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Hi Maggie,
Typical LL-37 dosing is 100-200mcg BID for 4-6 weeks. You can start low and then titrate up as long as the patient is tolerating well. In our practice, the dosing we use with our patients is 100mcg-200mcg BID for 4-6 weeks, so the daily dose is 200mcg-400mcg. We don’t typically go any longer than 6 weeks with the patient.
LL-37 is a great peptide but remember for your patients who have underlying autoimmune disorders, you need to be cautious. It activates your innate immunity, so it can aggravate certain conditions like active psoriasis/PsA, systemic lupus (SLE-spectrum), vasculitis and prothrombotic states due to NET-linked risk. It also amplifies type 1 IFN signaling, enhancing antigen presentation which can then skew Th1 responses potentially worsening autoimmune conditions and drive beta-cell injury in Type 1 DM patients. If autoimmune disease is present, just start low, 100mcg/day, and titrate up slowly but only continue to increase if tolerating well.
For more insight, here’s a detailed article discussing LL-37’s role in immune regulation and disease outcomes:
https://pmc.ncbi.nlm.nih.gov/articles/PMC7246396/
Hopefully this information was helpful.
Thank you
Hi Maggie,
I’m glad to hear that the extensive work-up for concerning etiologies, including a negative MRE regarding the possible NET, has been reassuring so far. Chronic stress and HPA axis dysfunction can certainly contribute to unintentional weight loss. Persistent activation of the HPA axis elevates cortisol levels, which promotes catabolism, impairs nutrient absorption, suppresses appetite in some cases, and disrupts overall metabolic homeostasis. During periods of stress, the brain can release damage-associated molecular patterns (DAMPs), which influence immune activity and may drive further inflammation. This is especially important when additional stressors like mold exposure are present, since environmental toxins can amplify both inflammatory and metabolic disturbances
Peptides That Can Help:
MK-677 (Ibutamoren, a GHRP-mimetic): This peptide stimulates endogenous growth hormone secretion, which can help increase appetite and support anabolism. Some patients experience mild water retention or bloating initially due to increased glucose and water uptake into cells, but this tends to stabilize. Typical protocols involve cycling off after 3 months of use to maintain effectiveness.
Oral BPC-157: BPC-157 is known for its gut-healing properties and may support nutrient absorption and improve gastrointestinal function, which is particularly important if malabsorption is suspected due to stress or inflammation, which in her case we can pretty much guarantee she is having malabsorption issues.
Selank: While not directly anabolic, Selank may help increase brain-derived neurotrophic factor (BDNF), levels of which can be depleted during chronic stress. By supporting BDNF, Selank may improve stress resilience and cognitive function. Additionally, Selank has anxiolytic properties that may help regulate stress response and HPA axis reactivity, thereby addressing one of the potential contributors to her unintentional weight loss.
Other Supportive Options:
Clinoptilolite (e.g., Med Therapy Pro or Med Darm-Repair): A naturally occurring volcanic ash mineral recognized for its ability to bind and remove mycotoxins and environmental toxins from the gut. This has scientifically shown that it can help restore gut barrier function, support the microbiome and enhance nutrient and mineral absorption. Even after she moves away from mold exposure, she could still continue the clinoptilolite just for ongoing protection against environmental toxins, including nanoparticles found in plastics.
Hopefully these recommendations are helpful! @justinbiofuse-net
Hi Bruce,
You have a couple of options for using Pinealon to support sleep:
Option 1: Circadian Reset Protocol
Have the patient complete a 10-day high-dose course to help reset the circadian rhythm.-
Dose: 5 mg in the morning and 5 mg in the evening for 10 days.
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After 10 days, transition to a maintenance dose of 3 mg daily.
Option 2: Standard Maintenance Approach
If the patient isn’t able to complete the 10-day high-dose reset, they can begin directly with the 3 mg daily dose.-
In our practice, we typically have patients inject in the morning, as this often helps reinforce the circadian rhythm for nighttime sleep.
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However, if sleep doesn’t improve with morning dosing, they can shift the injection to the evening to see if that timing works better.
Every patient responds differently, so it’s best to adjust timing based on individual results.
Hopefully this information was helpful! @bsloanephilaurology-com
Hi Dr. Baluch,
That’s a great question and actually one we get from many patients when they’re first starting treatment with us.
We do sometimes see certain lab values shift over time, but what we really care most about is how the patient is feeling and what they’re noticing in their day-to-day life, i.e. energy, recovery, focus, sleep, muscle growth, etc. While labs can provide useful data, they’re ultimately just a snapshot of one moment in time. What matters most is how the patient is feeling and functioning overall, as that tells us far more about how their body is truly responding. For patient populations who may not be able to communicate how they’re feeling, we rely on feedback from their caregivers to gauge progress and overall well-being.
