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Hyperinflammation plays an important role in severe and critical COVID-19. Using inconsistent criteria, many researchers define hyperinflammation as a form of very severe inflammation with cytokine storm. Therefore, COVID-19 patients are treated with anti-inflammatory drugs. These drugs appear to be less efficacious than expected and are sometimes accompanied by serious adverse effects. SARS-CoV-2 promotes cellular ATP release. Increased levels of extracellular ATP activate the purinergic receptors of the immune cells initiating the physiologic pro-inflammatory immune response. Persisting viral infection drives the ATP release even further leading to the activation of the P2X7 purinergic receptors (P2X7Rs) and a severe yet physiologic inflammation. Disease progression promotes prolonged vigorous activation of the P2X7R causing cell death and uncontrolled ATP release leading to cytokine storm and desensitisation of all other purinergic receptors of the immune cells. This results in immune paralysis with co-infections or secondary infections. We refer to this pathologic condition as hyperinflammation. The readily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immune function. The issue is that the half-maximal effective concentration for P2X7R inhibition of lidocaine is much higher than the maximal tolerable plasma concentration where adverse effects start to develop. To overcome this, we selectively inhibit the P2X7Rs of the immune cells of the lymphatic system inducing clonal expansion of Tregs in local lymph nodes. Subsequently, these Tregs migrate throughout the body exerting anti-inflammatory activities suppressing systemic and (distant) local hyperinflammation. We illustrate this with six critically ill COVID-19 patients treated with lidocaine., (© 2021. The Author(s).)

Background: Guidelines on home blood pressure measurement (HBPM) recommend taking at least 12 measurements. For screening purposes, however, it is preferred to reduce this number. We therefore derived and validated cut-off values to determine hypertension status after the first duplicate reading of a HBPM series in a web-based worksite health promotion programme., Method: Nine hundred forty-five employees were included in the derivation and 528 in the validation cohort, which was divided into a normal (n = 297) and increased cardiometabolic risk subgroup (n = 231), and a subgroup with a history of hypertension (n = 98). Six duplicate home measurements were collected during three consecutive days. Systolic and diastolic readings at the first duplicate measurement were used as predictors for hypertension in a multivariate logistic model. Cut-off values were determined using receiver operating characteristics analysis., Results: Upper (≥ 150 or ≥ 95 mmHg) and lower limit (<135 and <80 mmHg) cut-off values were derived to confirm or reject presence of hypertension after one duplicate reading. The area under the curve was 0.94 (standard error 0.01, 95% confidence interval 0.93-0.95). In 62.5% of participants, hypertension status was determined, with 1.1% false positive and 4.7% false negatives. Performance was similar in participants with high and low cardiometabolic risk, but worse in participants with a history of hypertension (10.4% false negatives)., Conclusion: One duplicate home reading is sufficient to accurately assess hypertension status in 62.5% of participants, leaving 37.5% in which the whole HBPM series needs to be completed. HBPM can thus be reliably used as screening tool for hypertension in a working population., (© The Author 2013. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Background: The health risk assessment (HRA) is a type of health promotion program frequently offered at the workplace. Insight into the underlying determinants of participation is needed to evaluate and implement these interventions., Objective: To analyze whether individual characteristics including demographics, health behavior, self-rated health, and work-related factors are associated with participation and nonparticipation in a Web-based HRA., Methods: Determinants of participation and nonparticipation were investigated in a cross-sectional study among individuals employed at five Dutch organizations. Multivariate logistic regression was performed to identify determinants of participation and nonparticipation in the HRA after controlling for organization and all other variables., Results: Of the 8431 employees who were invited, 31.9% (2686/8431) enrolled in the HRA. The online questionnaire was completed by 27.2% (1564/5745) of the nonparticipants. Determinants of participation were some periods of stress at home or work in the preceding year (OR 1.62, 95% CI 1.08-2.42), a decreasing number of weekdays on which at least 30 minutes were spent on moderate to vigorous physical activity (OR(dayPA)0.84, 95% CI 0.79-0.90), and increasing alcohol consumption. Determinants of nonparticipation were less-than-positive self-rated health (poor/very poor vs very good, OR 0.25, 95% CI 0.08-0.81) and tobacco use (at least weekly vs none, OR 0.65, 95% CI 0.46-0.90)., Conclusions: This study showed that with regard to isolated health behaviors (insufficient physical activity, excess alcohol consumption, and stress), those who could benefit most from the HRA were more likely to participate. However, tobacco users and those who rated their overall health as less than positive were less likely to participate. A strong communication strategy, with recruitment messages that take reasons for nonparticipation into account, could prove to be an essential tool for organizations trying to reach employees who are less likely to participate.

