Botanical Drug Research Articles

Effects of cannabinoids and cannabinoid‐enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes

Cannabidiol (CBD) and Δ(9) -tetrahydrocannabinol (THC) interact with transient receptor potential (TRP) channels and enzymes of the endocannabinoid system. The effects of 11 pure cannabinoids and botanical extracts [botanical drug substance (BDS)] from Cannabis varieties selected to contain a more abundant cannabinoid, on TRPV1, TRPV2, TRPM8, TRPA1, human recombinant diacylglycerol lipase α (DAGLα), rat brain fatty acid amide hydrolase (FAAH), COS cell monoacylglycerol lipase (MAGL), human recombinant N-acylethanolamine acid amide hydrolase (NAAA) and anandamide cellular uptake (ACU) by RBL-2H3 cells, were studied using fluorescence-based calcium assays in transfected cells and radiolabelled substrate-based enzymatic assays. Cannabinol (CBN), cannabichromene (CBC), the acids (CBDA, CBGA, THCA) and propyl homologues (CBDV, CBGV, THCV) of CBD, cannabigerol (CBG) and THC, and tetrahydrocannabivarin acid (THCVA) were also tested. CBD, CBG, CBGV and THCV stimulated and desensitized human TRPV1. CBC, CBD and CBN were potent rat TRPA1 agonists and desensitizers, but THCV-BDS was the most potent compound at this target. CBG-BDS and THCV-BDS were the most potent rat TRPM8 antagonists. All non-acid cannabinoids, except CBC and CBN, potently activated and desensitized rat TRPV2. CBDV and all the acids inhibited DAGLα. Some BDS, but not the pure compounds, inhibited MAGL. CBD was the only compound to inhibit FAAH, whereas the BDS of CBC > CBG > CBGV inhibited NAAA. CBC = CBG > CBD inhibited ACU, as did the BDS of THCVA, CBGV, CBDA and THCA, but the latter extracts were more potent inhibitors. These results are relevant to the analgesic, anti-inflammatory and anti-cancer effects of cannabinoids and Cannabis extracts.

Mitochondrial Pathway Mediates the Antileukemic Effects of Hemidesmus Indicus, a Promising Botanical Drug

BackgroundAlthough cancers are characterized by the deregulation of multiple signalling pathways, most current anticancer therapies involve the modulation of a single target. Because of the enormous biological diversity of cancer, strategic combination of agents targeted against the most critical of those alterations is needed. Due to their complex nature, plant products interact with numerous targets and influence several biochemical and molecular cascades. The interest in further development of botanical drugs has been increasing steadily and the FDA recently approved the first new botanical prescription drug. The present study is designed to explore the potential antileukemic properties of Hemidesmus indicus with a view to contributing to further development of botanical drugs. Hemidesmus was submitted to an extensive in vitro preclinical evaluation.Methodology/Principal FindingsA variety of cellular assays and flow cytometry, as well as a phytochemical screening, were performed on different leukemic cell lines. We have demonstrated that Hemidesmus modulated many components of intracellular signaling pathways involved in cell viability and proliferation and altered the protein expression, eventually leading to tumor cell death, mediated by a loss of mitochondrial transmembrane potential and increased Bax/Bcl-2 ratio. ADP, adenine nucleotide translocator and mitochondrial permeability transition pore inhibitors did not reverse Hemidesmus-induced mitochondrial depolarization. Hemidesmus induced a significant [Ca2+]i raise through the mobilization of intracellular Ca2+ stores. Moreover, Hemidesmus significantly enhanced the antitumor activity of three commonly used chemotherapeutic drugs (methotrexate, 6-thioguanine, cytarabine). A clinically relevant observation is that its cytotoxic activity was also recorded in primary cells from acute myeloid leukemic patients.Conclusions/SignificanceThese results indicate the molecular basis of the antileukemic effects of Hemidesmus and identify the mitochondrial pathways and [Ca2+]i as crucial actors in its anticancer activity. On these bases, we conclude that Hemidesmus can represent a valuable tool in the anticancer pharmacology, and should be considered for further investigations.

