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Objectives To systematically review Clinical Practice Guidelines (CPGs) for the management of menopause-related vasomotor symptoms (VMS) to 1) identify those that include Natural Health Products (NHPs); 2) identify which NHPs were included and the evidence supporting the recommendation for the place in therapy; and 3) compare methodological quality of the CPGs. Methods PubMed, EMBASE, Web of Science, BMJ Best Practice, DynaMed Plus and websites of gynecological and menopausal societies were searched (Jan 2000–Nov 2018). Records were screened to identify CPGs that were published in English, since 2000 and were for use in North America. CPGs were reviewed for inclusion of NHPs. Data regarding NHPs (evidence, recommendation) were extracted and analyzed. CPGs were critically appraised using the AGREE II tool. Results Five of six CPGs that met general inclusion criteria included NHPs. Black cohosh, isoflavones, soy food/extracts and phytoestrogens were included in all five CPGs. Comparative analysis of recommendations and level of supporting evidence revealed differences. All CPGs included recommendations regarding the use of NHPs in general, although recommendations differed. Four of five CPGs made recommendations for unique NHPs, however, recommendations differed. Using the AGREE II tool, CPGs scored well on domains for purpose and clarity. Lack of detailed description of methodology and author expertise affected scores in other domains. Conclusion Five CPGs included general recommendations for the role of NHPs in treating VMS, with recommendations ranging from use with caution to not recommended. There were inconsistencies among CPGs regarding NHPs included and what evidence was used in making recommendations.

OBJECTIVE To evaluate the efficacy of bioidentical progesterone cream in the treatment of menopause-related vasomotor symptoms. DATA SOURCES A systematic search (from time of inception to September 2012) of PubMed, EMBASE, International Pharmaceutical Abstracts, International Journal of Pharmaceutical Compounding, Cochrane, and CINAHL was conducted using the terms progesterone, vasomotor symptoms, night sweats, hot flash or flush, and randomized controlled trials (RCTs). Hand-searching of citations from relevant articles was also performed. STUDY SELECTION AND DATA EXTRACTION Articles selected for inclusion described RCTs evaluating the use of bioidentical progesterone cream for the treatment of menopause-related vasomotor symptoms. Studies included were placebo controlled and participants were postmenopausal women experiencing vasomotor symptoms. DATA SYNTHESIS Searching identified 3 published RCTs. Only one study, which used a bioidentical progesterone cream specifically compounded for the trial, found that the bioidentical progesterone was more effective than placebo in relieving menopause-related vasomotor symptoms. The 2 studies using manufactured bioidentical progesterone creams found that the creams were no more effective than placebo. Vaginal bleeding and headaches were the most commonly reported adverse effects in the studies. CONCLUSIONS Available evidence from RCTs does not support the efficacy of bioidentical progesterone cream for the management of menopause-related vasomotor symptoms. Adverse effects appear to be mild and self-limiting.

Increasing rates of adult obesity and its negative health consequences are likely to become an increasing burden to the Canadian health care system. Consumers are looking for treatment options and often try the natural health products that are heavily promoted as safe, fast and effective. In this case report, MH, a 57-year-old overweight female wanted advice regarding whether she should use the natural product Hoodia to help her attain her weight loss goals. A literature search was conducted using Medline, EMBASE, the Cochrane Library, Natural Medicines Comprehensive Database and IPA from inception to March 2009. The internet, files of the authors and bibliographies of articles were searched for additional references. No published, peer-reviewed randomized controlled trials examining efficacy of Hoodia were found. Unpublished data from two small trials reported promising results with no adverse events. However, this leaves many unanswered questions regarding the use of Hoodia for weight loss such as the appropriate dose and duration, short and long term safety and use in patients with concomitant diseases. Literature suggests that some commercial products may not actually contain Hoodia at all. Additionally, Hoodia is not yet listed in the Canadian Licensed Natural Health Products Database meaning products sold in Canada may not meet Canadian regulatory standards. Upon discussing this information, MH decided not to use Hoodia, and other evidence-based recommendations were discussed.