Objective: To evaluate the effect of participation in a comprehensive, Web-based worksite health promotion program on absenteeism., Methods: Study population consists of Dutch workers employed at a large financial services company. Linear regression was used to assess the impact of program attendance on the difference between baseline and follow-up absenteeism rates, controlling for gender, age, job level, years of employment, and noncompletion of the program., Results: Data from 20,797 individuals were analyzed; 3826 individuals enrolled in the program during the study period. A 20.3% reduction in absenteeism was shown among program attendees compared with nonparticipants during a median follow-up period of 23.3 months., Conclusions: Participating in the worksite health promotion program led to an immediate reduction in absenteeism. Improved psychological well-being, increased exercise, and weight reduction are possible pathways toward this reduction.

Background: Web-based health risk assessment (HRA) programs can be effective in primary prevention of cardiovascular diseases (CVD). Insight into determinants of participation could improve implementation in the workplace., Aims: To evaluate determinants of participation and reasons for non-participation in a web-based HRA offered to 5125 employees at four Dutch financial and information technology services companies., Methods: The study consisted of a questionnaire to compare sex, age, self-rated health, smoking, current work ability and sick leave between participants and non-participants in the HRA program, as well as reasons for non-participation., Results: HRA participation rate was 37% (1907/5125) and 14% of the non-participants (423/3102) completed the non-participant questionnaire. There were no differences between participants and non-participants in sex, education level, smoking, and current work ability. Compared with non-participants, participants were older (44 versus 41 years, P < 0.001). Among participants, 85% rated their health as 'good' or 'very good', compared with 78% among non-participants (P < 0.001); 88% of the participants reported fewer than 10 days sickness absence in the previous year, compared with 86% of the non-participants (P < 0.05). Reported reasons for non-participation included lack of time (39%) and not being aware of the opportunity to participate (11%)., Conclusions: Evaluation of demographic, health-related, and work-related determinants of participation in a web-based HRA showed differences between participants and non-participants in self-rated health and absenteeism. Implementing a less time-consuming HRA process and providing adequate information to employees prior to inviting them may be necessary to reach larger proportions of employees, including those with less favourable health and work characteristics.

