POIS treatment: theory & supplement stack

[nanna1]

Thanks POISrival for sharing your experience with antivirals on the thread "Acyclovir. A probable treatment that suggests POIS is a viral infection". I'll be following your updates and the experiences of others who are testing antivirals.

[aswinpras06]

Thanks Nanna1 for your replies and excellent scientific explanation. 

I am not a science student and a finance guy from my school finishing years and in my post graduation.  I did not take medicine though I had a chance to join (because of my good grades), due to the effects of pois from my teen years,which I am very much repenting now.  Any way internet now helps to a great extent.

Most of your valuable explanations are helping me to understand a few points, based on which I am posting.  Keep up your good work!

[Muon]

My Bell's Palsy (and/or POIS) could be caused by things other than viral infections. For example M. Pneumoniae is able to infect the CNS and causes neurological manifestions (chronic or acute) without airway related symtoms which is not often discussed in medical literature: http://www.pedneur.com/article/S0887-8994(09)00210-0/abstract
 
Frequent detection of Mycoplasma pneumoniae in Bell's palsy (26% M.Pneumoniae vs 16% VZV reactivation):
https://www.ncbi.nlm.nih.gov/pubmed/14576947
''According to our results, M. pneumoniae is frequently associated with Bell's palsy. Thus, a routine screening for this pathogen, even in the absence of respiratory symptoms, is necessary.''

Cytokine production in M. Pneumoniae infections:
Th1 cytokines, IFN-g, IL-12, IL-18:
http://journal.chestnet.org/article/S0012-3692(15)34861-3/abstract
IL-8:
http://www.pedneur.com/article/S0887-8994(05)00165-7/abstract

Btw IL-12, 15 and 18 are all IFN-g inducing parameters. I expect at least one of these being elevated aside from the discussion whatever the cause may be.

Increased IFN-g/Th1 dominance and decreased CD57+ NK cells could indicate the body is battling an infection. An orgasm decreases IFN-g which gives the pathogen (whatever it may be) time to replicate/reactivate and create symptoms like joint pain which is typical for M. pneumoniae but again rarely discussed in literature (so much focus on Pneumoniae). Also symptoms may endure for days or weeks just like POIS. I've seen a case report where a patient who had a chronic infection of this species and also had elevated EA-p138 but I can't seem to find it anymore.

And is someone familiar with Viral DNA testing by PCR?

http://www.imd-berlin.de/leistungsverzeichnis/parameter.html?tx_ajdiagnostics_analyse%5Banalyse%5D=31241&tx_ajdiagnostics_analyse%5Btitle%5D=Cytomegalievirus-DNA&tx_ajdiagnostics_analyse%5Bsynonym%5D=CMV&tx_ajdiagnostics_analyse%5Baction%5D=showmod&tx_ajdiagnostics_analyse%5Bcontroller%5D=Analyse&cHash=aa00dfe0034eafdf06412c4b765f0aeb

http://www.imd-berlin.de/leistungsverzeichnis/parameter.html?tx_ajdiagnostics_analyse%5Banalyse%5D=30786&tx_ajdiagnostics_analyse%5Btitle%5D=Varizella%20Zoster%20Virus%20%28VZV%29&tx_ajdiagnostics_analyse%5Bsynonym%5D=&tx_ajdiagnostics_analyse%5Baction%5D=showmod&tx_ajdiagnostics_analyse%5Bcontroller%5D=Analyse&cHash=5730c181adfd1a848072ea4f9a4e6d17

Is it reliable? And does a positive result mean anything?

I just stumbled accidentally upon an interesting article relating PE, IFN-g and serotonin.
''From these results it can be concluded that PE occurs because decreased levels of serotonin. Decreased levels of serotonin are associated with increased levels of IFN-y.'' https://ijbs-udayana.org/index.php/ijbs/article/view/104

''it is estimated that 90 percent of the body's serotonin is made in the digestive tract'':
http://www.caltech.edu/news/microbes-help-produce-serotonin-gut-46495

[Nas]

Hello,
I'm following this thread with great attention. I have been using acyclovir (antiviral) and posted about it in another thread.Then i read a comment there that the whole virus thing is being discussed here.
 This is so promising for me and makes me think that my improvement on acyclovir is not a fake psychological placebo effect. may be time has arrived to pay the viral infection thing a big share of concern. I had chicken pox and mumps when i was a kid and they were so bad.

