Beijing ambient particle exposure accelerates atherosclerosis in ApoE knockout mice

Background

Air pollution is associated with significant adverse health effects including increased cardiovascular morbidity and mortality. However research on the cardiovascular effect of “real-world” exposure to ambient particulate matter (PM) in susceptible animal model is very limited. In this study, we aimed to investigate the association between Beijing ambient particle exposure and the atherosclerosis development in the apolipoprotein E knockout mice (ApoE^−/− mice).

Methods

Two parallel exposure chambers were used for whole body exposure among ApoE knockout mice. One of the chambers was supplied with untreated ambient air (PM group) and the other chamber was treated with ambient air filtered by high-efficiency particulate air (HEPA) filter (FA group). Twenty mice were divided into two groups and exposed to ambient PM (n = 10 for PM group) or filtered air (n = 10 for FA group) for two months from January 18th to March 18th, 2010. During the exposure, the mass concentrations of PM_2.5 and PM₁₀ in the two chambers were continuously monitored. Additionally, a receptor source apportionment model of chemical mass balance using 19 organic tracers was applied to determine the contributions of sources on the PM_2.5 in terms of natural gas, diesel vehicle, gasoline vehicle, coal burning, vegetable debris, biomass burning and cooking. At the end of the two-month exposure, biomarkers of oxidative stress, inflammation and lipid metabolism in bronchoalveolar lavage fluid (BAL) and blood samples were determined and the plaque area on the aortic endothelium was quantified.

Results

In the experiment, the concentrations of PM₁₀ and PM_2.5 in PM chamber were 99.45 μg/m³ and 61.0 μg/m³ respectively, while PM_2.5 in FA chamber was 17.6 μg/m³. Source apportionment analysis by organic tracers showed that gasoline vehicle (39.9%) and coal burning (24.3%) emission were the two major sources contributing to the mass concentration of PM_2.5 in Beijing. Among the ApoE knockout mice, the PM group were significantly higher than the FA group in terms of serum total cholesterol, low-density lipoprotein, tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein as well as TNF-alpha and interleukin-6 in BAL. Also the total antioxidant capacity and oxidized low-density lipoprotein were significantly different between the two groups. In addition, pathological analysis of aortic arch reveals that the plaques area in the PM group increased significantly compared to the FA group.

Conclusions

Our results demonstrated that ambient PM exposure could induce considerable oxidative stress and systemic inflammation in ApoE knockout mice and contribute to the progression of atherosclerosis.     

Absence of adverse effect on thyroid function and red blood cells in a population of workers exposed to cobalt compounds

Context

Hypothyroidism has been observed in the fifties and sixties as an undesirable side-effect of cobalt therapy used for its erythropoietic properties in the treatment of anemia.

Objective

This study aims at evaluating the possible impact of both cumulative (long-term) and recent occupational exposure to cobalt on thyroid function and red blood cells.

Methods and setting

A cross-sectional survey was conducted from February 2008 to August 2009 in a population of 249 male workers from a cobalt production department in the North of Belgium. The possible effect of cobalt exposure on thyroid and red blood cells was investigated through multiple regression analyses.

Results

Blood cobalt ranged from undetectable to 3.20 μg/100 ml (median 0.10); urinary cobalt from 0.30 to 204.30 μg/g_creat (median 3.90) and long-term exposure to cobalt ranged from 0.15 to 6990.46 μg/g_creat·years (median 106.09). No effect of cobalt exposure on thyroid or red blood cell parameters was observed at these levels of exposure.

Conclusion

The results support the absence of effects on the thyroid and red blood cells when occupational exposure to cobalt is kept below the recommended biological limit of occupational exposure (15 μg Co/g_creat in urine).     

Co-exposure to lead increases the renal response to low levels of cadmium in metallurgy workers

Purpose

Research on the effect of co-exposure to Cd and Pb on the kidney is scarce. The objective of the present study was to assess the effect of co-exposure to these metals on biomarkers of early renal effect.

Methods

Cd in blood (Cd-B), Cd in urine (Cd-U), Pb in blood (Pb-B) and urinary renal biomarkers, i.e., microalbumin (μ-Alb), beta-2-microglobulin (β₂-MG), retinol binding protein (RBP), N-acetyl-β-d-glucosaminidase (NAG), intestinal alkaline phosphatase (IAP) were measured in 122 metallurgic refinery workers examined in a cross-sectional survey.

