I notice a lot of interest in OTC supplements and remedies for stone prevention. P harmala is a good example and has a very recent publication.
In addition, I am committed to the idea that informed patients do best for themselves, thence this site. Nothing can can inform a patient better than a look at the original science.
If I put the two together, this very new scientific paper on P Harmala is a perfect opportunity to learn about a possible new remedy and how to read a scientific paper.
The lovely image is the flower of P harmala. The link is to Wikipedia where I found it.
Follow the Money
Whether it begins that way or not, any science project must have an objective – a purpose. Find the purpose, keep your eyes on it, and you can understand papers about kidney stone disease. That is what I do when I write for you. Being a scientist, I can read into the smallest detail, but I always look closest at the main point of a paper, just as you can.
What is the Objective of a Science Project?
It is a noun – a thing. It is the gift of science to the people who have paid for it – tax payers in the US, certainly. If research is a search, and scientific research a search for new knowledge, the objective is precisely that new knowledge. It is the purpose of it all. It is what one is seeking to discover or invent. I have detailed my thinking on this matter in a recent article itself linked to a formal presentation I have given publically and put up on YouTube. Here is something more specific, one science project in detail.
In Medicine Objectives are Tests or Treatments
For medicine, what science can offer is new tests or treatments – that is all. Deeper science, about how diseases processes work, matters to patients only if it can lead to tests or treatments. Otherwise, it is basic science – how nature works. Wonderful, beautiful, but not of immediate interest here – for this site is for patients and their physicians.
Tests can be for diagnosis, progress of treatment, prediction of outcome (what will happen to someone who is ill), or risk of getting sick – so called risk factors. Treatments are obvious – preventions, cures, and in between – things that make us feel better or reduce harm. So the categories are broad. Broad or not, a paper has to point to tests or treatments if it is to be medical research.
The Meaning of Immediacy
But that is a bit too black and white. Sometimes a research is very close to a test or cure, sometimes very far away, so the space between ‘basic’ and clinical research is thicker than a line. For example, profound science concerning messenger RNA led rapidly to COVID-19 vaccines. In other cases, like this one – closer to home – this paper in Science proposed new ways to dissolve kidney stones. The science is lovely. That someday one might use this science to dissolve real stones in people is not an airy dream but is a dream unrealized. Someday is not now nor necessarily soon, nor even – in some cases – ever. So we want to isolate the objective and make some kind of judgment about immediacy.
Where Do We Find the Objective?
At the beginning, in the introduction to any scientific paper. It will be few words. Those words should say what it will be, a test, a treatment, or something more basic. The introduction to a scientific paper is itself not very long, a few paragraphs.You may need to look around for the objective because authors write toward their community of peers not the public. But the ‘it’, the objective, will always appear, and always a noun.
Pagana Harmala to Prevent Kidney Stones
An Ancient Kidney Stone Treatment
For example, this study seems to be about a possible kidney stone treatment. Pegana harmala is a plant, and an ancient stone medication. In their introduction the authors offer appropriate ancient and modern support for its benefits. One modern benefit was in expelling stones. In comparison to Tamsulosin, a recognized drug, P harmala was similarly effective. But the authors believe the case is not sufficient. Near the end of a long paragraph reciting evidence favoring the agent:
“However, the scientific evidence of the ethnopharmacological use and potential therapeutic effect of P. harmala in urolithiasis so far is insufficient.”
Given this, the objective must be more scientific evidence supporting P Harmala as a kidney stone treatment.
The most immediate research that can lead to a treatment now, right now, would be a trial – randomized, double blind, prospective – expensive. The trial is the one and only last step to the drugstore. But that is not what this paper and these scientists have in mind.
An Indirect Test of the Treatment
What is the paper about?
The authors left off with the insufficiency of the scientific evidence for P harmala, and go on to their remedy, their addition:
“Therefore, the in vivo effects of the seed extract of P. harmala and its major alkaloids on ethylene glycol (EG)-induced urolithiasis in rats were evaluated in this study by checking its mitigating effects on the antioxidant machinery, serum toxicity markers (i.e. nitrogenous waste, such as blood urea nitrogen (BUN), uric acid, urea, and creatinine), minerals (such as Ca, Mg, P, and oxalate), kidney injury marker 1 (KIM-1), and urinary markers (such as urine pH and urine output).”
What have we here?
It is the additional scientific evidence for the potential therapeutic effect of P harmala – their response to the insufficiency of what we have now. Most important it is something they can measure.
