Altered lung function relates to inflammation in an acute LPS mouse model.

Preclinical in vivo models of lipopolysaccharide (LPS) -induced acute lung injury are commonly used to recapitulate pathophysiological features of chronic obstructive pulmonary disease and acute exacerbations. The LPS-induced lung inflammation is well described; however, whether the inflammatory response relates temporally to specific alterations in lung function has not been elucidated. We have investigated the effects of acute LPS inhalation in mice up to 96 h post LPS. Quantitation of inflammatory cells and inflammatory mediators in bronchoalveolar lavage fluid and non-invasive and invasive lung function measurements were performed at corresponding time points. The inhibitory effect of the glucocorticoid, budesonide, on LPS-induced lung inflammation and lung function was determined. LPS inhalation induced distinct histopathological changes, and infiltration of inflammatory cells to the lungs peaked at 48 h. At this time point, significantly increased inflammatory mediators and significantly altered lung capacity and mechanics parameters were observed. Budesonide given per os prevented the LPS-induced lung inflammation and lung dysfunction. These results demonstrate a temporal relationship between the peak of inflammatory cell influx and significant impairment of lung function, suggestive of a causative role of inflammation. These results allow better understanding of the functional consequences of lung inflammation in respiratory diseases.

Evaluation of the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma (SOURCE): a randomised, placebo-controlled, phase 3 study.

BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. SOURCE evaluated the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma. METHODS: We conducted this phase 3, multicentre, randomised, double-blind, placebo-controlled study across 60 sites in seven countries. Participants aged 18-80 years with physician-diagnosed asthma, who had been receiving medium-dose or high-dose inhaled corticosteroids and had at least one asthma exacerbation in the 12 months before screening were eligible. Patients who were receiving medium-dose inhaled corticosteroids must have had their dose increased to a high dose for at least 3 months before screening. After an oral corticosteroid optimisation phase of up to 8 weeks, participants were randomly assigned according to a computer-generated fixed block randomisation sequence to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks during a 48 week treatment period (4 week induction phase, 36 week oral corticosteroid reduction phase, and 8 week maintenance phase). Randomisation was stratified by region. Participants, investigators, and site staff were masked to treatment assignment. The primary endpoint was the categorised percentage reduction from baseline in daily oral corticosteroid dose at week 48 without the loss of asthma control. Efficacy and safety endpoints were assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03406078. FINDINGS: Between March 5, 2018, and Sept 27, 2019, 150 participants were randomly assigned to receive tezepelumab 210 mg (n=74) or placebo (n=76). The cumulative odds of achieving a category of greater percentage reduction in an oral corticosteroid dose for daily maintenance at week 48 were similar with tezepelumab or placebo in the overall population (odds ratio [OR] 1·28 [95% CI 0·69-2·35], p=0·43; the primary endpoint was not met). The cumulative odds were higher with tezepelumab than with placebo in participants with baseline blood eosinophil counts of at least 150 cells per µL (2·58 [1·16-5·75]), but not in participants with counts below 150 cells per µL (0·40 [0·14-1·13]). Tezepelumab was well tolerated, with no safety concerns identified. 53 (72%) of 74 tezepelumab-assigned participants and 65 (86%) of 76 placebo-assigned participants reported an adverse event. Serious adverse events were reported in 12 (16%) participants in the tezepelumab group and 16 (21%) participants in the placebo group. INTERPRETATION: We did not observe a significant improvement in oral corticosteroid dose reduction with tezepelumab versus placebo in the overall population of this oral corticosteroid-sparing study, although an improvement was observed in participants with baseline blood eosinophil counts of at least 150 cells per µL. FUNDING: AstraZeneca and Amgen.

Some oxidative stress related parameters in patients with head and neck carcinoma.

Forty cases of head and neck cancer were studied for plasma superoxide dismutase, malondialdehyde and thiol levels and results were compared with a group of forty normal healthy volunteers. Mean plasma superoxide dismutase activity was not found to be altered while malondialdehyde concentration was significantly higher when compared with the control group. On the other hand, mean thiol level was significantly lowered. The data suggests increased level of oxidative stress in patients with head and neck cancer.

Effect of irbesartan on streptozotocin induced diabetic nephropathy: An interventionary study.