Novel botanical drug for the treatment of diabetic neuropathy

Diabetic neuropathy has multiple aspects of pathophysiology including metabolic derangements and alterations of microvessel with hyperglycemia. Currently, there is no effective long-term treatment based on the pathologic mechanisms. Nerve regeneration with nerve growth factor (NGF) has been on clinical trials as a treatment option. This article reviews an action of a herbal medicine, DA 9801, whose mechanism of action is related to NGF in treating diabetic neuropathy.

Identifi cation of Species-Diagnostic Inter Simple Sequence Repeat Markers for Ten Phyllanthus Species

Phyllanthus has been widely used in traditional medicine as an antipyretic, a diuretic, and to treat liver diseases and viral infections. Correct genotype identification of medicinal plant material remains important for the botanical drug industry. Limitations of chemical and morphological approaches for authentication have generated the need for newer methods in quality control of botanicals. In the present study, attempts were made to identify species-diagnostic markers for ten Phyllanthus species using the inter simple sequence repeat-polymerase chain reaction (ISSR-PCR) fingerprinting method. PCR amplification using seven ISSR primers resulted in significant polymorphism among the populations from different species. P. angustifolius and P. urinaria showed monomorphic frequency of maximum (63.88%) and minimum (20.64%), respectively. Seventeen species-diagnostic markers were identified for seven species (P. acidus, P. emblica, P. fraternus, P. urinaria, P. rotundifolius, P. amarus, and P. angustifolius) while no marker was detected for P. reticulatus, P. nivosus, and P. virgulatus. A maximum of six species-diagnostic markers were identified for P. acidus and a minimum of only one of 755 bp was available for P. amarus. Among the seventeen markers, nine were present in all individuals of particular species. The species-specific differences in fragment numbers and sizes could be used as diagnostic markers to distinguish the Phyllanthus species quickly.

Botanical Drugs, Synergy, and Network Pharmacology: Forth and Back to Intelligent Mixtures

For centuries the science of pharmacognosy has dominated rational drug development until it was gradually substituted by target-based drug discovery in the last fifty years. Pharmacognosy stems from the different systems of traditional herbal medicine and its "reverse pharmacology" approach has led to the discovery of numerous pharmacologically active molecules and drug leads for humankind. But do botanical drugs also provide effective mixtures? Nature has evolved distinct strategies to modulate biological processes, either by selectively targeting biological macromolecules or by creating molecular promiscuity or polypharmacology (one molecule binds to different targets). Widely claimed to be superior over monosubstances, mixtures of bioactive compounds in botanical drugs allegedly exert synergistic therapeutic effects. Despite evolutionary clues to molecular synergism in nature, sound experimental data are still widely lacking to support this assumption. In this short review, the emerging concept of network pharmacology is highlighted, and the importance of studying ligand-target networks for botanical drugs is emphasized. Furthermore, problems associated with studying mixtures of molecules with distinctly different pharmacodynamic properties are addressed. It is concluded that a better understanding of the polypharmacology and potential network pharmacology of botanical drugs is fundamental in the ongoing rationalization of phytotherapy.

Research progress on current pharmacokinetic evaluation of Chinese herbal medicines

In order to prove safety and efficacy, herbal medicines must undergo the rigorous scientific researches such as pharmacokinetic and bioavailability, before they are put on the market in the foreign countries. Botanical Drug Products promulgated by the US FDA could guide industry sponsors to develop herbal drugs, which was also an important reference for investigating Chinese herbal medicines. This paper reviews and discusses novel approaches for how to assess systemic exposure and pharmacokinetic of Chinese herbal medicines, which were in line with FDA guidance. This mainly focus on identifying pharmacokinetic markers of botanical products, integral pharmacokinetic study of multiple components, Biopharmaceutics drug disposition classification system, and population pharmacokinetic-pharmacodynamic study in herb-drug interaction.

