Story 1 It wasn’t two months into my fellowship in Clinical Chemistry, working late after the routine staff had left for the day. The phone rings (BRNNG! - [old phone-1978]), and I answer. I recognize the voice on the line as a world famous endocrinologist; I had attended his lecture this week, so the voice was familiar. Doc asks “So, how’s the thyroxine reading machine working today?” (me: Pause - What??? Doesn’t this eminent physician know that there isn’t “a thyroxine reading machine”? There are extraordinarily talented people working to add the right chemicals, isotopes, separating the phases, and putting the correct fraction in the isotope counter, then using log-logit transformation to calculate the thyroxine concentration, then entering the result on a piece of paper to be attached to the patients chart.) I think some more…what is this very smart, eloquent, courteous clinician really asking?…AHA, he is asking me if we had any problems in the Lab today. Moyer learning experience #1, learn how to understand the question to get to the useful answer. He want’s to know if the result is correct. I ask if I can call him back in 3 minutes after I review everything (no more than three minutes because I know he will move on to another chart and not take my return call). So, less than three minutes later I call back to say I reviewed all the the quality checks, and all indicators suggest the result is correct. His response, another learning experience for Moyer, “OK, just wanted to check before I change my diagnosis. The result didn’t fit with my expectation, so now that I believe it to be real, I will reconsider my initial diagnosis. Thanks for your help.” Moyer to self: Thank you Doc X for that valuable learning experience.
Story2 - Laetrile for cancer treatment - one of the world's greatest hoax.
In the early 1950s, amygdalin and a chemical derivative named laetrile began to be promoted as alternative cancer treatments. While amygdalin and laetrile were never approved for use in the United States, it's promotion was highly touted by a fake literature; treatment with laetrile was readily available in Mexico. Promotion of laetrile to treat cancer has been described in the medical literature as a canonical example of quackery and as the slickest, most sophisticated, and the most remunerative cancer promotion in medical history. Numerous scientific studies found these compounds to not only be clinically ineffective in treating cancer, but also potentially toxic or lethal when taken by mouth due to cyanide poisoning.
Amygdalin is a naturally occurring chemical found in many plants, most notably in the seeds of apricots, bitter almonds, apples, peaches, cherries and plums, and in the roots of manioc. Amygdalin is a cyanogenic glycoside; each molecule includes a nitrile group, which can be released as toxic cyanide by the action of a beta-glucosidase. Ingestions of amygdalin will result in release of cyanide into the human body that may lead to cyanide poisoning.
Because many cancer patients came to our medical center insisting on being treated with laetrile, we decided to perform a clinical study with sufficient safeguards to ensure participating patients were protected from anticipated cyanide toxicity. Prior to implementation, the study plan underwent extensive Human Study review by both Mayo Clinic and the National Cancer Institute to ensure patient safety and propriety; the study was carried out under standard Phase I pharmaceutical research protocol. Six patients with advanced cancer were treated with laetrile at standard doses employed by laetrile advocates. Biological specimens were collected to facilitate a thorough evaluation of cyanic exposure. During and following completion of the study, none of the patients exhibited signs or symptoms of cyanide intoxication, all of the biological samples collected demonstrated elevated cyanide levels. The study concluded that exposure to laetrile predisposed patients to significant cyanide body burden that could dispose them to cyanide toxicity.
Reports from this study (A Pharmacologic and Toxicologic Study of Amygdalin. CG Moertel, MM Ames, JS Kovach, TP Moyer, JR Rubin, JH Tinker. J American Medical Association 1981;245:591594. and Pharmacology f Amygdalin (Laetrile) in Cancer patients. MM Ames, TP Moyer, JS Kovach, CG Moertel, Rubin. Cancer Chemother Pharmacol 1981;6:51-77.) and numerous others (see Wikipedia) clearly showed the danger associated with laetrile therapy resulting in it subsequent dismissal as a legitimate therapy.
Story 3 - A case of gout treatment causing regional enteritis.
A 33 year old woman presented with a history of gut pain, commonly known as regional enteritis. She recited a prior history of joint pain that was ultimately associated with excess ingestion of red meat. Her home town physician diagnosed these symptoms as gout, advised her to reduce her meat consumption, and prescribed the common anti-gout medication, Zyloprim. After several months her joint inflammation resolved, but then she started to experience enteritis. Over time she described the painful experience of kidney stones, which she collected and presented to her physician at the time of examination. These kidney stones were sent to the lab for analysis. Surprisingly, the stones she submitted were not comprised of the common constituents of kidney stones, which are typically uric acid, oxalic acid, or calcium oxalate.