Background With Canadians increasing their use of the Internet to find health-related information, especially regarding natural health products (NHPs), there is a need for high-quality, evidence-based information on Web sites to aid consumers in making informed decisions regarding the appropriate and safe use of NHPs. Objective To determine the quality of Web sites that target consumers and advocate the use of NHPs in the management of osteoporosis in postmenopausal women. Methods Web sites were identified via the Google search engine using the key words “natural treatment osteoporosis.” The first pages of the first 91 Web sites identified were assessed for relevance based on the following criteria: (1) written in English, (2) contained consumer information, and (3) claimed a benefit of a single NHP in the management of osteoporosis. This task was completed by 2 investigators; differences were resolved by consensus after discussion with the third investigator. Quality of relevant sites was assessed using an expanded DISCERN instrument that also examined the evidence supporting the claim of benefit. Additionally, readability of the sites was assessed. Results Thirty-eight Web sites met the inclusion criteria. Using the DISCERN instrument, we found that many of the sites scored low, suggesting serious or extensive shortcomings. On many Web sites, benefit claims regarding calcium, vitamin D, phytoestrogens, dehydroepiandrosterone and vitamin K were consistent with empirical evidence. However, for other NHPs, many of these same sites made effectiveness claims that were not supported by current evidence from randomized controlled trials. Twenty-five sites did not provide information as to what resources were used to support their claims. The average reading grade score was grade 11.9 (based on US school grades) and the mean Flesch Reading Ease Score was 41.7. (A higher score out of 100 indicates ease of reading.) Conclusions Due to the poor quality and content from unknown sources found on some Web sites, consumers who access Web sites for information regarding the use of NHPs in osteoporosis should do so cautiously and discuss results with their healthcare providers.

The purpose of this project was to conduct a systematic review to identify instruments designed to evaluate the quality of randomized controlled trials (RCTs) of natural health products (NHPs). Instruments were examined for inclusion of items assessing methods, identity and content of the NHP, generalizability of results and instructions for use. Online databases, websites, textbooks and reference lists were searched to identify instruments. Relevance assessment and data extraction of articles were completed by two investigators and disagreements were settled by the third investigator. Data were analyzed using descriptive statistics. Of the 4442 citations identified, 29 were potentially relevant with 16 meeting the criteria for inclusion. None of the instruments stated they were validated; content in the four areas of interest varied considerably. The most common items included randomization sequence generation (100%), blinding (100%), allocation concealment (75%) and participant flow (75%). Only nine of the NHP instruments included at least one item to appraise the specific content of the NHP. The CONSORT Statement for Herbal Interventions most closely addressed the four areas of interest; however, this instrument was specific for herbs. There is a need for the development of a validated instrument for assessment of the quality of RCTs that would be useful for herbs as well as other NHPs.

Background: Consumers are increasingly looking to natural health products to manage specific diseases such as osteoporosis. As a result, healthcare providers need evidence-based information on which to base recommendations regarding use and efficacy. Objective: To identify natural health products (NHPs, ie, dietary supplements) advocated for the prevention and treatment of osteoporosis and systematically review the evidence from randomized controlled trials for the effect of NHPs on bone mineral density (BMD)/fracture rate in women. Methods: MEDLINE, Natural Medicines Comprehensive Database, and the Internet were initially searched to identify NHPs advocated for prevention and treatment of osteoporosis. For NHPs having evidence to support their claim, the aforementioned sources, along with International Pharmaceutical Abstracts, the Cochrane Library, the International Bibliographic Information on Dietary Supplements, the Cumulative Index to Nursing & Allied Health, and HerbMed, were searched to locate randomized controlled trials published in English between 1966 and October 2004. Bibliographies of identified articles were also searched. Randomized controlled trials were selected if they evaluated the use of a single NHP in women, using BMD/fracture rate as the outcome measure. NHPs were excluded from further evaluation if a review had already been published. Data were extracted using predetermined criteria and studies appraised using the Jadad scale. Forty-five NHPs were identified that the authors claimed to be beneficial in prevention and treatment of osteoporosis, with 15 having evidence to support their claim. Calcium; copper; evening primrose oil; fish oils; fluoride; magnesium; manganese; strontium; vitamin D; and black, green, and oolong tea did not meet study criteria. Results: Results from randomized controlled trials evaluating dehydroepiandrosterone (DHEA), phytoestrogens, and vitamin K2 (menaquinone or menatetrenone) were promising; however, study limitations suggest the need for confirmatory evidence. Conclusions: Although no definitive conclusions can be drawn, the relative safety of phytoestrogens, DHEA, and vitamin K2 at the studied doses, as well as preliminary positive results from randomized controlled trials, provides some initial support for the use of these NHPs in the prevention and treatment of osteoporosis in women.

