Drug Laws and Regulations, Relevant CAMS, CAM

mental health

*decent evidence suggesting efficacy - CBD (anxiety, inflammation) - kava (anxiety) - melatonin (sleep) *above have additive effects with sedatives - st. john's wart (depression) - drug interactions with antidepressants (SSRIs, SNRIs, MAOIs) *CYP inhibitors (drug interactions)

american botanical council market report 2021

*double amount of sales - sales not on exam - elder berry (immune health) - reduce severity and duration of cold and decrease duration of flu - ashwagandha (adaptogen) - increases body's ability to resist, or adapt, to stress, many uses - apple cider vinegar - generated from double fermentation of crushed apples (popular home remedy for decades) - quercetin - flavonoid against many diseases (antioxidant and anti-inflammatory properties)

genetic fingerprinting

*most important for authentication - important for multicomponent powdered mixtures - requires high quality DNA extraction - also requires use of conserved genomic region that can be used to differentiate components (often 18S rRNA) - compare with authenticated pure plant DNA

analytical chemical fingerprinting

*most important for authentication - important for multicomponent powdered mixtures - uses HPLC, LC -MS, GC and other separation/detection techniques - compare with authenticated pure samples - need to identify selected "marker" compounds

natural products association

*not just pharmaceuticals (natural home care, personal care, cosmetics) *do not memorize image

methods for natural product extraction

*not on exam - resource for how we can do things - macerate, decoction, ultrasonication, soxhiet extraction

medline plus

*specific examples not on exam - only tools and techniques

arctic root or golden root - efficacy

*there is no studies with sufficient evidence that suggests rhodiola is effective as any therapeutic - very little research - side effects: dizziness, dry mouth or excessive salivation - relatively safe to use, according to studies, for 6-12 weeks

national center for complementary and alternative medicine (NCCAM)

- "Herbs at a Glance" - current research - February 1st, 2023 - ingestion of Δ9-THC with CBD - suggests CBD can inhibit metabolism of THC generating increased effects at FDA-approved doses

complementary versus alternative

- C - if a non-mainstream approach is used together with conventional medicine, it's considered "complementary" - A - if a non-mainstream approach is used in place of conventional medicine, it's considered "alternative" *on exam

top selling herbal supplements in the US

- CBD (anxiety, inflammation) - kava (anxiety) - ginger (antiviral, inflammation) - elderberry (viral respiratory infection) - st. john's wart (depression) - cranberry (UTI) - garlic (BP, LDL) - berberine (LDL) - aloe (burns, laxative) - green tea (weight loss/energy)

adverse events of mental health herbal products

- CBD - sedation, liver damage/dysfunction in higher doses, dry mouth, nausea - melatonin - sedation, headache, dizziness - st john's wart - insomnia, anxiety, photosensitivity, dry mouth, dizziness, gastrointestinal symptoms, fatigue, headache, or sexual dysfunction

office of dietary supplements (ODS)

- Department of the National Institutes of Health (NIH) - gives generalized list of dietary supplement terms - polyphenols- "substances that naturally occur in plants" - anthocyanins - "group of pigments that naturally occur in some plants..." - Dietary Supplement Fact Sheet - gives information about specific dietary supplements (e.g., Ashwagandha, Ginseng, Vitamin B3 [Niacin])

dietary supplement listing act of 2022 (proposed)

- FDA doesn't know how many dietary supplement products are being sold in the US, who is selling them, and what types of products are being sold - act would require FDA create online tool that FDA, consumers, researchers, etc. can use to search for information about supplements - "list manufacturer contact information, names of products, ingredients, serving sizes, general safety information, health claims, allergens, safety warnings and precautions for all dietary supplements" - dietary supplement industry (powerful) against these regulations *would empower FDA - can contact companies about issues found with dietary supplements easier

legacy dietary supplement ingredients

- FDA must prove that a dietary supplement ingredient or product containing an ingredient or ingredients as unsafe for it to be removed from use in the US - no company needs FDAs approval to use dietary supplement ingredients in products and to sell them in interstate commerce

credible websites for CAM information

- Food and Drug Administration (FDA) - Office of Dietary Supplements (ODS) - National Center for Complementary and Alternative Medicine (NCCAM) - PubMed - MedlinePlus (from NIH) - ClinicalTrials.gov - TRC Natural Medicines (Natural Standard) - Cochrane Library - World Health Organization's (WHO) List of Essential Medicines

uconn library databases

- IBM micromedex - international pharmaceutical abstracts - lexicomp online - others

certification of CAM treatments

- United Stated Pharmacopeia (USP) - ConsumerLab.com - Natural Products Association (formerly National Nutritional Foods Association) - National Sanitation Foundation (NSF) International - not to be confused with National Science Foundation also NSF

herbal medicine preparations

- a tea, or infusion, made by adding boiling water to fresh or dried plant material and steeping - may be drunk hot or cold (tea = leaf and infusion = any plant) - a decoction, made by simmering in boiling water for longer periods than teas (some roots, bark, and berries require more forceful treatment to extract) - a tincture, made by soaking plant material in alcohol and water - sold as liquids and used for concentrating and preserving plant material - an extract, made by soaking plant material in liquid that removes specific types of chemicals - liquid can be used as is or evaporated to make a dry extract for use in capsules or tablets (polarity of solvent to extract specific molecules) *on exam

compound isolation and identification

- activity-guided isolation - chromatography using various sorbents and solvents following activity in bioassays - identification - spectroscopy of pure compounds using NMR, MS, NIR, IR, UV, CD, optical rotation, X-ray, Cryo-EM (how enzymes and small molecules interact - looking at them in real time)

obesity (weight loss supplements)

