Therapeutic Drug Monitoring for Tyrosine Kinase Inhibitors in Metastatic Renal Cell Carcinoma.

Inter-individual variability in drug response pose significant challenges to treatment with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC). TKIs meet traditional criteria for using therapeutic drug monitoring (TDM), but research is still limited. Understanding the role of TDM in individualizing treatment strategies could help optimize treatment. Here we review the state of knowledge of TDM for TKIs in mRCC treatment. A comprehensive literature review of original research studies focusing on TDM of TKIs in mRCC treatment, clinical in vivo studies reporting on pharmacokinetics-pharmacodynamics, therapeutic ranges, drug concentrations, dose adjustments, clinical outcomes, or other relevant aspects related to TDM. We reviewed studies involving human subjects published in peer-reviewed journals. A narrative synthesis approach was employed to summarize the findings. Key themes and trends related to TDM of TKIs in mRCC treatment were identified and synthesized to provide a comprehensive overview of the current state of knowledge. Our search yielded 25 articles. Most were observational. The most consistently reported association between plasma concentration and effect was pazopanib Ctrough >20 µg/mL, but this concentration was not significant across all studies. We found inconsistent evidence for sunitinib and cabozantinib. For axitinib, we found a clear exposure-response relationship, but research was too diverse to conclude on a therapeutic window to use for TDM. We found much heterogeneity between recommended time of measurement (minimum plasma concentration [Cmin], maximal plasma concentration [Cmax], area under the curve [AUC]) and large variation in plasma concentration associated with clinical outcomes, which makes it difficult to recommend specific concentration intervals based on 1 or more of these measurements. Results were more consistent with TKIs continuously administered. Further research is needed to elucidate the long-term impact of TDM to possibly establish standardized therapeutic intervals. Prospective studies are suggested. The application of TDM in TKI-combination therapy is warranted in future research.

Significantly higher use of polypharmacy in elderly with hip fracture treated with psychotropics.

INTRODUCTION: The high prevalence of chronic medical conditions among older adults leads to an increased use of prescription medications and a heightened risk of polypharmacy, raising the risk of falls and fractures. Psychotropic medications influence balance, and therefore our aim was to describe the use of psychotropic medications and the association with polypharmacy in elderly patients with a hip fracture. METHODS: A retrospective study of 200 patients aged 65 years or more admitted consecutively with a hip fracture. RESULTS: In total, 98 of the 200 patients used psychotropic medications. These 98 patients used a higher number of drugs at the time of admission (an average of eight (6-11) versus six (3-10), p less-than0.001), had a higher risk of using five or more medications (odds ratio (OR) = 5.9; 95% confidence interval (CI): 2.75-12.7; p less-than 0.001) and a higher risk of using ten or more medications (OR = 1.9; 95% CI: 1.05-3.5; p = 0.03). Furthermore, they were more likely to use analgesics (65.3% versus 48.0%; p = 0.01) and medications targeting the gastrointestinal tract (59.1% versus 40.2%; p = 0.01). CONCLUSIONS: Psychotropic medication use was frequent in elderly patients with a hip fracture and strongly associated with polypharmacy. Psychotropic medications may potentially be a trigger to perform medication review in elderly patients to prevent re-occurrence hip fractures. FUNDING: none. TRIAL REGISTRATION: not relevant.

Cystamine Treatment Fails to Prevent the Development of Pulmonary Hypertension in Chronic Hypoxic Rats.