For specific peptides like CJC/Ipamorelin or other GHRH/GHRPs, you can follow hormones such as:
- IGF-1, which tends to increase as growth hormone production improves
- Testosterone in males, since growth hormone is a master hormone that can help boost natural levels
- We also recommend tracking body composition through InBody or DEXA scans once a quarter to follow the changes in visceral fat mass vs. lean muscle mass (and many other important measurements).
Depending on the peptides you are using and the area you are focusing on, here are some other markers that can be helpful to follow:
- If you’re focusing on inflammation, following homocysteine and CRP can be helpful.
- For thyroid support, you can monitor thyroid antibodies to look for positive trends.
- If you’re working on immune mechanisms, especially in patients with low blood counts, checking a CBC with differential can provide insight into white cell activity and overall immune function.
- With GLP-1s, markers like fasting glucose, insulin, and A1C are good indicators of improvement.
- And if mitochondrial health is your focus, the Prodrome blood test is a great way to assess mitochondrial efficiency over time.
Beyond lab markers, depending on the patient population you’re working with, functional and behavioral changes can also be meaningful indicators of progress. For example, in patients with seizure disorders, tracking whether seizure frequency has decreased can be helpful or if they are bouncing back quicker after their seizures if they are still having them. In developmentally delayed children, parents may begin noticing new milestones being reached. For autistic children, improvements such as increased eye contact or fewer outbursts can be strong signs of progress. And in TBI patients, you might observe greater engagement in conversation or a reduction in seizure activity if present.
Tests that we try to avoid at our practice are the biological “age predictor” tests. We’ve seen patients who feel younger, stronger, and are clearly recovering faster, yet those tests come back showing them as two years older than before which then leaves the patient feeling defeated because they feel fantastic but in their eyes, they are doing worse than they were before. We just then educate the patient that based on what we know about how peptides work on cellular pathways, we know that’s simply not accurate, their cells are functioning better and more efficiently than before treatment and we remind them those test have no standardization, which is a reason why we don’t order them for our patients.
Overall, labs can help support the story, but the most meaningful data often comes from how our patients feel because that’s where we see the biggest transformation or what the caretakers are reporting they are seeing!
Presbyopia:
Haha, we wish we had a guaranteed fix for that one! While we can’t promise this will completely prevent you from needing reading glasses one day, these steps can definitely support long-term eye health and work in your favor.
One of the simplest and most effective things you can do is take a fish oil supplement that contains phospholipids. Phospholipid-bound omega-3s have better absorption and provide more direct support to cell membranes, helping protect against age-related changes in the ocular tissues. Resolvin is a great example of a phospholipid-bound fish oil, and most krill oils fall into this category as well.
Another option that has shown promising results in animal models for age-related visual decline is the mitochondrial peptide SS-31, which helps protect retinal cells and may slow visual impairment as we age. While neither of these can guarantee you’ll skip the reading glasses altogether, both can help preserve and protect your eye health over time.
I hope this information is helpful! @abaluchmdgmail-com
The GHRH can be taken year round no receptor issues.
They GHRP is the one we try to rotate or take a few days off a week like you have referenced.
Possible routine: 9 months rotate these
- Tesamorelin
- 1.25 mg (50 IU’s ) Daily am
- Do this for 3 months – 7 days a week
- 1.25 mg (50 IU’s ) Daily am
- CJC-1295/ Ipamorelin
- 100 Mcg (5 IU’s) every AM & PM
- Can also add third dose before or after a workout
- Do this for 3 months-5 days out of 7
- GHRP -MK0677
- 12.5 mg Orally BID
- Do this for 3 months-5 days out of 7
- 12.5 mg Orally BID
There are some other ways to go but this is a great start.
You also could just go CJC/Ipamorelin 3 months on and take 6 week break and then repeat.
Thank you! 🙂
I am assuming she had lumpectomy?
I would agree that hormonal therapy or radiation without surgery has minimal benefit. Assuming that she had lumpectomy, it should be understood that adding radiation and hormonal therapy does not change the 10-year survivorship which is 98 percent.
As you will see below these additional further treatments of radiation and hormonal therapy lead to a decreased recurrence at 10 years. So, it comes down to a discussion of decreasing recurrence versus the side effects of Radiation and hormonal therapy. Hormonal therapy statistics are based on 5 years of treatment which can be difficult with compliance because of the side effects
This becomes a decision between the doctor and the educated patient. Optimal treatment seems to vary among doctors.
Because of the variable rate of DCIS transformation into invasive cancer recent clinical trials will help give a better understanding of patients whose DCIS is monitored instead of surgery, as those new clinical trials shed new light on this potential. Presently, most of the focus is on reducing the risk of invasive cancer and treating DCIS like early-stage breast cancer with the treatment of lumpectomy, radiation and hormonal therapy.
