Ancient Drug Research Articles

Neuroprotection & Mechanism of Ethanol in Stroke and Traumatic Brain Injury Therapy: New Prospects for an Ancient Drug

Effective efforts to screen for agents that protect against the devastating effects of stroke have not produced viable results thus far. As a result this article reviews the possible role of ethanol as a neuroprotective agent in stroke and traumatic brain injury (TBI). Previous studies have associated ethanol consumption with a decreased risk of ischemic stroke, suggesting a neuroprotective mechanism. The translation of this clinical knowledge into basic science research with the goal of new therapy for acute stroke patients remains in its initial stages. In a recent study involving rats, we have shown that ethanol administration, in the correct dose after stroke onset, protects against ischemia-induced brain injury. The purpose of this paper is to discuss ethanol's neuroprotective properties in stroke when consumed as a preconditioning agent, in TBI with a positive blood alcohol content, and finally in stroke treatment, with the goal of using post-ischemia ethanol (PIE) therapy to ameliorate brain damage in the future.

Neuroprotection & Mechanism of Ethanol in Stroke and Traumatic Brain Injury Therapy: New Prospects for an Ancient Drug

Effective efforts to screen for agents that protect against the devastating effects of stroke have not produced viable results thus far. As a result this article reviews the possible role of ethanol as a neuroprotective agent in stroke and traumatic brain injury (TBI). Previous studies have associated ethanol consumption with a decreased risk of ischemic stroke, suggesting a neuroprotective mechanism. The translation of this clinical knowledge into basic science research with the goal of new therapy for acute stroke patients remains in its initial stages. In a recent study involving rats, we have shown that ethanol administration, in the correct dose after stroke onset, protects against ischemia-induced brain injury. The purpose of this paper is to discuss ethanol’s neuroprotective properties in stroke when consumed as a preconditioning agent, in TBI with a positive blood alcohol content, and finally in stroke treatment, with the goal of using post-ischemia ethanol (PIE) therapy to ameliorate brain damage in the future. Keywords: Ethanol, alcohol, stroke therapy, ischemia/reperfusion injury, traumatic brain injury therapy, neuroprotection

Arsenic Trioxide-induced Apoptosis is Associated with Induction of SHP-1 in Cutaneous T Cell Lymphoma

Abstract 4716Arsenic trioxide (As2O3) is an ancient drug which was used in traditional Chinese medicine. It has attracted worldwide interests because of its antitumor activity when used in acute promyelocytic leukemia (APL). What's more, the demethylation and antiapoptosis function can also be seen in many papers. The methylation status of SH2 containing phosphatase-1 (SHP-1) promoter is common in malignant hematological diseases, such as MDS. Inducing gene demethylation may be a mechanism of As2O3 in treating hematologic cancers. Whether As2O3 has the effects on demethylation of SHP-1 and on the proliferation and apoptosis of cutaneous T cell lymphoma cell lines, and what is the concrete mechanism? Our study aimed to solve these problems. Methods:The activity of As2O3 was analyzed in two cutaneous T cell lymphoma cell lines, including HuT 78 and HuT 102, and cells derived from cutaneous T cell lymphoma patients. All of the cells were treated with As2O3 of different concentration (2.5μmol/L, 5μmol/L, 7.5μmol/L) and different time (24h, 48h, 72h). The methylation status of SHP-1 promoter and the changes of methylation status after the treatment of As2O3 in the cells was detected by methylation specific polymerase chain reaction(MSP). Then the expression level of SHP-1 mRNA was analyzed by Real-time polymerase chain reaction (Real-time PCR). Meanwhile the proliferative inhibition rate was determined with MTT, and the apoptosis induced by As2O3 was detected by flow cytometry with Annexin V/PI staining. DAPI staining was also used to observe the morphological changes during the apoptosis procedure. Then we explore the possible mechanism of As2O3 in this malignancy. First, protein levels of SHP-1, STAT3, phospho-STAT3 were analyzed using Western blotting. In addition, Real-time PCR was also used to analyze the Bcl2, Bcl-xL, survivin, c-myc, Mcl-1, cyclin-D1 and VEGF mRNA expression level. Results:The MSP results indicated that the SHP-1 promoter in these cells was completely methylated and there was no unmethylation strap. The methylation straps of SHP-1 promoter treated with 5.0μmol/L As2O3 were weakened along with the prolonging of treatment time, meanwhile the unmethylation straps were enhanced. The expression levels of SHP-1 mRNA increased along with the increase of As2O3 concentration and treatment time(P<0.05). As2O3 induced significant inhibition on the proliferation and its inhibitory effects were enhanced along with the increase of concentration and time(P<0.05). We also certified that As2O3 could induce apoptosis of these cells and the apoptosis rates were significantly higher along with the increase of As2O3 concentration and treatment time(P<0.05). The SHP-1 protein was not detectable in untreated cells. After the treatment of As2O3, the expression of SHP-1 protein increased along with the prolonging of treatment time(P<0.05). Meanwhile, the level of STAT3 protein remained unchanged. Strikingly, phospho-STAT3 protein was constitutively expressed before treatment. With progressive demethylation and reexpression of SHP1, there was progressive down-regulation of phosphorylated STAT3. Bcl2, Bcl-xL, survivin and Mcl-1 mRNA, which were related to JAK/STAT pathway, were all downregulated. At the same time, the expression of VEGF, c-Myc and cyclin D1 mRNA were also reduced. Conclusion:The SHP-1 promoter in cutaneous T cell lymphoma cells is completely methylated resulting in the transcriptional silencing of SHP-1. As2O3 can induce the re-expression of SHP-1 mRNA and protein in cutaneous T cell lymphoma cells via the demethylation effect. What's more, As2O3 can inhibit proliferation and induce apoptosis of these cells. It is reported that, SHP-1 is the negative regulator of STAT3. Our results demonstrated that the demethylation leading to re-expression of SHP1 resulted in down-regulation of phosphorylation of STAT3, so did the target genes of STAT3, including Bcl2, Bcl-xL, survivin, Mcl-1, etc. That's the probable mechanism in this study. In conclusion, As2O3 may be beneficial for advanced-stage MF/SS. Disclosures:No relevant conflicts of interest to declare.