INTRODUCTION: Pulmonary hypertension is characterized by vasoconstriction and remodeling of pulmonary arteries, leading to right ventricular hypertrophy and failure. We have previously found upregulation of transglutaminase 2 (TG2) in the right ventricle of chronic hypoxic rats. The hypothesis of the present study was that treatment with the transglutaminase inhibitor, cystamine, would inhibit the development of pulmonary arterial remodeling, pulmonary hypertension, and right ventricular hypertrophy. METHODS: Effect of cystamine on transamidase activity was investigated in tissue homogenates. Wistar rats were exposed to chronic hypoxia and treated with vehicle, cystamine (40 mg/kg/day in mini-osmotic pumps), sildenafil (25 mg/kg/day), or the combination for 2 weeks. RESULTS: Cystamine concentration-dependently inhibited TG2 transamidase activity in liver and lung homogenates. In contrast to cystamine, sildenafil reduced right ventricular systolic pressure and hypertrophy and decreased pulmonary vascular resistance and muscularization in chronic hypoxic rats. Fibrosis in the lung tissue decreased in chronic hypoxic rats treated with cystamine. TG2 expression was similar in the right ventricle and lung tissue of drug and vehicle-treated hypoxic rats. DISCUSSION/CONCLUSIONS: Cystamine inhibited TG2 transamidase activity, but cystamine failed to prevent pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial muscularization in the chronic hypoxic rat.

Cardiovascular effects of current and future anti-obesity drugs.

The prevalence of obesity increases and is associated with increases in co-morbidities e.g. type 2 diabetes, hyperlipidemia, hypertension, obstructive sleep apnea, heart disease, stroke, asthma, several forms of cancer, depression, and may result in reduction of expected remaining lifespan. We have reviewed the adverse effects on the cardiovascular system of anti-obesity drugs now retracted from the market as well as the cardiovascular profile of current drugs and potential pathways which are considered for treatment of obesity. Fenfluramine, and sibutramine were withdrawn due to increased cardiovascular risk, while an inverse agonist at cannabinoid type 1 (CB1) receptors, rimonobant was withdrawn due to serious psychiatric problems. At present there are only few treatments available including orlistat and, phentermine alone or in combination with topiramate and lorcaserin, although cardiovascular side effects need to be clarified regarding phentermine and lorcaserin. Drugs approved for type 2 diabetes including glucagon like peptide (GLP-1) analogues and metformin also cause moderate weight losses and have a favourable cardiovascular profile, while the anti-obesity potential of nebivolol remains unexplored. Pathways with anti-obesity potential include sirtuin activation, blockade of transient receptor potential (TRPV1) channels, acetyl-CoA carboxylase 1 and 2 inhibitors, uncoupling protein activators, bile acids, crotonins, CB1 antagonists, but the cardiovascular profile remains to be investigated. For type 2 diabetes, new drug classes with possible advantageous cardiovascular profiles, e.g. GLP-1 analogues and sodium-glucose co-transport type 2 inhibitors, are associated with weight loss and are currently being evaluated as anti-obesity drugs.

Echocardiographic screening for pulmonary hypertension in stable COPD out-patients and NT-proBNP as a rule-out test.

UNLABELLED: Pulmonary hypertension (PH) worsens the prognosis in chronic obstructive pulmonary disease (COPD). The diagnosis of PH is established by right heart catheterisation (RHC), while echocardiography can be used for screening. We aimed to asses the outcome of echocardiographic screening for PH in a group of stable COPD out-patients, and to evaluate NT-proBNP as a first line screening tool. Criteria for PH on echocardiography were a tricuspid regurgitation pressure gradient > 40 mmHg, a tricuspid annular plane systolic excursion < 1.8 cm or right ventricular dilatation. Positively screened patients were asked to undergo RHC. Results (Mean ± SEM): 16 of 117 patients (14%) had PH on echocardiography. They had a higher mortality (hazard ratio for death: 2.7 ± 1.3, p = 0.037) and lower six minute walk test (224 ± 33 vs. 339 ± 15, p = 0.006). NT-proBNP below 95 ng/l excluded PH on echocardiography with a negative predictive value of 100 (95% CI: 89-100%). RHC was obtained in six patients screened positive. In three of these, PH was not confirmed. CONCLUSIONS: Signs of PH on echocardiography as defined here was found in 14% and had prognostic significance in COPD. A value of NT-proBNP less than 95 ng/l may be used to exclude signs of PH.