[Coumarin or DOAC in frail elderly patients with atrial fibrillation?] / Cumarine of DOAC bij kwetsbare ouderen met atriumfibrilleren?

OBJECTIVE: To investigate whether frail elderly people with atrial fibrillation (AF) who are currently using a vitamin K antagonist (VKA) should be switched to a direct-acting oral anticoagulant (DOAC). DESIGN: Randomized clinical trial. METHODS: 662 frail elderly AF patients were switched to a DOAC, and 661 patients continued their VKA. The primary endpoint was a major or clinically relevant non-major bleeding during 1 year of follow-up. Secondary endpoints included thrombo-embolic events. RESULTS: The mean age of the included patients was 83 years. In the 'switch to DOAC arm', 101 bleeding events (15.3%) occurred and in the 'continue with VKA arm', 62 bleeding events (9.4%); an increase of 69% more bleeding events (P-value 0.001). The number of thrombo-embolic events was not significantly different between both groups. CONCLUSION: Switching from a VKA to a DOAC in frail elderly people with AF leads to 69% more bleeding, without a difference in thrombo-embolic events.

Safety and Tolerability of Tecarfarin (ATI-5923) in Healthy Chinese Volunteers: Multiple Oral Dose-Escalation Phase I Trial.

BACKGROUND: Tecarfarin (ATI-5923), a structural analog of warfarin, was designed to provide more uniform and stable anticoagulation. OBJECTIVE: We aimed to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profile of tecarfarin when administered in multiple ascending doses (MADs) to healthy Chinese volunteers. METHODS: Forty healthy Chinese volunteers were enrolled into four sequential cohorts (10, 20, 30, and 40 mg), with 10 subjects in each cohort. Participants in the MAD study for each sequential cohort were dose-titrated to achieve the target international normalized ratio (INR 1.7-2.0) for 14 days. Safety and tolerability were assessed throughout the study. RESULTS: The pharmacokinetic and pharmacodynamic profile of tecarfarin was investigated in a healthy Chinese population. Dose titration of tecarfarin was necessary to keep the INR in the target range in all subjects in the 20, 30 and 40 mg cohorts and a few subjects (n = 3) in the 10 mg cohort. Tecarfarin was well tolerated without serious adverse events. Only one treatment-related adverse event (hematochezia) resulted in early withdrawal from the MAD 40 mg cohort. CONCLUSION: Tecarfarin was well-tolerated by Chinese volunteers. Dose titration was needed for tecarfarin doses larger than 20 mg to keep the INR in the target range. REGISTRATION: ClinicalTrials.gov identifier: NCT04627116.

Coumarin-Induced Hepatotoxicity: A Narrative Review.

Coumarin is an effective treatment for primary lymphoedema, as well as lymphoedema related to breast cancer radiotherapy or surgery. However, its clinical use is limited in several countries due to the possible occurrence of hepatotoxicity, mainly in the form of mild to moderate transaminase elevation. It is worth noting that only a few cases of severe hepatotoxicity have been described in the literature, with no reported cases of liver failure. Data available on coumarin absorption, distribution, metabolism, and excretion have been reviewed, focusing on hepatotoxicity studies carried out in vitro and in vivo. Finally, safety and tolerability data from clinical trials have been thoroughly discussed. Based on these data, coumarin-induced hepatotoxicity is restricted to a small subset of patients, probably due to the activation in these individuals of alternative metabolic pathways involving specific CYP450s isoforms. The aim of this work is to stimulate research to clearly identify patients at risk of developing hepatotoxicity following coumarin treatment. Early identification of this subset of patients could open the possibility of more safely exploiting the therapeutical properties of coumarin, allowing patients suffering from lymphoedema to benefit from the anti-oedematous activity of the treatment.

Factors associated with nonadherence to the use of coumarin derivatives or direct oral anticoagulants: A systematic review of observational studies.

Nonadherence to thromboprophylaxis treatment with oral anticoagulants (OAC) is a public health problem and may be associated with high mortality rates. We sought to synthesize the factors associated with nonadherence to therapy with coumarin derivatives or direct oral anticoagulants. A systematic review was performed at electronic databases Medline, Embase, CINAHL, Lilacs and grey literature (Google Scholar, MedNar, OpenGray, ProQuest Dissertations and Theses, and hand search). This study was conducted according to Cochrane's method and PRISMA. The registration on PROSPERO is CRD42020223555. Overall, 1270 studies were identified and nine studies were selected for this review. In hand searching, 77 studies were found, but none included. The associated factors with nonadherence were heterogeneous, and some factors were described as both risk and protection for nonadherence, with few variables showing consistent results among the studies. Variables reported only as risk factors were "male sex", "hospitalization", "Charlson score" and "bleeding", while "white race", CHA2 DS2 VASc (score range 2-9)" and "polypharmacy" were reported only as protective factors. Most studies did not present details in the description of concepts and methods to assess nonadherence. In clinical practice, the knowledge on factors associated with nonadherence is helpful to identifying patients at higher risk of complications that would benefit from individualized interventions.