Lets take a look at it. What we really want, a trial, would measure numbers of stones formed during a specific interval by those treated and untreated with P harmala. Instead they mean to produce crystals of calcium oxalate (the common stone crystal) in kidneys of rats by giving them antifreeze – ethylene glycol, which is metabolized to oxalic acid. The predictable masses of calcium oxalate crystals will damage the rat kidneys. Perhaps P harmala will mitigate damage, implying fewer crystals have formed. Less crystal, less stones – support for a trial, perhaps.
What are the Measurements?
If you look at what they write, the authors seem shy about crystals per se – their list does not mention them. Instead it is about kidney injury – oxidation products (not a good thing), reduced kidney function (BUN, uric acid, creatinine), magnesium, phosphate and oxalate, and KIM-1 (in kidney cells, and gets out when cells are injured).
So what are their nouns? If objectives are nouns can we identify them?
It is differences, differences in kidney injury markers between rats given ethylene glycol who do and do not also receive P harmala.
Indeed, they found differences – less kidney injury in rats given the seeds and specific molecules from the seeds. They concluded that in diseases resulting from calcium oxalate crystallization P harmala might indeed be reasonable, thus inching toward – one day – an actual human trial.
A Closer Look at Objectives
Injury or not in rat kidneys is not what humankind in general comes for, or wants to pay for. They want a treatment in the drugstore for kidney stone prevention. But to get the treatment, in this case P harmala, requires a chain of experiments leading to and justifying a human trial. But chains are made of links, so how do we link, for example, the present rat research to an ultimate trial?
The linker is logic, logic of a special kind. One might say it is the logic of scientific discovery.
The Modus Tollens
Many have encountered the modus tollens in school:
All cats are animals; if my pet is a cat then my pet is an animal; my pet is a pear tree. My pet is not an animal. That is one way to look at things.
All cats are animals; if my pet is a cat then my pet is an animal; my pet is a cat; my pet is an animal. Both examples begin with an ‘all’ statement that predicts necessary specific outcomes. Here is yet another;
All cats are animals; if my pet is a cat then my pet is an animal; my pet is an giraffe. So particular statements do not lead to a general statement. The modus tollens does not run backward.
If P harmala prevents new human stones, then the count of new stones will be lower in people given vs. not given P Harmala. That is the – rather simple – logic of the clinical trial. It could apply to refrigerators, or electric cars or anything else that does something we want done.
There is a lot more to say here, but I am done with it for now.
Lets apply this logic to the present P harmala study:
If P harmala can prevent new human kidney stones then measures of kidney injury will be lower in ethylene glycol treated rats given vs. not given P harmala.
The Chain of Logic
Clearly we need not one but a chain of logical statements. That chain must lead from the trial back down to the unfortunate rats given ethylene glycol. Here is my take on the most compact logical chain. I welcome others to try to make it shorter.
All calcium oxalate kidney stones require calcium oxalate crystals; if P harmala reduces kidney calcium oxalate crystals then P harmala must reduce calcium oxalate kidney stones
All rats metabolize ethylene glycol to oxalic acid; if we give rats ethylene glycol then the rats will produce oxalic acid
All rats will accumulate calcium oxalate crystals in their kidneys given sufficient* ethylene glycol; if we give rats sufficient* ethylene glycol then calcium oxalate crystals will accumulate in their kidneys
All kidney injury from ethylene glycol is from calcium oxalate crystals; if p harmala reduces kidney calcium oxalate crystals then injury must be less with than without added P harmala
“Sufficient” in this logic chain means one knows in advance an amount of ethylene glycol needed to create calcium oxalate crystal accumulation of a magnitude that always injures rat kidneys and also that amount of P harmala or its metabolites that can reduce measured injury. In other words the amounts are also ‘all’ statements determined in advance.
An Intact Logic Chain Supports this Paper
At this point we have come full cycle to the logical basis for the present research paper (just above: “If P harmala prevents new human kidney stones then measures of kidney injury will be lower in ethylene glycol treated rats given vs. not given P harmala.”)
One might say the scientists could have just quantified amounts of crystal, but that is not our concern here. Likewise there are a few issues. How sure are we that ethylene glycol is entirely innocent save calcium oxalate crystals? How well does injury track crystal amount? Most important, is this new evidence really taking us closer to a human trial?
These are issues for experts and not what I am about here. The main point is that anyone should be able to reason from what is desired (a kidney stone prevention in this case) and what is intended through measurement (effects of P harmala on kidney injury in rats given ethylene glycol).
All of us use chains of inference – logic chains – in our work, for example, in planning for retirement, choosing a new car. We just do it. To formalize it in real life is exhausting and often impossible for want of All statements. But in science, All statements abound and logic is not an ornament.
What Is the Answer?