Effect of irbesartan, an angiotensin II receptor antagonist, was studied in streptozotocin (STZ) induced diabetic nephropathy. Polyuria, proteinuria, blood urea, creatinine clearance, and urinary electrolytes were determined to assess kidney damage. There was a significant increase in urine volume, urinary protein and blood urea in STZ induced diabetic rats. On the other hand, irbesartan treatment resulted in a significant reduction in urinary protein and blood urea in these rats. Irbesartan treatment also improved creatinine clearance and exhibited a natriuretic effect in these animals. Results suggest that irbesartan treatment ameliorate STZ induced diabetic nephropathic changes, in rats.

Blood glutathione levels in head and neck malignancies.

Blood glutathione was estimated in fifty patients of head and neck cancer in the age group of 18-76 years and the results were compared with a group of normal healthy controls. Mean blood glutathione level was found to be significantly lowered in patients than the controls. Irrespective of the site, TNM classification, histopathology, and character of lesion, fall in blood glutathione was nearly same in all the patients. The mean level was significantly increased after radiotherapy when compared with the levels before radiotherapy. The decreased levels of GSH in-patients with head and neck cancer, observed in the present study, may be due to its increased utilization by the cells. The results suggest that patients with head and neck cancer have increased oxidative stress.

Effect of vitamin A supplementation on hematopoiesis in children with anemia.

Fifty children (1-4 years age) presenting with microcytic hypochromic anemia (hemoglobin less than 10g/dl) were studied in two groups of 25 each. Group I was supplemented with iron (ferrous sulphate 6 mg/kg/d) while group II in addition to iron was also supplemented with vitamin A (5000 IU/d). Hemoglobin concentration was found to be significantly increased after 4 weeks of iron supplementation. Rise in hemoglobin was comparatively more in-group II, as compared to group I, after 8 and 12 weeks. Serum iron was significantly higher after 4 weeks in both the groups. Packed cell volume (PCV) and retinol levels increased significantly in-group II only. The data suggests that supplementation of vitamin A improves hematopoiesis.

The discriminative stimulus effects of pentylenetetrazol as a model of anxiety: recent developments.

Pentylenetetrazol (PTZ), a GABA(A) receptor antagonist and prototypical anxiogenic drug, has been extensively utilized in animal models of anxiety. PTZ produces a reliable discriminative stimulus which is largely mediated by the GABA(A) receptor. Several classes of compounds can modulate the PTZ discriminative stimulus including 5-HT(1A), 5-HT(3), NMDA, glycine, and L-type calcium channel ligands. Spontaneous PTZ-lever responding is seen in trained rats during withdrawal from GABA(A) receptor compounds such as chlordiazepoxide and diazepam, and also ethanol, morphine, nicotine, cocaine, haloperidol, and phencyclidine. This effect is largely mediated by the GABA(A) receptor, which suggests that anxiety may be part of a generalized withdrawal syndrome mediated by the GABA(A) receptor. There are also important hormonal influences on PTZ. Corticosterone plays some role in mediation of its anxiogenic effects. There is a marked sex difference in response to the discriminative stimulus effects of PTZ, and estrogens appear to protect against its anxiogenic effects. Further work with the PTZ drug discrimination is warranted for characterization of anxiety during withdrawal, and the hormonal mechanisms of anxiety.

Effects of NG-nitro-L-arginine methyl ester, 7-nitro indazole, and agmatine on pentylenetetrazol-induced discriminative stimulus in Long-Evans rats.

This study was undertaken to determine any role that nitric oxide (NO) may play in the discriminative stimuli produced by pentylenetetrazol (PTZ). The PTZ-induced discriminative stimulus is pharmacologically similar to anxiety in humans and is used in a behavioral assay of anxiety (the PTZ model of anxiety). In the present study, effects of L-N(G)-nitro arginine methyl ester (L-NAME), 7-nitroindazole (7-NI) and agmatine, NO synthase (NOS) inhibitors, on PTZ-induced discriminative stimulus were investigated in male Long-Evans rats (330-350 g). Rats were trained to discriminate PTZ (16 mg/kg) from saline using a two-lever, food-reinforced choice procedure (FR 10). The rats that met the training criteria were injected with L-NAME (15, 30, and 60 mg/kg), 7-NI (15 and 30 mg/kg), agmatine (20, 40, and 60 mg/kg), and saline or vehicle intraperitoneally before each test. They were tested for the PTZ-discrimination to determine if the NOS inhibitors produce discriminative stimulus similar to PTZ or if they block PTZ-induced discrimination. Treatment with the NOS inhibitory drugs neither substituted for PTZ nor altered the PTZ lever selection in any other way. These findings suggest that PTZ-induced discriminative stimulus may not be related to NO-mediated central mechanisms.

Effects of GABA(A) compounds on mCPP drug discrimination in rats.

