all patients on antidepressant medication (statin-treated patients: n = 98,913; non-statin-treated patients: n = 789,683). Multivariate logistic regression analyses were conducted to calculate the risk of diagnosed MDD and prescription of antidepressant medication in patients treated with different types of statins and dosages compared to non-statin-treated patients.Results: In this study, there was an overrepresentation of MDD in statin-treated patients when compared to non-statin-treated patients (OR: 1.22, 95% CI: 1.20–1.25). However, there was a dose dependent relationship between statins and diagnosis of MDD. Compared to controls, the ORs of MDD were lower for low-dose statin-treated patients (simvastatin>0– < =10 mg:OR: 0.59, 95% CI: 0.54–0.64; atorvastatin>0– < =10 mg:OR:0.65, 95%CI: 0.59–0.70; rosuvastatin>0– < =10 mg:OR: 0.68, 95% CI: 0.53–0.85). In higher statin dosages there was an overrepresentation of MDD (simvastatin>40– < =60 mg:OR: 2.42, 95% CI: 2.18–2.70, >60–80 mg:OR: 5.27, 95% CI: 4.21–6.60; atorvastatin>40– < =60 mg:OR: 2.71, 95% CI: 1.98–3.72, >60– < =80 mg:OR: 3.73, 95% CI: 2.22–6.28; rosuvastatin>20– < =40 mg:OR: 2.09, 95% CI: 1.31–3.34). The results were confirmed in a sex-specific analysis and in a cohort of patients taking antidepressants, prescribed independently of inpatient care.Conclusions: This study shows that it is important to carefully re-investigate the relationship between statins and MDD. High-dose statin treatment was related to an overrepresentation, low-dose statin treatment to an underrepresentation of MDD.

Calcitriol Exerts Prophylactic Anti-Mycobacterium Effect In A Dose-Dependent Manner

2021 ◽  
Author(s):  
Jianguo Li ◽  
Zhen Li ◽  
Zefeng Gao ◽  
Juan Xia ◽  
Jia Cui ◽  
...  
Keyword(s):  
Vitamin D ◽  
1H Nmr ◽  
Low Dose ◽  
Bacterial Load ◽  
High Dose ◽  
Dependent Manner ◽  
Prophylactic Effect ◽  
Moderate Dose ◽  
Metabolism Pathway ◽  
Dose Dependent

Abstract Vitamin D was empirically applied for Tuberculosis (TB) treatment in the past, and is currently used as an adjuvant for TB therapy. Although an increasing pile of evidences suggests that vitamin D has no therapeutic effect against TB infection, the prophylactic effect of vitamin D in preventing TB remains largely undetermined. To experimentally valuate the potential prophylactic effect of calcitriol (the active form of vitamin D) against mycobacterium infection, we performed dose-gradient calcitriol soaking in 30-day-old zebrafish before Mycobacterium marinum (M. marinum) challenge through tail vein injection. 1H-NMR metabolomics analysis was further performed for illustration of potential mechanisms underlying the prophylactic effect of calcitriol against M. marinum. The results suggested that calcitriol exerts dose-dependent prophylactic anti-mycobacterium effects, i.e., the bacterial load and the corresponding inflammatory factors (IL-1β, TNF-α, and IFN-γ) expressions in M. marinum challenged zebrafish were reduced by low-dose (25 µg/L) or high-dose (2500 µg/L) calcitriol soaking, rather than by moderate-dose (250 µg/L) calcitriol soaking. Body weight of the M. marinum challenged zebrafish was recovered by high-dose prophylactic calcitriol soaking rather than by low-dose or moderate-dose calcitriol. The 1H-NMR metabolomic profiling identified 29 metabolites with altered abundance among the dose-gradient calcitriol groups, among which 22 metabolites were co-varied with the dose of calcitriol, the rest 7 metabolites were co-varied with the bacterial load and the inflammatory response in term of cytokine expression. Further pathway analysis indicated that the glycine, serine, and threonine metabolism pathway was the activated in both of the two metabolite groups, indicating that the pathway was altered by dose-gradient of calcitriol and was in response to M. marinum infection in zebrafish. The results of the present study suggested that the activation of glycine, serine and threonine metabolism pathway may play a potential role for the dose-dependent anti-mycobacterium effect induced by prophylactic calcitriol soaking.