- african mango - beta-glucans (soluble fibers) - bitter orange - caffeine - potential ceiling effect - calcium

st. john's wart (goatweed)

- alternative medicine for: depression and other mental diseases - dangerous or life-threatening interactions: antidepressants, birth control, heart medications, Statins, skin irritation with sun exposure

glucosamine

- amino sugar naturally produced by body - clinically suggested to help with osteoarthritis (many conflicting results though) - likely safe when given orally as glucosamine sulfate at 1000-1500mg per day for up to 3 years - alternative medicine for those who cannot take non-steroidal anti-inflammatory drugs - commonly combined with chondroitin - required for carbohydrate containing compound synthesis (tendons, ligaments, etc.) - these peptides potentially grow tendons back faster! - decent evident suggests there could be interactions with acetaminophen and antidiabetic drugs - some evidence suggests interactions with warfarin increasing risk of bruising and bleeding - also found in fungi

ashwagandha - effects

- anti-inflammatory - neuroprotective - sleep-induction - anxiolytic

issues with CAM efficacy

- appropriate assays for in vitro and in vivo testing - adulteration of CAM products before testing (secretly added) - natural variability of CAM products - clinical trials (long, expensive, laborious)

classes of pharmacologically active natural products - shikimate pathway

- aromatic amino acids - cinnamic acids - ligans/lignin - coumarins - flavonoids - quinones - xanthones *not in animal cells (only in bacteria, etc.)

common adaptogens

- ashwaghanda - ginseng - reishi - rhodiola - schisandra - holy basil

random

- can also be stratified random (one from each quaternary - giving average baseline) - B - principle units in C - specific locations - clusters - multiple samples of one or similar spots - D - systematic is the most ideal and the most difficult - equidistant E - spatial systematic sampling - roughly 1 in each section but not as uniform as B (F)

extraction types

- chemical extractions - MeOH, DCM, Ethyl Acetate, Acetone, Hexane, Chloroform - teas/infusions - decoctions - tinctures - extracts - common household solvents used for extractions - water, alcohol, glycerin, vinegar, oil

fish oil (omega fatty acids)

- classification of polyunsaturated fatty acids (PUFAs) - physiologically necessary for cell membrane formation - might be involved in: cardiovascular, infant, cancer, cognition, eyes, and other diseases - should not be taken with anticoagulants (e.g., warfarin) - demonstrated to have antiplatelet effects at high doses

mineral oil

- commonly named liquid paraffin - oily liquid composed of saturated hydrocarbons from petroleum - exposure has been linked to increased risk of nonmelanoma skin cancer - colorless, odorless and tasteless - common uses: laxatives - can interfere with absorption of fat-soluble vitamins

tiotropium

- compound was based on atropine from Atropa belladonna - treatment for chronic obstructive pulmonary disease (COPD) - bronchodilator

arctic root or golden root (rhodiola rosea)

- contains many active compounds that have multiple therapeutic effects ranging from adaptogen, antibacterial, antiviral, and more! - phenylpropanoid glycoside rhodosine thought to be responsible for adaptogenic effects - animal studies suggested increases in protection from stress as well as increased cognitive function and decreased fatigue

treaties governing collections

- convention on biological diversity (CBD) - united nations convention on the law of the seas (UNCLOS) - convention on international trade in endangered species (CITES)

garlic (allium sativum)

- currently promoted for high blood cholesterol and high blood pressure - most results suggest garlic can reduce total cholesterol and LDL levels, but the effect is small - some human research has suggested that garlic can act as an inhibitor for two cytochrome P450 enzymes (2E1 & 3A4) generating issues with drug metabolism - some evidence suggests that garlic and garlic extract lower blood glucose levels in healthy and diabetic individuals - traditionally used for diphtheria, cough, fever, bites, stings, hemorrhoids, worldwide - intake as food or supplement has not been associated with reducing gastric cancer risk

poisonous mushrooms

- death cap (Amanita phalloides) - destroying angels (Amanita spp.) - false morel (Gyromitra esculenta) - autumn skullcap (Galerina marginata) - webcaps (Cortinarius spp.) - conocybe filaris - poison fire coral (native to asia) - deadly dapperling - angel wing - fly agaric (Amanita muscaria) *and more

digoxin (not digitoxin)

- digoxin is an Rx drug, an extract of the Foxglove plant - blocks the Na+/K+ ATPase pump - positive inotropy (force of ventricular contraction) - enhances the parasympathetic tone on the heart (through vagal nerve stimulation) - negative chronotropy (SA nodal firing rate) - negative dromotropy (AV nodal conduction rate) - used for heart failure and atrial flutter/fibrillation - therapeutic range for heart failure 0.5-0.8ng/mL, minimizes the Na+/K+ ATPase effects but provides the parasympathetic enhancement - the DIG Trial showed increases in mortality when the serum digoxin concentration was >1.2 ng/mL even though patients felt better - DigfAb is the antidote if there is an overdose of digoxin h

drugs from marine organisms

- ecteinascidin-743 is an anticancer drug isolated from the marine tunicate Ecteinascidia turbinata - brentuximab vedotin is an anticancer antibody-drug conjugate (ADC) whose drug is derived from dolastatin 10, a compound isolated from marine cyanobacterium

world health organization's list of essential medicines

- ergometrine - postpartum haemorrhage - isolated from rye ergot fungus (Illegal in UK) - paclitaxel - atropine - cycloplegic (iritis treatment) - morphine and derivatives - acyclovir - HSV treatment - etc.