Ductal Carcinoma In Situ (DCIS)
- Non-invasive breast cancer
- Starts inside the milk duct and does not spread beyond the milk duct into surrounding breast tissue
- Can increase risk of developing invasive breast cancer later on in life
- Chances of recurrence are under 30%. They usually occur within 5-10 years after initial diagnosis
- Lumpectomy surgery without radiation=25%-30% chance of having a recurrence. Lumpectomy surgery with radiation=15% chance of having a recurrence
- Chemotherapy is usually not needed for treatment of DCIS
- Hormonal Therapy beneficial to prevent recurrence post-surgical – important to recognize the adverse events and different side effects associated between anastrozole and tamoxifen. Both have similar rates of recurrence with treatment. Reference below is a good read.
Tamoxifen
- Used for breast cancer treatment that has spread to other parts of the body in both men and women
- Used with Ductal Carcinoma in Situ to reduce risk of developing a more serious type of breast cancer
- Dual mechanism of action:
- Compete with 17B-estradiol (E2) at receptor site and block promotional role of E2 in breast cancer
- Bind to DNA after metabolic activation and to initiate carcinogenesis
KE4
- D-3HB may starve cancer cells
- In glioma and glioma-like stem cells KD altered energy metabolism resulting in increased reactive oxygen species (ROS) production and increase in apoptosis of tumor cells
- Adding D-3HB can potentially enhance anti-cancer effects of chemotherapy
- When using D-3HB patients do not need to follow the KD diet in order to achieve ketosis
To get the best benefit for the Ketone Esters our practice recommends using 5mL’s 4 times per day (Female). She can space it out every 3-4 hours but make sure her last dose is not after 7:00 PM so her sleep is not disturbed. If using at bedtime 2.5 mls for sleep nothing more. And before radiation recommend 30 min before 15 mls. This will give a higher nutritional ketosis around 2-3 millimole during the radiation treatment. If she is doing the Ketone Esters, she does not need to follow a strict ketogenic diet because the esters will help put her body in a ketogenic state. Ketogenic diet may be difficult during treatment with radiation. Intermittent fasting or the calorie restrictive Fasting Mimicking diet could add synergy to the program. Many nutritional options- but major goal would be more focused on glucose starvation of tumor.
We wish her the best with her treatment!
Here is a great article reviewing Ketone Esters that we recommend reviewing. Yao, Aliya, Zihua Li, Jinyan Lyu, Liusong Yu, Situ Wei, Lingyun Xue, Hui Wang, and Guo-Qiang Chen. “On the Nutritional and Therapeutic Effects of Ketone Body D-β-Hydroxybutyrate.” Applied Microbiology and Biotechnology 105, no. 16 (August 1, 2021): 6229–43. https://doi.org/10.1007/s00253-021-11482-w.
Anastrozole vs Tamoxifen to Prevent DCIS Recurrence: Key Difference May Be Side-Effect Profile
https://www.cuimc.columbia.edu/news/stage-zero-breast-cancer-whats-optimal-treatment-dcis
Hello!
GHRP has a saturation dose of about 100 mcg meaning above this you get minimal extra signaling with higher doses above saturation dose (In general but there are caveats to this statement)
You do not need worry with Ipamorelin in the short term with involution or receptor desensitization. It is the long term continued stimulation of GHRP receptors (not GHRH) above saturation dose where this would be an issue (greater than 3 months).
@michaelmedicalhealthinstitute-comHi!
We just have a few questions:
1: Where is the tear?
- Interstitial insertional or muscular tendonous junction
2: Was this patient ever immobilized? Was she using a cam walker during this treatment?
3: What was the mcg dosing of the BPC-157 she was using?
For an interstitial insertional tear (most typical for Achilles injuries) we typically will immobilize in a CAM walker for 4-6 weeks while we treat with TB-4 and BPC-157 sub q.
