Zantac kills in Synergy with Endotoxin

Pfizer has agreed to settle class action taken by thousands harmed by the drug. Here I look at the Ranitidine Injection Endotoxin story that is below the media radar

In the news, as my friend Mike Zimmer posted, is Pfizer Zantac.¹

Much focus on the Zantac Ranitidine disaster has been directed to Carcinogenic Nitrosamine NDMA (N-Nitrosodimethylamine, Dimethylnitrosamine, N,N-Dimethylnitrous amide²) contamination that the FDA showed increases on storage of tablets at room temperature. Here I focus on Zantac Jabs.

Note that to add to the confusion, Famotidine³ has been marketed under the brand name Zantac-360.

Zantac Jabs from Multiple Suppliers

The drug has been around for many years so patents have expired and various licences apply for generic manufacture of this WHO “Essential Medicine”.

US FAERS reported 7,009 Deaths from 111,694 Case Reports for Ranitidine between 1984 and 2021.

Brands of Ranitidine Jab

FDA slow to act

US FDA stated its reasons for ordering withdrawal of all forms of Ranitidine with this quote:

In September 2019, FDA learned that some common heartburn products (ranitidine, commonly known as Zantac, and nizatidine, commonly known as Axid) contained unacceptable levels of NDMA. FDA recommended that manufacturers voluntarily recall ranitidine and nizatidine products with NDMA levels above what the Agency considers acceptable. Recently, preliminary findings from FDA stability testing raised concerns that NDMA levels in some ranitidine products stored at room temperature can increase with time to unacceptable levels. FDA’s preliminary results using accelerated stability testing demonstrated that elevated levels of NDMA were measured in all products after 2 weeks. FDA’s testing suggests that NDMA levels increase with storage time. On April 1, 2020, FDA requested that all ranitidine products be withdrawn from the U.S. market.

Endotoxin known to be in Zantac Jabs

No mention of Endotoxin was present from US FDA in their notice to withdraw the drug.

However, some deep diving reveals that Zantac Ranitidine Jabs are known to be heavily contaminated with Endotoxin.

A 2003 paper by Silveira and coworkers measured Endotoxin in Ranitidine to be 1.2 to 2.4 EU/mg, or up to 60 EU per 25 ml dose.⁴

Side Effects of Zantac Jabs

In Australia Aspen Pharmacare Australia Pty Ltd is a Sponsor of the Jab and lists⁵ the following as Side Effects:

• allergic reaction, the signs may include:
  - skin reactions such as rash (red spots), itching, skin lumps or hives,
  - swelling of the eyelids, face, lips, tongue or other parts of the body
  - shortness of breath, trouble breathing, wheezing, chest pain or tightness,
  - unexplained fever and feeling faint, especially when standing up.

• severe stomach pain or a change in the type of pain

• yellow colouring of the skin or eyes (jaundice)

• confusion

• general illness associated with weight loss

• fever

• irregular heart beat (including unusually fast or slow heart beats)

• changes in heart beat

• chest infection

• pain or flaking skin where you had the injection

• headache

• joint or muscle pains

• dizziness

• depression

• constipation

• feeling sick (nausea) or vomiting

• diarrhoea

• breast tenderness and/or breast enlargement

• breast discharge

• changes in liver function tests

Wikipedia list⁶ of Adverse Events includes some reported in Clinical Trials:

• malaise

• dizziness

• somnolence

• insomnia

• vertigo

• mental confusion

• agitation

• depression

• hallucinations

As my readers know, all of the above are known effects of Endotoxin.

Synergy of Ranitidine and Endotoxin

In 2006 Luyendyk and coworkers conducted an interesting study using Rats that showed Endotoxin together with Ranitidine causes Liver Damage⁷ within hours that did not occur with Famotidine. They confirmed earlier work⁸⁹ that examined epigentic changes in gene expression associated with Hypoxia and Fibrin deposition.

Ranitidine is generally sold as the Hydrochloride salt: Dimethyl [(5-{[(2-{[1-(methylamino)-2-nitroethenyl]amino}ethyl)sulfanyl]methyl}furan-2-yl)methyl]amine, ranitidine hydrochloride. Here are the molecular structures of the 2 isomers.