Male Long-Evans rats were trained to discriminate mCPP (1.4 mg/kg, i.p.) from saline, using a two-lever, food-reinforced operant task. The GABA(A) antagonist, bicuculline (0.16-0.64 mg/kg), partially substituted for mCPP, whereas the benzodiazepine antagonist, flumazenil (1-10 mg/kg), and the benzodiazepine inverse agonist, Ro 15-4513 (0.25-2.5 mg/kg), failed to substitute for mCPP. Bicuculline produced no change in response rate, whereas Ro 15-4513 dose-dependently decreased responding. Flumazenil produced a small increase in response rates. Flumazenil (10 mg/kg), Ro 15-4513 (1.25 mg/kg), and the benzodiazepine agonists alprazolam (0.64 mg/kg) and diazepam (5 mg/kg) full agonist all failed to block the mCPP discriminative stimulus. When given in combination with mCPP, Ro15-4513 and alprazolam both produced lower response rates than did mCPP alone, whereas flumazenil and diazepam did not significantly alter response rates. These findings provide evidence that GABA(A) antagonists modulate the discriminative stimulus effects of mCPP, but that these effects are not mediated by activity at the benzodiazepine site.

Blood thiols and malondialdehyde levels in psoriasis.

Forty patients with psoriasis and forty healthy controls were enrolled to study the levels of total blood thiols (an important part of the body's antioxidant defence system) and plasma malondialdehyde (a lipid peroxidation product). The levels of total blood thiols in psoriatic patients in the acute phase were significantly lower than those in controls, but total blood thiol levels in psoriatic patients in the remission phase were not significantly different from those in controls. There was a significant difference between levels of total blood thiols of patients in the acute phase and in remission. The levels of plasma MDA were significantly raised in psoriatic patients in the acute phase as compared to those in controls and in patients in remission. The differences in levels of plasma MDA were not significant between control subjects and patients in remission. These findings suggest a role of oxidative stress in the etiopathogenesis of psoriasis.

Vitamin a status in children with diarrhoea.

Vitamin A status was measured in 50 pre-school children with acute and persistent diarrhoea. It was measured by (a) Fluorometric micromethod and (b) Conjunctival impression cytology (CIC). The results were compared with 25 normal children. Vitamin A status was lower in children with persistent diarrhoea whereas the results were comparable between the children with acute diarrhoea and control subjects.

C-reactive protein and uric Acid levels in patients with psoriasis.

Serum CRP and uric acid levels were estimated in twenty-five patients with psoriasis (group III) before and after 12 weeks of treatment. Results were compared with a group of 25 normal subjects (group I) and a group of 25 patients of various skin diseases other than psoriatic lesion (group II). Mean value for CRP was found to be increased by more than 20 folds in patients with psoriasis, which was subsequently reduced to nearly 50% of the initial value after 12 weeks of treatment. These patients also showed hyperuricemia. Nearly 25% of these patients also exhibited arthritis. It is thus suggested that both CRP and uric acid levels should be monitored in patients with psoriasis.

Role of vitamin d supplementation in hypertension.

Role of Vitamin D supplementation was studied in patients with hypertension. One hundred hypertensive patients (group I) were given conventional antihypertensive drugs while another 100 patients (group II), in addition, were supplemented with Vitamin D(3) (33,000 IU, after every 2 weeks, for 3 months). Besides diastolic and systolic blood pressure, serum calcium, phosphorous, alkaline phosphatase, albumin, albumin-corrected calcium, and 24 h urinary creatinine levels were estimated in both the groups before the start of treatment and after 3 months. Vitamin D supplementation showed a more significant decrease in systolic blood pressure. This group also showed a significant increase in serum calcium as well as albumin-corrected calcium with a decrease in phosphorous. Results of the study confirm that Vitamin D supplementation has a role in reducing blood pressure in hypertensive patients and that it should be supplemented with the antihypertensive drugs. More extensive studies with a larger group, to draw a definite conclusion, are in progress.

Effect of lacidipine pre-treatment on diabetic neuropathy in rats.