Hi POISrival,
How do you take acyclovir? is it one 200mg a day or more ?

[Muon]

Acording to Muons case and his labs- https://www.dropbox.com/sh/nc2dt6pcwd5xpmu/AACyyDE6uhY1DHn1fAuxw86Ja?dl=0&preview=Muon+3-6+Th1Th2+part2-4%2BIL4gen+14-08-2015.pdf

I find this- about th1 dominence- https://www.selfhacked.com/blog/supplements-foods-exercise-right-type-th1-vs-th2-dominance/

This realy make sense , if things this guy saying are true.

He sad that he is geneticly predisosed to all this conditions, and he cured him self by lectin avoidence.

He claim to be solved all his problems (genetics colerated) by his diet and suplemetation acording wich dominance th1 th2 lso th17 involwed...

He mention brain fog , autoimune conditions, inflamation ,infections, ebv virus , hpv, fatigue, ibs, low t3, hi cortisol (because HPA acsic must copesate vith hi cortisol), low pregnelone, and most of our symptoms an this linked to diet (LECTIN fod avoidence),damaged gut flora microbiota ,lectins couse also leaky gut=autoimune conditions etc...

My modher have reumatoid artrytis, and now autoimune hashimoto(" i am geneticly same like her") people here claim that they are lowered antibodies with diet avoidence food etc..

''Intestinal mycoplasma infection causes destruction of villi and compromise of the intestinal barrier. This allows accelerated damage by lectins in grains (especially wheat), beans, soy, nightshade vegetables, and dairy)''
https://rawlsmd.com/health-articles/mycoplasma-the-most-common-lyme-coinfection

[Hopeoneday]

Yess Muon I like this( resarch and conections to the root couse).
This is wery wery intresting. All this make hudge sense.
I will write post on this tumorow(all conections of me and this).

[aswinpras06]

Lyme disease can also cause many of the symptoms of Pois like brain fog,insomnia,slurring of speech
as per this article.  Infection as a cause for pois is now gaining ground, but the exact infection is not clear.

Boosting the immune system with good diet(lectin avoidance diet works for a few of us),supplements and good sleep will work for most of us, which further confirms infection by some virus or bacteria(dormant ones getting activated) is what most likely causing all our miseries.



http://drjaydavidson.com/lyme-disease-affect-brain/

[POISrival]

Hi Nas

I take acyclovir 400 mg twice per day for now.

[Hopeoneday]

Acording to this our imune sistem is always stayed active and newer become normal in balance like in normal people-

https://www.selfhacked.com/blog/supplements-foods-exercise-right-type-th1-vs-th2-dominance/


Inflammation after the following: Strep, mono (EBV), HPV, herpes, pneumonia, H. pylori or Cytomegalovirus. These are common infections that also invoke the Th1 system; in some people with a genetic predisposition like myself, the immune system remains active after these infections. In some environments, this may have been a survival advantage since you?d be more likely to survive into adulthood and bear offspring [R, R, R, R, R, R].

And becuse of that we maybe hawe trigered symptomes with eyaculation.


And this.

I hawe tick bayted in testicle at age 12, after that sewere pneumonia on both wings(hudge amount of antibiotics, after that severe acne(again some antibiotics for acne), in that period always sick because low imunity.
I think that i get pois in that periodand because genetics predisposition, guts destroyed because of all this antibiotics infections and bad diet at that period, autoimune stayed alert because all of that.

https://rawlsmd.com/health-articles/mycoplasma-the-most-common-lyme-coinfection


This is olso wery intresting(worning some troyan virus on site haw a aantivirus on comp).
https://fixyourgut.com/quinolone-antibiotics-and-their-effects-on-the-mitochondria-and-health/
 


lets resarch , i think that we are alone with this ilnes.

[Nas]

Hey Nanna,

So I reflected on Quantum's opinion about your theory and he makes a solid point about the problem with this theory. http://poiscenter.com/forums/index.php?topic=2659.msg23413#msg23413

One of the problem I noticed is here :

The immune cells attack the virus-infected cells with inflammation through neurotransmitters (histamine), cytokines (IL-8), and free radicals (hydrogen peroxide, nitric oxide).