Applied human psychopharmacology: the practical psychobiological consequences of some novel and ancient psychoactive drugs

Applied human psychopharmacology: the practical psychobiological consequences of some novel and ancient psychoactive drugs

Incentives for Drug Development — The Curious Case of Colchicine

Drs. Aaron Kesselheim and Daniel Solomon write that it came as a surprise to many patients and physicians that the FDA not only approved the new version of colchicine but also granted the manufacturer 3 years of market exclusivity for this ancient drug.

Arsenic Trioxide Controls the Fate of the PML-RARα Oncoprotein by Directly Binding PML

Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide (As2O3) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells, PML-RARalpha (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RARalpha degradation is triggered by their SUMOylation, but the mechanism by which As2O3 induces this posttranslational modification is unclear. Here we show that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RARalpha and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation. The identification of PML as a direct target of As2O3 provides new insights into the drug's mechanism of action and its specificity for APL.

Intravenous and Inhalational Colistin–Induced Respiratory Failure

The emergence of highly resistant gram-negative pathogens in hospitals around the world has placed emphasis on colistin, a seemingly ancient drug. Respiratory failure from colistin was reported in the years following its release; however, there are no recent reports of colistin-induced respiratory failure. We report a case of intravenous colistin- and, later, inhalational colistin-induced respiratory failure.

Arsenic trioxide

Background: The ancient drug, arsenic, has remarkable efficacy in the treatment of relapsed acute promyelocytic leukemia (APL) and this success has led to exploration of its use in other malignancies. Objective: To provide an overview of the mechanism of action of arsenic and summarize its development in the treatment of APL and other malignant disorders. Methods: A 20-year search of MEDLINE, EMBASE and Web of Science was conducted. Results/conclusions: A series of clinical trials with arsenic trioxide has confirmed its benefit in the therapy of APL. Its role in the treatment of other malignancies remains to be determined. Careful attention to the clinical management of patients on arsenic trioxide therapy can significantly lessen the risk of major side effects.

Anticancer Drugs Designed by Mother Nature: Ancient Drugs but Modern Targets

Nuclear factor-kappaBeta (NF-kappaBeta) is a transcription factor that is activated in response to various inflammatory stimuli such as cytokines, growth factors, hormones, mitogens, carcinogens, chemotherapeutic agents, viral products, eukaryotic parasites, endotoxin, fatty acids, metals, radiation, hypoxia, and psychological, physical, oxidative, and chemical stresses. In addition, constitutively active NF-kappaBeta is frequently encountered in a wide variety of tumors. Furthermore, NF-kappaBeta activation has been shown to regulate the expression of over 400 genes involved in cellular transformation, proliferation, inflammation, viral replication, antiapoptosis, angiogenesis, invasion and metastasis, oxidative stress, and osteoclastogenesis. Therefore, because of the critical role NF-kappaBeta plays in the pathogenesis of cancer, specific inhibitors of this factor are being sought. Agents that prevent cancer or inflammation have been found to suppress NF-kappaBeta activation. Numerous reports indicate that ancient plants and their components are potent as NF-kappaB inibitors. However, ancient medicine such as traditional Chinese medicine, Kampo, Ayurveda requires rediscovery in light of our current knowledge of allopathic (modern) medicine for the therapeutic and preventive purpose. In this review, we present evidence that numerous agents identified from fruits and vegetables can interfere with NF-kappaBeta pathway. The structure of drugs and their relationship with NF-kappaBeta inhibitory activity is discussed.

Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide: a paradigm of synergistic molecular targeting therapy

To turn a disease from highly fatal to highly curable is extremely difficult, especially when the disease is a type of cancer. However, we can gain some insight into how this can be done by looking back over the 50-year history of taming acute promyelocytic leukaemia (APL). APL is the M3 type of acute myeloid leukaemia characterized by an accumulation of abnormal promyelocytes in bone marrow, a severe bleeding tendency and the presence of the chromosomal translocation t(15;17) or variants. APL was considered the most fatal type of acute leukaemia five decades ago and the treatment of APL was a nightmare for physicians. Great efforts have been made by scientists worldwide to conquer this disease. The first use of chemotherapy (CT) was unsuccessful due to lack of supportive care and cytotoxic-agent-related exacerbated coagulopathy. The first breakthrough came from the use of anthracyclines which improved the complete remission (CR) rate, though the 5-year overall survival could only be attained in a small proportion of patients. A rational and intriguing hypothesis, to induce differentiation of APL cells rather than killing them, was raised in the 1970s. Laudably, the use of all-trans retinoic acid (ATRA) in treating APL resulted in terminal differentiation of APL cells and a 90-95% CR rate of patients, turning differentiation therapy in cancer treatment from hypothesis to practice. The combination of ATRA with CT further improved the 5-year overall survival. When arsenic trioxide (ATO) was used to treat relapsed APL not only the patients but also the ancient drug were revived. ATO exerts dose-dependent dual effects on APL cells: at low concentration, ATO induces partial differentiation, while at relatively high concentration, it triggers apoptosis. Of note, both ATRA and ATO trigger catabolism of the PML-RARalpha fusion protein which is the key player in APL leukaemogenesis generated from t(15;17), targeting the RARalpha (retinoic acid receptor alpha) or promyelocytic leukaemia (PML) moieties, respectively. Hence, in treating APL both ATRA and ATO represent paradigms for molecularly targeted therapy. At molecular level, ATRA and ATO synergistically modulate multiple downstream pathways/cascades. Strikingly, a clearance of PML-RARalpha transcript in an earlier and more thorough manner, and a higher quality remission and survival in newly diagnosed APL are achieved when ATRA is combined with ATO, as compared to either monotherapy, making APL a curable disease. Thus, the story of APL can serve as a model for the development of curative approaches for disease; it suggests that molecularly synergistic targeted therapies are powerful tools in cancer, and dissection of disease pathogenesis or anatomy of the cancer genome is critical in developing molecular target-based therapies.

Arsenic Trioxide in Hematological Malignancies: The New Discovery of an Ancient Drug

Currently, Arsenic Trioxide (ATO) is considered the treatment of choice for patients with relapsed acute promyelocytic leukemia (APL). Recently, a durable remission with minimal toxicity by single agent ATO or ATO + ATRA in newly diagnosed APL was reported by different groups. These regimens have minimal toxicity and can be administered on an outpatient basis after remission induction, thus they could become a real, less toxic and more economic option to ATRA + anthracyclines in particular in low risk APL, or in patients that cannot undergo chemotherapy because of age or comorbid conditions and in patients that refuse chemotherapy. Significantly, these therapies are a successful attempt to cure a tumoral disease without chemotherapy. The results of clinical trials of ATO administration as single agent in multiple myeloma (MM) and myelodisplastic syndromes (MDS) were encouraging and showed clinical effects but they were not close to APL success. On the contrary, results of clinical trials to treat non-APL acute myeloid leukemia (AML) were disappointing. We suggest that a combination therapy with drugs targeting specific pro-survival molecules or capable to enhance pro-apoptotic pathways may lead to an improvement of ATO efficacy against hematological malignancies, in particular AML. Our pre-clinical studies showed that ATO is capable to induce cell death in acute leukemia cells but the apoptotic function is limited since it can induce also a mechanism of cell defense by activating pro-survival molecules such as MEK-ERK, Bcl-xL, Bcl-2. By combining ATO with specific MEK inhibitors, we demonstrated that the block of MEK-ERK phosphorylation, the induction of Bad de-phosphorylation, and activation of p53AIP1 apoptotic pathway interrupt the pro-survival mechanisms of ATO and kill the leukemic cells by apoptotic synergism. Our results provide an experimental basis for combined or sequential treatment with MEK inhibitors and ATO in AML. The renaissance of ATO as a drug in moderne medicine may be considered, together with ATRA success, a victory of empirical analysis, that had (and has) great impact on Chinese culture.