Traditional Botanical Medicine: An Introduction

The role of traditional medicine in the well-being of mankind has certainly journeyed a long way. From an ancient era, in which knowledge was limited to a few traditional healers and dominated by the use of whole plants or crude drugs, the science has gradually evolved into a complete healthcare system with global recognition. Technologic advancements have facilitated traditional science to deliver numerous breakthrough botanicals with potency equivalent to those of conventional drugs. The renewed interest in traditional medicine is mainly attributed to its ability to prevent disease, promote health, and improve quality of life. Despite the support received from public bodies and research organizations, development of botanical medicines continues to be a challenging process. The present article gives a summarized description of the various difficulties encountered in the development and evaluation of botanical drugs, including isolation of active compounds and standardization of plant ingredients. It indicates a future direction of traditional medicine toward evidence-based evaluation of health claims through well-controlled safety and efficacy studies.

Inhibitory Effect of Standardized Cannabis sativa Extract and Its Ingredient Cannabidiol on Rat and Human Bladder Contractility

To evaluate the effect of a Cannabis sativa extract enriched in cannabidiol (CBD) botanic drug substance (BDS) and pure CBD, on bladder contractility in vitro. Cannabis based-medicines, including CBD-enriched extracts, have been shown to reduce urinary urgency, incontinence episodes, frequency, and nocturia in patients with multiple sclerosis. Strips were cut from male Wistar rats and the human bladder body and placed in organ baths containing Krebs solution. Contractions were induced by electrical field stimulation, acetylcholine, KCl, and α,β-methylene adenosine triphosphate. CBD BDS significantly reduced the contractions induced by acetylcholine, but not those induced with electrical field stimulation, KCl, or α,β-methylene adenosine triphosphate in the isolated rat bladder. The inhibitory effect of CBD BDS was not significantly modified by the cannabinoid or opioid receptor antagonists or by modulators of calcium levels, but it was increased by ruthenium red and capsazepine, 2 transient receptor potential vanilloid type-1 blockers. In humans, CBD BDS and pure CBD significantly reduced acetylcholine-induced contractions, an effect that was not changed by the transient receptor potential vanilloid type-1 blockers. Our data have suggested that CBD BDS reduces cholinergic-mediated contractility and that this effect is modulated by transient receptor potential vanilloid type-1 in rats but not in humans. CBD is the chemical ingredient of CBD BDS responsible for such activity. If confirmed in vivo, such results could provide a pharmacologic basis to explain, at least in part, the efficacy of Cannabis medicines in reducing incontinence episodes in patients with multiple sclerosis.

Botanical Drugs and Stem Cells

The potential to generate virtually any differentiated cell type from stem cells offers the possibility of creating new sources of cells for regenerative medicine. To realize this potential, it will be essential to control stem cell differentiation. Chinese herbal medicine is a major aspect of traditional Chinese medicine and is a rich source of unique chemicals. As such, individual herbs or extracts may play a role in the proliferation and differentiation of stem cells. In this review, we discuss some of the Chinese herbal medicines that are used to treat human diseases such as neuronal degenerative diseases, cardiovascular diseases, and osteoporosis. We also describe the relationship between Chinese herbal medicines and stem cell regulation.

Inhibitory effects of a traditional Chinese herbal formula TBL-II on type II collagen-induced arthritis in mice

