1636 replies to this topic

[invalidusername]

It is Elly Lilly and the Prozac launch all over again!

 

Ignoring the FDA's views about Kratom, they are for the most part there to protect this stuff. 

 

Be interested to see what comes of it...

[fishinghat]

You know Lyla brings up an interesting subject about information on the web. Anyone posting a "news" article on the internet is NOT covered by federal regulations in truth and liability for news organizations. This means that CNN, Fox News, MSNBC, local news stations which have internet sites ARE regulated and subject to FDC regulations because they are FDC registered news organizations. Most of the rest like WebMD, drugs.com, fiercepharma and so many others are not regulated. Now that doesn't mean what they post may not be true but should be taken with a grain of salt.

[invalidusername]

Absolutely - especially when you consider who is running the show behind sites such as WebMD.

[fishinghat]

Zantac (ranitidine)

Interesting that the theoretical and preliminary information has been available since 2012 with more detailed analysis starting in 2014. I know when I was working the FDA was about 12 years behind in their independent testing. I am sure it is probably worse now.

 

The most recent research demonstrates two ways of changing the production of Zantac that almost eliminates the NMDA contamination.

More to follow

https://www.ncbi.nlm...pubmed/28774600
Characterization of N-nitrosodimethylamine formation from the ozonation of ranitidine.
2017 May 28.
Abstract
N-nitrosodimethylamine (NDMA) is an emerging disinfection by-product which is formed during water disinfection in the presence of amine-based precursors. Ranitidine, as one kind of amine-based pharmaceuticals, has been identified as NDMA precursor with high NDMA molar conversion during chloramination. This study focused on the characterization of NDMA formation during ozonation of ranitidine. Influences of operational variables (ozone dose, pH value) and water matrix on NDMA generation as well as ranitidine degradation were evaluated. The results indicate high reactivity of ranitidine with ozone. Dimethylamine (DMA) and NDMA were generated due to ranitidine oxidation. High pH value caused more NDMA accumulation. NDMA formation was inhibited under acid conditions (pH≤5) mainly due to the protonation of amines. Water matrix such as HCO3- and humic acid impacted NDMA generation due to OH scavenging. Compared with OH, ozone molecules dominated the productions of DMA and NDMA. However, OH was a critical factor in NDMA degradation. Transformation products of ranitidine during ozonation were identified using gas chromatography-mass spectrometry. Among these products, just DMA and N,N-dimethylformamide could contribute to NDMA formation due to the DMA group in the molecular structures. The NDMA formation pathway from ranitidine ozonation was also proposed.

Note - Basically it says that the formation of NDMA is determined by the pH during ozonation (part of production process).

https://www.ncbi.nlm...pubmed/26992900
Oral intake of ranitidine increases urinary excretion of N-nitrosodimethylamine.
2016 Mar 18.
Abstract
The H2-receptor antagonist, ranitidine, is among the most widely used pharmaceuticals to treat gastroesophageal reflux disease and peptic ulcers. While previous studies have demonstrated that amines can form N-nitrosamines when exposed to nitrite at stomach-relevant pH, N-nitrosamine formation from ranitidine, an amine-based pharmaceutical, has not been demonstrated under these conditions. In this work, we confirmed the production of N-nitrosodimethylamine (NDMA), a potent carcinogen, by nitrosation of ranitidine under stomach-relevant pH conditions in vitro We also evaluated the urinary NDMA excretion attributable to ingestion of clinically used ranitidine doses. Urine samples collected from five female and five male, healthy adult volunteers over 24-h periods before and after consumption of 150mg ranitidine were analyzed for residual ranitidine, ranitidine metabolites, NDMA, total N-nitrosamines and dimethylamine. Following ranitidine intake, the urinary NDMA excreted over 24h increased 400-folds from 110 to 47 600ng, while total N-nitrosamines increased 5-folds. NDMA excretion rates after ranitidine intake equaled or exceeded those observed previously in patients with schistosomiasis, a disease wherein N-nitrosamines are implicated as the etiological agents for bladder cancer. Due to metabolism within the body, urinary NDMA measurements represent a lower-bound estimate of systemic NDMA exposure. Our results suggest a need to evaluate the risks attributable to NDMA associated with chronic consumption of ranitidine, and to identify alternative treatments that minimize exposure to N-nitrosamines.