We can go into more detail after you provide us with that information 🙂
Type 1 DM:
- Autoimmune disease that leads to destruction of insulin-producing pancreatic beta cells
- Believe to be have a strong link with HLA (DR & DQ) alleles
- Circulating pancreatic autoantibodies (islet cell cytoplasmic antibodies (ICA), antibodies to insulin (IAA), glutamic acid decarboxylase (GAD65), protein tyrosine phosphatase antibodies (IA-1) and zinc transporter8 (ZnT8)) indicate a risk of developing T1DM or already developed
- Potential cause for developing T1DM in patients at risk is a viral or environmental factor triggers autoimmune beta-cell destruction
- Occurs in 3 stages
- Requires Insulin Therapy
Type 2 DM:
- Metabolic Disorder
- Two primary leading causes:
- Defective insulin secretion by pancreatic B-cells
- Insulin secretion is reduced so the body’s ability to maintain physiological glucose levels is reduced
- Inability of insulin-sensitive tissues to respond appropriately to insulin
- Leads to high blood glucose levels
- Modifiable risk factors:
- Obesity
- Low physical activity
- Unhealthy diet
- Non-modifiable risk factors:
- Ethnicity
- Family history
- Does not necessarily require Insulin treatment
- Defective insulin secretion by pancreatic B-cells
Insulins Job in the Body:
- Allows glucose to enter muscle and adipose cells
- Stimulates liver to store glucose as glycogen and synthesize fatty acids
- Stimulates uptake of amino acids
- Inhibits breakdown of fat in adipose tissue
- Stimulates uptake of potassium into cells
Signaling Pathway for Insulin secretion:
- Release is triggered by response to high glucose concentration and glucose internalized through GLUT2 transporter in the beta cell of the pancreas
- Glucose catabolism increases ATP/ADP ratio
- ATP-dependent potassium channels are closed therefore membrane depolarization and opening of calcium channels
- Calcium influx triggers insulin exocytosis
- P2x, P2Y, SERCA and RYR (additional calcium channels) that are involved in calcium mobilization and insulin secretion
Glucagon Like Peptide-1 Receptor Agonists
- Stimulate insulin secretion after oral glucose via incretin effect
- When used to treat T2DM benefits are:
- Delayed gastric emptying
- Inhibiting production of glucagon from pancreatic alpha cells if blood sugar levels elevated
- Decrease pancreatic beta-cell apoptosis
- Promotes proliferation of beta-cells
- Weight loss
- Lowered HGB-A1C
- Other Benefits:
- Blood pressure was decreased
- Total cholesterol levels were decreased
- Risk of a cardiovascular event is decreased
- Increased glucose uptake in muscles
- Decreased glucose production in the liver
- Neuroprotective
- Increased satiety
Management of T1DM:
- Current “approved” management of T1DM is inulin & pramlintide
- Insulin does not target alpha cell dysfunction
- When a GLP-1RA is used in T1DM it addresses the alpha cell dysfunction which results in suppression of glucagon secretion. Patients who have T1DM cannot suppress glucagon during meals which results in postprandial hyperglycemia
- Studies have been done using Exenatide and Liraglutide for patients with T1DM and the results were decreases in total daily insulin requirements, weight loss and improvements in glycemic control
- Studies have shown positive results using a GLP-1RA in the management of T1DM
In our practice we are currently using Semaglutide as our GLP-1RA instead of Liraglutide(which we were using previous to semaglutide with success) and we have been implementing this therapy with T1DM. So far, we have had positive results where patients have been able to decrease the amount their insulin dose.
References:
Harris, Kira B., and Cassie L. Boland. “Adjunctive Role of Glucagon-Like Peptide-1 Receptor Agonists in the Management of Type 1 Diabetes Mellitus.” Pharmacotherapy 36, no. 9 (September 2016): 1011–20. https://doi.org/10.1002/phar.1804.
Zhao, Xin, Minghe Wang, Zhitong Wen, Zhihong Lu, Lijuan Cui, Chao Fu, Huan Xue, Yunfeng Liu, and Yi Zhang. “GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects.” Frontiers in Endocrinology 12 (2021): 1040. https://doi.org/10.3389/fendo.2021.721135.
Lucier, Jessica, and Ruth S. Weinstock. “Diabetes Mellitus Type 1.” In StatPearls. Treasure Island (FL): StatPearls Publishing, 2021. http://www.ncbi.nlm.nih.gov/books/NBK507713/.
Galicia-Garcia, Unai, Asier Benito-Vicente, Shifa Jebari, Asier Larrea-Sebal, Haziq Siddiqi, Kepa B. Uribe, Helena Ostolaza, and César Martín. “Pathophysiology of Type 2 Diabetes Mellitus.” International Journal of Molecular Sciences 21, no. 17 (August 30, 2020): 6275. https://doi.org/10.3390/ijms21176275.
Hou, June Chunqiu, Dumaine Williams, Jérôme Vicogne, and Jeffrey E. Pessin. “The Glucose Transporter 2 Undergoes Plasma Membrane Endocytosis and Lysosomal Degradation in a Secretagogue-Dependent Manner.” Endocrinology 150, no. 9 (September 2009): 4056–64. https://doi.org/10.1210/en.2008-1685.
We still do not have a specific cause for the nerve damage that occurs in GBS, but we know the persons immune system begins to attack the body itself. Majority of cases of Guillain-Barre Syndrome (GBS) the immune system damages the myelin sheath that surrounds the axons of many peripheral nerves. In some cases, GBS can actually damage the axon itself. The result of the damage means that nerves are unable to transmit signals efficiently which results in eventual muscle atrophy. Since GBS damages the nerves it is possible for patients to develop paresthesias and pain. Bacterial or viral infections could be a cause of GBS. There have been times where surgery or vaccinations could increase the risk of GBS. Zika virus has been reported as a cause of GBS.