Background: Primary prevention programs at the worksite can improve employee health and reduce the burden of cardiovascular disease. Programs that include a web-based health risk assessment (HRA) with tailored feedback hold the advantage of simultaneously increasing awareness of risk and enhancing initiation of health-behaviour change. In this study we evaluated initial health-behaviour change among employees who voluntarily participated in such a HRA program., Methods: We conducted a questionnaire survey among 2289 employees who voluntarily participated in a HRA program at seven Dutch worksites between 2007 and 2009. The HRA included a web-based questionnaire, biometric measurements, laboratory evaluation, and tailored feedback. The survey questionnaire assessed initial self-reported health-behaviour change and satisfaction with the web-based HRA, and was e-mailed four weeks after employees completed the HRA., Results: Response was received from 638 (28%) employees. Of all, 86% rated the program as positive, 74% recommended it to others, and 58% reported to have initiated overall health-behaviour change. Compared with employees at low CVD risk, those at high risk more often reported to have increased physical activity (OR 3.36, 95% CI 1.52-7.45). Obese employees more frequently reported to have increased physical activity (OR 3.35, 95% CI 1.72-6.54) and improved diet (OR 3.38, 95% CI 1.50-7.60). Being satisfied with the HRA program in general was associated with more frequent self-reported initiation of overall health-behaviour change (OR 2.77, 95% CI 1.73-4.44), increased physical activity (OR 1.89, 95% CI 1.06-3.39), and improved diet (OR 2.89, 95% CI 1.61-5.17)., Conclusions: More than half of the employees who voluntarily participated in a web-based HRA with tailored feedback, reported to have initiated health-behaviour change. Self-reported initiation of health-behaviour change was more frequent among those at high CVD risk and BMI levels. In general employees reported to be satisfied with the HRA, which was also positively associated with initiation of health-behaviour change. These findings indicate that among voluntary participating employees a web-based HRA with tailored feedback may motivate those in greatest need of health-behaviour change and may be a valuable component of workplace health promotion programs.

Introduction: A large proportion of the cardiovascular disease (CVD) burden can potentially be prevented by primary prevention programs addressing major causal risk factors. A Web-based health risk assessment (HRA) with tailored feedback for individual health promotion is a promising strategy. We evaluated the effect on CVD risk of such a program among employees of a Dutch worksite., Methods: We conducted a prospective follow-up study among 368 employees who voluntarily participated in a Web-based HRA program at a single Dutch worksite in 2008. The program included a multicomponent HRA through a Web-based electronic questionnaire, biometrics, and laboratory evaluation. The results were combined with health behavior change theory to generate tailored motivational and educational health advice. On request, a health counseling session with the program physician was available. Follow-up data on CVD risk were collected 1 year after initial participation. The primary outcome was a change in Framingham CVD risk at 6 months relative to baseline. We checked for a possible background effect of an increased health consciousness as a consequence of program introduction at the worksite by comparing baseline measurements of early program participants with baseline measurements of participants who completed the program 6 months later., Results: A total of 176 employees completed follow-up measurements after a mean of 7 months. There was a graded relation between CVD risk changes and baseline risk, with a relative reduction of 17.9% (P = 0.001) in the high-risk category (baseline CVD risk ≥ 20%). Changes were not explained by additional health counseling, medication, or an increase in health consciousness within the company., Conclusions: Voluntary participation in a Web-based HRA with tailored feedback at the worksite reduced CVD risk by nearly 18% among participants at high CVD risk and by nearly 5% among all participants. Web-based HRA could improve CVD risk in similar populations. Future research should focus on the persistence of the effects underlying the CVD risk reduction.

Purpose: We studied the ablative activity of intravesical apaziquone (EOquin) on a papillary marker tumor and determined the incidence of side effects., Materials and Methods: A total of 46 patients with multiple pTa or pT1 bladder tumors underwent visible lesion resection except for 1 marker tumor. Patients were then treated with 6 instillations of apaziquone at weekly intervals. The response was determined 2 to 4 weeks after the last instillation., Results: One patient withdrew informed consent and refused the last treatment due to side effects. A histologically proven complete response was seen in 30 patients. Progression to invasive stage was not observed. Local side effects in this study were comparable to those due to other chemotherapy instillations, such as mitomycin C and epirubicin, but less severe and less frequent compared to those of bacillus Calmette-Guerin instillations., Conclusions: The histological complete response rate after 6 consecutive instillations of apaziquone in patients with superficial bladder cancer was 67% (95% CI 51 to 80). Local side effects were comparable to side effects due to other chemotherapy instillations.

