Medical Devices Made of Substances: Possible Innovation and Opportunities for Complex Natural Products.

The novel Regulation 2017/745/EC on medical devices introduces and strengthens the role of "medical devices made of substances", which mostly include substances of natural origin. Natural products may follow different regulations, from food to therapeutics. Concerning their isolated constituents, extracts are characterized by a complexity that is not easily tackled from both a scientific and a regulatory point of view, but more importantly, from a therapeutic point of view. The evidence-based approach applied to isolated molecules requires appropriate evidence of quality, efficacy, and safety. The same needs must be reached for complex substances by finding appropriate methods to generate this evidence, and in addition, defining an appropriate regulatory field for them. From a scientific point of view, new methods, such as those proposed by systems biology, are available and applicable to complex substances. From a regulatory point of view, Directive 2001/83/EC on medicinal products seems to be modeled on single (or combinations of single) molecule products. On the other hand, Regulation 2017/745/EC on medical devices seems to apply to complex substances without derogating on quality, efficacy, and safety. The regulation specifically names and strengthens medical devices that include substances, mostly of natural origin, introducing the official term "medical devices made of substances". This paper discusses and proposes an interpretation of important terms connected to this legislation, regarding both scientific and regulatory issues, and the opportunities the regulation may give for innovation and therapeutic improvement with natural complex substances.

Safety of complementary and alternative medicine in children: A 16-years retrospective analysis of the Italian Phytovigilance system database.

BACKGROUND: Dietary supplements and homeopathic medicines are largely used in children as complementary and alternative medicine (CAM) to treat different health conditions. Safety of CAM is unknown when they are marketed. This study analysed suspected CAM-related adverse reaction (AR) in pediatric population. METHODS: The Italian Phytovigilance system was searched for reports of suspected AR related to CAM use in children (0-18 years) from 2002 to 2018. AR reports were evaluated and information about patient's demographic characteristics, suspected CAM, conventional medications, and ARs were collected. In particular, we evaluated whether patient's and CAM characteristics, and concomitant drugs could be potential predictors of ARs seriousness. RESULTS: We evaluated 206 pediatric CAM-related AR reports, of which 69 were serious. Patients were mostly treated with only one CAM (n = 193), and 39% of AR reports were related to products containing 2-5 components. Most reported ARs were related to dietary supplements (57.18%), and skin and subcutaneous tissue disorders (40.29%) were the most involved System Organ Class. CAM-related AR reported as serious were higher in subjects exposed to homeopathic medicines (ROR 3.13 [1.88-5.22]), to CAM in presence of concomitant medications (ROR 1.77 [1.01-3.10]), to CAM containing 2-4 components (ROR 2.18 [1.13-4.22]), and to more than three concomitant CAM (ROR 7.81 [1.97-32.69]). CONCLUSION: We provide new insights on factors that might increase the risk of serious AR associated with CAM use in children: products containing more than two components and simultaneously administered with conventional medications can represent a potential risk in children.

The Impact of Previous Pregnancy Loss on Lactating Behaviors and Use of Herbal Medicines during Breastfeeding: A Post Hoc Analysis of the Herbal Supplements in Breastfeeding InvesTigation (HaBIT).

INTRODUCTION: Complementary and alternative medicines (CAMs) are commonly used among lactating women, despite the poor knowledge of these products and of their safety. Perception of pregnancy- and breastfeeding-related difficulties and consequent use of CAMs may differ in bereaved women, by force of the distress related to previous loss, although no literature evidence is available. This Herbal supplements in Breastfeeding InvesTigation (HaBIT) post hoc analysis explored the impact of previous pregnancy loss on lactating behaviors and on use of CAMs during breastfeeding. METHODS: A web-based survey was conducted among lactating women with no previous alive child, resident in Tuscany (Italy). Data on lactating behavior and on CAMs use were collected and evaluated among women with previous pregnancy loss as compared to control women. RESULTS: Out of 476 women answering the questionnaire, 233 lactating women with one child were considered. Of them, 80 had history of pregnancy loss. Cesarean birth was significantly more frequent among women with history of pregnancy loss as compared to controls (41% versus 22%; p=0.004). Proportion, length of exclusive breastfeeding, and occurrence of breastfeeding-related complications were comparable among the two cohorts. More than half of women used CAMs during breastfeeding. Use of CAMs was more frequent among women with previous pregnancy loss (54% versus 68%; p=0.050), specifically considering herbal preparations (16% versus 30%; p=0.018). Major advisors for CAMs use were midwives. 18% and 23% of women without and with history of pregnancy loss declared no clear perception on CAMs efficacy and safety. CONCLUSION: Overcoming the social taboo of pregnancy loss and training healthcare professionals for an adequate management of the perinatal period are essential for an effective and safe care. Despite the common use and advice on CAMs use during breastfeeding, it is important to acknowledge that limited evidence supports their safety and efficacy during such critical period.