Many people suffer from a dormant virus yet they do not suffer from POIS like symptoms. And the immune system is supposed to keep the virus from activating yet in our case it activates.
You also mention that there are stress trigger elements in the activation yet many people have these elements in their day to day lives, yet no one complains from POIS like symptoms.

[nanna1]

Hi Nas and Quantum,

I have been thinking about the rarity issue with POIS, since the different herpes virus types are more common. I have an idea, but first I need to share some background.

  I believe this below figure from "Virus Infections in the Nervous System" explains the immune response and may answer questions about T cells and possible immune dysfunction arising from a herpes infection.

A more detailed explaination can be found here in the first 3 paragraphs of the section titled "State of the Art".

  Here is an update on the virus model. Herpes infection chronically elevates COX-2 in the infected cells (even while "dormant"). Arousal/stimulation/intercourse causes the release of neurotransmitters glutamate and norepinephrine.

  This model incorporates the immune response mechanism described here. In this case, chemotaxis means T cell movement to the site of infection, and chemokines (i.e. IL-8) are types of cytokines that tell the T cells where to go.

A conjecture about the rarity of POIS:
  Michael VanElzakker, the guy who proposed the vagus nerve infection hypothesis, believes that the causes of neurologic diseases are location specific. Meaning that the location of the infection will be the most important factor in creating symptoms of the disease. This seems to make sense. Alzheimers is largely a disease of the hippocampus and many different toxins, viruses, etc... in the hippocampus are independently associated with Alzheimers. Parkinson disease can be induced by various toxins and infections of the substantia nigra section of the brain. Muon recently pointed to the fact that Bell's palsy is independently associated with HSV-1, VZV and Mycoplasma pneumoniae infections. The main idea is that as the location of the infection changes, the type of disease changes.

  I think there could be a POIS area of the CNS that when infected causes POIS. If a person's herpes infection does not cover the "POIS area", they would not experience POIS even if they experience other illnesses. Moreover, if a person has a herpes infection that covers the POIS area and many other parts of the nervous system, they may have POIS and many other transient and chronic diseases associated with the total infection coverage of the virus. If this is true, then this "POIS area" should be located in a part of the CNS that is only active during orgasm and have a high density of glutamate receptors. This is not a theory or hypothesis for the rarity of POIS among herpes infected individuals since I don't have studies or data (brain autopsies) to back it up. So this is technically a guess based on the fact that other neurological diseases are location specific. Below is a philosophical diagram of this POIS area - herpes infection idea. 

With that said, I think an infection cause of POIS should have at least these two properties:
  1. able to be lay dormant (latent and not living).
  2. able to be triggered by erection/orgasm neurotransmitters (glutamate, norepinephrine and histamine).
All of the herpes viruses have these properties and are triggered through the arachidonic acid cascade (AA/COX-2/PGE₂/JNK).

 As far as solutions go, a methylation stack, vitamin D3 and a strong COX-2 inhibitor (taken with a prepack) may be the easiest and cheapest option for most people. Not all NSAID fit the medical definition of a COX-2 inhibitor. Over-the-counter NSAIDs like iboprofen and paracetamol do not function as COX-2 inhibitors and will not be effective. Indomethacin is effective as a prepack supplement. Celecoxib is the most often prescribed (non-OTC) COX-2 inhibitor and may be the best choice (taken with a prepack). I have not tried Celecoxib.
  I follow a low arachidonic acid (vegan) diet, so I don't need to take these meds to reduce PGE₂. But I do need to take B vitamins, methyl donors and omega-3s. As long as I keep the diet and stack, I have no POIS symptoms. I keep a mostly vegan diet also for general health reasons unrelated to POIS.

I know I rushed through that, but I am no longer on vacation and I need to finish some of my work before I go out of town. But I hope to give a more detailed post soon.

[Quantum]

Thanks Nanna, for taking the time to share your ideas on POIS pathophysiology, even if you have much work to do for your personal career.

Methylation support, vitamin D3, Cox-2, and other anti-inflammatory substances, including natural anti-oxidants, low-inflammation-induding diet, non-pharmacological stress-managing methods, all have been shown to help at least some members .  Even if we do not know yet if a chronic viral infection is implicated or not in POIS pathophysiology, it seems clear that blocking inflammation pathways in one or more of its paths, is beneficial.