Results and conclusions

The median Cd-B, Cd-U, Pb-B were: 0.8 μg/l (IQR = 0.5, 1.2), 0.5 μg/g creatinine (IQR = 0.3, 0.8) and 158.5 μg/l (IQR = 111.0, 219.3), respectively. The impact of Cd-B on the urinary excretion of NAG and IAP was only evident among workers with Pb-B concentrations ≥75th percentile. The association between Cd-U and the renal markers NAG and RBP was also evidenced when Pb-B ≥75th percentile. No statistically significant interaction terms were observed for the associations between Cd-B or Cd-U and the other renal markers under study (i.e., μ-Alb and β2-MG). Our findings indicate that Pb increases the impact of Cd exposure on early renal biomarkers.     

Manganese in plasma: A promising biomarker of exposure to Mn in welders. A pilot study

Background

There is raising concern about the potential neurotoxic effects of manganese (Mn) inhalation exposure in welders. Because most of the airborne particles in welding fume are in the respirable fraction, their bioavailability is likely to be higher than for coarser dust exposure. No well-validated biomarker for Mn exposure is available.

Objectives

To investigate the interest of measuring Mn in plasma (Mn-P) and urine (Mn-U) as biomarkers of exposure in a group of 28 welders whose tasks were only welding-related.

Methods

Ambient air exposure to Mn (Mn-air) was determined by personal full-shift measurements on Monday and Tuesday. On the same days, blood and urine samples were collected before and after the shift.

Results

Mn-air varied from 1.3 to 729 μg/m³ (GM 27.7). For Mn-U 65% of the values in welders were below the LOQ (0.20 μg/L). Compared to controls, the welders’ Mn-P averaged 33% higher (1.5 vs 2.0 μg/L). In welders, the after-shift Mn-P values correlated well with Mn-air above 10 μg/m³. In spite of similar Mn-air exposure on Monday and Tuesday, the relationships between Mn-air and after-shift Mn-P strikingly differed on Tuesday in that the inflection in the relationship was less obvious and the slope of the regression line (Mn-P after-shift/log Mn-air) for a doubling of log Mn-air was 2.3 times lower than on Monday. On Monday (the first day of the workweek), a Mn-P value of 2 μg/L could distinguish Mn-air exposure above or below 20 μg/m³ with a sensitivity of 69% and a specificity of 82%.

Conclusions

This preliminary study indicates that Mn-P is a promising biomarker of current exposure to Mn in welders and lends biological plausibility to the intended change for the Mn TLV-TWA of 20 μg/m³ proposed by ACGIH for respirable Mn particulate.     

Intravenous buprenorphine and norbuprenorphine pharmacokinetics in humans

Background

Prescribed sublingual (SL) buprenorphine is sometimes diverted for intravenous (IV) abuse, but no human pharmacokinetic data are available following high-dose IV buprenorphine.

Methods

Plasma was collected for 72 h after administration of placebo or 2, 4, 8, 12, or 16 mg IV buprenorphine in escalating order (single-blind, double-dummy) in 5 healthy male non-dependent opioid users. Buprenorphine and its primary active metabolite, norbuprenorphine, were quantified by liquid chromatography–tandem mass spectrometry with limits of quantitation of 0.1 μg/L.

Results

Maximum buprenorphine concentrations (mean ± SE) were detected 10 min after 2, 4, 8, 12, 16 mg IV: 19.3 ± 1.0, 44.5 ± 4.8, 85.2 ± 7.7, 124.6 ± 16.6, and 137.7 ± 18.8 μg/L, respectively. Maximum norbuprenorphine concentrations occurred 10–15 min (3.7 ± 0.7 μg/L) after 16 mg IV administration.

Conclusions

Buprenorphine concentrations increased in a significantly linear dose-dependent manner up to 12 mg IV buprenorphine. Thus, previously demonstrated pharmacodynamic ceiling effects (over 2–16 mg) are not due to pharmacokinetic adaptations within this range, although they may play a role at doses higher than 12 mg.     

Effects of water extracts of thyme (Thymus vulgaris) and ginger (Zingiber officinale Roscoe) on alcohol abuse

Introduction

Alcohol abuse has many harmful effects on human body. This study aimed to investigate the role of water extracts of thyme (Thymus vulgaris) and ginger (Zingiber officinale Roscoe) as natural product extracts to detoxify the injuries of alcohol abuse on liver and brain of mice.