On the Policy of the Italian Government in the Discovery, Development, and Access to Medicines.

This commentary outlines how discovery, development, and access to medicines are regulated and promoted in Italy by the government through the Ministry of University and Research, the Ministry of Health, and the Italian Medicines Agency. We describe and comment on the existing research programs stimulating preclinical, translational, and clinical research and how access to medicines and their pricing is regulated by Italy's National Health Service both at the national and regional levels. Finally, we describe the current scenario of industrial research and medicines manufacturing. The resulting picture shows a country in which high-level competitive research on medicines is promoted alongside an excellent national health system working toward fairness of access to health care services for all citizens and fiscal solidarity as a fundamental form of system financing. Critical challenges still exist, including the relative scarcity of public funding for research and the non-uniform access to the benefits of the National Health Service across Italian regions.

The use of complementary and alternative medicines during breastfeeding: results from the Herbal supplements in Breastfeeding InvesTigation (HaBIT) study.

AIMS: The use of complementary and alternative medicines (CAMs) during breastfeeding is increasing, mainly because of their presumed greater safety compared with conventional medications. However, CAMs can cause serious adverse effects, and there is limited high-quality evidence supporting their use during lactation. In Italy, specific investigations on the attitude of lactating women towards CAMs are lacking. The Herbal supplements in Breastfeeding InvesTigation (HaBIT) study aimed to explore attitudes to and knowledge on CAMs among lactating women. METHODS: A web-based survey was conducted over a 6-year period among lactating women resident in Tuscany, Italy. Data on lactating behaviour, CAMs use during pregnancy or breastfeeding, and women's knowledge about the efficacy and safety of CAMs were collected. RESULTS: A total of 388 lactating women answered the questionnaire. The majority of them were primiparae, with a high educational level. Of these, 204 women declared themselves to have used CAMs during breastfeeding. Moreover, 61% and 48% of subjects reported also using CAMs before and during pregnancy, respectively. A significant proportion of subjects were unable to identify correctly the types of CAMs they were using. Seventy-three per cent of women were convinced that CAMs were equally safe or safer than conventional medications; nevertheless, 65% of women admitted to have no scientific information about the potential risks of CAMs, and 14 CAMs users reported that they had experienced side effects. CONCLUSIONS: These results demonstrate the need for healthcare providers to increase the awareness of breastfeeding women about CAMs. Further research is needed to support the evidence base for nonpharmaceutical approaches for symptom control during breastfeeding.

Galenic Preparations of Therapeutic Cannabis sativa Differ in Cannabinoids Concentration: A Quantitative Analysis of Variability and Possible Clinical Implications.

Introduction: Magistral preparations of therapeutic cannabis are extracted from standardized products imported from Holland or from the Florence Military Pharmaceutical Chemical Works, but extraction protocols differ among galenic laboratories. This study assessed the inter-laboratory variability in concentrations of cannabidiol (CBD), cannabinol (CBN), tetrahydrocannabinol (THC), and tetrahydrocannabinolic acid (THCA) among different magistral oil preparations. Methods: 219 samples of Bediol, Bedrobinol, Bedrolite or FM-2 70 or 100 mg/ml in oil were collected from 3 laboratories. Concentrations of CBD, CBN, THC, and THCA were quantified by high-pressure liquid chromatography; inter-laboratories variability was assessed using the Kruskal-Wallis test. Results: A significant variability in CBD and THC concentrations was found for Bediol 70 mg/ml samples from 2 laboratories [for CBD: median 5.4 (range 4.8-6.6) vs. 6.1 (4.9-7.2) mg/ml, p = 0.033; for THC: 3.6 (3.1-3.9) vs. 4.0 (2.6-5.1) mg/ml, p = 0.020]. As for Bediol 100 mg/ml, a significant variability emerged in THC concentrations among the three considered laboratories [5.7 (-) vs. 4.2 (1.5-4.8) vs. 5.2 (4.2-6.9), p = 0.030]. No significant inter-laboratory variability emerged for Bedrocan and Bedrolite. Concentrations of CBD, CBN, and THC were

Astragali radix: could it be an adjuvant for oxaliplatin-induced neuropathy?