NOTE - Neither research refers to what brand of ranitidine was used and if the NDMA was formed in the stomach after ingestion of the ranitidine or if the NDMA was already present in the ranitidine before ingesting it.

https://www.ncbi.nlm...pubmed/29492817
Reduction of N-nitrosodimethylamine formation from ranitidine by ozonation preceding chloramination: influencing factors and mechanisms.
2018 Feb 28.
Abstract
Formation of toxic N-nitrosodimethylamine (NDMA) by chloramination of ranitidine, a drug to block histamine, was still an ongoing issue and posed a risk to human health. In this study, the effect of ozonation prior to chloramination on NDMA formation and the transformation pathway were determined. Influencing factors, including ozone dosages, pH, hydroxyl radical scavenger, bromide, and NOM, were studied. The results demonstrated that small ozone dosage (0.5 mg/L) could effectively control NDMA formation from subsequent chloramination (from 40 to 0.8%). The NDMA molar conversion was not only influenced by pH but also by ozone dosages at various pre-ozonation pH (reached the highest value of 5% at pH 8 with 0.5 mg/L O3 but decreased with the increasing pH with 1 mg/L O3). The NDMA molar yield by chloramination of ranitidine without pre-ozonation was reduced by the presence of bromide ion due to the decomposition of disinfectant. However, due to the formation of brominated intermediate substances (i.e., dimethylamine (DMA), dimethyl-aminomethyl furfuryl alcohol (DFUR)) with higher NDMA molar yield than their parent substances, more NDMA was formed than that without bromide ion upon ozonation. Natural organic matter (NOM) and hydroxyl radical scavenger (tert-butyl alcohol, tBA) enhanced NDMA generation because of the competition of ozone and more ranitidine left. The NDMA reduction mechanism by pre-ozonation during chloramination of ranitidine may be due to the production of oxidation products with less NDMA yield (such as DMA) than parent compound. Based on the result of Q-TOF and GC-MS/MS analysis, three possible transformation pathways were proposed. Different influences of oxidation conditions and water quality parameters suggest that strategies to reduce NDMA formation should vary with drinking water sources and choose optimal ozone dosage.

https://www.ncbi.nlm...pubmed/29597157
Nitrite ion mitigates the formation of N-nitrosodimethylamine (NDMA) during chloramination of ranitidine.
2018 Mar 28.
Abstract
Ranitidine (RNT) has been an important tertiary amine precursor of N-nitrosodimethylamine (NDMA) in chlorine-based water treatment, due to reaction with monochloramine (NH2Cl) with exceptionally high molar yields up to 90%. This study examined the effects of nitrite ions (NO2-) on the kinetics of NDMA formation during the chloramination of RNT under variable concentrations of dissolved oxygen (DO, 0.7-7.5mg/L), RNT (5-30μM), NH2Cl (5-20mM), NO2- or NO3- (0-2mM) and pH (5.6-8.6). In the absence of the NO2-, the ultimate molar yield of NDMA after 6h of reaction was primarily influenced by [DO] and pH, while marginally affected by initial [RNT] and [NH2Cl]. A kinetic model, prepared in accordance with the reaction sequence of NDMA formation, suggested that the rate determining step was accelerated with increasing [NH2Cl]0, [DO], and pH. A Kinetic study together with ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometer (UPLC-Q-TOF MS) and gas chromatography (GC)/TOF MS analyses in parallel demonstrated that the nitrite ion inhibited the nucleophilic substitution of the terminal amine on NH2Cl, and reduced the pseudo-steady state concentration of N-peroxyl radicals, significantly decreasing the ultimate yields of NDMA.