Making hypothesis, and refining them, like you do, and adjusitng your hypothesis according to new data and questions, can only help in solving the POIS puzzle.  You have a great scientific mind, and your positive involvement here is very good for all of the POIS community

[Hopeoneday]

Natural compounds and inflammatory pathway modulation
Inflammation triggers   
 Stress   Infection
 Radiation   Allergic immune response
 Trauma/injury   Arachidonic acid
Inflammatory diet   
 Inflammatory pathways   
 NF-Kβ   Leukotrienes
 IL-1,6   NO
 CRP   Lipoxygenase
 COX-1 and -2   TNF-α
 Prostaglandins   Adhesion molecules
 Thromboxanes   Reactive oxygen species (ROS)
 Collagenase/MVP   Cytokines
Conditions modulated   
 Pain   Atherosclerosis
 Inflammation   Thrombosis
 Insulin resistance   Autoimmune response
 Cancer   Neurodegeneration

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011108/

A major component of the inflammatory pathway is called the arachidonic acid pathway because arachidonic acid is immediately released from traumatized cellular membranes. Membrane-based arachidonic acid is transformed into prostaglandins and thromboxanes partly through the enzymatic action of cyclooxygenase (COX)[34,57]. There are two types of COX enzymes, COX-1 and COX-2. Both the enzymes act similarly, but selective inhibition (as accomplished by selective COX-2 inhibiting NSAIDs) can make a difference in terms of side effects.

Injury and celular trauma-AA acid relase.
Acordin to this science, AA is relesed only if there  celular trauma(injury).

Whot can else be involved here besades virus and posible odher infections?
Acute cronic stres(our glands in brain prmanent stucked in flight-fight mode?)
I think think is big posibility of delayed food senzibility like lectins for exepmle in some poisers(and this triger autoimunity, pois, anxiety, stres,brain fog, hi cortisol?)
People with a Th1 system out of control tend to release more cortisol than the average person because cortisol decreases Th1-related inflammation, so the body activates your HPA system every time you get a Th1 spike to keep things in balance.

[demografx]

Hi Nas and Quantum,

I have been thinking about the rarity issue with POIS, since the different herpes virus types are more common. I have an idea, but first I need to share some background.

  I believe this below figure from "Virus Infections in the Nervous System" explains the immune response and may answer questions about T cells and possible immune dysfunction arising from a herpes infection.

A more detailed explaination can be found here in the first 3 paragraphs of the section titled "State of the Art".

  Here is an update on the virus model. Herpes infection chronically elevates COX-2 in the infected cells (even while "dormant"). Arousal/stimulation/intercourse causes the release of neurotransmitters glutamate and norepinephrine.

  This model incorporates the immune response mechanism described here. In this case, chemotaxis means T cell movement to the site of infection, and chemokines (i.e. IL-8) are types of cytokines that tell the T cells where to go.

A conjecture about the rarity of POIS:
  Michael VanElzakker, the guy who proposed the vagus nerve infection hypothesis, believes that the causes of neurologic diseases are location specific. Meaning that the location of the infection will be the most important factor in creating symptoms of the disease. This seems to make sense. Alzheimers is largely a disease of the hippocampus and many different toxins, viruses, etc... in the hippocampus are independently associated with Alzheimers. Parkinson disease can be induced by various toxins and infections of the substantia nigra section of the brain. Muon recently pointed to the fact that Bell's palsy is independently associated with HSV-1, VZV and Mycoplasma pneumoniae infections. The main idea is that as the location of the infection changes, the type of disease changes.

  I think there could be a POIS area of the CNS that when infected causes POIS. If a person's herpes infection does not cover the "POIS area", they would not experience POIS even if they experience other illnesses. Moreover, if a person has a herpes infection that covers the POIS area and many other parts of the nervous system, they may have POIS and many other transient and chronic diseases associated with the total infection coverage of the virus. If this is true, then this "POIS area" should be located in a part of the CNS that is only active during orgasm and have a high density of glutamate receptors. This is not a theory or hypothesis for the rarity of POIS among herpes infected individuals since I don't have studies or data (brain autopsies) to back it up. So this is technically a guess based on the fact that other neurological diseases are location specific. Below is a philosophical diagram of this POIS area - herpes infection idea. 