Factor-guided diagnosis of coagulopathy associated with coumarin-contaminated synthetic cannabinoids.

Contamination of synthetic cannabinoids with toxic coumarin derivatives known as superwarfarins can induce a persistent coagulopathy. In comparison to warfarin, these derivatives have prolonged half-lives and laboratory assays for detection are not readily available in clinical practice. To our knowledge, factor-guided diagnosis of coagulopathy secondary to coumarin-contaminated synthetic cannabinoids has not been described previously. Our case report details a young adult who presented to the hospital with an acute elevation in INR without any reported past medical history or illicit substance use. Factor levels were obtained and resulted quickly revealing deficiencies in factors II, VII, IX, and X, which led to a possible diagnosis of coagulopathy secondary to coumarin-contaminated synthetic cannabinoids. Upon further questioning, the patient admitted to use of synthetic cannabinoids. A bromadiolone assay was sent for testing, which resulted positive after patient discharge. Toxic coumarin derivative assays are not immediately available for reference. Given the patient's confirmed synthetic cannabinoid consumption and the possibility of coagulopathy from coumarin-contamination, factor levels served as a guide for diagnosis and treatment prior to the confirmatory assay. Obtaining factor levels in patients with an unexplained coagulopathy and suspected cannabis or synthetic cannabinoid use may aid clinicians in a more prompt diagnosis and treatment.

Pharmacological report of recently designed multifunctional coumarin and coumarin-heterocycle derivatives.

Coumarin is a naturally available molecule and has been identified as a potent pharmacophore due to its pharmacological activity. Because of this, coumarin has been exploited synthetically to prepare a wide range of derivatives. In fact, most coumarin derivatives have been found to be less toxic, which is the most essential property for a drug molecule. Such molecules are being prepared for therapeutic use as broad-spectrum pharmacological agents. Microbial diseases including viral diseases have become very common and are responsible for many deaths worldwide. In particular, microbial drug resistance is a problem that needs to be tackled in an effective manner. Also, for Alzheimer's disease, which affects most elderly persons, no efficient chemotherapy exists. In addition, although diabetes, a metabolic syndrome, can be treated with many drugs, there is no complete cure. Thus, more potent antidiabetic agents are required for the management of diabetes. Likewise, for the treatment of a wide range of ailments caused by microbes, genetic factors, or lifestyle-related factors, an efficient drug regimen is needed. In view of this, coumarin derivatives are designed and evaluated. Here, coumarin derivatives that have been reported recently are compiled, classified and evaluated critically. This study briefly takes the structure-activity relationship into consideration and suggests the next suitable step. With a focus on the most potent molecules, the pharmacological activity of the evaluated molecules is described.

Naturally occurring coumestans from plants, their biological activities and therapeutic effects on human diseases.

Naturally occurring coumestans are known as a collection of plant-derived polycyclic aromatic secondary metabolites which are characterized by the presence of an oxygen heterocyclic four-ring system comprising a coumarin moiety and a benzofuran moiety sharing a CË­C bond. Recently, there is an increasing attention in excavating the medicinal potential of coumestans, particularly coumestrol, wedelolactone, psoralidin and glycyrol, in a variety of diseases. This review is a comprehensive inventory of the chemical structures of coumestans isolated from various plant sources during the period of 1956-2020, together with their reported biological activities. 120 molecules were collected and further classified as coumestans containing core skeleton, dimethylpyranocoumestans, furanocoumestans, O-glycosylated coumestans and others, which showed a wide range of pharmacological activities including estrogenic, anti-cancer, anti-inflammatory, anti-osteoporotic, organ protective, neuroprotective, anti-diabetic and anti-obesity, antimicrobial, immunosuppressive, antioxidant and skin-protective activities. Furthermore, this review focuses on the counteraction of coumestans against bone diseases and organ damages, and the involved molecular mechanisms, which could provide important information to better understand the medicinal values of these compounds. This review is intended to be instructive for the rational design and development of less toxic and more effective drugs with a coumestan scaffold.