What are GMPs?

- facility cleaning & pest control - maintaining & cleaning equipment - quality control procedures (test a certain amount of drugs out of a batch randomly) - lab and manufacturing operations - complaints process (if people have an issue, there is some place that they can go to make a complaint)

classes of pharmacologically active natural products - acetate pathway

- fatty acids - polyketides - aromatic - macrolide - prostaglandins - thomboxanes - leukotrienes

cardiovascular health/diabetes

- garlic (BP, LDL) - berberine (LDL) *know highlighted natural products for exam

adverse effects of cardiovascular health/diabetes herbal products

- garlic - garlic breathe, nausea, flatulence, mouth/throat irritation - berberine - rash, nausea, vomitting, constipation, dizziness

search engines - bad examples

- google - wikipedia - drugs.com - webMD - do not recommend to patients *starting points for basic information but not most accurate information

food and drug administration (FDA)

- has most approved drugs and dietary supplements - dietary supplement information - new information in dietary supplements - Dietary Supplement Ingredient Directory (Released March 6th, 2023) - currently a list of the following 27 ingredients: u 5-Alpha-Hydroxy-Laxogenin, Acacia rigidula, Biotin, BMPEA, Cannabidiol, Cesium chloride, Comfrey, DMAA, DMBA, DMHA, Ephedrine alkaloids, Higenamine, Higenamine HCl, Hordenine, Hordenine HCl, Kava, Kratom, Methylsynephrine, N-acetyl-L-cysteine, Octopamine, Phenibut, Picamilon, Pure and Highly Concentrated Caffeine, Pyridoxamine, Red yeast rice, Tianeptine, Vinpocetine *recommend to patients

cannabis - suggestions

- have been suggested to be helpful with: pain, decrease in opioid use, anxiety, epilepsy, HIV/AIDS symptoms, IBD and IBS, tourette's, MS, PTSD, sleep disorders - do not take with warfarin (Increases levels and clinical effects of warfarin) - not helpful in treating glaucoma - no specific dosing for THC - both THC and CBD are substrates and inhibitors of cytochrome P450 enzymes - much research is going on to verity the safety and efficacy of both CBD and THC usage as well as potential drug-drug interactions

mushroom supplements

- health focus - immune and cognitive health (last 4 years), energy and mood support, adaptogen - chaga [Inonotus obliquus] - Cordyceps sp. - Reishi [Ganoderma lucidum] - other mushrooms (lion's mane [Hericium erinaceus] & tukey tail) - mycelium - roots - fruiting bodies - What we typically think as mushrooms - according to ODS, not enough reliable information as dietary supplements

cardiac glycosides

- herbs that work like digoxin by blocking the Na+/K+ ATPase pump and enhancing vagal stimulation of the heart - used for heart failure, atrial flutter/fibrillation, atrial tachycardia - very dangerous, can't monitor blood concentrations - DigfAb is antidote in overdose

labeling

- identity of product (brand name) - net quantity of contents - ingredient list - address of manufacturer, packer, or distributor - nutrition facts box

macroscopic authentication

- important post processing macroscopic characteristics: - woody, herbaceous - leaf shape, size, and morphology - flower characteristics and morphology - root characteristics (texture, type) - not just for botanicals

microscopic authentication

- important post processing to establish authenticity - uses standard light microscopy and/or scanning electron microscopy microscopic characteristics: - absence/presence of trichomes (hairs), oil glands, canals, cell types - seed morphology - pollen morphology - any adulterations (e.g., herbal "viagra" adulterated with actual Viagra) - additives that are not naturally there

famous plant-derived anticancer agents

- indole alkaloids - taxane diterpenoids - camptothecin

natural product adaptogens

- introduced by russian toxicologist (Nikolay Lazarev) in 1957 - natural substances that are believed to help with stress and maintain homeostasis - often found in plants - "natural products that increase body's resistance to stresses such as trauma, anxiety, and bodily fatigue" - can be found in various pharmacological effects

camptothecin

- isolated from Camptotheca acuminata, a tree native to China - showed unacceptable myelosuppression - however found to act by interesting mechanism - many analogs: E.g., Topotecan, Exatecan and more!