With that said, I think an infection cause of POIS should have at least these two properties:
  1. able to be lay dormant (latent and not living).
  2. able to be triggered by erection/orgasm neurotransmitters (glutamate, norepinephrine and histamine).
All of the herpes viruses have these properties and are triggered through the arachidonic acid cascade (AA/COX-2/PGE₂/JNK).

 As far as solutions go, a methylation stack, vitamin D3 and a strong COX-2 inhibitor (taken with a prepack) may be the easiest and cheapest option for most people. Not all NSAID fit the medical definition of a COX-2 inhibitor. Over-the-counter NSAIDs like iboprofen and paracetamol do not function as COX-2 inhibitors and will not be effective. Indomethacin is effective as a prepack supplement. Celecoxib is the most often prescribed (non-OTC) COX-2 inhibitor and may be the best choice (taken with a prepack). I have not tried Celecoxib.
  I follow a low arachidonic acid (vegan) diet, so I don't need to take these meds to reduce PGE₂. But I do need to take B vitamins, methyl donors and omega-3s. As long as I keep the diet and stack, I have no POIS symptoms. I keep a mostly vegan diet also for general health reasons unrelated to POIS.

I know I rushed through that, but I am no longer on vacation and I need to finish some of my work before I go out of town. But I hope to give a more detailed post soon.

Thanks for the amazing graphics.
Demo

[Spartak]

Great job!

[Spartak]

I have question, if virus is the cause what might be some natural and safe methods to fight agianst it, or againat viruses in general?

[nanna1]

Hi Spartak,

  I think a virus-targeted stack should have vitamins D3, B6, B9, B12, C. There are ready-made stacks for this (Emergen-C and Airborne). I also think methyl-donors and methyl-cyclers are important (alphaGPC, TMG, SAMe, etc...). Methyl-groups on the virus DNA keep it dormant.

  The next step I would take in building an anti-virus stack is to find a way of dealing with the omega-6 arachidonic acid (AA). My strategy is to remove all arachidonic acid from my diet by doing a vegan diet. Vegan does not necessarily mean healthy. It just means there is no animal fat. In addition to the vegan diet (no AA), I also supplement omega-3 DHA and EPA. From reading post from others on the forum, I realized that the (vegan diet + omega-3) aspect of stack was prohibitive for most people for various reasons (cost, food preparation, lack of vegan protein sources, etc...). So I started this thread (Cost effective alternatives for omega-3) to look for an alternative way of cancelling out AA. The short answer is, there is no easy answer. There are many natural COX-2 and LOX-5 inhibitors, but they seem to have poor bioavailability.

"A famciclovir + celecoxib combination treatment is safe and efficacious in the treatment of fibromyalgia (Feb. 22 2017)":
  I want to point people to this study where they treat fibromyalgia in humans with an anti-viral (famciclovir) and a selective COX-2 inhibitor (celecoxib). In this study, they test the hypothesis that a dormant herpes virus is activated by stress and produces an immune response leading to disease (fibromyalgia). This could be viewed as the virus model for fibromyalgia.
Notice the date on the publication. This is new science!

"Migraine Headache Treated with Famciclovir and Celecoxib: A Case Report (Nov. 29 2017)":
  This study (in a human) test the idea of virus-induced migraine headaches. They treat migraines with the same medication combo anti-viral (famciclovir) and selective COX-2 inhibitor (celecoxib). The migraines were correlated with a specific location of the brain (please see Figure 1 brain MRI and caption). It took 5 days of treatment before the patient saw a general relief of symptoms.

Why do they need both famciclovir and celecoxib? I'm not sure right now. If anyone can explain the synergy between famciclovir and celecoxib, please do.

From the Discussion section of "A famciclovir + celecoxib combination treatment is safe and efficacious in the treatment of fibromyalgia":
  "...The clinical evidence supporting the drug combination (Famciclovir and Celecoxib) utilized in this study was first derived through care of the lead author's patients with irritable bowel syndrome (IBS). A number of chronic GI disorders, including IBS and reflux, are frequently comorbid with fibromyalgia (FM). IBS patients were initially treated with famciclovir, yet those also placed on celecoxib for arthritis were the patients who demonstrated a dramatic improvement. A number of these patients expressed gratitude that their fibromyalgia symptoms were also reduced with this combination therapy. This clinical experience led to the hypothesis that recurrent reactivation of a tissue-resident herpesvirus in genetically susceptible individuals could contribute to the symptoms of fibromyalgia..."