scholarly journals Dose-dependent roles of aspirin and other non-steroidal anti-inflammatory drugs in abnormal bone remodeling and skeletal regeneration

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yong Xie ◽  
Meng Pan ◽  
Yanpan Gao ◽  
Licheng Zhang ◽  
Wei Ge ◽  
...  
Keyword(s):  
Bone Formation ◽  
Bone Remodeling ◽  
Low Dose ◽  
High Dose ◽  
Dose Aspirin ◽  
Low Dose Aspirin ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
Dose Dependent ◽  
High Dose Aspirin

AbstractThe failure of remodeling process that constantly regenerates effete, aged bone is highly associated with bone nonunion and degenerative bone diseases. Numerous studies have demonstrated that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) activate cytokines and mediators on osteoclasts, osteoblasts and their constituent progenitor cells located around the remodeling area. These cells contribute to a complex metabolic scenario, resulting in degradative or synthetic functions for bone mineral tissues. The spatiotemporal effects of aspirin and NSAIDs in the bone remodeling are controversial according the specific therapeutic doses used for different clinical conditions. Herein, we review in vitro, in vivo, and clinical studies on the dose-dependent roles of aspirin and NSAIDs in bone remodeling. Our results show that low-dose aspirin (< 100 μg/mL), which is widely recommended for prevention of thrombosis, is very likely to be benefit for maintaining bone mass and qualities by activation of osteoblastic bone formation and inhibition of osteoclast activities via cyclooxygenase-independent manner. While, the roles of high-dose aspirin (150–300 μg/mL) and other NSAIDs in bone self-regeneration and fracture-healing process are difficult to elucidate owing to their dual effects on osteoclast activity and bone formation of osteoblast. In conclusion, this study highlighted the potential clinical applications of low-dose aspirin in abnormal bone remodeling as well as the risks of high-dose aspirin and other NSAIDs for relieving pain and anti-inflammation in fractures and orthopedic operations.

Effects of acetylsalicylic acid on pulmonary vascular tone and membrane permeability in blood-perfused dog lung

1993 ◽  
Vol 75 (6) ◽  
pp. 2561-2569 ◽  
Author(s):  
K. Kambara ◽  
M. Arakawa ◽  
T. Segawa ◽  
F. Ando ◽  
M. Ohno ◽  
...  
Keyword(s):  
Acetylsalicylic Acid ◽  
Extravascular Lung Water ◽  
Vascular Tone ◽  
Low Dose ◽  
Pressor Response ◽  
Plasma Concentrations ◽  
High Dose ◽  
Constant Flow ◽  
Lung Water ◽  
Pulmonary Vasoconstriction

We studied the effects of acetylsalicylic acid (ASA) on pressor response, microvascular filtration coefficient (Kf), extravascular lung water, and plasma concentrations of cyclooxygenase- and 5-lipoxygenase-derived products in 21 blood-perfused dog lungs with constant flow. The lungs were perfused for 1 h with an intrapulmonary injection of saline as vehicle (n = 5), a low dose of ASA [136 +/- 25 (SD) micrograms/ml perfusate; n = 5], a high dose of ASA (1,006 +/- 278 micrograms/ml perfusate; n = 6), or alloxan (1,000 mg; n = 5). Alloxan significantly increased Kf and extravascular lung water, whereas neither the low nor high dose of ASA increased Kf or extravascular lung water. The ASA-induced increase in vascular resistance did not correlate with the extent of the decrease in perfusate 6-keto-prostaglandin F1 alpha or the ratio of perfusate 6-ketoprostaglandin F1 alpha to thromboxane B2. Moreover, ASA did not enhance the generation of perfusate leukotrienes B4, D4, or E4. We conclude that pulmonary microvascular permeability is unaltered by ASA and that neither the decrease in plasma prostacyclin nor the increase in plasma sulfidopeptide leukotrienes may account for ASA-induced pulmonary vasoconstriction.

scholarly journals Intravenous administration of sodium propionate induces antidepressant or prodepressant effect in a dose dependent manner