TBL-II is the water extract of an anti-arthritic Chinese herbal formula Tongbiling (TBL), which has been used to treat rheumatoid arthritis (RA) for many years. We herein aimed to confirm its anti-arthritic effect and explore the potential mechanism of action on collagen-induced arthritis (CIA) in mice. Four weeks after the first collagen immunization, mice were treated with TBL-II orally at a lower dose of 100mg/kg/d and higher dose of 300 mg/kg/d for 2 or 8 weeks. The severity of arthritis was evaluated by symptoms, radiological scores and histological assessment. Levels of IL-1β, IL-6, TNFα and IgG2a type anti-collagen II (CII) antibody in serum were measured by ELISA. Competitive RT-PCR and immunohistochemical analysis were used to investigate MMP-2, -3, -9 mRNA and protein expression. Our results revealed treatment with higher dose of TBL-II for 2 weeks attenuated significantly acute inflammation, and decreased the amounts of IL-1β and TNFα in serum; treatment for 8 weeks could obviously suppress chronic inflammation, ameliorate cartilage and bone destruction, and reduce the levels of matrix metalloproteinase (MMP)-2, -3, -9 mRNA and protein expression in joints. The levels of IgG2a type anti-CII antibody in serum were significantly reduced by treatment with higher dose of TBL-II for either 2 or 8 weeks. In contrast, treatment with lower dose of TBL-II for 8 weeks had no effect on articular destruction. Our results suggested that TBL-II at higher dose not only ameliorated symptoms but also modified disease of CIA. TBL-II would be a potent candidate as a novel botanical drug for further investigation.

Antiosteoporotic Activity of Dioscorea alata L. cv. Phyto through Driving Mesenchymal Stem Cells Differentiation for Bone Formation.

The aim of this study was to evaluate the effect of an ethanol extract of the rhizomes of Dioscorea alata L. cv. Phyto, Dispo85E, on bone formation and to investigate the mechanisms involved. Our results showed that Dispo85E increased the activity of alkaline phosphatase (ALP) and bone nodule formation in primary bone marrow cultures. In addition, Dispo85E stimulated pluripotent C3H10T1/2 stem cells to differentiate into osteoblasts rather than adipocytes. Our in vivo data indicated that Dispo85E promotes osteoblastogenesis by increasing ALP activity and bone nodule formation in both intact and ovariectomized (OVX) mice. Microcomputed tomography (μCT) analysis also showed that Dispo85E ameliorates the deterioration of trabecular bone mineral density (tBMD), trabecular bone volume/total volume (BV/TV), and trabecular bone number (Tb.N) in OVX mice. Our results suggested that Dispo85E is a botanical drug with a novel mechanism that drives the lineage-specific differentiation of bone marrow stromal cells and is a candidate drug for osteoporosis therapy.

Correction of migration time of Paeoniae Radix in capillary electrophoresis by powerful one-marker technology.

The reproducibility in migration time is essential in the use of capillary electrophoresis to identify components in a complex sample or compare constituent differences for different botanical drug samples. A powerful one-marker technology for correcting migration time was proposed in this paper. This technology is practically simple compared with the multi-marker technologies developed in literature, due to only one marker required. Paeoniae Radix which is a crude drug used in many traditional prescriptions in China and Japan was selected as an example to verify the effectiveness of the powerful one-marker technology in analyzing complex botanical samples. Relative standard deviations in migration times treated with the powerful one-marker technology were below 0.5% for Paeoniae Radix analyzed during three different days. The technology was successfully applied to classify Paeoniae Radix from nine different growing regions. Based on their corrected electropherograms, Paeoniae Radix was classified into three groups which were in agreement with their real origins.

Recent Progress on Anticancer Candidates in Patents of Herbal Medicinal Products

Herbal medicines in treatment of cancer as complementary and alternative therapy are accepted increasingly with growing scientific evidences of biomedical research and clinical trials. Anticancer drugs discovered from herbal medicines have a long history and some of them have been used in clinical setting as the conventional anticancer drugs. Actually, herbal medicines are a source for anticancer drug discovery and drug development. Recently, research continuously focuses on clues from traditional use of herbal medicines to develop new anticancer drugs in single pure compounds. On the other hand, standardized various extracts or fractions with anticancer effects or with adjuvant therapy in cancer treatment coming from single or mixed herbs are also accepted forms as dietary supplements and botanical drug products in the US for current statutory regulations. In the present paper, we analyzed the patented agents in the US from herbal medicines in recent ten years, both as potential anticancer extracts/fractions (containing multi-components) and single pure compound(s) that act as new anticancer substances. This review also highlighted the advances in knowledge about quality control, safety, efficacy and recent progress in anticancer candidates in patents of botanical drug products from herbal medicines.