In that last line, the term "tissue-resident" means that the type of disease (fibromyalgia) is dependent on the location (a specific tissue) of the herpes infection.

  In an FDA Phase IIa Randomized, Double-Blind, Placebo-Controlled Study, Famciclovir + Celecoxib was both effective and safer than placebo:

"The safety profile was especially encouraging.  Despite the celecoxib component, gastrointestinal and nervous system treatment emergent adverse events were reported significantly more often in the placebo treatment group (GI:  29.0% vs 42.5%; nervous system:  17.4% vs 23.3%; active to placebo), and study completion rates favored active treatment over placebo (82.6% vs. 60.8%) (largely driven by higher placebo discontinuation rates due to adverse events and lack of efficacy). A Combination of Celecoxib and Famciclovir Is Efficacious in the Treatment of Fibromyalgia: Results of a Phase IIa Randomized, Double-Blind, Placebo-Controlled Study"

  For now, it seems that (COX-2 inhibitor) celecoxib is a real therapeutic for herpes-dependent diseases. I know celecoxib is not natural, but in terms of relief, I haven't seen a better supplemental alternative yet for dealing with AA. I haven't tried celecoxib, so I have no personal knowledge about how to take it other than some general advice about COX-2 inhibitors. Not all COX inhibitors have equal potency and effects. Anyone considering celecoxib should discuss this option with a physician or your primary care doctor about any health complications, drug interactions and dosing instructions.

On the thread "[UPDATED] Antivirals.", some POIScenter members are experimenting with an antiviral-only solution using Acyclovir (Zovirax).

Thanks Spartak for your comments and questions! If you or anyone else can find a better way of dealing with arachidonic acid, please post your idea!

[Spartak]

Thank you nanna1, very useful.

[romies]

  I believe this below figure from "Virus Infections in the Nervous System" explains the immune response and may answer questions about T cells and possible immune dysfunction arising from a herpes infection.
 As far as solutions go, a methylation stack, vitamin D3 and a strong COX-2 inhibitor (taken with a prepack) may be the easiest and cheapest option for most people. Not all NSAID fit the medical definition of a COX-2 inhibitor.

First, thanks for introducing that very good Cell review paper.

Secondly, I can vouch for the effectiveness of Celebrex (COX-2 inhibit) as one of my three pillars in the prepack that I take to cope with POIS (the other two being Quercetin and Cucumin+BioPeperin).

Celebrex is the only COX-2 that is still FDA-approved for human use in the US at this point.
Celebrex has a long half-life: 7.8 hrs
Celebrex penetrates brain-blood barrier very well.
Celebrex has the one of the lowest cardiovascular side-effect among common NSAIDs
   risks:
Naproxen < Celecoxib < Piroxicam < Ibuprofen < Meloxicam < Indomethacin < Diclofenac < Rofecoxib (at doses more than 25 mg)
     http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001388
     http://www.emedexpert.com/compare/nsaids.shtml

The effectiveness of Celebrex has been discussed many times before, including http://poiscenter.com/forums/index.php?topic=211.msg4801#msg4801. My personal experience is that Celebrex is best used as part of the prepack.  (no need for the morning after dose). Celebrex is also somewhat effective as an anti-dote to wet-dream for me, provided that I take it immediately after the ejaculation.

[romies]

Over-the-counter NSAIDs like iboprofen and paracetamol do not function as COX-2 inhibitors and will not be effective[/url]. Indomethacin is effective as a prepack supplement. Celecoxib is the most often prescribed (non-OTC) COX-2 inhibitor and may be the best choice (taken with a prepack). I have not tried Celecoxib.

My take on why ibuprofen is not effective:

Ibuprofen and Indomethacin do inhibit COX-2, but ibuprofen has really poor BBB permeability. Ibuprofen is not effective, if we assume COX-2 inhibition must occur inside CNS (I lean towards this hypothesis). And Ibuprofen's half life is too short, which suggests COX-2 might be suppressed for over 4-5 hrs post orgasm for a prepack to be completely effective.

Paracetamol:
it is not a NSAID, and does not have any of the goodies that COX-2 inhibitors can offer.