Background: P-glycoprotein (Pgp) expression has been reported to be associated with a poor prognosis in some malignancies such as neuroblastoma, soft tissue sarcoma and acute myeloid leukemia. The prognostic role of Pgp expression in breast cancer is still unclear. We investigated the expression of Pgp in primary and metastatic breast cancer tissues in relation to patient characteristics and treatment outcome., Patients and Methods: Pgp expression was evaluated in 92 primary and 12 metastatic breast cancers by the use of immunohisto/cytochemistry with three monoclonal antibodies (MAbs) (JSB-1, C219, MRK16), and an RNAse protection assay. Follow-up information was available for 77 primary breast cancer patients (median follow-up 42 months; range 2-63 months)., Results: Concordance among the anti-Pgp MAbs varied, the highest being between JSB-1 and MRK16 (71%; p=0.002). Pgp expression was more frequent in metastatic disease (58%) than in primary breast cancer (29%) (JSB-1; p=0.055). Pgp expression as assessed with JSB-1 (univariate analysis; p<0.05) was associated with shorter overall survival (OS). Nineteen (21%) primary breast cancers had Pgp expression in fibroblasts in desmoplastic stroma and this did not correlate with Pgp expression in the tumor. The combination of Pgp-positive tumor cells and Pgp-expressing fibroblasts was the strongest prognostic factor for OS by multivariate analysis. Subgroup analysis suggested that Pgp expression was associated with a shorter OS in tamoxifen-treated patients, but not in those who received chemotherapy (most often CMF)., Conclusions: Pgp expression in tumor cells, and especially when accompanied by Pgp expression in fibroblasts in desmoplastic stroma, has prognostic value in primary breast cancer patients and is likely to be a marker of a more malignant phenotype. Pgp expression of tumor cells might play a role in tamoxifen resistance. These findings may have important implications for teh treatment of breast cancer patients, and warrant further prospective investigation in a larger patient population.

Purpose: To achieve an adequate plasma concentration of bepridil, a calcium channel blocker, which reverts multidrug resistance (MDR) in vitro, when administered in combination with vinblastine in patients with advanced colorectal cancer, a tumor characterized by high MDR1 gene expression. To study the pharmacokinetics of both drugs, tolerability and antitumor activity in relation to the MDR1 expression in tumor tissue., Patients and Methods: Sixteen colorectal cancer patients entered the study. Bepridil was administered by central venous catheter as 5-mg/kg bolus over 30 minutes, followed by 12 mg/kg for 12 hours and 5 mg/kg for 24 hours. Vinblastine 5 mg/m2 was administered as an intravenous (i.v.) bolus 24.5 hours after the start of bepridil. MDR1/P-glycoprotein (Pgp) expression was assessed in 14 tumor samples by immunohistochemistry and RNase protection assay., Results: The bepridil plasma level was greater than 2 mumol/L at the time of vinblastine administration in all patients investigated. At the dose used in the study, bepridil produced a QTc-prolongation more than 50 ms, which prevented further dose escalation. However, cardiac toxicity was asymptomatic in all treated patients, and other side effects were mild. MDR1/Pgp expression was positive in nine of 14 cases. Of fifteen patients assessable for response, one complete remission of 8 months' duration and 14 progressions were observed. The responding patient attained complete remission again when re-treated on progression with vinblastine alone., Conclusion: Bepridil plasma concentrations needed in vitro to modulate MDR could be achieved in this study with tolerable toxicity; however, despite most tumors being MDR1/Pgp-positive, no response was obtained that could be attributed to the drug combination. Mechanisms of drug resistance other than MDR are probably implicated in drug resistance of colorectal cancer.

A M(r) 110,000 protein (p110) is overexpressed in P-glycoprotein-negative multidrug-resistant tumor cell lines of different histogenetic origins. These cell lines show an ATP-dependent drug accumulation defect, suggesting the presence of drug transporter molecules different from P-glycoprotein. Immunohistochemical staining with a p110-specific monoclonal antibody (LRP-56) showed that, like P-glycoprotein, the molecule has a high expression in normal epithelial cells and tissues chronically exposed to xenobiotics and potentially toxic agents, such as bronchial cells, cells lining the intestines, and kidney tubules. Staining of LRP-56 is primarily cytoplasmic, in a coarsely granular fashion, indicating that it reacts with a molecule closely associated with vesicular/lysosomal structures. Involvement of p110 in the energy-dependent drug transport process present in the cell lines is unknown.