Stimulatory effect of Echinacea purpurea extract on the trafficking activity of mouse dendritic cells: revealed by genomic and proteomic analyses

BackgroundSeveral Echinacea species have been used as nutraceuticals or botanical drugs for "immunostimulation", but scientific evidence supporting their therapeutic use is still controversial. In this study, a phytocompound mixture extracted from the butanol fraction (BF) of a stem and leaf (S+L) extract of E. purpurea ([BF/S+L/Ep]) containing stringently defined bioactive phytocompounds was obtained using standardized and published procedures. The transcriptomic and proteomic effects of this phytoextract on mouse bone marrow-derived dendritic cells (BMDCs) were analyzed using primary cultures.ResultsTreatment of BMDCs with [BF/S+L/Ep] did not significantly influence the phenotypic maturation activity of dendritic cells (DCs). Affymetrix DNA microarray and bioinformatics analyses of genes differentially expressed in DCs treated with [BF/S+L/Ep] for 4 or 12 h revealed that the majority of responsive genes were related to cell adhesion or motility (Cdh10, Itga6, Cdh1, Gja1 and Mmp8), or were chemokines (Cxcl2, Cxcl7) or signaling molecules (Nrxn1, Pkce and Acss1). TRANSPATH database analyses of gene expression and related signaling pathways in treated-DCs predicted the JNK, PP2C-α, AKT, ERK1/2 or MAPKAPK pathways as the putative targets of [BF/S+L/Ep]. In parallel, proteomic analysis showed that the expressions of metabolic-, cytoskeleton- or NF-κB signaling-related proteins were regulated by treatment with [BF/S+L/Ep]. In vitro flow cytometry analysis of chemotaxis-related receptors and in vivo cell trafficking assay further showed that DCs treated with [BF/S+L/Ep] were able to migrate more effectively to peripheral lymph node and spleen tissues than DCs treated as control groups.ConclusionResults from this study suggest that [BF/S+L/Ep] modulates DC mobility and related cellular physiology in the mouse immune system. Moreover, the signaling networks and molecules highlighted here are potential targets for nutritional or clinical application of Echinacea or other candidate medicinal plants.

Hepatocyte growth factor has a role in the amelioration of diabetic vascular complications via autophagic clearance of advanced glycation end products: Dispo85E, an HGF inducer, as a potential botanical drug

The aim of this study was to evaluate the effect and elucidate the potential mechanism of the extract of rhizomes from Dioscorea alata L. cv. Phyto, Dispo85E, on accelerating the elimination of advanced glycation end products (AGEs) in vitro and in vivo. Primary mouse nonparenchymal cells (NPCs) were used to evaluate the drug effect on AGEs clearance and autophagic-lysosomal activity. In an animal study, we used AGEs-induced diabetic mice to evaluate the drug effect on AGEs-induced vascular complications. Our results indicated that Dispo85E enhanced the endocytosis and degradation activity of AGEs in hepatic NPCs. Furthermore, the hepatocyte growth factor (HGF) expression level was positively correlated with the clearance capacity of the AGEs in NPCs after Dispo85E treatment. In addition, the effects of Dispo85E on the degradation and uptake capability of 14C-AGEs were abolished in the presence of an anti-HGF neutralizing antibody. We further demonstrated that recombinant mouse HGF could enhance the endocytosis and autophagic clearance of AGEs in NPCs. The in vivo data indicated that Dispo85E increased hepatic HGF messenger RNA expression levels and decreased serum AGEs level in diabetic mice. Moreover, the function of retina and kidneys was improved by Dispo85E treatment in AGEs-induced diabetic mice. These results suggest that HGF may have an important role in the elimination of AGEs. This study suggests that Dispo85E is a botanical drug with a novel mechanism that enhances the clearance of AGEs through HGF-induced autophagic-lysosomal pathway and is a candidate drug for the treatment of diabetic vascular complications.

