Orangutans Use Plant Extracts to Treat Pain


   Medicine is not exclusively a human invention. Many other animals, from insects to birds to nonhuman primates, have been known to self-medicate with plants and minerals for infections and other conditions. Behavioral ecologist Helen Morrogh-Bernard of the Borneo Nature Foundation has spent decades studying the island's orangutans and says she has now found evidence they use plants in a previously unseen medicinal way.


   During more than 20,000 hours of formal observation, Morrogh-Bernard and her colleagues watched 10 orangutans occasionally chew a particular plant (which is not part of their diet) into a foamy lather and then rub it into their fur. The apes spent up to 45 minutes at a time massaging the concoction onto their upper arms or legs. The researchers believe this behavior is the first known example of a nonhuman animal using a topical analgesic.


   Local people use the same plant—Dracaena cantleyi, an unremarkable-looking shrub with stalked leaves—to treat aches and pains. Morrogh-Bernard's co-authors at the Czech Academy of Sciences, Palacky University Olomouc and the Medical University of Vienna studied its chemistry. They added extracts from it to human cells that had been grown in a dish and had been artificially stimulated to produce cytokines, an immune system response that causes inflammation and discomfort. The plant extract reduced the production of several types of cytokines, the scientists reported in a study published last November in Scientific Reports.


   The results suggest that orangutans use the plant to reduce inflammation and treat pain, says Jacobus de Roode, a biologist at Emory University, who was not involved in the study. Such findings could help identify plants and chemicals that might be useful for human medications, de Roode says.


   In creatures such as insects, the ability to self-medicate is almost certainly innate; woolly bear caterpillars infected with parasitic flies seek out and eat plant substances that are toxic to the flies. But more complex animals may learn such tricks after an initial discovery by one member of their group. For example, an orangutan may have rubbed the plant on its skin to try to treat parasites and realized that it also had a pleasant pain-killing effect, says Michael Huffman, a primatologist at Kyoto University, who was not involved in the new research. That behavior may then have been passed on to other orangutans. Because this type of self-medication is seen only in south-central Borneo, Morrogh-Bernard says, it was probably learned locally.


   INTRODUCTION


   It wouldn’t come as a surprise to anyone that active pharmaceutical ingredients (APIs) come in a wide variety. Small molecule, large molecule, peptide, monoclonal antibody, innovative, generic; the list goes on. These molecules have the ability to cure or mitigate debilitating conditions that can change a person’s life forever. It makes sense, then, that these ingredients are of primary importance in a formulation, and appropriate measures should be taken to maintain their stability and efficacy. As these APIs become more complex, they also become increasingly vulnerable to a series of different degradation pathways. Changes in pH environments can cause acidification and lead to breakdown. Exposure to moisture can initiate hydrolysis and subsequently lead to the formation of secondary by products. Residual catalyst that isn’t removed from an excipient can trigger side reactions and perpetuate degradation of not just the API, but everything else in the formulation. To combat this, formulators will typically front-load their formulations to compensate for this anticipated loss. However, this does not end up being a practical solution, as the degradants are still forming, and becomes an even bigger concern when the cost of developing the formulation becomes even higher. As a result, the more practical solution is to ensure that the remaining ingredients in the formulation are of the highest quality and purity. This certifies the drug will not degrade, and that efficacy and longevity are maintained.


   IMPROVED DOCETAXEL RECOVERY VIA HIGH PURITY


   Docetaxel is a great example of where the importance of purity plays a meaningful role. This active, a member of the taxanes class of molecules, is used as a chemotherapy drug, primarily in the treatment of cancers, including breast, lung, prostate, and stomach. Figure 1 depicts the main degradation product for docetaxel, 7-epi-docetaxel. With the same molecular weight as docetaxel, 7-epi-docetaxel is an epimer – a structural stereoisomer with the hydroxyl group at the C7 position (“flipping” position). Literature on the stability of the taxanes suggests that this is a common degradation product for docetaxel at that site, either through a retro aldol reaction or formation of an enolate intermediate.1,2 The formation of 7-epi-docetaxel has been observed in basic and strongly acidic conditions and in the presence of electrophilic agents, though the epimerization can be inhibited in the presence of a metal salt.3 7-epi- docetaxel has been found to be less cytotoxic to leukemia cells compared to docetaxel, so the formation of this epimer could reduce the efficacy of the treatment.


   A study conducted on docetaxel comparing its stability in various grades of polysorbate 80 (Figure 2) showed that there is significantly improved (up to 80% higher) recovery after 12 weeks at 40°C, when using a high purity grade rather than a standard compendial grade. Additionally, the study showed that there is a much higher concentration of docetaxel degradants, including 7-epi-docetaxel, present after these same conditions when using a standard compendial grade. This enhanced profile of docetaxel when using a higher purity grade of polysorbate 80, both during standard and accelerated conditions, shows that there are significant benefits from selecting the right grade of excipient when formulating.


   MINIMIZING IMPURITY FORMATION OF ETOPOSIDE


   Another chemotherapy API that is heavily prone to degradation is etoposide. Used for treating testicular, lung, and ovarian cancer, there are more than 300 marketed products incorporating this sparingly water-soluble active, with the bulk of the formulations incorporating polysorbate 80. In this instance, the main degradation product of concern is cis-etoposide, a stereoisomer of the active. Etoposide contains a trans-fused lactone ring that is under considerable strain, and will readily convert to the more thermodynamically stable cis-fused ring, known as epimerization. This altered structure can be seen in Figure 3. Literature suggests that cis-etoposide is biologically inactive in vitro, so any unwarranted conformation can have direct consequences on drug absorption and effectiveness.5 As with docetaxel, a study was conducted with etoposide to look at its stability in various grades of excipients for 12 weeks at 40°C, and it was shown that significantly more cis-etoposide is formed when it is formulated with standard grade polysorbate 80, with API recovery varying anywhere from 17% – 85%. However, when formulated with the high-purity grade, little to no cis-etoposide is formed over the course of the 12 week study, with near 100% full etoposide recovery. The results (Figure 4) also show using high purity ingredients can promote analytical clarity from a data processing standpoint, as impurity formation can cause the appearance of additional peaks in a chromatogram, adding to the time it takes to complete analysis. This, ultimately, suggests that using higher purity ingredients is crucial to maintaining your desired API concentration in your formulation, both in the short-term and in the long-term.


