Theophylline binding to plasma proteins in patients with chronic obstructive pulmonary disease

The binding of theophylline to plasma proteins was studied in samples from healthy adults at different pH values and drug concentrations and in samples from patients with chronic obstructive pulmonary disease (COPD). Binding determinations were performed by ultrafiltration and drug concentrations were measured by high performance liquid chromatography. Total plasma levels of theophylline did not influence the degree of the binding. The percentage of bound theophylline was positively correlated with pH both in vitro (r = 0.998, p less than 0.005) and in vivo (r = 0.579, p less than 0.005). Mean theophylline binding values in vivo (mean 56.3 +/- 12.5) and in vitro (mean 48.3 +/- 9.4) were significantly different. The increase in theophylline free levels detected in COPD patients was partially dependent on low pH values but the influence of other factors must also be considered. The therapeutic implications of altered theophylline binding are discussed.     

Correction to: The incidence of skin melanoma in Gran Canaria (Canary Islands,Spain) is lower than expected in Southern Europe despite high-risk environmental conditions: an island-wide cross-sectional study

Cancer Causes & Control - A correction to this paper has been published: https://doi.org/10.1007/s10552-021-01437-x     

Kinin antagonist does not protect against the hypotensive response to endotoxin, anaphylaxis or acute pancreatitis

The vasodilator bradykinin (Bk) has long been though to participate in shock induced by endotoxemia, anaphylaxis and acute pancreatitis. Recently developed kinin antagonists have made it possible to test this hypothesis. We studied the effect of two of them. DArg0Hyp3-Thi5.8-DPhe7-Bk (45 and 220 micrograms/kg/min) and Lys-Lys-Hyp2-Thi5.8-DPhe7-Bk (100 micrograms/kg/min) on the early hypotensive response to Escherichia coli lipopolysaccharide (LPS). Rats infused with the antagonist vehicle were used as controls. At 45 micrograms/kg/min, DArg0-Hyp3-Thi5.8-dPhe7-Bk prevented the hypotensive response to high doses of Bk; however, neither antagonist prevented the hypotensive response to LPS. Circulating kinins measured 3 min after injecting LPS or vehicle were similar (16.3 +/- 1.4 vs. 26.0 +/- 7.2 pg/ml; P greater than .23). In allergically sensitized rats, 500 micrograms/kg/min DArg0-Hyp3-Thi5.8-DPhe-7-Bk did not alter the hypotensive (anaphylactic) response to antigen challenge (P greater than .38). Similarly, hypotension caused by development of acute pancreatitis in rats was not prevented by infusion of DArg0-Hyp3-Thi5.8-DPhe7-Bk at 200 micrograms/kg/min, 10 min) (P greater than .69). These results indicate that in the rate formation of kinins is not a major contributor to the hypotensive response observed in early endotoxemia, anaphylaxis and acute pancreatitis.     

Role of angiotensin II type 2 receptors and kinins in the cardioprotective effect of angiotensin II type 1 receptor antagonists in rats with heart failure

OBJECTIVES: We studied the role of angiotensin II type 2 (AT(2)) receptors and kinins in the cardioprotective effect of angiotensin II type 1 antagonists (AT(1)-ant) in rats with heart failure (HF) after myocardial infarction. BACKGROUND: The AT(1)-ant is as effective as angiotensin-converting enzyme inhibitors in treating HF, but the mechanisms whereby AT(1)-ant exert their benefits on HF in vivo are more complex than previously understood. METHODS: Brown Norway Katholiek rats (BNK), which are deficient in kinins because of a mutation in the kininogen gene, and their wild-type control (Brown Norway [BN]) underwent myocardial infarction. Two months later, they were treated for two months with: 1) vehicle; 2) AT(1)-ant (L158809, Merck, Rahway, New Jersey); 3) AT(1)-ant + AT(2)-ant (PD-123319, Parke Davis, Ann Arbor, Michigan); or 4) AT(1)-ant + kinin B(2) receptor antagonist (B(2)-ant) (icatibant) (only BN). We measured left ventricular weight (LVW) gravimetrically, myocyte cross-sectional area (MCSA) and interstitial collagen fraction (ICF) histologically, and ejection fraction by ventriculography. RESULTS: Development of HF was comparable in BN and BNK rats. The AT(1)-ant reduced LVW and MCSA and the AT(2)-ant blocked these effects in BN rats, but the B(2)-ant did not. The AT(1)-ant reduced LVW and MCSA in BNK rats, and this effect was reversed by the AT(2)-ant. In BN rats, ICF was reduced and LVEF increased by AT(1)-ant, and both AT(2)-ant and B(2)-ant reversed these effects. In BNK rats, the AT(1)-ant failed to reduce ICF, and its therapeutic effect on LVEF was significantly blunted. CONCLUSIONS: In HF, the AT(2) receptor plays an important role in the therapeutic effects of AT(1)-ant, and this effect may be mediated partly through kinins; however, kinins appear to play a lesser role in the antihypertrophic effect of AT(1)-ant.     