This lab report raised interest among the clinicians attending this patient, which lead to a case conference where alternative possibilities were discussed. Her astute physician asked the question "could these be stones result from the administration of Zyloprim?" Zyloprim, generic name allopurinol, is an FDA approved drug similar in chemical structure to uric acid. Under normal circumstances allopurinol is well tolerated by patients and does not cause kidney stones. The lab performed additional chemical analysis on the submitted stones to prove that the chemical present in these stones was oxypurinol, a natural metabolite of Zyloprim that is normally readily eliminated in the urine. Reduction in Zyloprim dose was recommended, and over months, the incidence of Zyloprim-related nephrolithiasis diminished.
This was the first reported case of Zyloprim-related nephrolithiasis. RM Stote, LH Smith, JW Dubb, TP Moyer F Alexander, JLA Roth. Oxypurinol Nephrolithiasis In Regional Enteritis Secondary to Allopurinol Therapy. Annals of Internal Medicine. 1980;92:384-385.
Story 4 - Cyclosporin blood levels.
Cyclosporin, also spelled ciclosporin and cyclosporine, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken orally or intravenously to reduce inflammation due to rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, eczema, and in organ transplant to prevent graft rejection. It is also used as eye drops for keratoconjunctivitis sicca (dry eyes).
Cyclosporin was isolated in 1971 from the fungus Tolypocladium inflatum and came into medical use in 1983. It is on the World Health Organization's List of Essential Medicines. In 2022, it was the 185th most commonly prescribed medication in the United States, with more than 2 million prescriptions.
Cyclosporin works by decreasing the function of lymphocytes. It does this by forming a complex with Cyclosporine to block the phosphatase activity of calcineurin, which in turn decreases the production of inflammatory cytokines by T-lymphocytes. Cyclosporin is indicated to treat and prevent graft-versus-host disease in bone marrow transplantation and to prevent rejection of kidney, heart, and liver transplants.
Cyclosporin was first used to interfere with graft vs host reaction following solid organ transplant by Dr. Thomas Starzl at the University of Pittsburg. Starzl's 1992 memoir explains that Cyclosporin was an epoch-making drug for solid organ transplantation. It greatly expanded the clinical applicability of such transplantation by substantially advancing anti-rejection pharmacotherapy. Put simply, the biggest limits of applying solid organ transplantation more widely is not the cost or surgical skill (as formidable as those are), but rather, the problem of allograft rejection and the scarcity of donor organs. Cyclosporin was a major advancement against the rejection component of the challenge.
Within the context of the major anti-rejection advantages offered by Cyclosporin treatment, patient management while taking Cyclosporin is complicated by the widely variable metabolism of the drug. Cyclosporin metabolism is controlled by the genetically variable enzyme Cytochrome P4503A4. There is no standard dose that results in optimal therapy; there is wide intra-individual variability in metabolism. The enzyme also experiences variable inhibition by a wide variety of common dietary ingredients. For example, ingestion of grapefruit juice will interrupt metabolism that can result in Cyclosporin toxicity.
The solution to this problem was in the Lab. Shortly after introduction of Cyclosporin, blood level monitoring became the standard of practice. Dose adjustments based on blood concentration of Cyclosporin immediately after transplant became mandated. If a patient showed any signs of rejection or Cyclosporin toxicity, blood specimens were drawn immediately to determine blood concentration that defined whether dose adjustments were needed. With careful Cyclosporin blood level monitoring, during the period of the 1980's the rate of success of solid organ transplant rose from less that 50% to greater than 95%. Monitoring Cyclosporin blood concentration played a major role in this success.
Mayo Clinic Lab played a significant role in this medical advancement: (Moyer TP, Charlson JR, Ebnet LE. Improved chromatography of cyclosporine. Ther Drug Monit. 1986; 8(4):466-8. PMID:3824434. Moyer TP, Johnson P, Faynor SM, Sterioff S. Cyclosporine: a review of drug monitoring problems and presentation of a simple, accurate liquid chromatographic procedure that solves these problems. Clin Biochem. 1986 Apr; 19(2):83-9. PMID:3518993. Post GR, Moyer TP, Anderson CF, Sterioff S. Long-term cyclosporine for renal allograft patients does not cause nephrotoxicity. Transplant Proc. 1987 Feb; 19(1 Pt 2):1761-3. PMID:3079036. de Groen PC, McCallum DK, Moyer TP, Wiesner RH. Pharmacokinetics of cyclosporine in patients with primary biliary cirrhosis. Transplant Proc. 1988 Apr; 20(2 Suppl 2):509-11. PMID:3363652. Moyer TP, et al. Consensus Document: Hawk's Cay meeting on therapeutic drug monitoring of cyclosporine. Transplantation Proceedings. 1990; 22(3):1357-61. PMID:2190399.)