natural product derivatives

- isolation - unmodified natural products that have similar structure or functionally to other natural products - semi-synthesis - modified structures to increase functionality (ex. docetaxel) - synthesis - fully synthetic analog to natural product to enhance therapeutic effect

melatonin - benefits

- jet lag - delayed sleep-wake phase disorder (DSWPD) - other sleep disorders in adults and children - anxiety before surgery

prostaglandins

- labor induction - pulmonary hypertension, glaucoma, ED - potent vasodilators - cyclopentane rings

ixabepilone

- lead compound was epothilone B isolated from Sorangium cellulosum (a myxobacterium) - anticancer

arteether

- lead structure was artemisinin ("qinghaosu"), a sesquiterpene lactone isolated from Artemisia annua, used in traditional Chinese medicine - low bioavailability - not monotherapy (WHO) - resistance

use of complementary medicines in children

- little is known about their effects and safety - much research has been performed but have not been tested in children or not enough evidence to show if it worked or not - most frequent natural products used for children - fish oil, melatonin, elderberry, echinacea, cranberry, lavender, garlic, ginseng - other include probiotics, chamomile, St. John's wort, peppermint, and more

melatonin - pharmacology

- major evidence of drug interactions with antihypertensive drugs - melatonin that is isolated from animal penial gland should be avoided due to possibilities of contamination - despite some laboratory results, no good evidence from clinical trials suggesting that this can be a treatment for COVID-19 - safe when used up to 8mg daily for up to 6 months or safe at 10mg for up to 2 months

regulation of herbal medicine - DSHEA

- manufacturer is responsible for ensuring that a dietary supplement or ingredient is safe before it is marketed - FDA is responsible for taking action against any unsafe dietary supplement product after it reaches the market - when a structure/function claim is placed on a dietary supplement label this disclaimer must be added: "This statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease"

CAM bioavailability is complex

- many potential bioactive components within CAM products, could have interactions with each other - potential off-target effects - various possibilities for mechanisms of action - can include several routes of metabolism that can affect bioavailability

pharmacognosy overview

- multidisciplinary field that combines aspects of botany, chemistry, pharmacology, and other related sciences - involves identification, isolation, and characterization of bioactive compounds from natural sources - safety, efficacy and quality as medicines - development in cosmetics, dietary supplements, existing therapies, etc. from natural products

psilocybe mushrooms

- mushrooms that produce psilocybin (schedule 1 controlled substance) - traditionally used in religious and spiritual rituals - psilocybin - indolealkylamine, single doses of synthetic at 0.2-0.6mg/kg have been used safely with appropriate medical supervision - being explored for many psychological disorders

quasi-health claims - requirements

- must have data to substantiate the quasi-health claim but do not have to send the information - must alert the FDA of your intention to use a quasi-health claim at least 30 days prior - FDA can intervene if it chooses and has substantive evidence that the claim is incorrect

lavender (lavandula angustifolia)

- native to mediterranean countries - small studies suggest oral intake of lavender oil is beneficial for anxiety, depression - aromatherapy using lavender oil has not been proven to help with any conditions except dysmenorrhea (limited) - side effects of oral intake: constipation, headaches, increase appetite, lower blood pressure (increase sedative effects of other medications) - both oral and topical applications known - contains many active compounds from flowers, leaves and oil

galantamine

- natural product first isolated from Galanthus woronowii in Russia in early 1950s - treatment for Alzheimer's Disease (neurodegenerative diseases) - acetylcholinesterase inhibitor

calanolide A

- natural product isolated from Malaysian rainforest tree Calophyllum lanigerum var. austrocoriaceum - anti-HIV activity with unique and specific mechanism - effective against AZT-resistant strains - currently undergoing Phase II clinical trials (as of 2019)

sources of drug molecules

- natural product screening - identification and isolation of biologically active compounds from natural sources (e.g., plants, animals, microorganisms) - random screening of synthetic compounds - high-throughput screening - rational drug design - uses structural information about targets and ligands to create leads - drug metabolism studies - metabolites of existing drugs are isolated and screened for activity, may have better pharmacologic properties (e.g., duration of action, absorption) - observation of side effects - approved drug may have side effects that make for another indication (e.g., class of histamine drugs became antipsychotics) - ex. drugs for ED originally for heart

herbal medicine and natural products medicine

- natural products medicines are distinct in that these involve the isolation and identification of single compounds, as well as requiring approval by the Food and Drug Administration (FDA) - one component of natural products research involves the identification of active constituent(s) from herbal medicines - knowing the active constituent(s) can help with standardization of herbal medicines as well as more accurate results from clinical trials

melatonin

- neurohormone primarily produced by pineal gland in response to dark - research suggests plays a vital role in body beyond just sleep - can be isolated from animals or microorganisms but is mostly synthesized

cochrane libraries

- non-profit organization worldwide - collection of databases - published by wiley - many language translations

cardiac glycosides - examples

- oleander (common or yellow) - squill - oubain - dogbane - lilly of the valley - wallflower

inflammation and anti-infective

- omega-3 FAs (inflammation, triglycerides) - antiplatelet and anticoag - ginger (antiviral, inflammation) - elderberry (viral respiratory infection) - echinacea (cold virus) - cranberry (UTI) - CYP3A4 inhibitor

adverse effects of inflammatory and infection control herbal products

- omega-3 FAs (inflammation, triglycerides) - fishy taste, nausea, diarrhea - ginger (antiviral, inflammation) - abdominal discomfort, heartburn, diarrhea, and mouth/throat irritation - elderberry (respiratory infection) - weakness, nausea, vomitting, stomach cramps, diarrhea, runny nose - echinacea - rash, nausea, stomach pain - cranberry - kidney stones, pain when urinating, nausea, diarrhea