Coumarin hybrid derivatives as promising leads to treat tuberculosis: Recent developments and critical aspects of structural design to exhibit anti-tubercular activity.

Tuberculosis (TB) is a highly contagious airborne disease with nearly 25% of the world's population infected with it. Challenges such as multi drug resistant TB (MDR-TB), extensive drug resistant TB (XDR-TB) and in rare cases totally drug resistant TB (TDR-TB) emphasizes the critical and urgent need in developing novel TB drugs. Moreover, the prolonged and multi drug treatment regime suffers a major drawback due to high toxicity and vulnerability in TB patients. This calls for intensified research efforts in identifying novel molecular scaffolds which can combat these issues with minimal side effects. In this pursuit, researchers have screened many bio-active molecules among which coumarin have been identified as promising candidates for TB drug discovery and development. Coumarins are naturally occurring compounds known for their low toxicity and varied biological activity. The biological spectrum of coumarin has intrigued medicinal researchers to investigate coumarin scaffolds for their relevance as anti-TB drugs. In this review we focus on the recent developments of coumarin and its critical aspects of structural design required to exhibit anti-tubercular (anti-TB) activity. The information provided will help medicinal chemists to design and identify newer molecular analogs for TB treatment and also broadens the scope of exploring future generation potent yet safer coumarin based anti-TB agents.

Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study.

BACKGROUND: CH5126766 (also known as VS-6766, and previously named RO5126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations. METHODS: We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or metastatic solid tumours. For the basket dose-expansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4·0 mg or 3·2 mg CH5126766 three times per week; (2) 4·0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4·0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509. FINDINGS: Between June 5, 2013, and Jan 10, 2019, 58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2·3 months (IQR 1·6-3·5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4·0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3·2 mg CH5126766 three times per week. 4·0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%]), hypoalbuminaemia (six [11%]), and fatigue (four [7%]). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11·6-47·8]) of 26 response-evaluable patients in the basket expansion achieved objective responses. INTERPRETATION: To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation. FUNDING: Chugai Pharmaceutical.

The Role of Acid Suppressants in the Prevention of Anticoagulant-Related Gastrointestinal Bleeding: A Systematic Review and Meta-Analysis.

Background/Aims: Although acid suppressants are widely used for the prevention or treatment of drug-induced upper gastrointestinal bleeding (GIB), evidence regarding the prevention of anticoagulant-related GIB is scarce. The aim of this study was to evaluate the protective effect of acid suppressants against anticoagulant-related GIB. Methods: A systematic review was conducted of studies that evaluated the protective effect of acid suppressants against anticoagulant-related GIB found in PubMed, the Cochrane library, Embase, and KoreaMed from the date of database inception to April 2018. Random effect model meta-analyses with sensitivity analyses were conducted. The methodological quality of each included publication was evaluated using the Risk of Bias Assessment Tool for Nonrandomized Studies. Publication bias was assessed. Results: In total, six nested case-control or cohort studies were identified and analyzed. Proton-pump inhibitors (PPI) had a protective effect against upper GIB in patients on dicumarinics (risk ratio [RR], 0.56; 95% confidence interval [CI], 0.38 to 0.83; I2, 0%); however, the histamine-2 receptor antagonist did not have the same effect (RR, 0.97; 95% CI, 0.52 to 1.81; I2, 0%). Acid suppressants did not have a protective effect against GIB in patients on dabigatran (hazard ratio, 0.78; 95% CI, 0.44 to 1.37; I2, 81.8%). Conclusions: The protective effect of PPIs against dicumarinics-related upper GIB was clear, while there was no evidence supporting the protective effect of acid suppressants against dabigatran-related GIB. However, in the absence of randomized trials demonstrating a lack of bias, solid conclusions cannot be drawn.

Therapeutic Evaluation of Synthetic Peucedanocoumarin III in an Animal Model of Parkinson's Disease.