P-glycoprotein, a transmembrane protein associated with multidrug resistance in cancer cells, is also expressed in normal tissues. To get more insight into the physiologic role of mdr1/P-glycoprotein, we investigated its expression in human fetal tissues after 7 to 38 weeks of gestation by an immunohistochemical technique, using three different monoclonal antibodies, and by a sensitive RNAse protection assay. Expression of mdr1-mRNA could already be demonstrated in the embryonal phase of human development, after 7 weeks of gestation. Comparing the adult with the fetal tissue distribution, differences were found in specific organs, such as adrenal, intestine, respiratory epithelium, and brain capillaries. In the fetal zone cells of the fetal adrenal cortex no staining was observed by immunohistochemistry, whereas the definitive zone showed increasing expression throughout gestation. Prenatal intestine did not show staining of the epithelium, although definite mdr1-mRNA expression was observed in late specimens. Interestingly, respiratory epithelium of main bronchi and pharynx, not expressing P-gp in adults, did stain positive. Expression of P-gp in brain capillaries was not observed before the third trimester of pregnancy, whereas in kidney and liver, mdr1-mRNA expression and staining for P-glycoprotein were detected in early fetal life (11 to 14 weeks). These findings suggest a pivotal role of P-glycoprotein in physiology of various organs already in early phases of human development and may help to identify its physiologic substrates.

The use of calcium antagonists as multidrug resistance reversing agents is limited by acute cardiac toxicity which, for verapamil, becomes prohibitive when concentrations in plasma approach those required in vitro for its action. A new calcium antagonist, bepridil, is as active as verapamil in reversing drug resistance in vitro. In addition, bepridil has some more favourable pharmacological properties compared with verapamil and other calcium antagonists. 14 patients with progressive advanced cancer, resistant to doxorubicin or epirubicin, were treated with the same anthracycline in combination with bepridil. Bepridil was administered in a continuous 36 h infusion at 22 mg/kg/36 h, with a dose scheme which should result in a steady state plasma concentration of approximately 5 mumol/l, able to reverse anthracycline resistance in vitro. Pharmacokinetic studies demonstrated a median bepridil plasma concentration of 5.3 mumol/l (range 2.6-19.3 mumol/l), at the time of administration of the anthracycline. No acute cardiac toxicity was observed and apparently bepiridil did not induce an increase or change in anthracycline toxicity. However, 2 patients developed overt chronic heart failure after treatment discontinuation, which caused 1 patient's death, and a significant reduction in left ventricular ejection fraction was seen in 4 patients. This chronic cardiac toxicity could be related to the total anthracycline dose received. 5 patients attained short lasting minor responses, 3 had stable disease and 6 progressed. Immunohistochemical studies in 7 tumours failed to reveal P-glycoprotein expression. Further trials with escalating doses of bepridil in combination with multiple drug resistance related anticancer agents are warranted.

Adult renal cell carcinoma (RCC) is clinically resistant to chemotherapy. However, in nephroblastoma (NBL) chemotherapy has increased survival dramatically. We studied the P-glycoprotein (P-gp) expression of 18 RCC and 9 NBL as well as 1 benign renal adenoma and fetal renal tissue using three different monoclonal antibodies (MRK-16, C-219, JSB-1). P-gp was found positive with all three antibodies in 12/18 RCC, while only 2 tumors were completely negative. Staining varied with respect to intensity and number of positive cells [5%-90%]. Intense staining was seen at the apical side of malignant tubules in well differentiated parts of RCC and in tubular structures of the benign renal adenoma. Poorly differentiated parts of the tumors showed less staining. In NBL blastemal parts were negative. In 4/8 specimens showing focal epithelial differentiation, however, the luminal side of more differentiated tubular structures did stain, strongly resembling P-gp staining in the developing fetal human kidney. These results indicate that P-gp expression in normal (fetal) human kidney as well as in benign and malignant tumors derived from this organ depends on the degree of differentiation of tubules, which may have implications for chemotherapy sensitivity in both malignant tumors.