Antibody therapy to human L1CAM in a transgenic mouse model blocks local tumor growth but induces EMT

L1 cell adhesion molecule (L1CAM) is overexpressed in many human cancers, confers bad prognosis and augments cell motility, invasion and metastasis. Results from xenograft mouse models suggested that L1CAM antibodies might be promising tools for cancer therapy. Here, we generated human L1CAM‐transgenic mice to study therapeutic efficacy and putative side effects in a model system. We established three transgenic lines (M2, M3 and F4) expressing the human L1CAM transgene in brain, kidney and colon with decreasing intensity (M2, M3 > F4). The expression pattern was similar to that of L1CAM in humans. No interference of the transgene with the expression of endogenous L1CAM was observed. Immunohistochemical analysis revealed correct expression of the transgene in mouse cortex and collective duct of the kidney. Injection of ¹²⁵I‐labeled L1CAM antibodies resulted in specific enrichment in the kidney but not in the brain. The injection of the therapeutic anti‐human L1CAM mAb L1‐9.3/2a into transgenic mice even at high doses did not cause behavioral changes or other side effects. Similar results were obtained using a mouse specific L1CAM mAb in normal mice. Tumor therapy experiments were performed using syngeneic mouse tumor cells (RET melanoma and Panc02 pancreatic adenocarcinoma) transduced with human L1CAM. MAb L1‐9.3/2a efficiently and specifically attenuated local tumor growth in both model systems without apparent side effects. The therapeutic effect was dependent on immune effector mechanisms. Analysis of Panc02‐huL1CAM tumors after therapy showed elevated levels of EGF and evidence of immune‐induced epithelial‐mesenchymal transition. The results suggest that our transgenic mice are valuable tools to study L1CAM‐based antibody therapy.     

Ameloblastoma: current etiopathological concepts and management

Ameloblastoma is a benign odontogenic tumor of epithelial origin. It is locally aggressive with unlimited growth capacity and has a high potential for malignant transformation as well as metastasis. Ameloblastoma has no established preventive measures although majority of patients are between ages 30 and 60 years. Molecular and genetic factors that promote oncogenic transformation of odontogenic epithelium to ameloblastoma are strongly linked to dysregulation of multiple genes associated with mitogen‐activated protein kinase, sonic hedgehog, and WNT/β‐catenin signaling pathways. Treatment of ameloblastoma is focused on surgical resection with a wide margin of normal tissue because of its high propensity for locoregional invasion; but this is often associated with significant patient morbidity. The relatively high recurrence rate of ameloblastoma is influenced by the type of molecular etiological factors, the management approach, and how early the patient presents for treatment. It is expected that further elucidation of molecular factors that orchestrate pathogenesis and recurrence of ameloblastoma will lead to new diagnostic markers and targeted drug therapies for ameloblastoma.     

How do short-term rates of femorotibial cartilage change compare to long-term changes? Four year follow-up data from the osteoarthritis initiative

OBJECTIVE: To compare unbiased estimates of short- vs long-term cartilage loss in osteoarthritic knees. METHOD: 441 knees [216 Kellgren Lawrence (KL) grade 2, 225 KL grade 3] from participants of the Osteoarthritis Initiative were studied over a 4-year period. Femorotibial cartilage thickness was determined using 3?T double echo steady state magnetic resonance imaging, the readers being blinded to time points. Because common measurement time points bias correlations, short-term change (year-1 to year-2: Y1?→?Y2) was compared with long-term change (baseline to year-4: BL?→?Y4), and initial (BL?→?Y1) with subsequent (Y2?→?Y4) observation periods. RESULTS: The mean femorotibial cartilage thickness change (standardized response mean) was?-1.2%/-0.8% (-0.42/-0.28) over 1 (BL?→?Y1/Y1?→?Y2),?-2.1%/-2.5% (-0.56/-0.55) over 2 (BL?→?Y2/Y2?→?Y4),?-3.3% (-0.63) over 3 (Y1?→?Y4), and?-4.5% (-0.78) over 4 years. Spearman correlations were 0.33 for Y1?→?Y2 vs BL?→?Y4, and 0.17 for BL?→?Y1 vs Y2?→?Y4 change. Percent agreement between knees showing progression during Y1?→?Y2 vs BL?→?Y4 was 59%, and 64% for BL?→?Y1 vs Y2?→?Y4. The area under the receiver operating characteristic curve was 0.66 for using Y1?→?Y2 to predict BL?→?Y4, and 0.59 for using BL?→?Y1 to predict Y2?→?Y4 change. CONCLUSION: Weak to moderate correlations and agreement were observed between individual short- vs long-term cartilage loss, and between initial and subsequent observation periods. Hence, longer observation periods are recommended to achieve robust results on cartilage loss in individual knees. At cohort and subcohort level (e.g., KLG3 vs KLG2 knees), the mean cartilage loss increased almost linearly with the length of the observation period and was constant throughout the study.