Materials and methods

Alcohol at a dose of 1.25 ml/50 ml water was orally administered at the first day of treatment with continuously increase of 1.25 ml per day to the end of experiment (14 days, 0.1 ml/45 g /d). Mice also were orally administered with alcohol and water extracts of thyme and ginger in concentration of 500 mg /kg body weight for 2 weeks.

Results

The results showed very highly significant increase in nitric oxide and malondialdehyde level in liver and brain and a very highly significant decrease in the total antioxidant capacity and glutathione peroxidase activity in alcoholic group. In addition, the liver function enzymes such as l-γ-glutamyl transpeptidase and butyryl cholinesterase activities showed very highly significant increase in alcoholic group. In contrast, the water extracts of thyme and ginger showed significant amelioration on these changes both in liver and brain tissues.

Conclusion

The water extracts of thyme and ginger has detoxifying and antioxidant effects. Therefore, it is recommended to use them to avoid alcohol toxicity.     

Pharmacokinetics of obidoxime in patients poisoned with organophosphorus compounds

Objectives

Reactivation of inhibited acetylcholinesterase (AChE) with oximes is a causal therapy of intoxication with organophosphorus compounds (OPs). Maximal oxime effects are expected when effective doses are administered as soon as possible and as long as reactivation can be anticipated. An obidoxime plasma level in the range of 10–20 μM was estimated as appropriate. The achievement of this target was assessed in 34 severely OP-poisoned patients.

Methods

After admission to the intensive care unit (ICU) the obidoxime regimen (250 mg i.v. as bolus, followed by 750 mg/24 h) was started and maintained as long as reactivation was possible. Plasma concentrations of obidoxime were determined by HPLC.

Results

A total amount of 2269 ± 1726 mg obidoxime was infused over 65 h ± 55 h resulting in a steady state plasma concentration of 14.5 ± 7.3 μM. Obidoxime was eliminated with t_1/2(1) 2.2 and t_1/2(2) 14 h. The volumes of distribution amounted to 0.32 ± 0.1 L/kg (V₍₁₎) and 0.28 ± 0.12 (V₍₂₎) L/kg. Postmortem examination of tissue in one patient showed obidoxime accumulation in cartilage, kidney and liver and pointed to brain concentrations similar to plasma concentration.

Conclusions

Using the suggested obidoxime regimen, the targeted plasma concentration could be achieved. Obidoxime was eliminated biphasically and was well tolerated. This result allows the recommendation of using this definite regimen for adults also in case of mass casualties.     

Nicotine impairs cyclooxygenase-2-dependent kinin-receptor-mediated murine airway relaxations

Introduction

Cigarette smoke induces local inflammation and airway hyperreactivity. In asthmatics, it worsens the symptoms and increases the risk for exacerbation. The present study investigates the effects of nicotine on airway relaxations in isolated murine tracheal segments.

Methods

Segments were cultured for 24 h in the presence of vehicle, nicotine (10 μM) and/or dexamethasone (1 μM). Airway relaxations were assessed in myographs after pre-contraction with carbachol (1 μM). Kinin receptors, cyclooxygenase (COX) and inflammatory mediator expressions were assessed by real-time PCR and confocal-microscopy-based immunohistochemistry.

Results

The organ culture procedure markedly increased bradykinin- (selective B₂ receptor agonist) and des-Arg⁹-bradykinin- (selective B₁ receptor agonist) induced relaxations, and slightly increased relaxation induced by isoprenaline, but not that induced by PGE₂. The kinin receptor mediated relaxations were epithelium-, COX-2- and EP2-receptor-dependent and accompanied by drastically enhanced mRNA levels of kinin receptors, as well as inflammatory mediators MCP-1 and iNOS. Increase in COX-2 and mPGES-1 was verified both at mRNA and protein levels.Nicotine selectively suppressed the organ-culture-enhanced relaxations induced by des-Arg⁹-bradykinin and bradykinin, at the same time reducing mPGES-1 mRNA and protein expressions. α7-nicotinic acetylcholine receptor inhibitors α-bungarotoxin and MG624 both blocked the nicotine effects on kinin B₂ receptors, but not those on B₁. Dexamethasone completely abolished kinin-induced relaxations.