Even though the measurements themselves are for experts to parse and vet, we ourselves can do reasonably well. Here is KIM-1, a marker of kidney cell injury. Control is just rats. EG is rats given ethylene glycol – antifreeze. Indeed the kidney cells show serious injury that is from – our logic tells us – calcium oxalate crystals. The other EG bars are the experiment. PE is a control for ether, the carrier for the purified chemicals from P harmala thought to make them good treatments. TE is seed extract, what you can make from seeds on sale seemingly everywhere. B is an extract in butanol of mixed active molecules, and P1 and P2 are purified harmine and harmalicidine HCL, respectively – two plant chemicals.
What about ‘STD”? It is standard care – in Saudi Arabia and/ or Egypt where this work was done. What is this treatment? It is cystone, an herbal treatment. I have not studied its effects, but one paper from Mayo Clinic showed it neither improved 24 hour urine stone risk nor reduced kidney stone burden or passage.
The graph is very clear. The seed extract had hardly any effect on KIM-1, and none of the other products brought its level down to control. Curiously, it was cystone that did best. So cell injury, presumably from calcium oxalate crystals, was by no means prevented. It was reduced by the purified products P1 and P2.
There are two measures here. NFkB is part of the native immune response that reacts rapidly to invaders like bacteria but also notices crystals. TNF-α is produced by macrophages and promotes inflammation. Ethylene glycol raised both. The pattern of response to the treatments resembles what we saw for KIM-1, Seed extract (TE) was without effect. The pure molecule P2 and cystone brought levels near to control though not completely.
What Have I Brought You With This Example?
Two Objectives Linked by Logic
All science has two objectives.
One is public facing – in this case a stone prevention. It links the work to humanity, to the service science owes to those who support it through their taxes and good will.
The other is measurement facing – in this case reduction or not of kidney injury by P harmala in rats given ethylene glycol. It links the public facing objective to testing by measurements that can be objectively verified by any who choose to replicate the original work.
Between the two, the public facing and the experimental objective is the iron logic chain, the modus tollens.
This paper on a herbal stone prevention candidate has both objectives and a logic chain, as expected, and has served us well as an illustration.
A Rather Negative Result
Certainly the seed extract did almost nothing to reduce injury and inflammation. One purified molecule showed promise. So by logic, the seeds themselves are not promising as a stone reduction. As for the harmalicidine, it is a ‘perhaps’, meaning a long way from the drug store. So the work gives a reasonably answer, perhaps not quite what the authors hoped for.
The Length of the Chain
In a way the length, meaning the number of logical steps, is at least 4, so the test of the main proposition – that P harmala reduces calcium oxalate crystallization – is indirect to that extent. Add to that the rather negative results for P harmala seeds, what we have available right now, one cannot be enthusiastic about this plant as a stone remedy.
The Logic Might be Less than Rigorous
Rat kidneys are not the same as human and we did not make similarity of the two an explicit necessary statement. I left that out to center attention on the main issues but in reality the ‘relevance’ of an animal model to human disease is always at issue. Everyone who reads this site knows that primary formation of calcium oxalate crystals in human kidneys is not a feature of common calcium oxalate stones. Rather, calcium phosphate forms and fosters calcium oxalate in the renal collecting system. This is yet another fact which we did not include as a necessary logical statement.
A fuller logic chain for this paper would greatly lessen its relevance to human disease. But that is not on point for this article, as I have used it to illustrate the process of science as well to gauge the value of P harmala as a stone treatment.
The Impregnable Forest of Measurement
You will note I guided you through that forest. That is what experts do. A published paper will be reviewed by experts. We can assume the measurements mean what they are said to mean and ask what they are intended to accomplish – for people, and in satisfaction of the modus tollens. To all but the most interior to a field the measurements cannot be critically evaluated.
That latter is why peer review is crucial – for the measurements. Any reasonable person can judge the worth of the desired objective, and the tightness of the logic to the measurement facing objective. That is more than enough to judge the general value and meaning of a paper. The answer from the measurements is also usually obvious. The abstract, curiously, is a good place to look for it because editors usually demand the answer be prominent at the front of the paper.
What About P harmala for Stone Prevention?
Not now, maybe not ever.
It is not the one study that makes me say that. It is the authors. They are experts concerning this plant and believe the science is lacking to support a trial – thus this paper. The paper shows the plant itself is extremely weak at preventing kidney injury in a model of calcium oxalate crystal induced injury. That means there is little evidence it prevents calcium oxalate crystals. The purified chemicals did better but their use in humans is far away.
What About Cystone?
Doesn’t it look good?? It reduced inflammation so well!
But in the one study with patients it failed. Even so, I will track down what else has been found out about it, and write it up.
My guess is No.