   Nutrients


   It shows you some key health nutrition ingredients that impact your health. You can use the label to support your personal dietary needs – look for foods that contain more of the nutrients you want to get more of and less of the nutrients you may want to limit.


   Nutrients to get less of: Saturated Fat, Sodium, and Added Sugars.


   Saturated fat, sodium, and added sugars are nutrients listed on the label that may be associated with adverse health effects – and Americans generally consume too much of them, according to the recommended limits for these nutrients. They are identified as nutrients to get less of. Eating too much saturated fat and sodium, for example, is associated with an increased risk of developing some health conditions, like cardiovascular disease and high blood pressure. Consuming too much added sugars can make it hard to meet important nutrient needs while staying within calorie limits.


   What are Added Sugars and How are they Different from Total Sugars?


   Total Sugars on the Nutrition Facts label includes sugars naturally present in many nutritious foods and beverages, such as sugar in milk and fruit as well as any added sugars that may be present in the product. No Daily Reference Value has been established for total sugars because no recommendation has been made for the total amount to eat in a day.


   Added Sugars on the Nutrition Facts label include sugars that are added during the processing of foods (such as sucrose or dextrose), foods packaged as sweeteners (such as table sugar), sugars from syrups and honey, and sugars from concentrated fruit or vegetable juices. Diets high in calories from added sugars can make it difficult to meet daily recommended levels of important nutrients while staying within calorie limits.


   Note: Having the word “includes” before Added Sugars on the label indicates that Added Sugars are included in the number of grams of Total Sugars in the product.


   Introduction


   The flavor of herbs comes from oils in the cell walls of plants. Leaves, flowers, stems, and seeds of herbs can all be dried. Heat, low humidity, and air movement are needed to dry herbs. Some methods include air-drying, seed harvesting, dehydrator drying, and microwave drying. Sun drying and oven drying have limitations.


   When to Harvest Herbs


   Most herbs are best for drying just before the flowers first open. New leaves at the tip of the plant will have the most concentrated flavor. Flowering herbs tend to be somewhat bitter. Herbs will have more of their essential oils if harvested on a sunny day in mid-morning after the dew has evaporated. Use scissors to cut the stems just above a leaf or pair of leaves. Leave 4 to 6 inches of stem for later growth. It can also be herb and fruit powder.


   Preparing Herbs for Drying


   Remove any bruised, soiled, or imperfect leaves and stems. Inspect plants, especially seeds, for insects.


   Rinse the stems in cool water and gently shake to remove excess moisture. Then gently pat dry with a paper towel. Another option is to remove moisture using a salad spinner. Remove as much moisture as possible.


   Methods of Drying Herbs


   Less tender herbs such as sage, thyme, and winter savory are the easiest to dry. They can be tied into small bundles and air-dried. Tender-leaf herbs such as basil, tarragon, lemon balm, and the mints have a high moisture content and will mold if not dried quickly.


   Air-Drying


   For air-drying to be successful, humidity must be low and good air circulation must be available. Stems of herbs such as mint, sage, or thyme can be tied in a small cluster and hung in a dry area with good air circulation. If you use a rubber band to tie them, it will tighten as the stems dry and stems will not fall out of the cluster. Clusters of dried herbs may look attractive decorating a kitchen or fireplace, but care must be taken to avoid humidity and dust. Hang herbs away from the sink, stove, or dishwasher where there is a lot of moisture. Keep dust off herbs by covering them with a paper bag punched with holes. The holes will allow air to circulate. If drying seedy herbs, place them in the bag so that the bag can catch the falling seeds. When drying leafy herbs, place the bag over the herbs as a dust shield.


   Herbs with small leaves can be laid out on a fine stainless steel or food-safe plastic screen or paper towels to air-dry. When dried, just strip the leaves from the stem to store. For herbs with larger leaves, remove the leaves from the stems and lay them on screens or paper towels without allowing the leaves to touch. Up to five layers of herbs and paper towels can be dried by this method. It may be necessary to change paper towels as they absorb moisture from the herbs.


   Microwave Drying


   Parsley, basil, and celery leaves dry well in some microwave ovens. A microwave oven with a wattage rating of 1,000 or higher may heat too fast to use this method. Read the manufacturer's directions to see if you can do this in your oven. Arrange washed and dried herbs one layer thick between microwave-safe paper towels. The length of time will depend on the amount of herbs and the power level of the microwave oven. Microwave on high for 2 to 3 minutes per cup. Start with 1 minute, mix after every 30 seconds, and continue checking for dryness. Remove from oven; cool. Rub between paper towels to crumble or wait to crumble until ready to use. Repeat with remaining herbs. Caution: Watch carefully! If there is not adequate volume, the paper towels can catch fire.


   Seed Harvesting


   The seeds of dill, caraway, mustard, and fennel can be left on the plant until mature. Cut flower stalks or pull entire plant from the ground, hang upside down, and shake seeds out when dry. Examine seeds for insects. Husks can be removed from seeds by rubbing the seeds between the hands and blowing away the chaff. Check for insects and treat dried seeds as described under "Treatment of Air-Dried Herbs and Seeds" below.