https://www.ncbi.nlm...pubmed/24968236
Formation mechanism of NDMA from ranitidine, trimethylamine, and other tertiary amines during chloramination: a computational study.
2014 Jul 9.
Abstract
Chloramination of drinking waters has been associated with N-nitrosodimethylamine (NDMA) formation as a disinfection byproduct. NDMA is classified as a probable carcinogen and thus its formation during chloramination has recently become the focus of considerable research interest. In this study, the formation mechanisms of NDMA from ranitidine and trimethylamine (TMA), as models of tertiary amines, during chloramination were investigated by using density functional theory (DFT). A new four-step formation pathway of NDMA was proposed involving nucleophilic substitution by chloramine, oxidation, and dehydration followed by nitrosation. The results suggested that nitrosation reaction is the rate-limiting step and determines the NDMA yield for tertiary amines. When 45 other tertiary amines were examined, the proposed mechanism was found to be more applicable to aromatic tertiary amines, and there may be still some additional factors or pathways that need to be considered for aliphatic tertiary amines. The heterolytic ONN(Me)2-R(+) bond dissociation energy to release NDMA and carbocation R(+) was found to be a criterion for evaluating the reactivity of aromatic tertiary amines. A structure-activity study indicates that tertiary amines with benzyl, aromatic heterocyclic ring, and diene-substituted methenyl adjacent to the DMA moiety are potentially significant NDMA precursors. The findings of this study are helpful for understanding NDMA formation mechanism and predicting NDMA yield of a precursor.

https://www.ncbi.nlm...pubmed/23182669
Formation of NDMA from ranitidine and sumatriptan: the role of pH.
2012 Nov 14.
Abstract
N-nitrosodimethylamine (NDMA) is an emerging disinfection by-product (DBP) which can be formed via the chloramination of amine-based precursors. The formation of NDMA is mainly determined by the speciation of chloramines and the precursor amine groups, both of which are highly dependent on pH. The impact of pH on NDMA formation has been studied for the model precursor dimethylamine (DMA) and natural organic matter (NOM), but little is known for amine-based pharmaceuticals which have been newly identified as a group of potential NDMA precursors, especially in waters impacted by treated wastewater effluents. This study investigates the role of pH in the formation of NDMA from two amine-based pharmaceuticals, ranitidine and sumatriptan, under drinking water relevant conditions. The results indicate that pH affects both the ultimate NDMA formation as well as the reaction kinetics. The maximum NDMA formation typically occurs in the pH range of 7-8. At lower pH, the reaction is limited due to the lack of non-protonated amines. At higher pH, although the initial reaction is enhanced by the increasing amount of non-protonated amines, the ultimate NDMA formation is limited because of the lack of dichloramine.

https://www.ncbi.nlm...pubmed/22967139
NDMA formation by chloramination of ranitidine: kinetics and mechanism.
2012 Sep 26.
Abstract
The kinetics of decomposition of the pharmaceutical ranitidine (a major precursor of NDMA) during chloramination was investigated and some decomposition byproducts were identified by using high performance liquid chromatography coupled with mass spectrometry (HPLC-MS). The reaction between monochloramine and ranitidine followed second order kinetics and was acid-catalyzed. Decomposition of ranitidine formed different byproducts depending on the applied monochloramine concentration. Most identified products were chlorinated and hydroxylated analogues of ranitidine. In excess of monochloramine, nucleophilic substitution between ranitidine and monochloramine led to byproducts that are critical intermediates involved in the formation of NDMA, for example, a carbocation formed from the decomposition of the methylfuran moiety of ranitidine. A complete mechanism is proposed to explain the high formation yield of NDMA from chloramination of ranitidine. These results are of great importance to understand the formation of NDMA by chloramination of tertiary amines.