Neurotoxicity is a major side effect of platinum derivatives both during and after treatment. In the absence of effective pharmacological compounds, the opportunity to identify safe adjuvant treatments among medicinal plants seems appropriate. Astragali radix is an adaptogenic herbal product recently analyzed in platinum-treated cancer patients. With the aim of evaluating the anti-neuropathic profile of Astragali radix, a previously characterized aqueous (Aqu) and two hydroalcoholic (20%HA and 50%HA) extracts were tested in a rat model of oxaliplatin-induced neuropathy. Repeated administrations significantly reduced oxaliplatin-dependent hypersensitivity with 50%HA, the most effective, fully preventing mechanical and thermal hypersensitivity. Ex vivo, 50%HA reduced morphometric and molecular alterations induced by oxaliplatin in peripheral nerve and dorsal-root-ganglia. In the spinal cord and in brain areas, 50%HA significantly decreased activation of microglia and astrocytes. Furthermore, 50%HA prevented the nephro- and hepato-toxicity induced by the anticancer drug. The protective effect of 50%HA did not alter oxaliplatin-induced apoptosis in colon tumors of Pirc rats, an Apc-driven model of colon carcinogenesis. The hydroalcoholic extract (50%HA) of Astragali radix relieves pain and promotes the rescue mechanisms that protect nervous tissue from the damages triggering chronic pain. A safe profile strongly suggests the usefulness of this natural product in oxaliplatin-induced neuropathy.

In Vitro Evidence for the Use of Astragali Radix Extracts as Adjuvant against Oxaliplatin-Induced Neurotoxicity.

The repeated exposure to the anticancer drug oxaliplatin induces a disabling, painful neuropathy. The current pharmacological treatments are unsatisfactory and unable to modify the complex nervous damage induced by the platin derivative. Recently, we described a system of cellular measures of oxidative stress as a method for studying features of oxaliplatin neurotoxicity and screening new compounds able to reduce oxaliplatin-induced neuropathy. Based on this experimental design, the protective properties of Astragali radix were studied comparing aqueous and two hydroalcoholic root extracts. Aqueous and the 20 % hydroalcoholic (20 % water) extract were prepared from plant material, while the 50 % hydroalcoholic (50 % water) extract was a commercial one. All of the extracts were characterized in terms of drug extract ratio and content of typical isoflavonoids, Astragaloside IV, and related saponins. Furthermore, the molecular weight of the polysaccharide fraction was evaluated by light scattering analysis. Oxaliplatin increased the superoxide anion production both in the neuronal-derived cell line SH-SY5Y and in primary cultures of rat cortical astrocytes. Aqueous and the 50 % hydroalcoholic extract (50 µg/mL) showed significant antioxidant effects. In astrocytes, aqueous and the 50 % hydroalcoholic extract showed protective effects against oxaliplatin-induced lipid peroxidation (malonyl dialdehyde levels), protein (carbonylated proteins), and DNA oxidation (8-OH-2-dG levels). The 50 % hydroalcoholic extract was the most active in preventing the activation of the apoptotic enzyme caspase-3 and it was the only able to stimulate astrocyte viability. None of the tested extracts interfered with the toxicity elicited by oxaliplatin in the human colon adenocarcinoma cell line HT-29. The pharmacological profile of Astragali radix extracts, in particular, the aqueous and 50 % hydroalcoholic extracts, makes these natural products candidates as therapeutic adjuvant agents against oxaliplatin neurotoxicity.

Pharmacovigilance of herb-drug interactions among preoperative patients.

The Pharmacovigilance Center of the University of Florence conducted a survey across 3 hospitals in Tuscany (Empoli, Florence, and Prato) on a sample population consisting of 478 patients admitted to the hospital for a preoperative assessment before surgical intervention. The aim of the study was to assess the concomitant use of herbal remedies (HRs) and prescribed medications and to evaluate the most important potential interactions. Almost 50% of the patients surveyed-238 of 478 (49.8 %)-used at least 1 HR. Among them, 55 (23.1%) were actually exposed to at least 1 potential interaction. In particular, 42 participants had an HR-drug interaction and 17 participants had a dietary supplement drug interaction. A large percentage of patients undergoing surgery take HRs that could potentially interact with drugs administered perioperatively. Antihypertensive, antiplatelet, anticoagulant, and central nervous system (CNS) agents were the main products involved. The use of HRs is not devoid of risks and adverse effects due to potential interactions that may be serious or even lifethreatening. HR-drug interactions should be deeply investigated, especially in high-risk patient populations. Health care professionals should pay close attention and always investigate the consumption of HRs among their patients.

Herbalists' perception of risks involving commonly sold medicinal plants in Italy.