Comparison of rutin and syringin content between tissue culturing seedlings and botanical drug of Saussurea involucrata

To compare the rutin and syringin content in tissue culturing seedlings and in botanical drug of Saussurea involucrata. The HPLC with Hydro-RP C18 (4.6 mm x 250 mm, 5 microm) column was used, a mixture of acetonitrile-water (5:95) was used as a mobile phase, with flow rate of 1 mL x min(-1), column temperature at 25 degrees C and detection wavelength at 220 nm. The effective constituents of tissue culturing seedlings were almost similar to the botanical drug. And syringin in tissue culturing seedlings was increased 4.35 times. It has a good prospect to acquire high-quality S. involucrata by tissue culturing seedlings.

Development of a grape seed polyphenolic extract with anti-oligomeric activity as a novel treatment in progressive supranuclear palsy and other tauopathies.

A diverse group of neurodegenerative diseases - including progressive supranuclear palsy (PSP), corticobasal degeneration and Alzheimer's disease among others, collectively referred to as tauopathies - are characterized by progressive, age-dependent intracellular formations of misfolded protein aggregates that play key roles in the initiation and progression of neuropathogenesis. Recent studies from our laboratory reveal that grape seed-derived polyphenolic extracts (GSPE) potently prevent tau fibrillization into neurotoxic aggregates and therapeutically promote the dissociation of preformed tau aggregates [J. Alzheimer's Dis. (2009) vol. 16, pp. 433]. Based on our extensive bioavailability, bioactivity and functional preclinical studies, combined with the safety of GSPE in laboratory animals and in humans, we initiated a series of studies exploring the role of GSPE (Meganatural-Az(®) GSPE) as a potential novel botanical drug for the treatment of certain forms of tauopathies including PSP, a neurodegenerative disorder involving the accumulation and deposition of misfolded tau proteins in the brain characterized, in part, by abnormal intracellular tau inclusions in specific anatomical areas involving astrocytes, oligodendrocytes and neurons [J. Neuropathol. Exp. Neurol. (2002) vol. 61, pp. 33]. In this mini-review article, we discuss the biochemical characterization of GSPE in our laboratory and its potential preventative and therapeutic role in model systems of abnormal tau processing pertinent to PSP and related tauopathies.

A comprehensive platform for quality control of botanical drugs (PhytomicsQC): a case study of Huangqin Tang (HQT) and PHY906

BackgroundEstablishing botanical extracts as globally-accepted polychemical medicines and a new paradigm for disease treatment, requires the development of high-level quality control metrics. Based on comprehensive chemical and biological fingerprints correlated with pharmacology, we propose a general approach called PhytomicsQC to botanical quality control.MethodsIncorporating the state-of-the-art analytical methodologies, PhytomicsQC was employed in this study and included the use of liquid chromatography/mass spectrometry (LC/MS) for chemical characterization and chemical fingerprinting, differential cellular gene expression for bioresponse fingerprinting and animal pharmacology for in vivo validation. A statistical pattern comparison method, Phytomics Similarity Index (PSI), based on intensities and intensity ratios, was used to determine the similarity of the chemical and bioresponse fingerprints among different manufactured batches.ResultsEighteen batch samples of Huangqin Tang (HQT) and its pharmaceutical grade version (PHY906) were analyzed using the PhytomicsQC platform analysis. Comparative analysis of the batch samples with a clinically tested standardized batch obtained values of PSI similarity between 0.67 and 0.99.ConclusionWith rigorous quality control using analytically sensitive and comprehensive chemical and biological fingerprinting, botanical formulations manufactured under standardized manufacturing protocols can produce highly consistent batches of products.