Conclusion

It is tempting to conclude that a local inflammatory process per se could have a bronchoprotective component by increasing COX-2 mediated airway relaxations and that nicotine could impede this safety mechanism. Dexamethasone further reduced airway inflammation together with relaxations. This might contribute to the steroid resistance seen in some patients with asthma.     

Sensory and pulmonary effects of acute exposure to sulfur dioxide (SO2)

Background

Exposure to sulfur dioxide (SO₂) affects large populations worldwide. Pulmonary effects have been reported at concentrations relevant in the general (<0.5 ppm) and working environment (>0.5 ppm). SO₂ is an irritant but the existing studies often emphasize only pulmonary effects and no clear dose–response relationship has yet been described.

Objectives

Using a multi-level, multi-method approach, odor annoyance, sensory irritation and pulmonary effects of SO₂ were to be investigated in an experimental exposure study.

Methods

Eye blink frequency, rhinomanometry, spirometry and symptom ratings of acute health effects were assessed before, during, and after the exposures. Each session lasted 4 h and concentrations of 0.5, 1, and 2 ppm were investigated and compared to a control condition using clean air. Sixteen human volunteers (8 females/8 males) participated and during exposure light physical exercise was simulated with bicycle ergometry.

Results

Eye blink frequency, nasal airflow, and lung function were not affected by the acute SO₂ exposure investigated. These physiological responses to moderate SO₂ exposures were not significantly affected by gender. Regarding subjectively measured chemosensory sensations, only odor annoyance ratings increased in a dose-dependent manner, but the average magnitudes were labeled weak to moderate.

Conclusions

In healthy volunteers, without hyperresponsiveness to SO₂, no dose-dependent effects of acute SO₂ exposures up to 2 ppm could be measured. Due to olfactory perceptions subjects were aware of the different SO₂ exposures but the associated annoyance was relatively low.     

A novel strategy to design sustained-release poorly water-soluble drug mesoporous silica microparticles based on supercritical fluid technique

Background

The organic solvent solution immersion method was often used to achieve the loading of the drugs into mesoporous silica, but the drugs that have loaded into the pores of the mesoporous silica would inevitable migrate from the inside to the external surface or near the outside surface during the process of drying. Hence, it often leads to the pores of mesoporous materials not be fully utilized, and results in a low drug loading efficiency and a fast releasing rate.

Objective

The purpose of this study was to develop a novel drug loading strategy to avoid soluble component migration during the process of drying, then, to prepare poorly water-soluble drug mesoporous silica microparticles with higher drug loading efficiency and longer sustained-release time.

Method

Ibuprofen was used as model drug. The microparticles were prepared by a novel method based on mesoporous silica and supercritical fluid (SCF) technique. The drug-loaded mesoporous silica microparticles prepared by SCF technique were analyzed by thermogravimetric analysis (TGA), N₂ adsorption/desorption, scanning electron microscopy (SEM), powder X-ray diffraction (XRD) and differential scanning calorimetry (DSC). In vitro releasing study was used to evaluate the sustained-release effect of the drug-loaded microparticles.

Results

By virtue of the high diffusibility and the high dissolving capacity of the supercritical carbon dioxide (SCF-CO₂), the poorly water-soluble drugs, ibuprofen, entered the pores of the mesoporous silica. The amount and the depth of ibuprofen entered the pores of the mesoporous silica by SCF technique were both larger than those by the solution immersion method. It was found that ibuprofen loaded into the mesoporous silica by SCF technique was amorphous and the largest amount of the ibuprofen loaded into the mesoporous silica by SCF technique could reach 386 mg/g (w/w, ibuprofen/SiO₂), it was more than that by the solution immersion method. In vitro releasing study showed that the sustained-release effect of ibuprofen in the samples prepared by SCF technique was 50% in 15 min and 90% in 60 min. It was longer than that prepared by the solution immersion method.

Conclusion

Present study showed that sustained-release poorly water-soluble drug mesoporous silica microparticle based on SCF technique has twofold advantages. One is the larger drug loading amount in internal pores of the mesoporous silica, the other is the longer drug releasing time.     