Arsenic Trioxide (ATO) Downregulates the Expression of the AML1/MDS1/EVI-1 (AME) Oncoprotein and Induces Differentiation and Apoptosis in AME-Leukemic Cells.

Arsenic is an ancient drug, used for many centuries to treat a broad range of ailments including cancer but was largely abandoned in the early 20th century. In the 1990s arsenic trioxide (ATO) was rediscovered as an effective treatment for patients suffering from acute promyelocytic leukemia (APL). ATO has been shown to specifically target the fusion protein resulting from the t(15;17) translocation, PML/RARα, and subsequently stimulate differentiation and apoptosis of APL cells both in vitro and in vivo. The success in using ATO as a targeted therapy for APL underscores the importance of matching the right drug to patients with appropriate molecular targets. We previously reported that expression of the AML1/MDS1/EVI1 (AME) transcription factor fusion protein [a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of chronic myelogenous leukemia during the blast phase and in some patients with de novo and therapy-related myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML)] in mouse bone marrow cells by retroviral transduction impaired hematopoiesis and eventually induced an AML in mice. Our results established a causal role of AME in t(3;21)-positive myeloid malignancies. We went on to examine whether ATO could target AME. We found that ATO treatment downregulated forced-expressed AME protein in Bosc23 (a cell line derived from human 293 kidney cell line) and BM6-4 cells, a primary myeloid blast cell line derived from bone marrow of a mouse with AME-induced AML, in a dose dependent manner (within therapeutic relevant dosage range). We also found that ATO inhibited proliferation of BM6-4 cells, induced these cells to differentiate into macrophages and induced apoptosis in a dose dependent manner. Our results suggest that ATO could be used as a targeted therapy for t(3;21)-positive MDS and AML. The in vivo effect of ATO in the AME mouse model and mechanism of ATO-induced AME downregulation is under investigation. Such research may extend ATO therapy to other hematological malignancies and help to identify new therapeutic targets for human cancer.

Figs--the earliest known ancient drug for cutaneous anthrax.

Anthrax is an often fatal bacterial infection, occurring in cutaneous, inhalational, gastrointestinal, and meningeal forms. Evaluation of anthrax treatment from ancient history may help healthcare providers to handle this serious disease more efficiently. To evaluate the biblical descriptions of anthrax, focusing on its therapy in ancient times. All biblical texts associated with anthrax were examined and passages relating to this disease were studied closely. Biblical passages such as: "Take a cluster of figs. And they took and laid it on the boil [anthrax], and he recovered," and "Let them take a cluster of figs, and lay it upon the boil [anthrax], and he shall recover," convincingly indicate that figs have healing properties in cutaneous anthrax lesions. On the basis of this study, the National Institutes of Health together with the pharmaceutical industry may consider to work on isolation of compounds from fig plants to develop products against cutaneous and possibly other forms of anthrax once screening tests are completed.

Mössbauer Studies in Chinese Archaeology: A Review

The Mossbauer effect has been applied to a wide variety of objects related to Chinese archaeology. Besides ceramic artifacts, materials like porcelain, glazes, bronzes, ancient coins, ancient mineral drugs, and even fossils were studied. This article reviews these applications with particular emphasis on the study of the famous terracotta warriors and horses of the Qin Dynasty.

Postoperative atrial fibrillation after heart surgery: What are the goals of prevention?

Colchicine, a natural and ancient drug still used today, is traditionally considered the staple therapy for gout and a second-line treatment for pericarditis, as well as a basic part of familial Mediterranean fever and Behcet's disease management. It is commonly classified as an anti-inflammatory agent, although its mechanism of action does not involve the arachidonic acid pathway affected by non-steroid anti-inflammatory drugs and glucocorticoids. Colchicine inhibits microtubule polymerization by binding to tubulin, thus affecting any process that requires cytoskeletal changes, including cell mitosis and neutrophil motility. Recent studies suggest that colchicine may prove to be useful in a much wider spectrum of cardiovascular diseases than previously suspected, rekindling the interest in this old drug. In this review we briefly present the biochemical characteristics, mechanism of action and side-effects of colchicine, as well as examine what is currently known about the promising role of colchicine in cardiovascular medicine beyond pericardial disease.