OBJECTIVE: To review the scientific literature to identify reports of the effects of natural health products (NHPs) on blood pressure. DATA SOURCES: Electronic databases (MEDLINE [1965–May 2004] via PubMed, the Cochrane Library [1995–May 2004], International Pharmaceutical Abstracts [1970–May 2004], Iowa Drug Information Services [1965–May 2004]) were searched using the key words medicine, herbal plants, medicinal plant preparations, phytotherapy, angiosperms/therapeutic use, gymnosperms/therapeutic use, ethnopharmacology, pharmacognosy, blood pressure, hypertension, hypotension, and diuretic. Searches were not limited by date, language, or publication type. Review articles and texts, as well as reference lists of relevant articles, were used to identify additional reports. STUDY SELECTION AND DATA EXTRACTION: Articles (English-language after 1980) were assigned to the following categories: human study, case report, animal study, in vitro study, or theoretical prediction based on chemical constituents. Discussions of mechanisms of action were noted. DATA SYNTHESIS: A comprehensive search of the scientific literature identified NHPs capable of affecting blood pressure. Case reports and clearly defined mechanisms of action provided strong evidence for the ability of ephedra and licorice to increase blood pressure. Coenzyme Q10 was reported to decrease systolic and diastolic blood pressure, although the mechanism is unclear. The clinical significance of the blood pressure effects of other NHPs is unclear due to lack of conclusive in vivo data, as well as substantial variability in the chemical content of preparations of NHPs. CONCLUSIONS: Among published information, there is little definitive evidence with regard to the impact of NHPs on blood pressure. Additionally, effects may vary in a given patient with the formulation and standardization of a particular product. Until research better characterizes the effect of NHPs on blood pressure, patients should be encouraged to talk with their healthcare provider before starting or stopping any herbal product.

Objectives: To investigate Nova Scotia (NS) pharmacists´ knowledge and beliefs regarding the use of bioidentical hormones (BHs) for the management of menopause related symptoms. Methods: Using Dillman´s tailored design methodology, an invitation to complete the web-based questionnaire was emailed to pharmacists in NS as part of the Dalhousie College of Pharmacy Continuing Pharmacy Education Department´s (CPE) weekly email update. Data was analyzed using descriptive statistics. Results: Of approximately 1300 e-mails sent, 113 pharmacists completed the questionnaire (response rate 8.7%). The majority of respondents (94%) knew that BHs were not free from adverse drug reactions. More than 50% were aware that conjugated equine estrogens and medroxyprogesterone acetate were not examples of BHs. For seven of eleven knowledge questions, 33-45% indicated that they did not know the answer. When asked about their beliefs regarding BHs, many believed that BHs were similar in efficacy (49%) or more effective (21%) than conventional hormone therapy (CHT) for vasomotor symptoms. Most respondents also believed that both BHs and CHT had similar safety profiles. Additionally, responding pharmacists indicated that more education would be helpful, especially in the area of safety and efficacy of BHTs compared to CHT. Conclusion: NS pharmacists knew BHs were not free of adverse effects, however knowledge was lacking in other areas. This may reflect the level of coverage of this topic in pharmacy school curriculums and in the pharmacy literature. Results indicate a need for additional education of NS pharmacists with respect to BHs, which could be accomplished through modification of undergraduate pharmacy programs and supplementary CPE.

In the last decade, the use of bioidentical hormones (BHs) to treat menopause-related symptoms has become increasingly popular. However, the many different definitions of BHs have led to a great deal of confusion often making it difficult for health care providers to discuss this area with patients.Objective: The purpose of this paper was to produce a concise definition of bioidentical hormones, based on a review of the literature.Methods: Searches, using systematic review methodology, were conducted from inception to June 2010 in PubMed, EMBASE, IPA, The Journal of International Compounding and the Internet to identify definitions of bioidentical hormones. There were no restrictions on type, date or language of publication. Included papers/website included those that contained a definition of BHs. Definitions were extracted, similarities and differences summarized, and these were then examined to produce a concise definition.Results: Sixty-three definitions were found. Based on the analysis of similarities and differences, the following definition, comprised of three components (term being defined; category to which term belongs; distinctive characteristics of term) was produced: “Bioidentical hormones are chemical substances that are identical in molecular structure to human hormones.”Conclusions: This definition clearly and concisely explains the meaning of BHs which should lead to a common understanding of the term and limit confusion among health care providers, the general public and the scientific community. Keywords