how to find accurate information on CAM

- one of major challenges with CAM/herbal medicines is finding reliable information - knowing credible sources is crucial for accurate representation of CAMs and dietary supplements - need to have a good list of reputable websites to share with patients - in the end, there are several sources of good information available online, but it can be challenging to determine the validity of websites

berberine

- originally used in traditional chinese medicine - helps to strengthen heartbeat, kill bacteria, regular sugar in blood and reduce swelling - isoquinoline alkaloid - has been shown safe at 1.5g/day for 6 months or 1g orally for 2 years - do not take with cyclosporine - might have interactions with CYP3A4 substrates

drugs from terrestrial plants

- paclitaxel (Taxol®) is a major anticancer agent isolated from Taxus brevifolia Bark - morphine is the prototypical opioid pain medicine isolated from Papaver somniferum

taxane diterpenoids

- paclitaxel (Taxol®) is a major anticancer agent isolated from Taxus brevifolia bark - now produced by semi-synthesis obtained from Taxus baccata ornamental yews (renewable)

natural product adaptogens - examples

- panax ginseng - eleutherococcus senticosus - maral root - magnolia berry - rhodiola rosea - ashwaganda

drugs from microbes

- penicillin is a first in class antibiotic and was isolated from penicillium fungi - ixabepilone is an anticancer drug derived from epothilone B isolated from Sorangium cellulosum

authentication of botanicals

- plant sourcing - classical authentication techniques - macroscopic authentication - genetic fingerprinting - analytical chemical fingerprinting

patient populations that should avoid using CAMs due to safety

- pregnant and breastfeeding - liver disesases - reasons: often contain many compounds, some need to be processed by liver enzymes (either that be active or not)

challenges in drug discovery from natural sources

- procurement of raw materials - most appropriate method of sample collection - whether to collect in US or abroad - following laws and regulations - appropriate high-throughput screening bioassays - scale-up of active compounds - compounds are generally isolated in very small quantities - compound development - there can be post harvesting changes to plant metabolites (e.g., ↓Senkyunolide A, ↑ Salvianolic Acid B)

evaluation

- purity and authentication - bioavailability - safety - efficacy

united states pharmacopeia (USP)

- quality supplements - ingredient verification program - tested and continued to be tested as they make more batches *read the picture

How to collect?

- random - ethnobotanical - chemotaxonomical - literature-based - biodiversity-based - ecological

plant sourcing

- seed stock - germplasm propagation - living genetic resources like seeds, tissues, etc. - field collection - growth in controlled environment (ex. greenhouse)

Morinda citrifolia (noni)

- small evergreen tree in open coastal regions and forest areas from tropical Asia and Polynesia - used for many diseases, including diabetes, hypertension, and cancer - isoamericanin A was very potent in free radical-scavenging assay - juice contains a high amount of potassium (liver and kidney problems)

apple cider vinegar (ACV)

- staple pantry item and common home remedy - low quality evidence for positive impacts on blood sugar, cholesterol, and weight loss - small studies suggested positive impacts to glucose and lipid profiles - high quality research is lacking on metabolism and weight loss - some ACV products have been adulterated or modified with other plant-based ingredients (e.g., Garcina cambogia; common weight loss) - recommended dosages vary and labels do not consistently report ingredient amounts - acidic side effects: skin irritation, low potassium, chemical burns, teeth erosion

NIH-ODS

- supplements for exercise and athletic performance - has blurbs for each thing - drop down menu *all on ODS website

natural products/pharmacognosy/biodiversity prospecting

- systematic search for biochemical and genetic information from natural sources - can be developed into commercially valuable products for pharmaceutical, agricultural, and other applications

classical authentication techniques

- taxonomical classification - organoleptic characterization (smell, taste, color) - collection location - processing techniques (drying method, time, temperature) - help determine if you have the correct botanicals - photo (in habitat and post harvest) - voucher specimen (second collection of organism for proof) - can be kept for other organisms to confirm species (e.g., Botryllus schlosseri)

what to collect?

- terrestrial plants - marine organisms (23%) - terrestrial microbes *some overlap

conclusions

- the DSHEA 1994 act delineated what dietary supplements are and what dietary supplement manufacturers are required to do (small step) - since the FDA doesn't need to be alerted a dietary supplement product is being sold in the US, they are generally unaware and does not have the resources to exhaustively review the product - dietary supplements are innocent until proven guilty by the FDA and the bar to remove a product is high

conclusions

- there are a LOT of herbal products but most of the sales involve a few dietary supplement ingredients - pharmacists are commonly asked to recommend of critique a natural product and need to understand the level of evidence to recommend a therapy - pharmacist lie at the intersection of dietary supplement and prescription or OTC medication worlds and need to understand the potential for drug interactions and adverse events - pharmacists (PharmD's) are who patients usually ask about all this information

physalis philadelphica (tomatillos)

- tomatillos are used in foods such as enchiladas and salsas in Latin America - an extract of the fruits was found to induce quinone reductase, a detoxifying enzyme

purified natural products

- typically become FDA approved drugs - a few herbal medicines fall into this category

where to collect?