You are on the right path by starting him on the immune peptides TA1 and TB4. He should remain on those peptides. Are you able to provide an update as to how he is doing since starting the TA1 and TB4? Both work on myelin sheath regeneration which is important for this patient.
Adding the pentadecapeptide BPC-157 could be beneficial for this patient. BPC-157 is a gastric peptide but it has been used to help in various CNS-disorders. It is cytoprotective. BPC has a stimulatory effect on the Egr-1 gene, NPB2 gene, FAK-paxillin and JAK-2 signaling pathways. When given peripherally BPC-157 induces a release of serotonin, specifically nigrostriatal regions. This release of serotonin has an influence on serotonergic and dopaminergic systems. It also protects somatosensory neurons and improves nerve regeneration.
Also adding on CJC/Ipamorelin, which is a GHRH/GHRP would be extremely helpful for this patient. Administration of CJC/Ipa works on the anterior pituitary and will stimulate the pulsatile release of endogenous GH. CJC/Ipamorelin keeps a balance of AMPK and mTOR and helps with protein synthesis. You can start this patient on 5 IUs in the AM and 5 IUs in the PM.
It would also not be a bad idea to have the patient supplementing with phospholipids, such as Sunflower Lecithin. Ideally, he would take 5-10 grams/day. The Lecithin comes in pills, powders or oils.
ProdromeGlia-a plasmalogen precursor (Alkylglycerol), is another supplement that could help the patient out. Glia insulates neurons. It helps boost the patients Omega-9 and is a pre-cursor for your peroxisomes to make plasmalogens. They can take 30 drops in the evening with food. The CJC/IPA works on improving your mitochondrial and peroxisomal function so by supplementing ProdromeGlia you are giving your body the building blocks that it needs.
Make sure the patient is on a B-vitamin complex and B-12 vitamin. Preferably sublingual that way it is absorbed directly in the blood stream and does not need to be digested in the stomach before getting to the liver.
Here is a great overview of Guillain-Barre syndrome: “Guillain-Barré Syndrome Fact Sheet | National Institute of Neurological Disorders and Stroke.” Accessed October 8, 2021. https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Guillain-Barr%C3%A9-Syndrome-Fact-Sheet.
Sikiric, Predrag, Sven Seiwerth, Rudolf Rucman, Danijela Kolenc, Lovorka Batelja Vuletic, Domagoj Drmic, Tihomir Grgic, et al. “Brain-Gut Axis and Pentadecapeptide BPC 157: Theoretical and Practical Implications.” Current Neuropharmacology 14, no. 8 (November 2016): 857–65. https://doi.org/10.2174/1570159X13666160502153022.
- Chronic metabolic acidosis exists normally in humans eating ordinary diets that yield normal net rates of EAP (endogenous acid production). The diets have an excess of noncarbonic acids (sulfuric acid) instead of a base (bicarbonate)
- These diets have been linked to nephrolithiasis and osteoporosis
- Low grade Acidosis increases with age resulting from kidney function declining with age
- This acidosis contributes to the loss of skeletal muscle mass that occurs with aging
- Chronic metabolic acidosis induces muscle protein breakdown but when the acidosis is corrected the effects are reversed
- This leads to stimulation of ATP and ubiquitin-dependent proteolytically released branch chain amino acid (valine, leucine and isoleucine) preventing reuptake for protein synthesis
- Nonbranched chain amino acids, especially glutamine, are released and are made available to the kidney
- The kidney excretes ammonium ( releasing H ions to balance ph from acid diet and eliminates muscle N
- The degradation in muscle increases the production of nitrogen (N) end products that are eliminated in urine
- N loss occurs when endogenous acid production is abnormally high (i.e. chronic ketoacidosis) or when acid excretory and/or bicarbonate reabsorpitve capacity of kidney is impaired (i.e. advanced renal insufficiency)
- N metabolism is a direct result of the acidosis.
