Phase 1 study of APTO-253 HCl, an inducer of KLF4, in patients with advanced or metastatic solid tumors.

INTRODUCTION: This phase I, multicenter, open-label, single-arm, dose-escalation study evaluated the safety, pharmacokinetics and antitumor activity of APTO-253, an inducer of the transcription factor KLF4, in adults with advanced solid tumors. METHODS: APTO-253 was administered IV on days 1 and 2, and 15 and 16 of each 28 day cycle; the dose were escalated from 20 to 387 mg/m(2) in 9 cohorts until DLT was observed. RESULTS: Thirty-two patients were treated on this trial (50 % colon cancer, 22 % other gastrointenstinal malignancies and 18 % non-small cell lung cancer). Fatigue was the only drug-related treatment-emergent adverse event to occur in >10 % of patients. Dose-limiting toxicities of hypersensitivity reaction and transient hypotension despite prophylaxis occurred at 387 mg/m(2) which led to identification of 298 mg/m(2) as the MTD. Only 1 patient had any drug-related treatment-emergent grade 3 adverse event at or below 229 mg/m(2). A total of 21 patients underwent at least one restaging after 2 cycles; 11 patients discontinued prior to the end of cycle 2 due to adverse events (9) or disease progression (2). The best overall response was stable disease (SD) in 5 of these 21 (23.8 %) with durations ranging from 3.6 to 8.4 months. CONCLUSION: APTO-253 was well tolerated at the Phase 2 recommended dose and produced evidence of antitumor activity in the form of stable disease in patients with advanced solid tumors. Based on the drug levels achieved and the lower frequency of treatment-emergent adverse events encountered, 229 mg/m(2) was selected as the recommended Phase 2 dose. Overall APTO-253 was found to be well tolerated and to have favorable pharmacokinetics, and treatment was associated with stable disease in 5 of 21 (24 %) of patients with far advanced solid tumors.

Danshen (Chinese medicinal herb) preparations for acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is the most important cause of morbidity from ischaemic heart disease, and is among the leading causes of death in the western world. Danshen, a Chinese herbal medicine, is widely used in China for treatment of several diseases, including AMI. OBJECTIVES: To assess the effects (both benefits and harms) of danshen preparations for AMI. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (issue 4, 2006), MEDLINE (1966-2006), EMBASE (1980-2006), and the Chinese Biomedical Database (CBM) (1982-2006). We also handsearched 75 Chinese medical journals. SELECTION CRITERIA: Randomised controlled trials (RCTs) lasting at least 7 days were sought. Since it seemed evident that few RCTs were available, we also considered other controlled studies. DATA COLLECTION AND ANALYSIS: Eligibility and trial quality were assessed by three reviewers. MAIN RESULTS: Six studies comprised of 2368 participants were included. Only one trial was judged to be a genuine RCT and showed no statistically significant difference in reduction of total mortality (Peto OR 0.55, 95% CI 0.23 to 1.32), but a quasi-RCT reported a reduced total mortality (Peto OR 0.42, 95% CI 0.23 to 0.77). Pooling these trials yielded an approximate halving of mortality in those patients treated with danshen preparations plus usual care compared with usual care alone (Peto OR 0.46, 95% CI 0.28 to 0.75). AUTHORS' CONCLUSIONS: The evidence to support use of danshen preparations is too weak to make any judgement about its effects. Evidence from RCTs is insufficient and of low quality. The safety of danshen preparations is unproven, although some adverse events have been reported. More evidence from high quality trials is needed to support the clinical use of danshen preparations.

Phosphatase and tensin homologue deleted on chromosome ten (PTEN) as a molecular target in lung epithelial wound repair.

BACKGROUND AND PURPOSE: Epithelial injury contributes to lung pathogenesis. Our work and that of others have identified the phosphoinositide-3 kinase (PI3K)/Akt pathway as a vital component of survival in lung epithelia. Therefore, we hypothesized that pharmacological inhibition of PTEN, a major suppressor of this pathway, would enhance wound closure and restore lung epithelial monolayer integrity following injury. EXPERIMENTAL APPROACH: We evaluated the ability of two bisperoxovanadium derivatives, bpV(phen) and bpV(pic), in differentiated primary human airway epithelia and BEAS2B cultures for their ability to inhibit PTEN, activate the PI3K/Akt pathway and restore epithelial monolayer integrity following mechanical injury. KEY RESULTS: BpV(phen) and bpV(pic) induced Akt phosphorylation in primary and BEAS2B cells in a dose and time dependent manner. Minimal toxicity was observed as measured by lactate dehydrogenase (LDH) release. To verify that Akt phosphorylation is specifically induced by PTEN inhibition, the PTEN positive cell line, DU145, and two PTEN negative cell lines, LNCaP and PC3, were examined. PTEN positive cells demonstrated a dose responsive increase in Akt phosphorylation whereas PTEN negative cells showed no response indicating that bpV(phen) directly suppresses PTEN without affecting auxiliary pathways. Next, we observed that exposure to either compound resulted in accelerated wound closure following mechanical injury. Similar effects were observed after transfection with a dominant negative isoform of PTEN and PTEN specific siRNA. CONCLUSIONS AND IMPLICATIONS: From these studies, we conclude that PTEN is a valid target for future studies directed at restoring epithelial barrier function after lung injury.

Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use.