- united states (or country of origin same as country of laboratory - easier) - foreign countries and bringing stuff back is harder - have to give the country credit (helps first world countries)

melatonin - uses

- used in short-term is safe for children but more studies needed including for long-term usage - people with epilepsy or on blood thinners need to be weary of the interactions with melatonin and be monitored - 2017 study most of the tested melatonin products did not contain what was listed on the product label (26% actually had serotonin; can be harmful)

standardization of herbal medicines

- used to ensure batch-to-batch consistency; can involve identifying specific compounds that can be used to manufacture a consistent product; can also provide a measure of quality control - dietary supplements are not required to be standardized in the US - thus "standardization" may mean many different things -presence of the word "standardized" on a supplement label does not necessarily indicate product quality - ideally, compounds for standardization would be the biological active constituents and each lot - however, the active components of most botanicals have not been identified

elder berry (lavandula angustifolia)

- used to support immune heath, reduce symptoms from cold/flu or other upper respiratory infections - generally recognized as safe (GRAS) - 2021 suggested reduces duration of cold and flu - COVID-19 misconceptions in 2020 - no published literature on elder berry and SARS-CoV-2 - also has been traditionally used as diuretic, laxative, diaphoretic and immune system stimulation - WARNING: unripe, green elderberries contain cyanide-producing chemicals - cooking eliminates toxin

examples of dietary supplements

- vitamin or mineral - herb or botanical - amino acid - a concentrate, metabolite, constituent, extract, or any of the ingredient types above

ashwagandha (withania somnifera)

- well known adaptogen widely used in ayurveda, traditional indian medicine - increases in morning cortisol levels - sometimes adulterated with withania coagulans (studies have suggested to have multiple therapeutic effects) - demonstrated safe when used up to 1000mg/day for 12 weeks - decent evidence suggest interactions with antidiabetic drugs and thyroid hormone - normally well tolerated common side effects are: GI upset, nausea, vomiting (do not really occur in common doses) - witheraferin A (Digotoxin) and DigfAb - similar

top 10 selling american botanical council from 2020

1. CBD oil - CBD oil is derived from the cannabis plant and is believed to have therapeutic benefits for a range of conditions 7. elderberry supplements - elderberry is a fruit that is high in antioxidants and is believed to have immune-boosting properties 8. echinacea supplements - echinacea is a plant that has been used for centuries as a natural remedy for colds and flu 9. fish oil supplements - fish oil is rich in omega-3 fatty acids, which are essential for brain and heart health *from GNC, whole foods (supplement stores)

natural product drug discovery and development

1. determine which drugs we are largely interested in during medicinal chemistry and molecular modeling 2. bioassays 3. lead optimization - medicinal chemistry and combinatorial chemistry 4. lead development - PK, tox, ADME, drug delivery 5. clinical trials

top 40 selling herbal products in US (2018)

2. echinacea 4. elderberry 5. green tea 6. ginger 8. garlic

FDA funding - a barrier to optimal safety

45% of FDA's funding is through user fees and those units that do not collect user fees and underfunded - FDA cannot evaluate many dietary supplement products or explore the safety of ingredients with current funding mechanism - FDA cannot inspect many dietary supplement manufacturing facilities, especially if they are located outside the US - approval of new drugs - pristine and well funded - other sectors of the FDA - under austerity measures - taxpayer stingy to the FDA

natural product drug discovery

60-70% of all new chemical entities come from natural product or natural product derivative

natural products as drugs (small molecules)

64% of all small molecule NCEs derived in some way from natural products

fruit juices and drug interactions

CYP3A4 - oxidation of xenobiotics - grapefruit - pomegranate P-gp (MDR-1/ABCB1) - important for substrate uptake and efflux pysiochemical interactions - chemical incompatibility - ex. precipitation

DSHEA rules and limitations

DSHEA 1994 - defined dietary supplement and dietary ingredients - required ingredient and nutritional labeling - delineated claims and nutritional support statements that could be made - empowered FDA to enforce GMP regulations - required dietary ingredients not on market as of october 1994 to be subject to new dietary ingredient (NDI) notification to the FDA

GMP

DSHEA 1994 allows FDA to enforce GMP - if FDA proves a company's failure to meet GMP, can render the drug product adultered under 402(g) of the federal food drug and cosmetics act - drug can be removed from the market

regulation of herbal medicine

FDA regulates both finished dietary supplement products and dietary ingredients under a different set of regulations than those covering "conventional" foods and drug products (prescription and Over-the-Counter)

national sanitation foundation (NSF)

NSF Certifications - Non-GMO - organic - Plant-Based - NSF/ANSI 173 (dietary Supplements) *impartially reviewed

herbal medicine - an herb

a plant or plant part used for its scent, flavor or therapeutic properties - herbal medicine products are dietary supplements that people take to improve their health - many herbs have been used for a long time for claimed health benefits - sold as tablets, capsules, powders, teas, extracts and fresh or dried plants - however, some can cause health problems, some are not effective and some may interact with other drugs you are taking

bioassay screening

a procedure for determining the concentration or biological activity of a substance (e.g. vitamiFn, hormone, plant growth factor, antibiotic, enzyme, [compound]) by measuring its effect on an organism or tissue compared with a standard preparation - can develop a bioassay depending on what pathogen you are looking for - bioassays targeting a certain disease