As many women experiencing symptoms of premenstrual syndrome (PMS) seek relief from natural products (NP), health care providers should have quality information available to aid women in making evidence-based decisions regarding use of these products.To identify herbs, vitamins and minerals advocated for the treatment of PMS and/or PMDD and to systematically review evidence from randomized controlled trials (RCTs) to determine their efficacy in reducing severity of PMS/PMDD symptoms.Searches were conducted from inception to April 2008 in Clinical Evidence, The Cochrane Library, Embase, IBID, IPA, Mayoclinic, Medscape, MEDLINE Plus, Natural Medicines Comprehensive Database and the Internet to identify RCTs of herbs, vitamins or minerals advocated for PMS. Bibliographies of articles were also examined. Included studies were published in English or French. Studies were excluded if patient satisfaction was the sole outcome measure or if the comparator was not placebo or recognized therapy.Sixty-two herbs, vitamins and minerals were identified for which claims of benefit for PMS were made, with RCT evidence found for only 10. Heterogeneity of length of trials, specific products and doses, and outcome measures precluded meta-analysis for any NP. Data supports the use of calcium for PMS, and suggests that chasteberry and vitamin B6 may be effective. Preliminary data shows some benefit with ginkgo, magnesium pyrrolidone, saffron, St. John's Wort, soy and vitamin E. No evidence of benefit with evening primrose oil or magnesium oxide was found.Only calcium had good quality evidence to support its use in PMS. Further research is needed, using RCTs of adequate length, sufficient sample size, well-characterized products and measuring the effect on severity of individual PMS symptoms.

Background The efficacy of natural products (NPs) is being evaluated using randomized controlled trials (RCTs) with increasing frequency, yet a search of the literature did not identify a widely accepted critical appraisal instrument developed specifically for use with NPs. The purpose of this project was to develop and evaluate a critical appraisal instrument that is sufficiently rigorous to be used in evaluating RCTs of conventional medicines, and also has a section specific for use with single entity NPs, including herbs and natural sourced chemicals. Methods Three phases of the project included: 1) using experts and a Delphi process to reach consensus on a list of items essential in describing the identity of an NP; 2) compiling a list of non-NP items important for evaluating the quality of an RCT using systematic review methodology to identify published instruments and then compiling item categories that were part of a validated instrument and/or had empirical evidence to support their inclusion and 3) conducting a field test to compare the new instrument to a published instrument for usefulness in evaluating the quality of 3 RCTs of a NP and in applying results to practice. Results Two Delphi rounds resulted in a list of 15 items essential in describing NPs. Seventeen item categories fitting inclusion criteria were identified from published instruments for conventional medicines. The new assessment instrument was assembled based on content of the two lists and the addition of a Reviewer's Conclusion section. The field test of the new instrument showed good criterion validity. Participants found it useful in translating evidence from RCTs to practice. Conclusion A new instrument for the critical appraisal of RCTs of NPs was developed and tested. The instrument is distinct from other available assessment instruments for RCTs of NPs in its systematic development and validation. The instrument is ready to be used by pharmacy students, health care practitioners and academics and will continue to be refined as required.

BackgroundNatural health products (NHPs) such as herbs, vitamins and homeopathic medicines, are currently available for sale in most Canadian pharmacies. However, most pharmacists report that they have limited knowledge about these products which have been regulated in Canada as a specific sub-category of drugs. In this paper, consumers' and practicing pharmacists' perceptions of pharmacists' professional responsibilities with respect to NHPs are examined.MethodsA total of 16 focus groups were conducted with consumers (n = 50) and pharmacists (n = 47) from four different cities across Canada (Vancouver, Edmonton, Toronto, and Halifax).ResultsIn this paper, we illustrate the ways in which pharmacists' professional responsibilities are impacted by changing consumer needs. Many consumers in the study utilized a wide range of information resources that may or may not have included pharmacists. Nevertheless, the majority of consumers and pharmacists agreed that pharmacists should be knowledgeable about NHPs and felt that pharmacists should be able to manage drug-NHPs interactions as well as identify and evaluate the variety of information available to help consumers make informed decisions.ConclusionThis paper demonstrates that consumers' expectations and behaviour significantly impact pharmacists' perceptions of their professional responsibilities with respect to NHPs.

