MD, PhD, FMedSci, FRSB, FRCP, FRCPEd

For some time now, I got the impression that the research literature of alternative medicine is yielding more and more animal experiments. But impressions can of course be misleading, so I did a small statistical analysis. I went on to Medline, searched for all papers on ‘complementary/alternative medicine’, and counted the number of animal studies as well as clinical studies (including observational studies but excluding surveys) amongst the first 100 hits.

The results confirmed the above-named impression. There were:

  • 30 animal studies,
  • 12 clinical trials,
  • the rest was made up of other pre-clinical studies (mostly in-vitro studies), comments and other types of publications.

I find this dominance of animal studies surprising, particularly as I got the impression that many were odd, meaningless and not followed by adequate further research. But again, this is just an impression. Let’s see some data. Here are the first 3 papers listed:

Paper number 1

BACKGROUND:

Essential hypertension is mainly caused by endothelial dysfunction which results from nitric oxide (NO) deficiency. The present study was design to evaluate the protective effect of Bidens pilosa ethylene acetate extract (Bp) on L-NAME induced hypertension and oxidative stress in rats.

METHODS:

Male Wistar rats were used to induce hypertension by the administration of L-NAME (a non-pecific nitric oxide inhibitor) (50 mg/kg/day). The others groups were receiving concomitantly L-NAME plus Bp extract (75 and 150 mg/kg/day) or losartan (25 mg/kg/day). All the treatments were given orally for 4 weeks. At the end of the treatment, the hemodynamic parameters were recorded using the direct cannulation method. The effects of the extract on lipid profile, kidney and liver functions as well as oxidative stress markers were evaluated by colorimetric method. Results were expressed as the mean ± SEM. The difference between the groups was compared using one-way analysis of variance (ANOVA) followed by the Duncan’s post hoc test.

RESULTS:

Animals receiving L-NAME presented high blood pressure, normal heart rate and lipid profile as well as NO depletion, liver and kidney injuries and oxidative stress. The concomitant treatment with L-NAME and Bp or losartan succeeded to prevent the raised of blood pressure and all the other injuries without affecting the heart rate.

CONCLUSION:

These results confirm the antihypertensive effects of Bidens pilosa and highlight its protective properties in L-NAME model of hypertension in rat, probably due to the presence of Quercetin 3,3 ‘-dimethyl ether 7-0-β-D-glucopyranoside.

Paper number 2

BACKGROUND:

Oxidative stress has a pivotal role in the pathogenesis and development of diabetic peripheral neuropathy (DPN), the most common and debilitating complications of diabetes mellitus. There is accumulating evidence that Juglans regia L. (GRL) leaf extract, a rich source of phenolic components, has hypoglycemic and antioxidative properties. This study aimed to determine the protective effects of Juglans regia L. leaf extract against streptozotocin-induced diabetic neuropathy in rat.

METHODS:

The DPN rat model was generated by intraperitoneal injection of a single 55 mg/kg dose of streptozotocin (STZ). A subset of the STZ-induced diabetic rats intragastically administered with GRL leaf extract (200 mg/kg/day) before or after the onset of neuropathy, whereas other diabetic rats received only isotonic saline as the same volume of GRL leaf extract. To evaluate the effects of GRL leaf extract on the diabetic neuropathy various parameters, including histopathology and immunohistochemistry of apoptotic and inflammatory factors were assessed along with nociceptive and biochemical assessments.

RESULTS:

Degeneration of the sciatic nerves which was detected in the STZ-diabetic rats attenuated after GRL leaf extract administration. Greater caspase-3, COX-2, and iNOS expression could be detected in the STZ-diabetic rats, which were significantly attenuated after GRL leaf extract administration. Also, attenuation of lipid peroxidation and nociceptive response along with improved antioxidant status in the sciatic nerve of diabetic rats were detected after GRL leaf extract administration. In other word, GRL leaf extract ameliorated the behavioral and structural indices of diabetic neuropathy even after the onset of neuropathy, in addition to blood sugar reduction.

CONCLUSION:

Our results suggest that GRL leaf extract exert preventive and curative effects against STZ-induced diabetic neuropathy in rats which might be due to its antioxidant, anti-inflammatory, and antiapoptotic properties.

Paper number 3

BACKGROUND:

Many people still experience pain and inflammation regardless of the available drugs for treatments. In addition, the available drugs have many side effects, which necessitated a quest for new drugs from several sources in which medicinal plants are the major one. This study evaluated the analgesic and anti- inflammatory activity of the solvent fractions of Moringa stenopetala in rodent models of pain and inflammation.