DSHEA definitions - dietary supplement

a product intended to supplement the diet that bears or contains one or more dietary ingredients - is give as a tablet, capsule, powder, softgel, gelcap, or liquid form - is not conventional food or a sole item of meal or the diet - is not a conventional food or sole item of meal or the diet - is labeled as a dietary supplement

cancer chemoprevention

a strategy of cancer control by administration of synthetic or natural compounds to reverse or suppress the process of carcinogenesis

cannabinoids as potential drugs

aim - produce desired therapeutic effect without euphoriant effect - Δ9-THC used in synthetic form, presumably easier to produce as a pure entity - symptomatic relief in MS and other neurological effects - suggested to show promise here but all anecdotal reports as well as some failed reports - sativex: only given to patients who have failed to standard MS treatments - convincing clinical evidence is not yet available

quinones

antioxidant (scavenge free radicals)

natural products that cause bleeding

antithrombotics (antiplatelet drugs and anticoagulants) should be avoided with - garlic, ginger, ginkgo, ginseng (American, Panax, Siberian), white willow - alfalfa, anise, bilberry, bladderwrack, bromelain, cat's claw, chamomile, coleus, cordyceps, dong qui, evening primrose, fenugreek, feverfew, grape seed, green tea, guggul, horse chestnuts, horseradish, licorice, prickly pear, red clover, sweet clover, SAM-e, turmeric

garlic - possible efficacy

atherosclerosis, diabetes, endometriosis, hyperlipidemia, hypertension, NAFLD, periodontitis

literature-based

based on what other people have looked at in the past

steroids

can also treat bone degenerative diseases

truth about silver

can lead to argyria - rare disorder due to the chronic exposure or ingestion of colloidal silver - skin color change to grey-blue - permanent - can be dangerous to health according to NIH - no known function or benefits to body when taken by mouth - it can interact with certain medications - not Regulated by FDA - even larger region if it is orally ingested *most homeopathic remedies are not evidence-based

common natural product discovery pipeline

collection, extraction, bioassays, isolation, characterization

berberine - dr. white

combo therapy worked much better than berberine by itself

most common herbal supplements and uses according to john hopkins

completely different list of most common supplements - some similarities like garlic, ginseng, echinacea *not fine details, just trends and how different organizations analyze them

peptides, proteins, amino acid derivatives

dietary supplement for bone and joint health and mood and emotional well being (not a prescribed drug) - alternative medicine

issue with standardization

dietary supplements are not required to be standardized in the US - thus "standardization" may mean many different things - presence of the word "standardized" on a supplement label does not necessarily indicate product quality

carbohydrates

essential energy source

conclusion

evaluation - authentication plays a vital role in verifying you have the correct botanical - bioavailability is complex and can lead to potential off-target effects due to non-specificity of CAMs - efficacy of CAMs can be problematic - standardization can help to make sure we have batch-to-batch consistency but is different in terms of supplements databases - many sites to find scientifically accurate information on CAMs - many rumors and misleading information as well, difficult to determine validity of websites certifications - help to verify that a supplement is being rigorously tested - look for the following seals on exam - means that you have a verified product

aromatic amino acids

ex. l-dopda

ethnobotanical

ex. native american 4 important products (picture) - the scientific study of the traditional knowledge and customs of a people concerning plants and their medical, religious, and other uses - cedar: antibiotic, antioxidant, anti-inflammatory - sage: antifungal, antiviral, antioxidant type II diabetes and Salvia officinalis (garden sage) lowering of plasma glucose in those at risk - anthropological training as well

cinnamic acids

flavoring and a few pharmaceuticals

ligans/lignin

flax seeds, sesame seeds - found there is effects with diseases like cancer, CV, etc.

standard fractionation scheme

further isolation

liver health, burns, laxative, weight loss/energy, menopause, prostate

green tea (weight loss/energy) *not too much on exam besides highlighted

CAM safety

history of use or other evidence of safety - published literature - unpublished toxicology or clinical studies - historical descriptions of use or preparation of the same or similar ingredient - traditional consumption a food and impact on diseases - conditions of use must be the same or very similar and foods are typically eaten intermittently unlike modern use of CAM products

processing samples & isolating bacteria

homogenize it and extract some of the microorganisms on there

ecological

https://www.iucnredlist.org/ - some microorganisms and other types are just as important

standardization - active constituents

ideally, compounds for standardization would be the biological active constituents and each lot - however, the active components of most botanicals have not been identified

old dietary ingredient list

if it was not commonly used as a "dietary supplement: ingredient before 1994, the FDA must approve the new dietary ingredient (NDI) - others were grandfathered in