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Chunyan Hao ◽  
Zefeng Gao ◽  
XianJun Liu ◽  
Zhijiang Rong ◽  
Jingjing Jia ◽  
...  
Keyword(s):  
Body Weight ◽  
Low Dose ◽  
Antidepressant Effect ◽  
High Dose ◽  
Mild Stress ◽  
Dependent Manner ◽  
Reward Seeking ◽  
Metabolomic Profiling ◽  
Hydroxyanthranilic Acid ◽  
Dose Dependent

AbstractPropionate has been reported to exert antidepressant effects, but high-dose propionate may induce autism-like symptoms in experimental animals through induction of dysbiosis of neurotransmitters. The bi-directional effects of propionate seem to be dose-dependent. However, due to the pathological discrepancies between depression and autism, conclusions drawn from autism may not be simply transferable to depression. The effect and underlying action mechanisms of high-dose propionate on depression remains undetermined. To investigate the effects of propionate on depression, propionate dose gradients were intravenously administrated to rats exposed to chronic unpredictable mild stress (CUMS) for 1 week. Results of these behavioral tests demonstrate that low-dose propionate (2 mg/kg body weight/day) induces antidepressant effect through bodyweight recovery, elevated reward-seeking behaviors, and reduced depression-like behaviors, while high-dose propionate (200 mg/kg body weight/day) induces prodepressant effects opposite of those of low-dose propionate. A comprehensive profiling of neurotransmitters in the hippocampus demonstrated that CUMS induces reduction of NE (Norepinephrine), DA (Dopamine). GABA (γ-aminobutyric acid) was recovered by low-dose propionate, while high-dose propionate exerted more complicated effects on neurotransmitters, including reduction of NE, DA, 5-Hydroxytryptamine and Tryptophan, and increase of GABA, Kynurenine, Homovanillic acid, 3-hydroxyanthranilic acid, 3-hydroxykynurenine, 3,4-dihydroxyphenylacetic acid, and 3-methoxytyramine. The neurotransmitters disturbed by high-dose propionate suggest metabolic disorders in the hippocampus, which were confirmed by the clear group separation in PCA of metabolomic profiling. The results of this study demonstrate the double-edged dose-dependent effects of propionate on depression and suggest potential cumulative toxicity of propionate as a food additive to mood disorders.

scholarly journals Ketamine Inhibits Lung Fluid Clearance through Reducing Alveolar Sodium Transport

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Yong Cui ◽  
Hongguang Nie ◽  
Hong Ma ◽  
Lei Chen ◽  
Lin Zhang ◽  
...  
Keyword(s):  
Pulmonary Edema ◽  
Clinical Evidence ◽  
Ex Vivo ◽  
A549 Cells ◽  
Intratracheal Instillation ◽  
Lung Fluid ◽  
Whole Cell Patch Clamp ◽  
Dose Dependent Fashion ◽  
Dose Dependent ◽  
Lung Lobes

Ketamine is a broadly used anaesthetic for analgosedation. Accumulating clinical evidence shows that ketamine causes pulmonary edema with unknown mechanisms. We measured the effects of ketamine on alveolar fluid clearance in human lung lobesex vivo. Our results showed that intratracheal instillation of ketamine markedly decreased the reabsorption of 5% bovine serum albumin instillate. In the presence of amiloride (a specific ENaC blocker), fluid resolution was not further decreased, suggesting that ketamine could decrease amiloride-sensitive fraction of AFC associated with ENaC. Moreover, we measured the regulation of amiloride-sensitive currents by ketamine in A549 cells using whole-cell patch clamp mode. Our results suggested that ketamine decreased amiloride-sensitive Na+currents (ENaC activity) in a dose-dependent fashion. These data demonstrate that reduction in lung ENaC activity and lung fluid clearance following administration of ketamine may be the crucial step of the pathogenesis of resultant pulmonary edema.

