Lung cell reactions in guinea pigs after inhalation of asbestos (amosite)

To study the long-term effect of inhaled asbestos, guinea-pigs were exposed to airborne amosite at a concentration of 49 mg/m3, 2 h/day for 3 or 6 weeks and examined up to 2 years after exposure. Macrophages in lung lavage fluid (LLF) were increased at 16, 24 and 93 weeks and lymphocytes at 24 weeks. Examination of lung wall cells (LWC) 2 years after exposure compared to cells obtained by LLF showed higher proportions of LWC lymphocytes and neutrophils. Percoll gradient centrifugation of these cells showed a higher proportion of high density macrophages in LLF from the amosite-exposed animal and an increased number of low density lymphocytes in the LW. Cathepsin D was increased in LLF at 8 and 24 weeks and in alveolar macrophages 24 weeks and 2 years after exposure. Fibroblast cultures exposed to LLF did not show any statistical significant changes in their collagen synthesis. Histology 93 weeks after exposure showed macrophage and mediastinal lymph node accumulation of asbestos, as well as collagen in alveolar walls. Granulomas were found in the vicinity of blood vessels and in connection with the bronchioles. The data suggest that amosite at low doses ultimately causes fibrosis with a reaction pattern different from that seen in silicosis. The inflammation and fibrosis seems to develop only within the interstitium.     

Bronchial hyperresponsiveness, epithelial damage, and airway eosinophilia after single and repeated allergen exposure in a rat model of anhydride-induced asthma

Bronchial hyperresponsiveness (BHR) and damage of the epithelium, as well as eosinophilia in the airway wall, induced by trimellitic anhydride (TMA) in sensitized brown Norway rats were studied. Rats were challenged once or seven times with aerosol of TMA conjugated to rat serum albumin (TMA-RSA) 3 weeks after intradermal TMA sensitization. Airway responsiveness (-log PC₃₀₀ of acetylcholine i.v.) was measured 24 h after allergen challenge. Epithelial lesion and eosinophil infiltration in the airway walls were quantified under light microscopy, and TMA-specific IgE and IgG in serum were evaluated with ELISA. High levels of TMA-specific IgE and IgG were found in all rats in the sensitized groups compared to nonsensitized groups ( P < 0.001). Repeated allergen challenges of 0.03% TMA-RSA for 7 consecutive days enhanced the level of TMA-specific IgG, compared to single challenge ( P < 0.05). Single allergen challenge of 0.3% TMA-RSA had a nonsignificant tendency to produce BHR in sensitized rats compared to nonsensitized rats ( P =0.06). However, repeated allergen challenges (0.003% and 0.03% TMA-RSA for 7 consecutive days) produced significant BHR in sensitized rats ( P < 0.05). Furthermore, repeated low-dose (0.003%) TMA-RSA challenge produced more BHR than a 10 times higher single dose (0.03%) ( P < 0.05). Slight damage of the airway epithelium was seen in sensitized and repeat-challenged groups. However, bronchial eosinophilia was found in the sensitized and single-challenged groups, but not in nonsensitized nonchallenged, and sensitized repeat-challenged groups ( P < 0.005). We conclude that the brown Norway rat can be sensitized with TMA, and that repeated low-dose allergen challenges produce slight epithelial damage and BHR which is independent of ongoing eosinophilia in the airway wall.     

Continuous inhibition of 11β‐hydroxysteroid dehydrogenase type I in adipose tissue leads to tachyphylaxis in humans and rats but not in mice

Background and Purpose

11β‐hydroxysteroid dehydrogenase type I (11β‐HSD1), a target for Type 2 diabetes mellitus, converts inactive glucocorticoids into bioactive forms, increasing tissue concentrations. We have compared the pharmacokinetic‐pharmacodynamic (PK/PD) relationship of target inhibition after acute and repeat administration of inhibitors of 11β‐HSD1 activity in human, rat and mouse adipose tissue (AT).

Experimental Approach

Studies included abdominally obese human volunteers, rats and mice. Two specific 11β‐HSD1 inhibitors (AZD8329 and COMPOUND‐20) were administered as single oral doses or repeat daily doses for 7–9 days. 11β‐HSD1 activity in AT was measured ex vivo by conversion of ³H‐cortisone to ³H‐cortisol.

Key Results

In human and rat AT, inhibition of 11β‐HSD1 activity was lost after repeat dosing of AZD8329, compared with acute administration. Similarly, in rat AT, there was loss of inhibition of 11β‐HSD1 activity after repeat dosing with COMPOUND‐20 with continuous drug cover, but effects were substantially reduced if a ‘drug holiday’ period was maintained daily. Inhibition of 11β‐HSD1 activity was not lost in mouse AT after continuous cover with COMPOUND‐20 for 7 days.

Conclusions and Implications

Human and rat AT, but not mouse AT, exhibited tachyphylaxis for inhibition of 11β‐HSD1 activity after repeat dosing. Translation of observed efficacy in murine disease models to human for 11β‐HSD1 inhibitors may be misleading. Investigators of the effects of 11β‐HSD1 inhibitors should confirm that desired levels of enzyme inhibition in AT can be maintained over time after repeat dosing and not rely on results following a single dose.