NDIs

if you have a NDI, you must notify the FDA and cannot sell a product containing the NDI for 75-days - if the FDA does not take steps to stop you, you can sell it via interstate commerce thereafter - the FDA doesn't have to approve that the product is safe just cannot prove that it is unsafe

leukotrienes

inflammatory mediators from leukocytes - leukotriene modifying drugs - inflammation, immune dysfunction, IBS, etc. - caution in liver and kidney issues

coumarins

interacts with many drugs - GI bleeding with NSAIDs - ginger, garlic, st. john's wart interact - warfarin

intellectual property rights

legal rights of ownership that individuals and corporations have over products of creativity and inventiveness - patents (inventions) - copyrights (writings, music, drama, art) - trademarks (name or symbol) - trade secrets (formula or method)

chemotaxonomical

look at molecules with similar structure from other organisms and see how those molecules are related to what we are trying to treat

examples of bioassays

malaria, leishmaniasis, chagas' disease, dengue fever, cancer - bioassays targeting these things - helps determine new compounds that might be of interest for whatever you are studying

adverse event reporting

manufacturers, packers, or distributors must be on the product labeling - with contact information (address) - whomever is on the label has to have a mechanism to collect and assess adverse events that are reported to them (responsibility) - whomever is on the label must submit serious ADEs to FDA within 15 business days - death, hospitalization, persistent disability, incapacity, or birth defect

semi-purified natural products

many herbal medicines fall into this category

natural product drugs

medications from natural sources - complex molecules that have specific functions in host organism (ex. defenses or communication) - extremely hard to synthesize

complementary and alternative medicine (CAM)

medicines that are not conventional - can be "complementary" or "alternative" - not all have been scientifically validated

standard extraction scheme

miscibility

alkaloids

morphine, caffeine, nicotine - a lot of therapeutic applications

crude drug

most herbal medicines fall into this category

misinformation on CAMs and herbal medicines

myths - mother's homeopathic remedy - "natural" remedy - cure-all - colloidal silver (silver water)

NB

natural product botanical drug (defined mixture

berberine - origins

origins: - european barberry - goldenseal - goldthread - oregon grape - phellodendron - tree turmeric

health claims

petition the FDA for a claim if a published authoritative body (national academies, NIH, CDC) with responsibility for public health protection said that there is reason to believe in the benefits of the potential product

thromboxanes

platelet aggregation

berberine - efficacy

possibly effective for: - canker sores - diabetes - H. pylori - hyperlipidemia - high blood pressure - polycystic ovary syndrome (PCOS)

herbal medicine

products made from botanicals, or plants, that are used to treat diseases or to maintain health - also called herbal supplements

botanical dietary supplements (BDS)

products made from plants or plant parts - may contain one or more active ingredient including other compounds - not required to undergo rigorous clinical testing before being publicly sold (Safety and efficacy)

pearson v. shalala lawsuit

quasi-health claims - first amendment case ruling - FDA cannot reject a quasi-health claim that may or may not be misleading unless the FDA ALSO finds that no disclaimer that would eliminate the misconception is found *do not have to know the name but know the FDA was forced into this

comsumer lab

same thing as USP but in a different manner - insight into specific supplements

fatty acids

soaps, detergents

How do we fix issues with evaluation?

standardization

chemical abstracts service scifinder

structure based searches

drugbank online

structure based searches - similar structures - similar effects

quasi-health claims

supports heart, eye, liver, etc. - are not specific about a disease or disorder - use term support and talks about something in the body - disclaimer: this statement has not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any diseased

classes of pharmacologically active natural products - mevalonate and deoxyxylulose pathways

terpenoids - monoterpenes - iridoids - sesquiterpenes - diterpenes - triterpenes - steroids

cannabis (all products derived from cannabis sativa)

tetrahydrocannabinol (THC) - psychoactive constituent - marinol and syndros (synthetic THC, FDA approved) - used to treat nausea and vomiting in cancer as well as weight loss and appetite in HIV/AIDS - defined as any product with >0.3% THC - when directly infused into a tumor mass has demonstrated tumor eradication cannabidiols (CBD) - non-psychoactive constituent - over-the-counter can contain more or less than what is written on label and could even include contaminants - doses up to 10-25mg/kg daily doses in adults and 2-50mg/kg in children

bioavailability

the degree to which a drug or other substance becomes available to the target tissue after administration

efficacy

the extent to which a specific intervention, procedure, regimen, or service produces a beneficial result - in vitro efficacy: does it work in enzymes and/or cells? - in vivo efficacy: does it work in animal models? - clinical efficacy: does it work in humans?

pharmacognosy

the study of the physical, chemical, biochemical and biological properties of drugs, drug substances, or potential drugs or drug substances of natural origin as well as the search for new drugs from natural sources - regulated by the american society of pharmacognosy

(t/f) CAM bioavailability is complex

true

(t/f) COVID skewed herbal supplement sales

true; people were trying to find alternatives and lists may be different now

biodiversity-based

understanding the biodiversity is changing and climate change

standardization of herbal medicines - consistency

used to ensure batch-to-batch consistency; can involve identifying specific compounds that can be used to manufacture a consistent product; can also provide a measure of quality control

cardiac glycosides

used to treat congestive heart failure (also digotoxin)

acai

very little research - preliminary study - fruit pulp and reduction of blood sugar and cholesterol - potential exposure to Chagas Disease from parasite - drinking unprocessed acai juice fecal contamination - issue - treatment: Benznidazole (antiprotozoal)

indole alkaloids

vinblastine and vincristine were isolated from madagascan periwinkle - known as Vinca alkaloids in medical literature

dietary supplements before 1994

were regulated as "food" but dietary supplements did not fit into a binary food/drug regulatory system - this resulted in the dietary supplement health and education act (DSHEA) in 1994