Phase Ib dose-escalation study of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, administered by intravenous (IV) infusions in patients with metastatic colorectal carcinoma (mCRC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3608-3608 ◽  
Author(s):  
Jeeyun Lee ◽  
Young Suk Park ◽  
James Burke ◽  
Ho Yeong Lim ◽  
Jihye Lee ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Dose Escalation ◽  
Low Dose ◽  
High Dose ◽  
Pharmacokinetic Studies ◽  
Systemic Delivery ◽  
Dose Escalation Study ◽  
Gm Csf ◽  
Anti Tumor Activity ◽  
Dose Dependent

3608^ Background: Pexa-Vec is an EGFR-targeted vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating direct oncolysis, tumor vascular disruption and anti-tumor immunity (Nat Rev Cancer 2009). Dose-dependent IV Pexa-Vec delivery was defined previously (Nature2011). This study was designed to assess the safety, maximal tolerated dose and anti-tumor activity of Pexa-Vec administered IV in patients with mCRC after failure of standard therapies. Methods: Nine patients were treated at 1 of 3 dose levels (106, 107 or 3x107pfu/kg IV every 2 weeks x 4) in a standard 3+3 dose-escalation design; 6 additional patients were enrolled at the MFD. Anti-tumor activity according to RECIST was determined using serial CT scans. Pharmacokinetic studies were also performed. Data summarized prior to database lock. Results: 15 patients with mCRC refractory to irinotecan, oxaliplatin, and 5-FU were treated (median lines of therapy 5; range 2-7); 13 of 15 received prior anti-angiogenic agents, and 11 of 12 KRAS WT tumors failed cetuximab. Adverse events were generally grade 1/2 and included: fever (93%), chills (93%), headache (60%), nausea (60%), and hypotension (40%). No dose-limiting toxicities or grade 3/4 events were reported. Only patients treated at high-dose (Cohort 3 & Expansion) exhibited a pustular rash (n=9; 78%). Pexa-Vec genomes detected in blood acutely were above the dose threshold for systemic delivery. Notably, clearance was not more rapid with repeated IV treatments despite the induction of humoral immunity. Furthermore, patients at the top dose level exhibited increased disease stabilization at Week 4 (89% high-dose (n= 9) versus 33% low-dose (n=6)). A trend (p=0.16) towards increased overall survival at high vs low-dose Pexa-Vec was observed with 78% high-dose patients still alive between 5 and 13 mos. Conclusions: Repeat IV Pexa-Vec was well-tolerated with transient flu-like symptoms. Dose-dependent safety, pharmacokinetics and anti-tumor activity were described in treatment-refractory mCRC patients. Clinical trial information: NCT01380600.

scholarly journals Efficacy and Safety of Daikenchuto for Constipation and Dose-Dependent Differences in Clinical Effects

2018 ◽  
Vol 2018 ◽  
pp. 1-7
Author(s):  
Tatsuya Hirose ◽  
Yasutaka Shinoda ◽  
Ayaka Kuroda ◽  
Aya Yoshida ◽  
Machiko Mitsuoka ◽  
...  
Keyword(s):  
Dose Group ◽  
Low Dose ◽  
Clinical Laboratory ◽  
Laboratory Data ◽  
High Dose ◽  
Clinical Effects ◽  
Efficacy And Safety ◽  
Watery Stool ◽  
Group 4 ◽  
Dose Dependent

Background. Daikenchuto (DKT) is a Kampo medicine used for the treatment of constipation. In this study, we evaluated the effectiveness of DKT against constipation. Patients and Methods. Thirty-three patients administered DKT for constipation were selected and divided into low-dose (7.5 g DKT; n=22) and high-dose (15 g DKT; n=11) groups. We retrospectively evaluated weekly defaecation frequency, side effects, and clinical laboratory data. Results. Median defaecation frequencies after DKT administration (5, 5.5, 5, and 8 for the first, second, third, and fourth weeks, resp.) were significantly higher than that before DKT administration (2) in all 33 cases (P<0.01). One case (3%) of watery stool, one case of loose stools (3%), and no cases of abdominal pain (0%) were observed. Median defaecation frequencies in the high-dose group (7 and 9) were significantly higher than those in the low-dose group (4 and 3) in the first (P=0.0133) and second (P=0.0101) weeks, respectively. There was no significant change in clinical laboratory values. Conclusion. We suggest that DKT increases defaecation frequency and is safe for treating constipation.

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