Abbreviations

11β‐HSD1

11β‐hydroxysteroid dehydrogenase type I

PK/PD

pharmacokinetic‐pharmacodynamic

AT

adipose tissue

DIO

diet induced obese

IHC

International Conference on Harmonisation

GCP

Good Clinical Practice

b.i.d.

twice daily

u.i.d.

once daily

HPMC

hydroxypropylmethylcellulose

IC₇₀

concentration that delivers 70% of the maximum effect

IC₉₀

concentration that delivers 90% of the maximum effect

fu

fraction unbound

C_max

maximum achieved concentration

C_min

minimum or trough concentration

E₀

baseline

E_max

maximum effect

ANCOVA

analysis of covariance

     

Direct measurements of the permeability surface area for insulin and glucose in human skeletal muscle

To elucidate mechanisms regulating capillary transport of insulin and glucose, we directly calculated the permeability surface (PS) area product for glucose and insulin in muscle. Intramuscular microdialysis in combination with the forearm model and blood flow measurements was performed in healthy males, studied during an oral glucose tolerance test or during a one-step or two-step euglycemic hyperinsulinemic clamp. PS for glucose increased significantly from 0.29 +/- 0.1 to 0.64 +/- 0.2 ml/min.100 g after oral glucose tolerance test, and glucose uptake increased from 1.2 +/- 0.4 to 2.6 +/- 0.6 micro mol/min.100 g (P < 0.05). During one-step hyperinsulinemic clamp (plasma insulin, 1.962 pmol/liter), PS for glucose increased from 0.2 +/- 0.1 to 2.3 +/- 0.9 ml/min.100 g (P < 0.05), and glucose uptake increased from 0.6 +/- 0.2 to 5.0 +/- 1.4 micro mol/min.100 g (P < 0.05). During the two-step clamp (plasma insulin, 1380 +/- 408 and 3846 +/- 348 pmol/liter), the arterial-interstitial difference and PS for insulin were constant. The PS for glucose tended to increase (P = not significant), whereas skeletal muscle blood flow increased from 4.4 +/- 0.7 to 6.2 +/- 0.8 ml/min.100 ml (P < 0.05). The present data show that PS for glucose is markedly increased by oral glucose, whereas a further vasodilation exerted by high insulin concentrations may not be physiologically relevant for capillary delivery of either glucose or insulin in resting muscle.     

Effect of Dapagliflozin in DAPA-HF According to Background Glucose-Lowering Therapy

OBJECTIVETo determine whether the benefits of dapagliflozin in patients with heart failure and reduced ejection fraction (HFrEF) and type 2 diabetes in the Dapagliflozin And Prevention of Adverse-Outcomes in Heart Failure trial (DAPA-HF) varied by background glucose-lowering therapy (GLT).RESEARCH DESIGN AND METHODSWe examined the effect of study treatment by the use or not of GLT and by GLT classes and combinations. The primary outcome was a composite of worsening heart failure (hospitalization or urgent visit requiring intravenous therapy) or cardiovascular death.RESULTSIn the 2,139 type 2 diabetes patients, the effect of dapagliflozin on the primary outcome was consistent by GLT use or no use (hazard ratio 0.72 [95% CI 0.58–0.88] vs. 0.86 [0.60–1.23]; interaction P = 0.39) and across GLT classes.CONCLUSIONSIn DAPA-HF, dapagliflozin improved outcomes irrespective of use or no use of GLT or by GLT type used in patients with type 2 diabetes and HFrEF.     

Treatment compliance in patients with aggressive periodontitis – a retrospective case-control study

Objective: To investigate if differences according to discontinuation of treatment could be identified between patients with aggressive periodontitis and chronic periodontitis at two specialist clinics of periodontology irrespective of the effects of background factors.

Materials and methods: This is a retrospective case-control study. The variables were registered from dental records. The population consisted of patients referred to two specialist clinics of periodontology during three years. A study group was included consisting of 234 patients with a diagnosis of aggressive periodontitis. A control group with a diagnosis of chronic periodontitis was randomly selected.

Results: In total, 234 patients (4% of the referrals) with a diagnosis of aggressive periodontitis were referred to the two periodontal clinics during a period of three years. Forty-two per cent of the non-compliant patients were smokers compared to 31% for the compliers and this difference was statistically significant. Patients with aggressive periodontitis interrupted their periodontal treatment significantly more frequently (46%) compared to those patients with chronic periodontitis (34%). The non-compliant patients had significantly deeper periodontal pockets at baseline as well as significantly more sites with bleeding at probing. In a stepwise logistic regression analysis, aggressive periodontitis, smoking and the relative frequency of sites with periodontal pockets >4?mm at baseline were the remaining variables with a significant influence on the incidence of interrupting ongoing periodontal treatment.

Conclusions: The patient group with aggressive periodontitis interrupted the periodontal treatment significantly more often irrespective of background factors and risk factors, which may be regarded as a major health problem.