The motor and nonmotor symptoms of Parkinson's disease (PD) correlate with the formation and propagation of aberrant α-synuclein aggregation. This protein accumulation is a pathological hallmark of the disease. Our group recently showed that peucedanocoumarin III (PCIII) possesses the ability to disaggregate ß sheet aggregate structures, including α-synuclein fibrils. This finding suggests that PCIII could be a therapeutic lead compound in PD treatment. However, the translational value of PCIII and its safety information have never been explored in relevant animal models of PD. Therefore, we first designed and validated a sequence of chemical reactions for the large scale organic synthesis of pure PCIII in a racemic mixture. The synthetic PCIII racemate facilitated clearance of repeated ß sheet aggregate (ß23), and prevented ß23-induced cell toxicity to a similar extent to that of purified PCIII. Given these properties, the synthetic PCIII's neuroprotective function was assessed in 6-hydroxydopamine (6-OHDA)-induced PD mouse models. The PCIII treatment (1 mg/kg/day) in a 6-OHDA-induced PD mouse model markedly suppressed Lewy-like inclusions and prevented dopaminergic neuron loss. To evaluate the safety profiles of PCIII, high dose PCIII (10 mg/kg/day) was administered intraperitoneally to two-month-old mice. Following 7 days of PCIII treatment, PCIII distributed to various tissues, with substantial penetration into brains. The mice that were treated with high dose PCIII had no structural abnormalities in the major organs or neuroinflammation. In addition, high dose PCIII (10 mg/kg/day) in mice had no adverse impact on motor function. These findings suggest that PCIII has a relatively high therapeutic index. Given the favorable safety features of PCIII and neuroprotective function in the PD mouse model, it may become a promising disease-modifying therapy in PD to regulate pathogenic α-synuclein aggregation.

Low-molecular-weight-heparin versus a coumarin for the prevention of recurrent venous thromboembolism in high- and low-risk patients with active cancer: a post hoc analysis of the CLOT Study.

In patients with active cancer and acute venous thromboembolism (VTE), the low-molecular-weight-heparin (LMWH) dalteparin is more effective than vitamin K antagonist (VKA) in reducing the risk of recurrent venous thromboembolism (rVTE) without increasing the risk of bleeding. However, the relative benefit of LMWH versus VKA in patients with active cancer at high or low risk of rVTE and bleeding is unclear. This post hoc analysis used data from the CLOT study to explore the efficacy and safety of LMWH versus VKA in preventing recurrent thrombosis in high- and low-risk patients with active cancer. High-risk patients were defined by metastatic disease and/or antineoplastic treatment at baseline; low-risk patients presented with neither. Among high-risk patients, rVTE occurred in 25/318 (8%) (LMWH) versus 53/314 (17%) (VKA) (hazard ratio, 0.44; p = 0.001). No significant difference was detected in the rate of major or any bleeding. The 6-month mortality rate was 40% (LMWH) versus 41% (VKA). In low-risk patients, 2/20 (10%) (LMWH) had rVTE versus 0/24 (0%) (VKA) (hazard ratio, not estimable; p = 0.998). No significant difference was detected in the rate of major or any bleeding. The 6-month mortality rate was 20% (LMWH) versus 29% (VKA). In patients with cancer-associated thrombosis at high risk of rVTE and bleeding, the LMWH dalteparin was more effective than VKA in reducing the risk of rVTE without increasing the risk of bleeding. No difference in rate of rVTE or bleeding was observed between LMWH and VKA among low-risk patients.

Safety and Effectiveness of Bipolar Transurethral Resection of the Prostate in Patients Under Ongoing Oral Anticoagulation with Coumarins or Antiplatelet Drug Therapy Compared to Patients Without Anticoagulation/Antiplatelet Therapy.

Objective: To determine whether transurethral resection of the prostate (TURP) is safe and effective in patients under ongoing therapeutic oral anticoagulation (OAC) or antiplatelet drug (APD) therapy. Patients and Methods: We analyzed data on 276 consecutive TURP patients under ongoing APD therapy with acetylsalicylic acid (n = 130) or clopidogrel (n = 16) or ongoing OAC with phenprocoumon (n = 57), without stopping or bridging the medication, compared to 73 TURP patients without APD/OAC. Results: Outcomes of patients under acetylsalicylic acid were comparable to the controls. Under ongoing OAC therapy TURP patients tended to need slightly longer bladder irrigation (median 24 hours vs 22 hours, p = 0.06), needed longer transurethral catheterization (median 42 hours vs 24 hours, p = 0.031), were threefold more likely to have postoperative urinary retention (18% vs 6%, p = 0.04), had slightly longer hospital stays (median 4 days vs 3 days, p = 0.008), and tended to need more blood transfusions (9% vs 1%, p = 0.09), compared to controls. TURP patients under ongoing APD therapy with clopidogrel needed slightly longer bladder irrigation (median 24 hours vs 22 hours, p = 0.006), received more blood transfusions (19% vs 1%, p = 0.017), and had more rehospitalizations (19% vs 3%, p = 0.039). The significant functional improvement 1, 3, and 12 months after TURP was similar in all groups. Conclusions: Ongoing APD therapy with acetylsalicylic acid does not significantly impact TURP outcomes in terms of bleeding complications. Patients under ongoing therapeutic OAC with phenprocoumon or APD with clopidogrel can safely undergo TURP with an increased risk of bleeding complications, blood transfusions, and longer hospitalization.

Effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy on management of breast cancer-related lymphedema.

PURPOSE: To assess the effectiveness and safety of a product containing diosmin, coumarin, and arbutin (Linfadren®) in addition to complex decongestive therapy (CDT) on the management of patients with a breast cancer-related lymphedema (BCRL). METHODS: Fifty outpatients (average age of 56.2 ± 2.7 years, range 28-71) with a BCRL were enrolled for this study. Patients were randomly assigned (1:1 ratio) to receive either CDT consisting of skin care, manual lymphatic drainage, remedial exercises, and elastic compression garment (control group, n = 25) or CDT plus Linfadren® (study group, n = 25). Patients were evaluated before and after treatment and 3 months after the end of treatment. Primary outcomes were reduction of upper limb excess volume (EV) and percentage reduction of excess volume (%REV). Secondary outcomes were improvement in Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire, and patient's perception of treatment effectiveness (PPTE). RESULTS: Addition of Linfadren® to CDT yielded an additional reduction of primary outcomes both after treatment (EV, - 521 ml vs. - 256 ml, P < 0.0001; %REV, - 66.4% vs. - 34%, P = 0.02) and at 3-month follow-up (EV, - 59 ml vs. + 24 ml, P < 0.0001; %REV, - 73.6% vs. - 31.4%, P = 0.004). Moreover, statistically significant differences were found between the two groups for the secondary outcomes after treatment (QuickDASH, P = 0.006; PPTE, P = 0.03) and at 3-month follow-up (QuickDASH, P = 0.006; PPTE, P = 0.02). No patient showed adverse events. CONCLUSIONS: Linfadren® in addition to CDT was a safe and effective therapy for reducing BCRL and was better than CDT alone.

Sensitization to fragrances in Spain: A 5-year multicentre study (2011-2015).

BACKGROUND: Fragrance chemicals constitute the second most frequent cause of contact allergy in Spain. There are no data available concerning the individual fragrances that are most frequently involved. OBJECTIVES: To describe the diagnostic contribution provided by specific fragrance series to the results obtained with baseline series fragrance markers by correlating the results of both series. MATERIALS AND METHODS: We performed a 5-year retrospective study of fragrance marker-positive patients tested with specific fragrance series in 23 Spanish centres. We collected the demographic and clinical characteristics, and compared the results of patch tests obtained from different suppliers. RESULTS: Of 19 588 patients patch tested with the Spanish baseline series, 1590 (8.1%) reacted positively to a fragrance marker. Of these, 1013 (63.7%) were patch tested with a fragrance series, and 664 patients reacted positively to at least one individual fragrance other than hydroxyisohexyl 3-cyclohexene carboxaldehyde. Geraniol was the most frequent allergen. Positive reactions to substances not included in fragrance mix (FM) I or FM II were found in 230 patients. Of the 436 FM I-positive patients and the 419 FM II-positive patients, 184 (42%) and 64 (39.1%), respectively, had no positive reactions to fragrance series. In the case of FM I, negative results were more common when individual fragrances were patch tested at low concentrations. CONCLUSIONS: We recommend patch testing all patients positive for any fragrance marker with a specific fragrance series. The correlation between the results of baseline series and fragrance series could be improved by increasing the concentrations of individual fragrances.

Molecular Pathway of Psoralidin-Induced Apoptosis in HepG2 Cell Line.