Calcium channel blockers, calmodulin inhibitors, and some other classes of non-related compounds reverse multi-drug resistance. In the present study, we found that several resistance modifiers are more toxic for MDR cells than for the corresponding sensitive parent cells, whereas others show the opposite effect. Several calcium channel blockers including bepridil, diltiazem, nifedipine and verapamil, as well as the calmodulin inhibitor trifluoperazine, were more toxic for several MDR cell lines than for the parent cell lines. In contrast, cross-resistance for cyclosporin A and the verapamil analogue Ro II-2933/001 was observed in the MDR/sensitive cell couple CHRC5/AUXB1, probably due to a concentration-dependent stimulation of cell growth in the range of 0-4 microM cyclosporin A and of 1-4 microM Ro II-2933/001. In partially revertant CHRC5 cells, growth inhibition by Ro II-2933/001 at concentrations below I microM, as seen in CHRC5 cells, changed into growth stimulation, and the collateral sensitivity to verapamil and bepridil disappeared almost completely. In the MDR cells CHRC5, 2780AD and DC3F/DMXX, cross-resistance to another calcium channel blocking agent, Ro II-1781/001 (tiapamil), was observed as well. This compound showed exceptional behavior: it induced marked potentiation of Dx cytotoxicity as well as stimulation of Dx accumulation in AUXB1 cells, even at low tiapamil concentrations, but not in the CHRC5 cells, even at high concentrations. It is concluded that resistance modifiers can selectively influence growth of MDR cells via more than one process, and resulting in either strong growth inhibition in MDR cells relative to the effect on sensitive cells or in growth stimulation.

P-glycoprotein is a molecule strongly associated with multi-drug resistance to certain cytostatic drugs, including adriamycin, vincristine, and daunorubicin. Using 3 monoclonal antibodies directed at different epitopes of this molecule (JSB-1, MRK16, C219) we investigated the tissue distribution of P-glycoprotein in normal and malignant human tissues, employing a routine immunoperoxidase technique. P-glycoprotein was found in the gastrointestinal epithelium, epithelia of the bronchi, mammary gland, pancreatic ducts, renal tubules, prostate gland, salivary gland, sweat glands of the skin, as well as in bile canaliculi and ductules, the adrenal and in endothelium of capillaries in various organs, most notably the brain. Mostly the pattern of reactivity of the 3 antibodies was similar, but some distinctly different staining reactions were seen. Reactivity was found in a variety of human tumors, arising from tissues normally expressing P-glycoprotein. Knowledge of the distribution and function of this molecule in both normal and malignant tissues may predict resistance and thus may influence choice of therapy. The role of P-glycoprotein in normal tissues and its implications for chemotherapy is discussed.

The kinetics and short-term (10 weeks) effects of trimazosin, an alpha 1-adrenoreceptor antagonist, on renal function and blood pressure in patients with moderate chronic renal insufficiency and hypertension, have been studied for the first time. Eight patients in whom the blood pressure was not normalized with a diuretic alone underwent pharmacokinetic studies and assessment of the renal function during a 10-week period of trimazosin therapy. Trimazosin significantly lowered blood pressure (recumbent and upright) without significantly altering renal function. Renal vascular resistance was decreased by 14%. Fractional sodium excretion, proteinuria and laboratory serum tests remained unchanged. Neither body weight nor pulse rate were affected. Moderate renal insufficiency did not modify the pharmacokinetics of the drug. Thus, trimazosin, as second-step antihypertensive agent, appeared to be safe and effective in patients with moderate renal insufficiency and hypertension, without exerting favourable or adverse renal effects during short-term therapy.