Danshen, the dried root of Salvia miltiorrhiza, has been widely used in China and, to a lesser extent, in Japan, the United States, and other European countries for the treatment of cardiovascular and cerebrovascular diseases. In China, the specific clinical use is angina pectoris, hyperlipidemia, and acute ischemic stroke. The current review covers its traditional uses, chemical constituents, pharmacological activities, pharmacokinetics, clinical applications, and potential herb-drug interactions based on information obtained in both the English and Chinese literature. Although numerous clinical trials have demonstrated that certain Danshen products in China are effective and safe for the treatment of cardiovascular diseases, most of these lack sufficient quality. Therefore, large randomized clinical trials and further scientific research to determine its mechanism of actions will be necessary to ensure the safety, effectiveness, and better understanding of its action.

Induction of apoptosis in yeast and mammalian cells by exposure to 1,10-phenanthroline metal complexes.

1,10-Phenanthroline (phen) and metal-phen complexes display fungicidal and fungiststic activity, disrupt mitochondrial function and induce oxidative stress. We have examined the effect of these drugs on the structure of yeast and mammalian cell organelles and the integrity of cellular DNA. Exposure of Candida albicans to [Mn(phen)2(mal)].2H2O or [Ag2(phen)3(mal)].2H2O (mal H2 = malonic acid) resulted in DNA degradation whereas exposure to phen or [Cu(phen)2(mal)].2H2O did not. All drugs induced extensive changes to the internal structure of yeast cells including retraction of the cytoplasm, nuclear fragmentation and disruption of the mitochondrion. In the case of cultured mammalian cells [Cu(phen)2(mal)].2H2O induced apoptosis as evidenced by the ladder pattern of DNA fragments following gel electrophoresis and also the blebbing of the cell membrane. The other drugs produced non-specific DNA degradation in mammalian cells. In conclusion, phen and metal-phen complexes have the potential to induce apoptosis in fungal and mammalian cells. Given their distinct mode of action compared to conventional anti-fungal drugs, phen and metal-phen complexes may represent a novel group of anti-fungal agents for use either in combination with existing drugs or in cases where resistance to conventional drugs has emerged.

Impaired protein binding of Chinese medicine DanShen in uremic sera and sera with hyperbilirubinemia: rapid assessment of total and free DanShen concentrations using the fluorescence polarization immunoassay for digoxin.

DanShen is a Chinese medicine that is used to treat cardiovascular disorders. DanShen is moderately to strongly protein bound, mainly to albumin. Because impaired protein binding of albumin-bound drugs in uremia has been reported, we studied protein binding of DanShen by measuring the digoxin-like immunoreactive component of this Chinese medicine. We observed a significantly higher percentage of free fraction of DanShen in uremic sera in vitro. Impaired protein binding of DanShen was also observed in sera from patients with liver disease, who had elevated concentrations of bilirubin. Treating uremic sera with activated charcoal significantly improved the protein binding of DanShen, indicating that uremic compounds are responsible for the impaired protein binding of DanShen. On the other hand, when various amounts of bilirubin were added to aliquots of the normal pool supplemented with DanShen, we observed only a modest displacement of DanShen from the protein-binding sites by bilirubin, indicating that hypoalbuminemia may play a major role in impaired protein binding of DanShen in sera with elevated bilirubin concentrations. We conclude that protein binding of DanShen is lower in uremic sera and in sera with elevated bilirubin concentrations.

Interaction between warfarin and danshen (Salvia miltiorrhiza).

OBJECTIVE: To discuss the potential for an adverse interaction between the Chinese herb danshen, the dry root and rhizome of Salvia miltiorrhiza Bge, and warfarin. DATA SOURCES: A MEDLINE search was performed (from January 1966 through October 2000) using the key words danshen and Salvia miltiorrhiza. All articles written in English or with an English extract were considered for review. STUDY SELECTION AND DATA EXTRACTION: All studies of antithrombotic effects of danshen or interaction between danshen and warfarin were evaluated. Previous case reports of an adverse interaction between danshen and warfarin were reviewed. DATA SYNTHESIS: Danshen is commonly used in mainland China for the treatment of atherosclerosis-related disorders such as cardiovascular and cerebrovascular diseases. Danshen can affect hemostasis in several ways, including inhibition of platelet aggregation, interference with the extrinsic blood coagulation, antithrombin III-like activity, and promotion of fibrinolytic activity. Single-dose and steady-state studies in rats indicated that danshen increased the absorption rate constants, AUCs, maximum concentrations, and elimination half-lives, but decreased the clearances and apparent volume of distribution of both R- and S-warfarin. Consequently, the anticoagulant response to warfarin was exaggerated. Three cases have previously been published reporting gross overanticoagulation and bleeding complications when patients receiving chronic warfarin therapy also took danshen. CONCLUSIONS: Because of both pharmacokinetic and pharmacodynamic interactions, danshen should be avoided in patients taking warfarin.

A taste of Chinese medicine!

We report a case of profound anticoagulation caused by interaction between warfarin and danshen, a widely used Chinese herbal medicine, in a patient who had undergone mitral valve replacement. Patients taking warfarin should be warned not to take this herb. In addition, physicians should be alert to the possibility of an interaction with herbal medicine when anticoagulation control becomes difficult and no other causes are apparent.

Chinese herbs and warfarin potentiation by 'danshen'.

Drug interactions with warfarin can be dangerous and although common drug interactions are now well recognized those with Chinese herbs are not widely appreciated. 'Danshen' is a herbal medicine often used for various complaints, particularly cardiovascular, in the Chinese community. We report a case of danshen-induced overcoagulation with severe and dangerous abnormalities of clotting in a patient with rheumatic heart disease.