- Releasing increased amounts of amino acids (glutamine) can increase excretion of acid (ammonium getting rid of the H ions ) mitigating the severity of the acidosis
- KHCO3 can potentially prevent continuing age-related loss of muscle mass and restore previous deficits. It reduces the net endogenous acid production and corrects previous low grade metabolic acidosis state
- Administration of ammonium chloride or increased dietary protein intake leads to urinary calcium excretion which results in inhibition of net renal tubular calcium reabsorption, lack of intestinal calcium absorption and stimulation of bone resorption leading to negative calcium balance
- KHCO3 but not NaHCO3 reduce urinary Ca excretion no matter what their dietary Ca intake is
- Ca retention during KHCO3 administration occurred without changes in net intestinal Ca absorption indicating it was the result of renal Ca retention or enhanced Ca retention in bone or a combination of the two
- Potassium, independent of HCO3 could reduce urinary Ca excretion
- KHCO3 could stimulate renal tubular Ca reabsorption
- Intermittently higher serum K+ levels during KHCO3 administration might enhance tubular K+ entry in ascending loop of Henle resulting in a more positive luminal voltage which enhances tubular Ca and Mg reabsorption
- Failure of NaHCO3 to reduce urinary Ca excretion could be a consequence of natriuresis
- Both NaHCO3 and KHCO3 administration resulted in more positive Na or K balances and a more negative acid balance (this is why one may consideration of the Alka seltzer Gold )
- Alka Seltzer Gold Ingredients
- Anhydrous citric acid 1000mg
- Antacid-Potassium bicarbonate 344 mg
- Antacid-Sodium bicarbonate 1050 mg
- Both NaHCO3 and KHCO3 administration likely resulted in deposition of the salts into the bones
- Metabolic acidosis, high protein diets and animal proteins result in increased urinary Ca excretion but ingesting a diet containing more vegetables and fruits or supplementing KHCO3 and less protein can enhance Ca retention and protect skeletal mass
- Lower dietary NaCl content would minimize urinary Ca excretion and protect bone
Take away points from the Beverly Hills Mastermind 6
- Normal pH in the body is between 7.35-7.45 but even the slightest change in pH (even in the normal range) can have a significant effect on your metabolism
- When the body is trying to keep an acid/alkaline balance there is an increase in protons. This increase in protons will go to the muscle and pull-out amino acids. The kidney then converts the amino acid into ammonia and excretes it. This process is the start of sarcopenia and proteolysis
- Increase in protons leads to mitochondria backing up and building up ROS and free radicals which leads to lipid peroxidation, carbonalyation of proteins and DNA damage which sets the cell up for senescence
- Low grade acidosis sends a message to your pituitary gland to force a release of cortisol. This is not a direct affect on the adrenal gland, this is indirect from the pituitary with ACTH release.
- NADPH production is increased in acidosis and works on 11 B-hydroxysteroid dehydrogenase-1 which causes cortisone to convert to cortisol
- NADPH needs to work with an antioxidant to prevent unfavorable changes in cellular redox
- Chronic acidosis leads to osteoporosis because the body is pulling out Ca and Mg from the bone to try to balance the low grade acidosis . Osteoclast are activated by NFK-B/RANKL which then sets off an inflammatory cascade.
- Citrate is metabolized into HCO3. The cell is trying to compensate the acidosis by keeping citrate in the cell. Under a stable Acid/Base state , Ca is excreted by the kidneys and citrate follows. Ca oxalate without citrate is less soluble resulting in formation of kidney stones
Here is a great resource that goes discusses Potassium bicarbonate, but not sodium bicarbonate, reduces urinary calcium excretion and improves calcium balance in healthy men that is worth the read: Lemann, Jacob, Richard W. Gray, and Joan A. Pleuss. “Potassium Bicarbonate, but Not Sodium Bicarbonate, Reduces Urinary Calcium Excretion and Improves Calcium Balance in Healthy Men.” Kidney International 35, no. 2 (February 1989): 688–95. https://doi.org/10.1038/ki.1989.40.
Here is another great resource that discusses Potassium Bicarbonate Reduces Urinary Nitrogen Excretion in Postmenopausal Women: Frassetto, L, R Curtis Morris, and A Sebastian. “Potassium Bicarbonate Reduces Urinary Nitrogen Excretion in Postmenopausal Women” 82, no. 1 (1997): 6.
Growth Hormone:
- Secreted from secretagogue in anterior pituitary
- As we age there is a decrease in GH and IGF-1 which leads to a decrease in cell efficiency
- Hypothalamus secretes GHRH that signals the anterior pituitary secretagogue to start making GH and attempt to release but somatostatin from the hypothalamus has inhibitory effect on the release. To ensure this release within 20 minutes a sub q injection of a GHRP is utilized to release this inhibition. It also has synergizing effects with the GHRH making the amplitude and pulse of the GH release bigger from the anterior pituitary
- Works by activation of ERK1/2 and JAK/STAT3 signaling pathways
CJC-1295/Ipamorelin
- GHRH/GHRP
- Mimics pulse and amplitude of your own GH release
- Optimizes NAD+/NADH pool, NADP/NADPH pool, SIRT and FOXO gene activation, beta oxidation of fatty acids, TCA cycle, oxidative phosphorylation
- Activates signal cascading of AMPK, PCG-1alpha, PPAR-gamma, alpha, NFR1 &2 and TFAM
- Decreases IL2, IL6 and upregulates IL10
- Blocks transcription of NF-kB
- Pleiotropic effects – through GH receptor and GHRH Receptors
- CJC-1295 (Current CJC1295 from pharmacy is MOD GFR(1-29) without DAC )
- 29 amino acids
- True CJC 1292 is MOD GRF (1-29) also known as CJC 1295 with DAC (Drug affinity complex)
- Analogue of GHRH
- Promotes muscle growth and fat burning
- Helpful in people looking to slow aging
- May improve sleep
- Makes the pituitary follow a natural pulsatile release
- Can be dosed twice/week at 100mcg or 100mcg daily if treatment is short-term
- Ipamorelin
- Suppresses somatostatin
- Increases bone growth
Dosing:
- 1 mcg/kg
- Saturation dose of 100mcg is typically used
- Typical dosing varies from 3 times a day to once a day depending on desired results.