Phase II study of PHY906 plus capecitabine (CAP) in pts with gemcitabine-refractory pancreatic cancer (PC) and measurement of cytokines.

e14540 Background: Oral CAP offers convenience as a palliative chemotherapeutic option, however, diarrhea and HFS may compromise its efficacy. Pts in USA cannot tolerate CAP 1,250 mg/m2 BID D1-14 without experiencing toxicities. PHY906, a traditional Chinese botanical formula has shown synergistic anti-tumor activity with CAP as well as cytoprotective anti-diarrheal effect in preclinical and phase I studies (ASCO 2007, 2008). These data provide a strong rationale for extending this combination into PC. Methods: PC pts with prior gemcitabine received CAP 1,500 mg/m2 BID D1-7 and PHY906 800 mg/m2 BID D1-4 q 2 wks. AEs were assessed per NCI CTCAE v3.0 and response per RECIST q 6 wks. Primary objective was OS and secondary aim to determine effect of PHY906 on cytokines and chemokines including IL-2, IL-4, IL-5, IL-6, IL-10, MCP-1, TNF-a, IFN-g, VEGF, FGF-B, GM-CSF, G-CSF using a cytometric bead array assay. Results: Twenty-five pts were enrolled: 25 received study drug (evaluable for safety); 23 received at least 1 cycle (evaluable for efficacy). Median age was 60yr (range 45-84), 10 F and 15 M, with a median ECOG PS of 1 (range 0-2). Predominant AEs included grade 3 diarrhea (n = 3), grade 3 fatigue (n = 3) and grade 3 HFS (n = 1). Among 23 pts, 2 achieved PR (9%), 10 had stable disease (43%) resulting in disease control rate of 52%. All intent-to-treat pts reached mPFS of 10 wks (r: 0.4-51) and mOS of 12 wks (r: 0.4-63). For 18 pts who received > = 2 cycles, mPFS was 13 wks and mOS 31 wks. 9-mth survival rate was 22%. Preliminary correlative studies showed that none of the cytokines except serum IL-6 was reversely correlated with survival. QOL data is currently under evaluation. Conclusions: This is the first clinical study to evaluate a botanical drug PHY906 plus CAP in PC. Our results suggest that PHY906 can increase therapeutic index of CAP by reducing diarrhea and HFS. This combination appears a safe and feasible salvage therapy after gemcitabine failure and warrants further investigation in a randomized study against CAP. Recent studies have indicated role of IL-6 in tumor progression and tumor cachexia, suggesting a need to investigate its relation to pathophysiology of PC and development of anti-IL-6 therapeutics. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration PhytoCeutica PhytoCeutica Bayer, Bristol-Myers Squibb, Genentech, Novartis, Roche, sanofi-aventis Enzon, Merck, PhytoCeutica, Roche, Taiho Pharmaceutical

Botanicals in Dermatology

Botanical extracts and single compounds are increasingly used in cosmetics but also in over-the-counter drugs and food supplements. The focus of the present review is on controlled clinical trials with botanicals in the treatment of acne, inflammatory skin diseases, skin infections, UV-induced skin damage, skin cancer, alopecia, vitiligo, and wounds. Studies with botanical cosmetics and drugs are discussed, as well as studies with botanical food supplements. Experimental research on botanicals was considered to a limited extent when it seemed promising for clinical use in the near future. In acne therapy, Mahonia, tea tree oil, and Saccharomyces may have the potential to become standard treatments. Mahonia, Hypericum, Glycyrrhiza and some traditional Chinese medicines appear promising for atopic dermatitis. Some plant-derived substances like dithranol and methoxsalen (8-methoxypsoralen) [in combination with UVA] are already accepted as standard treatments in psoriasis; Mahonia and Capsicum (capsaicin) are the next candidates suggested by present evidence. Oral administration and topical application of antioxidant plant extracts (green and black tea, carotenoids, coffee, and many flavonoids from fruits and vegetables) can protect skin from UV-induced erythema, early aging, and irradiation-induced cancer. Hair loss and vitiligo are also traditional fields of application for botanicals. According to the number and quality of clinical trials with botanicals, the best evidence exists for the treatment of inflammatory skin diseases, i.e. atopic dermatitis and psoriasis. However, many more controlled clinical studies are needed to determine the efficacy and risks of plant-derived products in dermatology. Safety aspects, especially related to sensitization and photodermatitis, have to be taken into account. Therefore, clinicians should not only be informed of the beneficial effects but also the specific adverse effects of botanicals used for dermatologic disorders and cosmetic purposes.