METHODS:

Successive soxhlet and maceration were used as methods of extractions using solvents of increasing polarity; chloroform, methanol and water. Swiss albino mice models were used in radiant tail flick latency, acetic acid induced writhing and carrageenan induced paw edema to assess the analgesic and anti-inflammatory activities. The test groups received different doses (100 mg/kg, 200 mg/kg and 400 mg/kg) of the three fractions (chloroform, methanol and aqueous). The positive control groups received morphine (20 mg/kg) or aspirin (100 mg/kg or 150 mg/kg) based on the respective models. The negative control groups received the 10 ml/kg of vehicles (distilled water or 2% Tween 80).

RESULTS:

In all models, the chloroform fraction had protections only at a dose of 400 mg/kg. However, the methanol and aqueous fraction at all doses have shown significant central and peripheral analgesic activities with a comparable result to the standards. The aqueous and methanol fractions significantly reduced carrageenan induced inflammation in a dose dependent manner, in which the highest reduction of inflammation was observed in aqueous fraction at 400 mg/kg.

CONCLUSION:

This study provided evidence on the traditionally claimed uses of the plant in pain and inflammatory diseases, and Moringa stenopetala could be potential source for development of new analgesic and anti-inflammatory drugs.

END OF QUOTE

I may be wrong, but I have my doubts that these papers are useful (and there are many that are far worse than these 3. Take for instance this one that I blogged about previously). Animal studies could clearly be helpful, but they have to fulfil certain conditions.

Medline is currently littered with dubious animal experiments which never seem to be followed up with further research. Without subsequent research verifying whether the effects observed in animals might have any meaning for treating humans, such studies are, I think, in danger of being a waste of animals, money and time. It is my impression – one that would be difficult to back up by hard data – that most of these dubious animal studies are never followed by further research. If true, this would render them meaningless and arguably unethical.

Yet I am not an expert in pre-clinical research and would be most interested to hear your opinion on this matter.

5 Responses to Animal experiments in alternative medicine research – a new and odd phenomenon

  • Your conclusion raises a very interesting (albiet not new) question which can be separated into parts.

    Is there a quality below which an experiment should not use live animal testing?

    Are there some treatment modalities so absurd (disconnected from the realities of nature) or inhumane as to disqualify them from consideration?

    There are many examples out there that meet both criteria.

    Thank you Edzard for continuing to explore the animal world… I know you will find veterinary science fascinating.

  • I notice that all these studies originate from ‘developing’ countries, and having done my PhD in drug discovery in South Africa, I might be able to shed some light on the issue.

    There is an immense pressure to ‘catch-up’ to the West and hence the cook book is usually followed blindly (because it ‘worked’ for the West!!). Step 1 large scale screening using in vitro bioassays. Step 2 take the most promising ‘hits’ and do animal studies etc. Problem is that not much thought goes into the whole process especially not what a promising hit is. The practical experience is usually also lacking, but, because the cookbook says that you must move from in vitro to in vivo, that is then exactly what will happen. So, I would agree that the bulk of animal studies is in effect completely unnecessary and animal cruelty.

    A second issue is that being able to use ‘big scientific words’ is for many enough to provide them with a good income, high social status etc and hence going through the motions (cookbook) knowing that you will never actually produce a new drug is okay because the objective is the former, and not the latter. Limited resources and facilities also play a role but I have not been at any university in the world where researchers do not complain about this issue.

    Third issue is that drug discovery takes a lot of time and money and as soon as people have spend a couple of years and lots of money on identifying a couple of lead compounds they tend to continue, even if the results are bad (low activity, high toxs, crap bioavailability). There is an inability to stop when the results aren’t good enough. The students need to get their PhD done, the funding body wants to see results (or progress), the University management wants results and nobody can just admit that this study gave negative results. And very few can cut their losses early on in the pipeline and move on to the next project. I for example have found that a particular type of lead compound is quite toxic but even after 10-15 years my former Uni is still publishing papers on this compounds’ bioactivity (not in animals but in vitro studies).

    And that brings me to the fourth issue. The sole objective of modern day academic science is not to develop a new drug (solve a problem) but to continue to write about your attempts to do so eg publish or perish. With all the time spend writing papers/proposals etc I don’t have high hopes for many new drugs coming from universities. And as universities are increasingly managed as commercial companies with their product (or currency) being the number of publications, it is not hard to see why these types of papers will become more common – it ticks all the boxes for the bureaucrats.

    There will probably be many more issues, but I think I’ll stop here.

