Clinical Usefulness of Different Types of Medical Research

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imagesDr Carrie Decker ND, explores some of the main methodologies and practices employed in  translational research. Supporting patients in their health with nutritional supplements and botanical therapies often requires one to draw upon a wide variety of academic resources. This ranges from clinical training and continuing education to searchable databases which provide easy access to a broad spectrum of research on nutritional supplements. Anyone who has ever looked for clinical studies on the topic of nutritional or botanical interventions understands this research is far lacking, is often poor quality or a non-placebo controlled study, and the population size, if human data exists, is small. For this reason, it is important to understand what can best be gained from other types of studies.

Ethnobotany

Ethnobotany surveys, or cultural studies of traditional plant use, are often a starting point for investigating the potential benefits of a botanical substance. Regional use of plants which are widely available still is common practice in locations where medicine has not evolved to that of modern hospitals, pharmaceuticals, and other interventions. An excellent example of a medical practice with a strong cultural tradition is Chinese medicine, which has a long history of plant and other naturally-derived supplement use. The most common and effective botanicals from these cultural surveys are then assessed with modern chemistry and analytical techniques for substances which may be therapeutically active and fall in categories such as alkaloids, flavonoids, phenols, and saponins. From this stems the next level of investigation: the in vitro study.

In vitro studies

In vitro studies often look at things on a cellular level, and are a wonderful setting in which the impact of botanical or nutritional substances on various metabolic pathways, markers of antioxidant status, cellular transcription of DNA, and many other things can be assessed. These findings are highly suggestive of potential impacts that these substances may have at a cellular level, but one must remember that whenever anything is outside of its natural setting function can be impacted. There are many reasons for this: cell culture differences from extracellular fluids, the absence of cell-matrix or cell-cell mechanotransduction, and isolation from communication with other cells are a few.

Animal studies

Although often the subject of scrutiny, animal studies are the next natural step to investigate the impact of substances on the body and its systems as a whole. Although we don’t like to think about it from an animal rights standpoint, it is important to know if something is safe prior to proceeding to human settings. With genetic manipulation, we are able to study the impact of substances on many animal models of human diseases. As an example, genetically altered mice exist which develop breast cancer at a predictable age. With a model such as this, we are able to study the many mechanisms by which an anti-cancer therapy may be effective: does it impact overall tumour burden, does it impact blood vessel angiogenesis in the tumour environment, and how are blood levels of inflammatory markers or antioxidant levels changed. Then, with excised cells we can see how they differ in function, transcription of DNA, and other aspects from the animal population not receiving the therapeutic agent. Obviously, this is a much better model of the systemic environment, however animal models, particularly those which involve an induced disease state, are not identical to human conditions.

Human studies

Human studies, of course, are the gold standard of investigation for any potential therapeutic agent. Prior to larger double-blind, randomized, placebo-controlled clinical trials pilot studies are often done to investigate the impact on smaller populations and possibly determine the most effective dosage and parameters to follow in larger clinical studies. At times these studies may be done first with a healthy population to demonstrate safety, depending on the potential risk of the intervention. In clinical trials, the standard of care may also be required to ensure the optimal treatment of subjects in the study. For example, a disease condition of hypertension is associated with health risks while that of vasomotor symptoms associated with menopause is not (at least on paper!) so in the former it may be required that blood pressure continue to be managed with appropriate medications while an additional supplemental intervention is evaluated.

If one has ever tried to calculate potential human dosages based on those utilized in animal studies, if only scaled up by weight, they likely found that clinically unrealistic dosages seem to be required. Simply scaling up by weight isn’t the correct means of determining an appropriate human dosage, as normalization by body surface area (BSA) must occur. A paper on this topic by Reagan-Shaw S, et al in 2008,[1] was published shortly after erroneous information concerning resveratrol dosing in popular media occurred. In this example,[2] a murine study with dosing of resveratrol of 22.4 mg/kg was scaled up in an uneducated fashion by those in popular press and reported to be a dosage of 1344 mg for a 60-kg human. The appropriate formula for calculating human equivalency dosage (HED) in mg/kg is:

Thus, the equivalent dosage of resveratrol for a 60-kg human would be 109 mg using the approximate weight and BSA data for animals and humans found in the table below.

 

Conversion factor table
Species Weight (kg) Body Surface Area (m^2) Weight/BSA (K_m)
Adult Human 60 1.6 37.5
Adult Child 20 0.8 25.0
Baboon 12 0.6 20.0
Dog 10 0.5 20.0
Monkey 3 0.24 12.5
Rabbit 1.8 0.15 12.0
Guinea pig 1.4 0.05 28.0
Rat 0.15 0.025 6.0
Hamster 0.08 0.02 4.0
Mouse 0.02 0.007 2.9

 

 

More recently, it has also been recommended that for interspecies scaling one must justify dosage with physiologic, pharmacokinetic, and toxicology data rather than simple BSA conversion.[3] Also, for anyone who has worked with nutritional and botanical supplements, most understand certain herbs such as turmeric are significantly more absorbed if phospholipid complexed or combined with piperine, an alkaloid from black pepper.[4] For data such as this, specific compounds must be studied.

Translation of cellular studies to clinical settings?

I recently had the chance to attend at talk on the topic of recent botanical research and herb-drug interactions given by Tieraona Low Dog, MD, an internationally recognized expert in the fields of integrative medicine, dietary supplements, herbal medicine and women’s health.  In Dr. Low Dog’s talk, one of the studies highlighted was a recent publication on the topic of pharmacokinetic interactions between drugs and botanical dietary supplements.[5] This review highlighted the disparities which exist between interactions suggested by in vitro studies and the observations in human clinical trials. For example, while preclinical predictions that ginkgo (Ginkgo biloba) inhibits CYP1A2, CYP2C9, CYP2C19, CYP2D6, and/or CYP3A enzymes, clinical studies did not demonstrate any effect. Similar findings were discussed on commonly used substances including saw palmetto, milk thistle, ginseng (Panax spp.), green tea, and kava kava. Noteworthy supplements which were demonstrated in clinical settings to have an impact on CYP450 enzymes were echinacea, goldenseal, and St. John’s wort. This doesn’t mean that some of these herbs won’t have medication interactions due to their intended therapeutic effect (ie kava kava in combination with anti-anxiety medications), but they are unlikely to impact therapeutic levels of medications such as anti-epileptics and anti-coagulants which are tightly controlled to a therapeutic level.

In summary, the vast array of information and studies on all these different levels should be collectively assessed for appropriate understanding how nutritional supplements may impact human biology. Fortunately, many nutritional substances are normal to the body, whether it be a vitamin or mineral, or substance contained in foods. Thus, when research has not yet advanced to the clinical settings, we can safely implement naturally supportive therapies.

References

[1] Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008 Mar;22(3):659-61. View Abstract

[2] Baur JA, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006 Nov 16;444(7117):337-42. View Full Paper

[3] Blanchard OL, Smoliga JM. Translating dosages from animal models to human clinical trials–revisiting body surface area scaling. FASEB J. 2015 May;29(5):1629-34. View Full Paper

[4] Anand P, et al. Bioavailability of curcumin: problems and promises. Mol Pharm. 2007 Nov-Dec;4(6):807-18. View Abstract

[5] Sprouse AA, van Breemen RB. Pharmacokinetic Interactions between Drugs and Botanical Dietary Supplements. Drug Metab Dispos. 2016 Feb;44(2):162-71. View Full Paper

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