 

[fishinghat]

N-Nitrosodimethylamine

It is toxic to the liver and other organs and is a probable human carcinogen. It is also used to create cancer in rats for cancer research. Wiki

Its occurrence has been documented in many drinking water sources.

When administered to rats, mice and rabbits, it is ... metabolized rapidly, with a half-life of approximately 4 hr.
Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982., p. 2787

Toxicity
N-Nitrosodimethylamine is highly toxic, especially to the liver, and is a known carcinogen in lab animals. The EPA classifies NDMA as a probable human carcinogen. The US Environmental Protection Agency has determined that the maximal admissible concentration of NDMA in drinking water is 7 ng/L.[6] The EPA has not yet set a regulatory maximal contaminant level (MCL) for drinking water. At high doses, it is a "potent hepatotoxin that can cause fibrosis of the liver" in rats.[7] The induction of liver tumors in rats after chronic exposure to low doses is well documented.[8] Its toxic effects on humans are inferred from animal experiments but not well-established experimentally.

 

NDMA's contamination of drinking water is of particular concern due to the minute concentrations at which it is harmful, the difficulty in detecting it at these concentrations, and to the difficulty in removing it from drinking water. It does not readily biodegrade, adsorb, or volatilize. As such, it cannot be removed by activated carbon and travels easily through soils. Relatively high levels of UV radiation in the 200 to 260 nm range breaks the N–N bond and can thus be used to degrade NDMA. Additionally, reverse osmosis is able to remove approximately 50% of NDMA.[9]

 

It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act (42 U.S.C. 11002) and is subject to strict reporting requirements by facilities that produce, store, or use it in significant quantities.[10] Wiki

https://www.scienced...sodimethylamine
Details on cancer causing effects of NMDA.

[fishinghat]

N-Nitrosodimethylamine has been found in not only ranitidine but also in Valsartan. The FDA has recalled all Valsartan.

 

https://www.fda.gov/...idine-medicines
Current FDA policy on Zantac.

https://www.fda.gov/...ples-ranitidine
Detailed information from the FDA.

"Although NDMA may cause harm in large amounts, the levels the FDA is finding in ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods."
Note - Very cancer causing and found in many many foods, drinking water and some meds.

[fishinghat]

Lyla, I would like to express my sincere appreciation for bring this to our attention It is very important. Thank you so much.

 

I guess I won't be recommending Zantac anymore.

[ForLyla]

Apparently researchers at Stanford discovered this in 2016. What's your experience been with it IUN? Have you taken it frequently?

[fishinghat]

I don't know about IUN but I certainly have. All of my psychiatrists have urge its use as a ppi if you are on an antidepressant because it is the safest. Oh well. Live and learn.

[ForLyla]

Have you taken it consecutively over the course of several days? Did you have any side effects? I'm really not feeling good this week

[invalidusername]

Yes - this is really good info to bring to the attention of the forum. 

 

Yes, I did take Zantac over the course of a few days Lyla, but this was when I had what turned out to be a hiatus hernia - nothing to do with AD's - although anything is possible I guess! Aside from being very slightly drowsy, I do not recall any other issues with it. I think I took the course of tablets for 7 days IIRC at which time the hospital had made the diagnosis and gave me another PPI med. 

 

Fortunately, the acid issue cleared itself up so I didn't take the PPI's as I was already suffering the aftermath of several SSRI's...

[ForLyla]

I also have a hiatal hernia. So I should be ok then after only taking it for a week? I think some people take this every day on a regular basis, dont they?

From my understanding, ndma is formed in the stomach from the ranitidine itself. So this class of drug is one of the most common around and they've been giving us this poison since 1981?!? This will emerge to be quite the scandal I think and may eliminate ranitidine from being sold commercially altogether.

[fishinghat]

I was taking it 30 days on and 30 days off during my stomach issues during withdrawal. I did that several times as well as to help some other unrelated stomach issues I had developed years ago.