Ranitidine has a different structure and includes the Tertiary Amine centre not found in Famotidine. Tertiary amine centres are the ones subject to forming Nitrosamines, famous for their Carcinogenicity. Researchers in Saudi Arabia Food and Drug Authority (SFDA) reached this conclusion ahead of me, simply by inspection and their knowledge of chemistry.¹⁰

Nitric Oxide Production is expected

As mentioned in a number of my articles, Endotoxin induces numerous changes in expression of Nitric Oxide with numerous consequences.¹¹ As shown in this Figure from Cinelli and coworkers, Nitric Oxide production is induced by Endotoxin hitting the TLR4 and Interferon gamma.¹²

At left, Endotoxin (LPS LipoPolySaccharide), TLR4 Toll-Like Receptor 4, TRAF6 , MyD88 , IKK , IκB inhibitory κB, iNOS Inducible Nitric Oxide Synthase, NF-κB Nuclear Factor κB, NO Nitric Oxide

At right IFN-γ Interferon γ, IFNR Interferom Receptor, JAK Janus Kinases, STAT-1α Signal Transducer and Activator of Transcription 1α, IRF-1 Interferon Regulatory Factor 1, P Phosphate.

The review by Cinelli et al. provides much more detailed description on the pathways to Nitric Oxide production and the effects on various cells and organs.

Summary

It should have been obvious to all drug companies making Zantac Ranitidine Jabs, and Regulators in all countries, that the Endotoxin contamination would induce Nitric Oxide that would in turn form Carcinogenic Nitrosamines.

Where are the Endotoxin measurements on each Batch?

1. Pfizer Agrees to Settle More than 10,000 Zantac Cancer Suits

2. https://en.wikipedia.org/wiki/N-Nitrosodimethylamine

3.

4. Rosimar L. Silveira; Simone S. Andrade; Cleber A. Schmidt; Renata G. Casali; Sérgio L. Dalmora. 2003. COMPARATIVE EVALUATION OF PYROGENS TESTS IN PHARMACEUTICAL PRODUCTS. Brazilian Journal of Microbiology (2004) 35:48-53

5. https://www.nps.org.au/medicine-finder/zantac-concentrate-for-injection

6. https://en.wikipedia.org/wiki/Ranitidine

7. James P. Luyendyk, Lois D. Lehman-McKeeman, David M. Nelson, Vasanthi M. Bhaskaran, Timothy P. Reilly, Bruce D. Car, Glenn H. Cantor, Jane F. Maddox, Patricia E. Ganey, and Robert A. Roth. 2006. Unique Gene Expression and Hepatocellular Injury in the Lipopolysaccharide-Ranitidine Drug Idiosyncrasy Rat Model: Comparison with Famotidine. https://academic.oup.com/toxsci/article/90/2/569/1658572

8. JAMES P. LUYENDYK, JANE F. MADDOX, GREGORY N. COSMA, PATRICIA E. GANEY, GARY L. COCKERELL, and ROBERT A. ROTH. 2003. Ranitidine Treatment during a Modest Inflammatory Response Precipitates Idiosyncrasy-Like Liver Injury in Rats. https://jpet.aspetjournals.org/content/307/1/9

9. James P. Luyendyk, William B. Mattes, Lyle D. Burgoon, Timothy R. Zacharewski, Jane F. Maddox, Gregory N. Cosma, Patricia E. Ganey, and Robert A. Roth. 2004. Gene Expression Analysis Points to Hemostasis in Livers of Rats Cotreated with Lipopolysaccharide and Ranitidine. https://academic.oup.com/toxsci/article/80/1/203/1674928

10. Fahad S Aldawsari, Yahya M. Alshehry, and Thamer S. Alghamdi. 2021. N-nitrosodimethylamine (NDMA) contamination of ranitidine products: A review of recent findings. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9261846/

11.

12. Maris A. Cinelli, Ha T. Do, Galen P. Miley, Richard B. Silverman. 2020. Inducible Nitric Oxide Synthase: Regulation, Structure, and Inhibition. https://onlinelibrary.wiley.com/doi/10.1002/med.21599