TNF/TNFR1 pathway and endoplasmic reticulum stress are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes

Background and purpose

Quinolones cause obvious cartilaginous lesions in juvenile animals by chondrocyte apoptosis, which results in the restriction of their use in pediatric and adolescent patients. Studies showed that chondrocytes can be induced to produce TNFα, and the cisternae of the endoplasmic reticulum in quinolone-treated chondrocytes become dilated. We investigated whether TNF/TNFR₁ pathway and endoplasmic reticulum stress (ERs) are involved in ofloxacin (a typical quinolone)-induced apoptosis of juvenile canine chondrocytes.

Experimental approach

Canine juvenile chondrocytes were treated with ofloxacin. Cell survival and apoptosis rates were determined with MTT method and flow cytometry, respectively. The gene expression levels of the related signaling molecules (TNFα, TNFR₁, TRADD, FADD and caspase-8) in death receptor pathways and main apoptosis-related molecules (calpain, caspase-12, GADD153 and GRP78) in ERs were measured by qRT-PCR. The gene expression of TNFR₁ was suppressed with its siRNA. The protein levels of TNFα, TNFR₁ and caspase-12 were assayed using Western blotting.

Key results

The survival rates decreased while apoptosis rates increased after the chondrocytes were treated with ofloxacin. The mRNA levels of the measured apoptosis-related molecules in death receptor pathways and ERs, and the protein levels of TNFα, TNFR₁ and caspase-12 increased after the chondrocytes were exposed to ofloxacin. The downregulated mRNA expressions of TNFR₁, Caspase-8 and TRADD, and the decreased apoptosis rates of the ofloxacin-treated chondrocytes occurred after TNFR₁–siRNA interference.

Conclusions and implications

Ofloxacin-induced chondrocyte apoptosis in a time- and concentration-dependent fashion. TNF/TNFR₁ pathway and ERs are involved in ofloxacin-induced apoptosis of juvenile canine chondrocytes in the early stage.     

Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

Aims

To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension.

Methods and results

Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91^phox (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91^phox, ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats.

Conclusion

These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension.     

Establishing the optimal nebulization system for paclitaxel,docetaxel, cisplatin,carboplatin and gemcitabine: Back to drawing the residual cup

Background

Chemotherapy drugs have still the major disadvantage of non-specific cytotoxic effects. Although, new drugs targeting the genome of the tumor are already in the market, doublet chemotherapy regimens still remain the cornerstone of lung cancer treatment. Novel modalities of administration are under investigation such as; aerosol, intratumoral and intravascular.

Materials and methods

In the present study five chemotherapy drugs; paclitaxel, docetaxel, gemcitabine, carboplatin and cisplatin were nebulized with three different jet nebulizers (Maxineb^®, Sunmist^®, Invacare^®) and six different residual cups at different concentrations. The purpose of the study was to identify the “ideal” combination of nebulizer-residual cup design-drug–drug loading for a future concept of aerosol chemotherapy in lung cancer patients. The Mastersizer^® 2000 was used to evaluate the aerosol droplet mass median aerodynamic diameter.

Results

The drug, nebulizer and residual cup design greatly influences the producing droplet size (p < 0.005, in each case). However; the design of the residual cup is the most important factor affecting the produced droplet size (F = 834.6, p < 0.001). The drug loading plays a vital role in the production of the desired droplet size (F = 10.42, p < 0.001). The smallest droplet size was produced at 8 ml loading (1.26 μm), while it remained the same at 2, 4 and 6 mls of drug loading.

Conclusion

The ideal nebulizer would be Maxineb^®, with a large residual cup (10 ml maximum loading capacity) and 8 mls loading and the drug with efficient pulmonary deposition would be docetaxel.     

Regulation of iron metabolism-related genes in diethylnitrosamine-induced mouse liver tumors

Background

It has been suggested that the altered iron metabolism in liver tumors, characterized by the iron-deficient phenotype, is of importance for tumor growth.

Aim

This study was performed to elucidate the mechanisms underlying iron deficiency in liver tumors by examining how the liver tumor development affects the expression of iron metabolism-related genes.

Methods

Iron metabolism reference values were analyzed in the sera of diethylnitrosamine-induced hepatocellular adenoma-bearing mice. Expression of iron metabolism-related genes was analyzed in adenomas and surrounding non-tumor tissues, and a subgroup of adenoma-bearing mice loaded with iron 72 h before sacrifice.

