Derivation and validation of Pd/Pa in the assessment of residual ischemia post-intervention: A prospective all-comer registry.

BACKGROUND: Measurement of post-percutaneous coronary intervention (PCI) fractional flow reserve (FFR) demonstrates residual ischemia in a large percentage of cases deemed angiographically successful which, in turn, has been associated with worse long-term outcomes. It has recently been shown that a resting pressure index, Pd/Pa, has prognostic value post stenting, however, its diagnostic value relative to FFR post-PCI has not been evaluated. METHODS: The diagnostic accuracy of Pd/Pa in identifying ischemia (FFR≤0.80) pre- and post-PCI was evaluated. Three patient subsets were analyzed. A reference pre-PCI cohort of 1,255 patients (1,560 vessels) was used to measure the accuracy of pre-PCI Pd/Pa vs. FFR. A derivation post-PCI group of 574 patient (664 vessels) was then used to calculate the diagnostic accuracy of post-PCI Pd/Pa vs. FFR. A final prospective validation cohort of 230 patients (255 vessels) was used to test and validate the diagnostic performance of post-PCI Pd/Pa. RESULTS: Median Pd/Pa and FFR were 0.90 (IQR 0.90-0.98) and 0.80 (IQR 0.71-0.88) in the reference pre-PCI model, 0.96 (IQR 0.93-1.00) and 0.87 (IQR 0.77-0.90) in the post-PCI derivation model, and 0.94 (IQR 0.89-0.97) and 0.84 (IQR 0.77-0.90) in the post-PCI validation model respectively. There was a strong linear correlation between Pd/Pa and FFR in all three models (p < 0.0001). Using ROC analysis, the optimal Pd/Pa cutoff value to predict a FFR ≤ 0.80 was ≤0.92 (AUC 0.87) in the pre-PCI model, ≤0.93 (AUC 0.85) in the post-PCI derivation model, and ≤ 0.90 (AUC 0.91) in the post-PCI validation model. Using a hybrid strategy of post-PCI Pd/Pa and post-PCI FFR when necessary (25% patients), overall diagnostic accuracy was improved to 95%. CONCLUSIONS: Pd/Pa has excellent diagnostic accuracy for identifying ischemia post-intervention. Using a hybrid strategy of post-PCI Pd/Pa first, and FFR afterwards, if required, adenosine administration can be avoided in over 75% of physiologic assessments post intervention.

Synthesis of quinazolines as tyrosine kinase inhibitors.

In the present review, the discovery and development of quinazoline as tyrosine kinase inhibitors has been described. The synthesis of most potent quinazoline inhibitors of EGFR, VEGFR and PDGRF has been discussed. Structure activity relationship for quinazoline as tyrosine kinase inhibitors has been established. It was found that C-4, C-6 and C-7 positions in quinazoline are appropriate sites for designing new tyrosine kinase inhibitors. This review should help the medicinal chemist in designing more effective tyrosine kinase inhibitors.

Protective effects of Terminalia arjuna against Doxorubicin-induced cardiotoxicity.

Terminalia arjuna has been marked as a potential cardioprotective agent since vedic period. The present study was aimed to investigate the effects of butanolic fraction of Terminalia arjuna bark (TA-05) on Doxorubicin (Dox)-induced cardiotoxicity. Male wistar rats were used as in vivo model for the study. TA-05 was administered orally to Wistar rats at different doses (0.42 mg/kg, 0.85 mg/kg, 1.7 mg/kg, 3.4 mg/kg and 6.8 mg/kg) for 6 days/week for 4 weeks. Thereafter, all the animals except saline and TA-05-treated controls were administered 20 mg/kg Dox intraperitonially. There was a significant decrease in myocardial superoxide dismutase (38.94%) and reduced glutathione (23.84%) in animals treated with Dox. Concurrently marked increase in serum creatine kinase-MB (CKMB) activity (48.11%) as well as increase in extent of lipid peroxidation (2.55-fold) was reported. Co-treatment of TA-05 and Dox resulted in an increase in the cardiac antioxidant enzymes, decrease in serum CKMB levels and reduction in lipid peroxidation as compared to Dox-treated animals. Electron microscopic studies in Dox-treated animals revealed mitochondrial swelling, Z-band disarray, focal dilatation of smooth endoplasmic reticulum (SER) and lipid inclusions, whereas the concurrent administration of TA-05 led to a lesser degree of Dox-induced histological alterations. These findings suggest that butanolic fraction of Terminalia arjuna bark has protective effects against Dox-induced cardiotoxicity and may have potential as a cardioprotective agent.

Synthesis and structure-activity relationships of potent antitumor active quinoline and naphthyridine derivatives.