The juice of freshly macerated unripe hulls of the black walnut (Juglans nigra) has been used for many years in folk medicine as a treatment for localized, topical fungal infections such as ringworm. It has been proposed that the biological activity of the walnut hulls is due to the presence of the simple naphthoquinone, juglone (5-hydroxy-1,4-naphthoquinone), which has been isolated from the unripe hulls by sublimation. Since the fresh juice of unripe walnut hulls is utilized for the treatment of ringworm, and since it has been speculated that the activity is due to the presence of juglone, it was of interest to determine the efficacy of juglone as compared to standard commercially available antifungal agents. The comparative efficacy was determined by evaluation of the minimum inhibitory concentration (MIC) values of juglone and the standard antifungal agents clotrimazole, triacetin, tolnaftate, griseofulvin, zinc undecylenate, selenium sulfide as well as two investigational antifungal antibiotics, liriodenine and liriodenine methiodide, for two dermatophytes, Trichophyton mentagrophytes and Microsporum gypseum. MIC values for juglone showed it to have moderate antifungal activity and to be as effective as certain commercially available antifungal agents such as zinc undecylenate and selenium sulfide.

The root of Heracleum maximum Bartr. (Umbelliferae), known to possess direct antifungal and anti-mycobacterial properties, has been reported anecdotally to possess antiviral properties. It was therefore hypothesized that the plant may have immunostimulant properties. This hypothesis was tested using a macrophage activation assay to evaluate the ability of aqueous extracts of the root of Heracleum maximum to stimulate IL-6 production. All Heracleum maximum extracts were found to stimulate IL-6 and produced a steep dose-response curve. With the assay performed twice in the absence of the macrophage primer, IFN-gamma, the mean IL-6 production in the setting of the strongest extract was 3648pg/ml (95% CI 3361-3935) and 5430pg/ml (95% CI 4976-5885) as compared to 2722pg/ml (95% CI 2620-2824) and 6772pg/ml (95% CI 6282-7262) produced by the LPS positive control, respectively. In the presence of IFN-gamma, the strongest extract produced a mean concentration of IL-6 of 21804pg/ml (95% CI 19755-23854) surpassing the 14893pg/ml (13159-16628) produced by the LPS+IFN-gamma positive control. These positive results confirm the hypothesis of immunostimulation and thus support the anecdotal reports of antiviral activity.

Microbial metabolism studies of crisnatol (1), a new DNA interca-lator, has resulted in the isolation and characterization of a major metabolite identified as the C-l hydroxylated crisnatol (2). The structure of the metabolite was established by comparison of its spectral data to that of crisnatol. Complete 13C-NMR assignments for crisnatol and its C-l hydroxylated metabolite were also made.

We have identified a novel nonsteroidal ecdysteroid agonist. This compound was isolated from a methanol extract of Ajuga reptans L. (Lamiaceae) and the structure was identified by spectroscopic methods as 8- O -acetylharpagide. We have characterised this compound as an ecdysteroid agonist in a transactivation assay using β-galactosidase as the reporter gene regulated by ecdysteroid response elements. In this assay, 8- O -acetylharpagide has an EC 50 of 22 μM. The compound also competes with tritiated-ponasterone A for binding to the Drosophila ecdysteroid receptor. Finally, it induces differentiation of Drosophila Kc cells as would be expected of an ecdysteroid agonist. This iridoid glycoside is common to several plant species and may play a role in the natural defense mechanisms of plants.

gamma-Pyrone-3-acetic acid (L-741,494) is a novel metabolite produced by a culture of the fungal genus Xylaria. This substance is a water-soluble, competitive, irreversible inhibitor of Interleukin-1 beta Converting Enzyme that is inactive against papain and trypsin. It has a mol wt of 154 and an empirical formula of C7H6O4. We propose the name xylaric acid for this compound.

Curcuma comosa is a member of the economically important plant family, Zingiberaceae. A methanolic extract of C. comosa was shown to be nematocidal when tested against the free-living nematode Caenorhabditis elegans. Five diphenylheptanoids [1-5], one new and four known, have been isolated and shown to be responsible for the activity. This is the first report of three of these compounds [1, 2, 4] being isolated from a natural source.