Results

Iron content of the adenoma tissues was 2.0–2.5-fold lower compared to surrounding and age-matched control tissues. There was no significant difference in serum iron levels between the adenoma-bearing and control mice, while the adenoma-bearing mice exhibited a 2.4-fold lower level of serum transferrin saturation. Expression of iron metabolism-related genes was dysregulated in the adenomas. Iron loading affected protein expression similarly in the adenomas and surrounding tissues suggesting that iron-responsive regulation of the proteins was not impaired. However, the mRNA expression for ceruloplasmin and divalent metal transporter 1 (DMT1) IRE(+) in the adenomas was altered independently of iron status, and the dysregulation may contribute to diminished iron content.

Conclusion

These findings suggest that diethylnitrosamine-induced liver adenoma-bearing mice have abnormal iron metabolism and that dysregulation of iron metabolism-related genes contributes to iron deficiency in the adenomas.     

Behavioral treatment for marijuana dependence: Randomized trial of contingency management and self-efficacy enhancement

Objective

The purpose of the present study was to develop a treatment for marijuana dependence specifically designed to enhance self-efficacy.

Method

The participants were 215 marijuana-dependent men and women randomized to one of three 9-week outpatient treatments: a condition intended to enhance self-efficacy through successful completion of treatment-related tasks (motivational enhancement plus cognitive-behavioral treatment plus contingency management reinforcing completion of treatment homework; MET + CBT + CM_Homework); a condition that controlled for all elements except for reinforcement of homework (MET + CBT + contingency management reinforcing drug abstinence; MET + CBT + CM_Abstinence); or a case management control condition (CaseM). Participants in the two MET + CBT conditions were also asked to complete interactive voice recordings three times per week during treatment to confirm homework completion.

Results

All patients showed modest improvements over time through 14 months, with few between-treatment effects on outcomes. Latent Class Growth Models, however, indicated that a subsample of patients did extremely well over time. This subsample was more likely to have been treated in the CM_Abstinence condition. In turn, this treatment effect appears to have been accounted for by days of continuous abstinence accrued during treatment, and by pre-post increases in self-efficacy.

Conclusions

The most effective treatments may be those that elicit abstinence while increasing self-efficacy.     

Ex vivo study of bevacizumab transport through porcine nasal mucosa

Introduction

Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder associated with abnormal angiogenesis and disabling epistaxis, for which bevacizumab is reported to be a new therapeutic option. In the present study, bevacizumab transport in porcine nasal mucosa was investigated to determine antibody bioavailability.

Material and methods

Transmucosal absorption of bevacizumab was examined by using nasal mucosa specimens mounted onto static vertical diffusion cells then treated with bevacizumab solution (25 mg mL⁻¹, 500 μg) for 2.5 h. Bevacizumab concentrations were measured by enzyme-linked immunosorbent assays. Mucosal integrity was examined by histological examination of treated mucosa.

Results

Transmucosal transport of bevacizumab followed a Fickian diffusion process (permeability coefficient: [0.63 ± 22] × 10⁻⁶ cm s⁻¹; and steady-state flux: 56.4 ± 19.6 μg cm⁻² h⁻¹). Total recovery of bevacizumab throughout the 2.5 h experiment was 83% of the initial dose distributed (i) at the mucosal surface (263 ± 73 μg; ∼53%) and (ii) into (95 ± 14 μg; ∼19%) and through (56 ± 26 μg; ∼11%) the mucosa. There was no evidence of any noticeable histological effects, confirming the harmlessness of nasal bevacizumab delivery.

Conclusion

In the present study, absorption of bevacizumab into nasal mucosa was demonstrated, providing new fundamentals that are mandatory for further clinical trials in HHT patients.     

The effects of dopaminergic drugs in the dorsal hippocampus of mice in the nicotine-induced anxiogenic-like response

Rationale

Nicotine, an active alkaloid of tobacco has an acetylcholine property that alters anxiety-like behaviors in rodents. Moreover, several investigations suggest that the mesolimbic/cortical dopamine systems to be involved in the drugs affecting anxiety. The dopaminergic modulation of acetylcholine synaptic transmission has also been also suggested by different studies. Furthermore, modulation of such behaviors in rodents may be mediated through the dorsal hippocampus.

Objectives

In the present study, a possible role of the dorsal hippocampal acetylcholine receptor mechanism in nicotine's influence on anxiogenic-like responses has been investigated.