OBJECTIVE: Although there are several studies which have investigated pharmacists' knowledge of the safety of medicinal plants (MPs), no studies have examined herbalists' perception of risks associated with MPs. METHODS: We conducted a survey of 159 herbalists (participation rate 85.9%) in the region of Tuscany (Italy). Data were collected by means of a semi-structured questionnaire using a face-to-face interview. Risk perception was rated on a 10 cm Visual Analogic Scale (VAS). Herbalists' scores were then compared with those reported by a group of 10 experts in herbal medicine. RESULTS: When the overall risk was examined, herbalists had a low perception of the risks (VAS median ranged between 1.5 and 3.2) associated with the use of most MPs (Allium sativum, Aloe vera gel, Echinacea spp., Escholtzia californica, Harpagophytum procumbens, and propolis). They had an intermediate or high perception of risks associated with use of Cimicifuga racemosa, Citrus aurantium, and Panax ginseng (median ranged between 3.5 and 5.0), and for anthraquinone laxatives (median 7.2). Although the overall risk perceived by experts was generally higher than that reported by herbalists, differences were statistically significant only for Allium sativum and Escholtzia californica. CONCLUSION: The study shows that herbalists in Tuscany are knowledgeable about the relative risks of MPs when compared with experts in herbal medicine.

Is green tea a potential trigger for autoimmune hepatitis?

A case of autoimmune liver hepatitis is reported: the onset was triggered by consumption of green tea infusion in a patient taking oral contraceptives and irbesartan. We hypothesize that our patient, carrying genetic variant of hepatic metabolism making her particularly susceptible to oxidative stress, developed an abnormal response to a mild toxic insult, afforded by a combination of agents (oral contraceptives+irbesartan+green tea) that normally would not be able to cause damage. Her particular hepatic metabolism further increased the drugs' concentration, favoring the haptenization of liver proteins, eventually leading to the development of an autoimmune hepatitis.

Complementary and Alternative Drugs Use among Preoperative Patients: A Cross-Sectional Study in Italy.

Complementary and alternative drugs (CADs) are widely used in preoperative patients and may lead to potential interactions and adverse reactions. The aim of our study is to evaluate the prevalence and the predictors of CADs use among preoperative patients using data from an Italian survey. This cross-sectional study, which enrolled 478 patients (response rate: 83.5%), was carried out in three Tuscany hospitals (Italy). The prevalence of CADs use was 49.8%: 233 out of 238 participants used herbal products and/or dietary supplements. Valeriana officinalis was the most reported product (19.4%). According to univariate analysis, users were commonly identified among middle-aged or older patients; unadjusted ORs were 2.1 (95% CI: 1.3-3.3) for patients aged 48-69 years, and 3.0 (95% CI: 1.9-4.7) for those of 70-95 years, when compared with individuals aged 18-47 years. Except for education and gender, adjusted estimates showed consistent results with univariate analyses: direct association was observed with higher education, and-although not significantly-with female gender. The high prevalence of CAD use in preoperative period could be suggestive of a certain risk of adverse effects due to CADs interactions. A careful medical history of CADs consumption should be ascertained before surgery.

Two contemporary cases of hepatitis associated with Teucrium chamaedrys L. decoction use: case reports and review of literature.

Teucrium chamaedrys L. is a herbaceous plant common in European woods that has been used for many purposes for centuries. Recently, T. chamaedrys L. has become popular as a slimming decoction without any scientific proof of efficacy notwithstanding its well-known hepatotoxicity. Hydroalcoholic extracts are currently used as flavourings in the preparation of wines, bitters and liqueurs. Teucrin A and teuchamaedryn A are the major toxic components of the diterpenoid fraction of T. chamaedrys L.

Interactions between Natural Health Products and Oral Anticoagulants: Spontaneous Reports in the Italian Surveillance System of Natural Health Products.

Introduction. The safety of vitamin K antagonists (VKA) use can be compromised by many popular herbal supplements taken by individuals. The literature reports that 30% of warfarin-treated patients self-medicates with herbs. Possible interactions represent an health risk. We aimed to identify all herbs-oral anticoagulants interactions collected in the Italian database of suspected adverse reactions to "natural health" products. Methods. The Italian database of spontaneous reports of suspected adverse reactions to natural products was analyzed to address herb-VKAs interactions. Results. From 2002 to 2009, we identified 12 reports with 7 cases of INR reduction in patients treated with warfarin (n = 3) and acenocoumarol (n = 4), and 5 cases of INR increase (all warfarin associated). It was reported 8 different herbal products as possibly interacting. Discussion. Our study confirms the risk of interactions, highlighting the difficulty to characterize them and their mechanisms and, finally, prevent their onset. The reported data underline the urgent need of healthcare providers being aware of the possible interaction between natural products and VKA, also because of the critical clinical conditions affecting patients. This is the first step to have the best approach to understand possible INR alterations linked to herb-VKA interaction and to rightly educate patients in treatment with VKA.