Objective. To reach consensus on core competency statements for natural health products (NHPs) for Canadian pharmacy students. Methods. Four rounds of a modified Delphi method were used to achieve consensus on core competency statements for NHPs. Pharmacy educators from Canada and the United States, and representatives from Canadian pharmacy organizations ranked their agreement using a 5-point Likert scale. Results. Consensus was achieved on 3 NHP-related core competency statements: (1) to incorporate NHP knowledge when providing pharmaceutical care; (2) to access and critically appraise NHP-related information sources; and (3) to provide appropriate education to patients and other health care providers on the effectiveness, potential adverse effects, and drug interactions of NHPs. Conclusions. Consensus was reached among leaders in NHP education on 3 NHP-related core competency statements. Implementation of these competencies would ensure that graduating Canadian pharmacists would be able to fulfill their professional responsibilities related to NHPs.

1. A total of 114 microorganisms were evaluated for their ability to metabolize the antifungal drimane sesquiterpene, muzigadial. 2. Cryptococcus neoformans was found to convert muzigadial to one major metabolite, identified as a hemiacetal. 3. Streptomyces platensis produced three metabolites: the hemiacetal, its corresponding lactone, and the epoxide of the hemiacetal. 4. Streptomyces spectabilis produced the hemiacetal as well as the epoxy hemiacetal. 5. The proposed structures of all of the metabolites were based on comparisons of the spectroscopic data (1H- and 13C-n.m.r. spectra and mass spectra) between the metabolites and the parent compound. 6. Antimicrobial evaluation of the microbial metabolites indicate that metabolism decreases antifungal activity.

To determine fourth-year Canadian pharmacy students' knowledge of herbal medicine and whether that knowledge is associated with mandatory instruction in herbal medicine.Standardized multiple-choice tests assessing students' herbal knowledge were distributed to all fourth-year BSc pharmacy students at 5 pharmacy schools in Canada.The Quebec response rate was too low to include in the analysis. Herbal knowledge test scores were positively associated with having previously taken an herbal medicine class and completion of a pharmacy practicum. However, postsecondary education, age, and gender were not associated with herbal knowledge test scores. Students at the University of British Columbia had the highest score, followed by Alberta, Nova Scotia, and Ontario.Pharmacy students' knowledge of herbal medicine varies depending on the school attended and higher herbal knowledge test scores appear to be most closely related to mandatory herbal instruction.

Objective: Although natural health products (NHPs) are widely sold in pharmacies, the professional responsibilities of pharmacists with respect to these products have not been well defined. This study addressed the question: what are the pharmacist and consumer perspectives on the professional responsibilities of pharmacists with respect to NHPs? Method: Focus groups with practicing pharmacists and consumers were held in 4 different cities across Canada (Vancouver, Edmonton, Toronto, and Halifax) for a total of 16 focus groups. Current and potential professional responsibilities of pharmacists with respect to NHPs were discussed in each group. Verbatim transcripts of each group were assessed using qualitative content analysis. Results: Both pharmacists and consumers were supportive of pharmacists’ involvement with natural health products and the need for pharmacists to have more education on them. The management of interactions between pharmaceuticals and NHPs and the provision of counselling on NHPs were identified as the primary responsibilities for pharmacists. Participants perceived NHPs as being distinct from other over-the-counter products and voiced concerns about the safety, efficacy, and product quality of NHPs, which may pose a barrier for pharmacists in performing these roles. Conclusion: Pharmacists and consumers agree that pharmacists have a significant role to play in counselling patients about natural health products, especially about the potential for drugNHP interactions. However, in order for pharmacists to fulfill this role, additional education about NHPs is needed both in undergraduate and continuing education programs. Standards of practice for this role would also help pharmacists understand their professional responsibilities. I was inspired to undertake this study because I believe pharmacists have an opportunity to develop a unique and credible professional role for themselves as expert advisers on natural health products in order to reduce the risks associated with the use of these products. D. Kwan

Methyl p-coumarate has been isolated from the roots and stems of Comptonia peregrina , a plant used by North American Indians, settlers and herbalists to treat a variety of skin conditions. Pharmacological testing has proven this compound to be cytotoxic.