- Cycling
- 5 days on and 2 days off can run continuous with this protocol.
- Alternative is 7 days a week for 12 weeks then 6 weeks off and repeat
When giving any GHRH/GHRP it is extremely important to discuss timing with the patients. The patient can take it first thing in the morning and wait 20-30 minutes to eat and then in the evening once they have gone 1.5 hours without eating. Fats and Carbohydrates will blunt GH release, proteins have no effect. For patients looking for muscle gain and fat loss they can take a dose within 90 minutes after exercise.
Dr. Seeds Peptide Therapy: Foundation course has a great overview of GHRH/GHRP for you to refer back to and reference!
- Tripeptide (Lys-Pro-Val)
- Anti-inflammatory
- PepT1 is a di/tripeptide transporter expressed in small intestine and induced in colon during IBD
- Nanomolar concentrations of KPV inhibit activation of NF-kappaB and MAP kinase (MAPK) inflammatory signaling pathways and reduce pro-inflammatory cytokine secretion
- KPV acts via PepT1 expressed in immune and intestinal epithelial cells.
- Melanocortin system
- 5 transmembrane G protein-coupled receptors PLUS 2 endogenous antagonists
- Melanocortin’s comprise adrenocorticotropic hormone (ACTH), a-, b- and y-melanocyte-stimulating hormones
- C-terminal tripeptide derivatives of a-MSH (i.e., KPV) and KdPT possess anti-inflammatory properties
- KPV weakens inflammatory response in colonic epithelium and intestinal immune cells that lead to a reduction in IBD
- Mice were given KPV who had experimental colitis induced by dextran sulfate sodium (DDS) and trinitrobenzene sulfonic acid (TNBS). Index of neutrophilic infiltration myeloperoxidase (MPO) activity was assessed, and the results showed approximately a 50% decrease in MPO activity in the mice treated with oral KPV. This study also led to a belief that KPV has a non-receptor-dependent immunoregulatory effect. Mice who were given the DDS had a decrease in the expression of pro-inflammatory cytokine mRNA levels of IL-6 but did not change the expression of IL-10 mRNA suggesting KPV acts by decreasing pro-inflammatory cytokines instead of increasing anti-inflammatory one.
- Hyaluronic acid lysine-proline-valine nanoparticles (HA-KPV-NPs) can enhance mucosal healing AND regulate inflammatory response with ulcerative colitis.
- Oral HA-KPV-NPs encapsulated in a hydrogel exhibited higher potency for preventing epithelial injury
- Questioning if KPV can be used in other inflammatory diseases i.e., lung inflammation in COVID-19
- KPV effect on MAPK pathway:
- IL-1B induces rapid phosphorylation of ERK1/2, JNK and p38 in Caco2-BBE cells BUT when treated with KPV there was a strong decrease in IL-1B-induced MAPK phosphorylation
Duration of treatment:
As long as it takes to treat the inflammatory process! In our clinical practice we typically extend 3-6 months beyond once we have the clinical symptoms under control.
We have not experienced any contraindications using this small peptide and we have been happy with both oral and subq use for inflammatory disease. We are very encouraged with this new nanoparticle approach and believe this is the potential future of improved treatments for gut dysbiosis!
References:
Dinparastisaleh, Roshan, and Mehdi Mirsaeidi. “Antifibrotic and Anti-Inflammatory Actions of α-Melanocytic Hormone: New Roles for an Old Player.” Pharmaceuticals 14, no. 1 (January 8, 2021): 45. https://doi.org/10.3390/ph14010045.
Dalmasso, Guillaume, Laetitia Charrier-Hisamuddin, Hang Thi Thu Nguyen, Yutao Yan, Shanthi Sitaraman, and Didier Merlin. “PepT1-Mediated Tripeptide KPV Uptake Reduces Intestinal Inflammation.” Gastroenterology 134, no. 1 (January 2008): 166–78. https://doi.org/10.1053/j.gastro.2007.10.026
Hello Robin!
Your sense is correct that the GH effect effects sex hormone secretion!