Drug preparation in evidence? An unusual plant and bone assemblage from the Pompeian countryside, Italy

In 1996 a farmhouse (villa rustica) was excavated near Pompeii (Naples, southern Italy). The villa had the typical characters of other farmhouses of the same period (ca A.D. 79) found in the area. The content of one of thedolia (storage vats) found in the cellar is discussed here and an interpretation of the assemblage is provided. The deposit found at the bottom of the storage vat produced a high percentage of seeds of plants known for their medicinal properties, such asPapaver somniferum (opium poppy). Associated with the residue there were also bones of reptiles and amphibians. It is suggested that the assemblage may represent the residue of a medicinal preparation. Its content includes many plants used in the preparation of ancient drugs calledMithridatium andTheriac. Further indirect archaeological evidence that supports this hypothesis will also be discussed.

Antiinflammatory and antifibrotic properties of colchicine: implications for idiopathic pulmonary fibrosis.

The ancient drug colchicine has repeatedly been proposed as a novel drug for therapy of pulmonary fibrosis. The present study was undertaken to add to the knowledge on colchicine's antiinflammatory and antifibrotic properties and thus help determine its actual rank in the treatment of pulmonary fibrosis. In vitro cell culture experiments with stimulated and unstimulated normal donor peripheral blood mononuclear cells (PMNC) and a human lung fibroblast cell line (WI-38) were used to determine the effects of colchicine on PMNC cytokine release (interleukin-6 and tumor necrosis factor-alpha) as well as on fibroblast proliferation and collagen synthesis rates. Reverse transcriptase polymerase chain amplifications of alpha 1 (III) collagen were done to detect collagen messenger ribonucleic acid (mRNA) expression. Colchicine did not significantly modulate tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) release of PMNC. Colchicine inhibited fibroblast proliferation and total collagen synthesis significantly at concentrations obtainable in serum in vivo. Transcription of the alpha 1 (III) collagen gene into mRNA continued under colchicine. We conclude that colchicine is a potent in vitro inhibitor of fibroblast functions in terms of proliferation and collagen synthesis. The mechanism of collagen inhibition is more likely an inhibition of cellular collagen secretion than a switch off of collagen mRNA transcription. On the other hand, although colchicine is known to inhibit many leukocyte functions, it is a poor inhibitor of cytokines known to be important for fibrogenesis (e.g. IL-6, TNF-alpha, IL-1, platelet-derived growth factor, and transforming growth factor-beta). This makes colchicine, at least from a theoretical standpoint and as concluded from in vitro studies, a preferable candidate for a combined therapeutic strategy.

Mössbauer study of Chinese ancient mineral drugs

About 100 crude Chinese mineral drug samples were investigated with Mossbauer spectroscopy, X-ray diffraction analysis and atomic absorption spectroscopy. The classifications, species and components of Chinese mineral drugs will be elucidated. The pharmaceutic and curative mechanisms of these mineral drugs will be discussed.

Colchicine: a state-of-the-art review.

Colchicine is an ancient drug that is attracting renewed interest because of its actions at a subcellular level. Specifically, it interferes with microtubule growth and therefore affects mitosis and other microtubule-dependent functions. Various mechanisms have been proposed to account for the action of colchicine in acute gouty arthritis, its interaction with cellular membrane and cyclic 3',5'-adenosine monophosphate, and its action in amyloidosis. Pharmacokinetic studies have been relatively limited and their results somewhat contradictory, with mean terminal elimination half-lives of 19 minutes to 9 hours being reported. Some of these differences may be attributed to assay difficulties. Colchicine can cause gastrointestinal side effects and should be used with care to protect patients from toxic doses. Colchicine-induced myopathy and neuropathy may be more frequent than previously recognized, and therefore patients receiving long-term therapy should be monitored carefully. Bone marrow depression has been reported, primarily in cases of acute colchicine intoxication, and intravenous administration of the drug has been associated with severe pancytopenia and death. Colchicine intoxication causes multiple organ failure. Because of its cytogenic effects and reported association with Down's syndrome, the agent should not be used by pregnant women.

Antibodies and digitalis: The modern revolution in the use of an ancient drug

Although digitalis glycosides have been widely used in clinical medicine since the classic description by William Withering in 1785, it was not until the advent of a specific immunoassay that their clinical pharmacology could be examined intensively under a wide variety of circumstances. The insights gained into the relations among dosage, plasma concentration, bioavailability, distribution, metabolism, excretion and interactions with other drugs and the manifestations of toxicity certainly have reduced the frequency of adverse reactions to this highly toxic but useful group of drugs. More recently, antibodies have also been utilized as specific antidotes for digitalis toxicity, with dramatic life-saving effect.