  • I’ve done a brief internet check on the first study. Not good.

    According to Bilanda et al. Bidens pilosa extract is a traditional medicine used to treat 40 categories of illness. A veritable wonder plant!

    According to Bairwa et al. 2010, it has Antibacterial, Anti-inflammatory, Antiallergic , Antimalarial, T helper cell modulator, Immunosuppressive, Antihyperglycemic, Anti-hypertensive, Antiulcerogenic, Hepatoprotective, Anti-leukemic, Anticancer, Antipyretic, Anti-virus, Anti-angiogenic, Antirheumatic and Antibiotic properties!

    http://www.derpharmachemica.com/pharma-chemica/an-updated-review-on-bidens-pilosa-l.pdf

    Miraculous cure-all or credulous cure-all?

    If not a miraculous cure-all can it help at all?

    The study by Bilanda et al. merely replicates a study by two of the other authors, Kamtchouing and Dimo, published in 1999: Dimo et al. PMID: 10216804.

    That is a long time for no progress whatsoever to have been made, even by drug development time scales. No clinical trials, not even a testable drug, no nothing – just a repeat rat experiment after nearly 20 years, on a raw plant extract. Literally a waste of time.

    Pre-clinical trials are vital, primarily for safety reasons, in order to establish first dose estimates for first-in-human trials. The vast majority of of drugs never reach human trials and of those that do, the vast majority never get licensed. But the process does at least eliminate a huge number of useless and/or dangerous potential medicines.

    Bidens pilosa extract for hypertension, is no out-of-Africa repeat of Artemisinin. The latter out-of-China drug emerged after the testing and rejection of thousands of traditional Chinese medicines. Pre-clinical trials on monkeys, as well as mice, lead on to successful clinical trials.

    Science can turn a traditional medicine into a successful modern medicine. Traditional medicine without the aid of science is stuck in the past.

  • I have the impression that unsuccessful medicines (of all types) often follow an inverted evidence pyramid. In the usual process of drug discovery a huge amount of experimentation has to be done in vitro before the first ‘hit’ emerges. Modifying a ‘hit’ to make a lead takes more pre-clinical research: things like formulation and product stability testing are accompanied by animal research to investigate pharmacokinetics, toxicology, etc. Finally a potential medicine emerges from this narrowing-down pyramid base that can be submitted for clinical testing. The clinical testing also follows a sort of narrowing-down process, until the drug, if successful, emerges at the pinnacle of the evidence pyramid: a successful, phase 3, prospective, randomized, double-blind clinical trial.

    For pseudo-medicines, this process goes into reverse. Someone gets an idea for a new ‘medicine’ they’ve pulled out of the back of their neck or based on trivial observations. The product is tested in a small number of patients, with weakly diagnosed diseases, and several of the patients provide positive anecdotes that the treatment worked for them. For non-critically minded believers, that’s evidence enough. The treatment may be deemed worthy of an RCT, several of which show equivocal or negative results. At that point, believers in the not yet scientifically demonstrated efficacy of the treatment begin to undertake pre-clinical research, including animal experimentation, in a vain effort to provide explanations why the medicine fails in proper clinical trials. The pre-clinical work is typically of low or no quality, but believers consider it demonstrates why critics are wrong to suggest the medicine, like the famous emperor, is wearing no clothes.

    Thus the evidence base is assembled backwards from the normal, rational discovery approach that begins in the lab and ends with the patient.

  • As a vet this aspect of alt med research is particularly disturbing, it is a sheer waste of animal lives.

    I wrote a blog post of my own on the subject a while back: http://aillas.blogspot.co.uk/2016/03/homeopathic-hypocracy-and-vivisection.html which highlights the fact that, despite claiming they would never use vivisection, vet homeopaths are still happy to cite papers which use it. Almost as if they hadn’t actually read them and were simply copying the references blindly!

    “The most shocking aspect of the list though wasn’t the misleading promise of ‘truth’ from the BAHVS, it was the scale of the vivisection involved. In the name of the gentle art of homeopathy, hundreds of laboratory mammals were variously burned with lasers, scalded, incised, crushed, irradiated, had their jaw and leg bones fractured, were poisoned with strychnine, injected with formaldehyde, dry-cleaning fluid and cancer cells, and infected with sleeping-sickness. One experiment in a later section measured the effect of homeopathy in mice on “writhing induced by intraperitoneal acetic acid”. And it wasn’t just mammals. One paper involved a group of unfortunate snails having their equivalent of a central nervous system dissected out for study.”

    Niall

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