OBJECTIVE: The present study was planned to evaluate the effects of lacidipine on STZ induced diabetic neuropathy. MATERIAL AND METHODS: Streptozotocin (STZ) induced diabetic neuropathy in rats was monitored by measuring blood sugar levels, motor nerve conduction velocity (MNCV), nociception and histopathology of tibial nerve. Forty rats were divided in to four groups of 10 each. Group I: Control (vehicle). Group II: STZ (50mg/kg, iv, single injection). Group III: Lacidipine (0.5 mg/kg, po, daily + STZ). Group IV: STZ + insulin (4 unit/kg, sc, bid). Similar protocol was used for other parameters also. RESULTS: Lacidipine pre-treatment failed to reduce blood sugar levels in diabetic rats but prevented deterioration of motor nerve conduction velocity as compared to STZ diabetic rats. Hyperalgesia induced by STZ was antagonized by lacidipine. Histology of nerve showed less structural damage in lacidipine pre-treated group. DISCUSSION AND CONCLUSION: Thus, lacidipine prevents the development of neuropathic changes induced by STZ in rats.

Parathyroid and calcium status in patients with thalassemia.

Thirty patients with thalassemia major receiving repeated blood transfusion were studied to see their serum parathyroid hormone (PTH) and calcium status. Serum PTH, serum and 24 h urinary calcium, and serum alkaline phosphatase, phosphorus, and albumin-corrected calcium levels were determined. Half of these patients, in addition to transfusion, were also supplemented with vitamin D (60,000 IU for 10d) and calcium (1500 mg/day for 3 months). Serum PTH, and serum and 24 h urinary calcium concentrations of the patients receiving transfusions were found to be significantly reduced while their serum alkaline phosphatase, phosphorus, and albumin-corrected calcium levels were not significantly altered when compared to the respective mean values for the control group. Vitamin D and calcium supplementation significantly increased their serum PTH and calcium levels. Supplementations also increased urinary excretion of calcium. The results thus suggest that patients with thalassemia have hypoparathyroidism and reduced serum calcium concentrations that in turn were improved with vitamin D and calcium supplementation.

Biochemical effects of irbesartan in experimental diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is one of the most common causes of end-stage renal failure. The pathogenesis of progressive renal damage is multifactorial and the mechanism by which hyperglycemia causes microangiopathy in diabetic glomeruli is still poorly understood. Because the renin angiotensin system has been reported to be an important contributory factor in the pathophysiology of DN, exogenous administration of angiotensin II receptor antagonist may be beneficial in counteracting some biochemical or functional changes of DN. AIMS: The present study was therefore undertaken to evaluate the preventive role of irbesartan in streptozotocin (STZ)-induced DN in rats. METHODS AND MATERIAL: STZ-induced DN in rats was assessed biochemically by measuring urine volume, protein and electrolytes as well as blood urea and creatinine clearance. RESULTS: Marked hyperglycemia, polyuria, proteinuria and uremia along with a reduction in urine electrolytes and creatinine clearance were observed in STZ diabetic rats. Pre-treatment with irbesartan (20 mg/kg, p.o. 5 days prior to STZ and continued for 16 weeks) also significantly altered these parameters towards normal, except blood glucose. CONCLUSION: Pre-treatment with insulin reversed the parameters of DN. The data suggest that irbesartan prevents the development of STZ-induced DN in rats.

Sensitivity of disease parameters to flexible budesonide/formoterol treatment in an allergic rat model.

RATIONALE: Clinical studies show that flexible dosing (maintenance and symptom-driven dose adjustments) of budesonide and formoterol (BUD/FORM) improves control of asthma exacerbations as compared to fixed maintenance dosing protocols (maintenance therapy) even when the latter utilize higher BUD/FORM doses. This suggests that dose-response relationships for certain pathobiologic mechanisms in asthma shift over time. Here, we have conducted animal studies to address this issue. OBJECTIVES: (1) To test in an animal asthma-like model whether it is possible to achieve the same or greater pharmacological control over bronchoconstriction and airway/lung inflammation, and with less total drug used, by flexible BUD/FORM dosing (upward adjustment of doses) in association with allergen challenges. (2) To determine whether the benefit requires adjustment of both drug components. METHODS: Rats sensitized on days 0 and 7 were challenged intratracheally with ovalbumin on days 14 and 21. On days 13-21, rats were treated intratracheally with fixed maintenance or flexible BUD/FORM combinations. On day 22, rats were challenged with methacholine and lungs were harvested for analysis. RESULTS: A flexible BUD/FORM dosing regimen (using 3.3 times less total drug than the fixed maintenance high dose regimen), delivered the same or greater reductions of excised lung gas volume (a measure of gas trapped in lung by bronchoconstriction) and lung weight (a measure of inflammatory oedema). When either BUD or FORM alone was increased on days of challenge, the benefit of the flexible dose upward adjustment was lost. CONCLUSIONS: Flexible dosing of the BUD/FORM combination improves the pharmacological inhibition of allergen-induced bronchoconstriction and an inflammatory oedema in an allergic asthma-like rat model.