The disease of cancer has been ranked second after cardiovascular diseases and plant-derived molecules have played an important role for the treatment of cancer. Nine cytotoxic plant-derived molecules such as vinblastine, vincristine, navelbine, etoposide, teniposide, taxol, taxotere, topotecan and irinotecan have been approved as anticancer drugs. Recently, epothilones are being emerging as future potential anti-tumor agents. However, targeted cancer therapy has now been rapidly expanding and small organic molecules are being exploited for this purpose. Amongst target specific small organic molecules, quinazoline was found as one of the most successful chemical class in cancer chemotherapy as three drugs namely Gefitinib, Erlotinib and Canertinib belong to this series. Now, quinazoline related chemical classes such as quinolines and naphthyridines are being exploited in cancer chemotherapy and a number of molecules such as compounds EKB-569 (52), HKI-272 (78) and SNS-595 (127a) are in different phases of clinical trials. This review presents the synthesis of quinolines and naphthyridines derivatives, screened for anticancer activity since year 2000. The synthesis of most potent derivatives in each prototype has been delineated. A brief structure activity relationship for each prototype has also been discussed. It has been observed that aniline group at C-4, aminoacrylamide substituents at C-6, cyano group at C-3 and alkoxy groups at C-7 in the quinoline ring play an important role for optimal activity. While aminopyrrolidine functionality at C-7, 2'-thiazolyl at N-1 and carboxy group at C-3 in 1,8-naphthyridine ring are essential for eliciting the cytotoxicity. This review would help the medicinal chemist to design and synthesize molecules for targeted cancer chemotherapy.

Anticancer and anti-inflammatory activities of 1,8-naphthyridine-3-carboxamide derivatives.

Several 1,8-naphthyridine-3-carboxamide derivatives (8-23) were synthesized and tested for in vitro cytotoxicity against eight cancer cell lines and a normal cell line. Compound 12 exhibited high cytotoxicity (IC(50)=1.37microM) in HBL-100 (breast) cell line while compounds 17 (IC(50)=3.7microM) and 22 (IC(50)=3.0microM) have shown high cytotoxicity in KB (oral) and SW-620 (colon) cell lines, respectively. The synthesized 1,8-naphthyridine-3-carboxamides were also evaluated for anti-inflammatory and myeloprotective activities, indicated by modulation in cytokine and chemokine levels secreted by dendritic cells.

Synthesis and evaluation of 4/5-hydroxy-2,3-diaryl(substituted)-cyclopent-2-en-1-ones as cis-restricted analogues of combretastatin A-4 as novel anticancer agents.

A new series of 2,3-diaryl-4/5-hydroxy-cyclopent-2-en-1-one analogues replacing the cis double bond of combretastatin A-4 (CA-4) by 4/5-hydroxy cyclopentenone moieties was designed and synthesized. The analogues displayed potent cytotoxic activity (IC50<1 microg/mL) against a panel of human cancer cell lines and endothelial cells. The most potent analogues 11 and 42 belonging to the 5-hydroxy cyclopentenone class were further evaluated for their mechanism of action. Both of the analogues led to cell cycle arrest at G2/M phase and induced apoptosis in endothelial cells. Antitubulin property of 42 was superior to 11 and comparable to CA-4. The compound 42 had better aqueous solubility, metabolic stability, and pharmacokinetic profile than CA-4 and also demonstrated significant tumor regression in the human colon xenograft model. Our data suggests that cis-restricted analogues of CA-4 are a new class of molecules that have the potential to be developed as novel agents for the treatment of cancer.

Synthesis of 13-amino costunolide derivatives as anticancer agents.

A number of costunolide derivatives (4a-p) have been synthesized and evaluated for their in vitro cytotoxicity against eight tumor and a non-tumor cell lines. Compound 4d showed around 2-fold better cytotoxicity against SW-620 (colon) cell line with improved safety index than costunolide (1). While compounds 4e, 4g, and 4p have shown around 2- to 3-fold better cytotoxicity against MIAPaCa2 (pancreas), K-562 (leukemia) and PA-1 (ovary) cell lines as well as better safety index in comparison to costunolide (1). Compound 4p also exhibited cytotoxicity against HBL100 (breast) cell line with 2-fold better safety index. Structure-activity relationship has been described.

Betulinic acid derivatives as anticancer agents: structure activity relationship.

Betulinic acid, a pentacyclic triterpene, is widely distributed throughout the tropics. It possesses several biological properties such as anticancer, anti-inflammatory, antiviral, antiseptic, antimalarial, spermicidal, antimicrobial, antileshmanial, antihelmentic and antifeedent activities. However, betulinic acid was highly regarded for its anticancer and anti-HIV activities. Anticancer role of betulinic acid appeared by inducing apoptosis in cells irrespective of their p53 status. Due to high order safety in betulinic acid, a number of structural modifications carried out to improve its potency and efficacy. The C-1, C-2, C-3, C-4, C-20 and C-28 positions are the diversity centers in betulinic acid, and the derivatives resulted on various structural modifications at these positions screened for their anticancer activity. This review presents the structure activity relationship carried out on C-1, C-2, C-3, C-4, C-20, C-28, A-ring, D-ring and E-ring modified betulinic acid derivatives. We have compiled the most active betulinic acid derivatives along with their activity profile in each series. Structure activity relationship studies revealed that C-28 carboxylic acid was essential for the cytotoxicity. The halo substituent at C-2 position in betulinic acid enhanced the cytotoxicity. Though the relation of the cytotoxicity with the nature of substituents at C-3 position could not be generalized but the ester functionality appeared to be a better substituent for enhancing the cytotoxicity. An interesting observation is that the three rings skeleton (A, B and C rings) had played an important role in eliciting anticancer activity, which could be a new molecular skeleton to design new anticancer drugs.