Methods

During test sessions, the hole-board was used to investigate the effects of SCH23390, sulpiride, SKF38393 and quipirole on nicotine response in mice.

Results

Intraperitoneal (i.p.) administration of nicotine (0.5 mg/kg) decreased the number of head dips but had no effect on other behaviors. Intra-dorsal hippocampal injections of ineffective doses of SCH23390 (SCH; 0.125 and 0.25 μg/mouse) or sulpiride (SUL; 0.5 and 0.75 μg/mouse) reversed head dips induced by nicotine but did not impact other exploratory behaviors. Furthermore, co-administration of ineffective doses of SKF38393 (SKF; 4 μg/mouse, dorsal hippocampus) or quipirole (QUI; 0.5 μg/mouse) in conjunction with an ineffective dose of nicotine (0.25 mg/kg, i.p.) decreased head dips induced by nicotine, but were otherwise ineffective.

Conclusion

These results may indicate a modulatory effect for the dorsal hippocampus dopamine receptors (D₁ and D₂) on an anxiogenic-like response induced by nicotine.     

Differential effects of acute and chronic treatment with the α2-adrenergic agonist,lofexidine, on cocaine self-administration in rhesus monkeys

Background

Lofexidine, an α₂-adrenergic agonist, is being investigated as a treatment for reducing opioid withdrawal symptoms and blocking stress-induced relapse to cocaine taking. Opioid abusers are often polydrug abusers and cocaine is one frequent drug of choice. However, relatively little is known about lofexidine interactions with cocaine. The present study investigated the effects of acute and chronic treatment with lofexidine in a pre-clinical model of cocaine self-administration.

Methods

Male rhesus monkeys were trained to respond for food (1 g) and cocaine (0.01 mg/kg/injection) under a fixed ratio 30 (FR30) or a second order FR2 (VR16:S) schedule of reinforcement. Systematic observations of behavior were conducted during and after chronic treatment with lofexidine.

Results

Acute treatment with lofexidine (0.1 or 0.32 mg/kg, IM) significantly reduced cocaine self-administration but responding for food was less effected. In contrast, chronic treatment (7–10 days) with lofexidine (0.1–0.32 mg/kg/h, IV) produced a leftward shift in the cocaine self-administration dose–effect curve, but had no effect on food-maintained responding. Lofexidine did not produce any observable side effects during or after treatment.

Conclusions

Lofexidine potentiated cocaine's reinforcing effects during chronic treatment. These data suggest that it is unlikely to be effective as a cocaine abuse medication and could enhance risk for cocaine abuse in polydrug abusers.     

Further experimentation of inhaled; Lantus,Actrapid and Humulin with todays’ production systems

Background

Several aerosol production systems have been used for aerosol insulin production. However; since the first studies several new models of jet-nebulizers and ultrasound nebulizers have been introduced in the market.

Materials and methods

Three different models of jet-nebulizers (different brands, same properties) and three different ultrasound nebulizers (different brands, same properties). Six residual cups (2 small ≤ 6 ml and 3 large ≤ 8 ml) were used for the jet-nebulizers. The ultrasound nebulizers were used with their facemasks or with their inlets which were included in the purchase package.

Results

Ultrasound nebulizers; LANTUS produces by far the lowest mean droplets (2.44) half the size of the other two drugs (4.43 = 4.97). GIMA nebulizer is the most efficient producing one third of the droplet size of SHIMED and one second of EASYNEB (2.06 < 3.15 < 6.62). Finally, the 4 ml loading concentration is more suitable for supporting the production of smaller droplets (3.65 < 4.24). Drugs and nebulizers act interactively yielding very large droplets when ACTRAPID and HUMULIN are administered in joint with SHIMED nebulizer (9.59 = 7.72). Jet-nebulizers; HUMULIN again is the least preferred insulin since it hardly reaches the low but equal performance of others at the loading level of 6 ml. Residual cups E and B produce uniquely lower mean droplets at loading level 6.

Conclusions

Ultrasound nebulizers; the best suggested combination should be LANTUS insulin, GIMA nebulizer administered at loading dose of 4 ml jet-nebulizers. A global review can give the best combination: the lowest mean droplets are produced when the drugs LANTUS (mostly) and ACTRAPID are administered, applying the SUNMIST nebulizer in concert with residual cup B at loading levels of 6 ml.