OBJECTIVE: To test the role of psoralidin in human liver cancer HepG2 cells in vitro. METHODS: Cell viability was assessed by methylthiazolyldiphenyl-tetrazolum bromide assay and apoptotic cells were labeled by annexin V then sorted by flow cytometry. Protein expressions of caspase-3, caspase-8, caspase-9, Bax, Bid, Bcl-2, Bcl-xL and p53 were examined by western blot while activity of caspase-3, -8 and -9 were also determined. RESULTS: Psoralidin reduces cell viability greatly in a time dependent manner (64%, 40%, 21%, 12% at 2, 6, 24 and 48 h treatment with 64 µmol/L psoralidin respectively) and up-regulates activities of caspase-3, -8 and -9 in a concentration dependent manner (between 4 to 64 µmol/L). Psoralidin also increases the expression of pro-apoptosis genes Bax, Bid and p53 while decreases the expression of pro-survival genes Bcl-2 and Bcl-xL, both in a concentration dependent manner between 4 and 64 µmol/L (P<0.05 at 16 and 64 µmol/L). Caspase-3 inhibitor (Ac-DEVD-CHO at concentrations between 10 to 20 µmol/L), p53 inhibitor (pifithrin-α at 5 µmol/L) and cyclosporin A can attenuate the apoptotic effect of psoralidin. CONCLUSION: The cytotoxic role of psoralidin might work through both intrinsic and extrinsic apoptotic pathway.

Effect of CYP4F2, VKORC1, and CYP2C9 in Influencing Coumarin Dose: A Single-Patient Data Meta-Analysis in More Than 15,000 Individuals.

The cytochrome P450 (CYP)4F2 gene is known to influence mean coumarin dose. The aim of the present study was to undertake a meta-analysis at the individual patients level to capture the possible effect of ethnicity, gene-gene interaction, or other drugs on the association and to verify if inclusion of CYP4F2*3 variant into dosing algorithms improves the prediction of mean coumarin dose. We asked the authors of our previous meta-analysis (30 articles) and of 38 new articles retrieved by a systematic review to send us individual patients' data. The final collection consists of 15,754 patients split into a derivation and validation cohort. The CYP4F2*3 polymorphism was consistently associated with an increase in mean coumarin dose (+9% (95% confidence interval (CI) 7-10%), with a higher effect in women, in patients taking acenocoumarol, and in white patients. The inclusion of the CYP4F2*3 in dosing algorithms slightly improved the prediction of stable coumarin dose. New pharmacogenetic equations potentially useful for clinical practice were derived.

Rational design of coumarin derivatives as antituberculosis agents.

AIM: A series of coumarin derivatives was designed as potential antituberculosis agents. RESULTS: The compounds were screened against active and dormant Mycobacterium tuberculosis (Mtb). Compounds 3k and 3n were found to have the most promising activity against replicating MtbH37Rv exhibiting minimum inhibitory concentration of 4.63 and 9.75 µM respectively. The compounds were also effective against dormant MtbH37Rv exhibiting more potency than the standard drugs, isoniazid and rifampicin. The compounds were found to be non-cytotoxic against human cell lines. CONCLUSION: This study provides promising antituberculosis agents that are effective against replicating as well as dormant Mtb and can thus act as potential leads for further development.

Assessment of the skin sensitizing potential of chemicals, contained in foods and/or cosmetic ingredients, using a modified local lymph node assay with an elicitation phase (LLNA:DAE) method.

We evaluated the skin sensitizing potential of 10 natural organic chemicals, or their derivatives, which are included in foods and/or skin products, using a modified local lymph node assay (LLNA), with an elicitation phase (LLNA:DAE). The following compounds were tested: carminic acid, esculetin, 4-methyl esculetin, coumarin, quercetin, curcumin, naringenin, chlorogenic acid, isoscopoletin, and shikonin. Esculetin, 4-methyl esculetin, isoscopoletin, and shikonin yielded positive results. In particular, shikonin at a very low concentration (0.05%) induced an elicitation response. In conclusion, four of the 10 natural organic chemicals tested had a skin sensitization potential, with shikonin producing serious reaction even at a very low concentration.

Safety evaluation of auraptene in rats in acute and subacute toxicity studies.

Auraptene (AUR) is a natural, bioactive, monoterpene coumarin ether. It has anti-inflammatory, anti-carcinogenic, anti-bacterial, neuroprotective, and hepatoprotective properties. The aim of the present study was to assess the acute and subacute toxicity of oral administration of AUR in rats by evaluating clinical signs, haematology, biochemical factors, pathological changes and immune-toxicity. Acute administration of AUR in doses of 125, 250, 500, 1000 and 2000 mg/kg body weight had no mortality or clinical signs in a period of two days. To evaluate subacute toxicity, AUR was administrated for 28 days by oral gavage in doses of 125 and 250 mg/kg. There were significant differences in the haematological and biochemical data of the treated and untreated groups. However, almost all haematological differences were within normal reference ranges. Subacute administration of AUR showed no toxic histopathological effects on organ tissue. Evaluation of immune-toxicity also revealed no significant differences between treatment and untreated groups.