[ForLyla]

FH how long ago? Btw what kind of diet did you guys follow? Apparently I'm still super sensitive to sugar - even to fruit. Too many carbs bug me a lot.

[fishinghat]

I have been on and off Zantac from about 2004 until yesterday.  lol 

 

I suffer from certain metabolic conditions that restrict my diet so I was not able to change my diet for my withdrawal. There is a section or two on what foods to eat to raise your gaba, serotonin and other neurotransmitters in the ebook.

[invalidusername]

This ebook is really working out - I am so happy!!

 

I was quite stubborn and didn't change much in the way of diet, but then again, I am already a vegetarian, I do not smoke or drink alcohol... and as a rule, I cut out refined sugars.

[ForLyla]

Sorry what is the ebook called? I'm having a rough day today. I had a small coffee last night because I had a long drive and needed something to keep me awake... wondering if that can be the culprit or maybe just the drive itself. Feeling really out of it.

[invalidusername]

eBook can be downloaded from the following post Lyla;

 

https://www.cymbalta...tion-the-ebook/

[fishinghat]

Probably from both.

[invalidusername]

Sorry Lyla - didn't see that part. Yes - as Hat said. Coffee more so if you are not used to having caffeine in your system. I have been caffeine-free for over 2 years with exception of one cup of regular tea (which was meant to be decaf), and that played havoc with me for the following 24 hours.

[ForLyla]

I always knew caffeine was a no no but at this point I didn't think I'd be that sensitive to it. I had a tiny cup! Guess I'm not as healed as I thought because I'm miserable today.

[invalidusername]

When you are that sensitive, it doesn't take much.

 

I remember a while back when I had a sore throat and my friend made me a drink of what I thought was honey and lemon. It did have honey, but the rest was a lemsip, or what my friend said was "only a small amount of paracetamol".

 

But alas, I am hugely allergic, so there we were legging it to the hospital before my already swollen glands met with my progressively swelling throat courtesy of my anaphylaxis!! 

 

No such thing as a "small" amount in these circumstances!!

[ForLyla]

Oh geez. That's rough! I'm so sensitive to stuff still but I have no discipline. I know a few bites of chocolate cake will make me feel bad but I have it anyway. I need to try harder.

[invalidusername]

You can't beat a good bit of choccy cake!! Life's too short not to!

[ForLyla]

My stomach has been aching a lot the last few days and my acid is back. I started taking famotidine because I need something. Does anyone know if there's interactions with that one?

[Polly38]

Hi ForLyla

I'm new here and weaning off Duloxetine. I'm down to 28 beads now and my stomach is in a mess, so I just wanted to let you know you are not alone. This journey is so tough! Where are you on your weaning journey?

Polly

[fishinghat]

Famotidine (Pepcid) is a histamine H2 receptor antagonist has no effect on the cytochrome P450 enzyme system, and does not appear to interact with other drugs.[23]

Wiki reference...
Humphries TJ, Merritt GJ (August 1999). "Review article: drug interactions with agents used to treat acid-related diseases". Aliment. Pharmacol. Ther. 13 (Suppl 3): 18–26
 

[invalidusername]

There's your answer Lyla! I am sorry to hear that it has come back. Sometimes there just seems to be no rhyme or reason to these things. Sincerely hope things improve.

[ForLyla]

Ya I've been in a bad way the last week or two. It's so discouraging because I had about 2 or 3 weeks there where I felt pretty great overall. Is it common to get stomach pain with this stuff? I went in for a gastroscopy and colonoscopy 2 years ago and everything was normal except I had mild gastritis. I'm assuming my gastritis is back although I have no idea why. It was always brought on by stress before and I felt fine before this came on. The only thing is that I haven't been sleeping well because of the baby. 

[fishinghat]

Serotonin is the most common in the intestinal tract. During Cymbalta withdrawal these receptors in the GI tract are basically uncontrolled leading to many GI aliments. Antidepressant withdrawal almost always causes gastritis and/or irritable bowel.