- In young women, IGF-1 not only acts on theca cells of the ovary to promote androgen production, but also acts synergistically with FSH to increase aromatase activity, thereby stimulating estrogen production
- GH release increases IGF-1 production. It is believed that declining IGF-1 leads to reproductive senescence, so increasing IGF-1 can possibly extend reproduction!
- In young individuals, GH contributes to the regulation of puberty and fertility via HPG axis stimulation through changes in the levels of SS and/or gonadotropin secretion
- GH specifically acts on its receptors in the ovary to promote steroidogenesis and gametogenesis via gonadotropin-independent stimulation of progesterone (P4) and estrogen (E2), inhibition of follicular apoptosis and upregulation of ovarian LH receptors
- Treatment with GH has been shown to reinstate normal ovarian activity in GH insufficient girls and women, who suffer from delayed puberty, abnormal menstrual cycling and infertility
- GH administration to women with amenorrhea increases plasma E2 levels, LH pulse frequency and reduces LH pulse amplitude
Growth Hormone:
- 191 amino acid protein that binds to the growth hormone receptor (GHR)
- GHR mainly is detected in the liver, but has been found in the ovary and testes
- GH and IGF modulate the following signal transduction pathways:
- MAP kinase/ERK
- Jak/STAT
- PI3K/AKT
For further in-depth review please go to the Hormone Therapies Foundation course. This gives an excellent review of cellular pathways with Growth hormone and IGF-1 influences on the ovary and the testes.
Here is a brief summary below:
So, with the injection of a GHRH/GHRP like the CJC1295/Ipamorelin you are using with this patient these peptides set off a cascade of endogenous GH release and because of the Ipamorelin there is no somatostatin inhibition on this release from the anterior pituitary.
GH has an effect on every cell that has a GH- receptors (GHR) .GH and IGF-1 will activate kisspeptin which is released in the hypothalamus and activates Gonadotropin releasing Hormone (GnRH) which activates LH and FSH release in the anterior pituitary. Also, GnRH is also independently activated by IGF-1.
GH, FSH and LH signal the ovary. This induces thecal cells, production of sex steroids mainly estradiol which influences the ovary and in general circulation leads to pituitary LH release and with further Somatostatin inhibition leading to more GH release.
If you take a look at this effect in older females who are post-menopausal you can see this study confirmed that GH does not alter sex steroid production and has no effect on LH. Even with increases in IGF-1 there are no effects on the HPG (hypothalamus-Pituitary-Gonadal) axis as we see in pre and perimenopausal females. This can certainly be attributed to the senescence that takes place in the astrocytes of the hypothalamus where estrogen signaling promotes progesterone production and eventual LH release.
Resources:
Muniyappa R, Sullivan SD, Tella SH, Abel BS, Harman SM, Blackman MR. Effects of growth hormone administration on luteinizing hormone secretion in healthy older men and women. Physiol Rep. 2017;5(23):e13516. doi:10.14814/phy2.13516
This is a great reference article that discusses the Growth Hormone and Insulin-Like Growth Factor Action in Reproductive Tissues: Ipsa, Emina, Vinicius F. Cruzat, Jackob N. Kagize, John L. Yovich, and Kevin N. Keane. “Growth Hormone and Insulin-Like Growth Factor Action in Reproductive Tissues.” Frontiers in Endocrinology 10 (2019): 777. https://doi.org/10.3389/fendo.2019.00777.
Our approach in our SSRP Clinical practice is to better understand the mechanisms of disease and then implement plan. Here are some of our thoughts, please note we have taken a different approach than current recommendations of NSAIDS, steroids, bisphosphonates, methotrexate, sulfasalazine, and newer immunotherapies.
Our treatment recommendations are for an adult as referenced in this question. Pediatric dosing would vary.
CRMO Pathophysiology:
- Defect in the TLR4/MAPK/inflammasome signaling cascade leads to an imbalance in cytokine expression in monocytes, specifically inflammatory monocytes.
- Toll-like receptors (TLRs) and NOD-like receptors (NLRs) sense danger signals
- Danger signals activate inflammasomes and IL-1B is secreted
- IL-10 and IL-19 expression is reduced
- JNK and p38 MAPK are not affected therefore pro-inflammatory cytokines (TNFa, IL-6, IL-1B, IL-20) are still expressed
- TNFa, IL-6, IL-20 and IL-1B increase interaction of RANK and RANKL receptors.
CRMO Overview:
- Autoinflammatory bone disorder. It is NON-BACTERIAL (though some studies show Cutibacterium (formerly Propionibacterium) acnes plays a role in the pathogenesis )
- Believed to have defects on the TLR4/MAPK/inflammasome signaling cascade (leads to imbalance in cytokine expression in monocytes)
- Studies have shown the disbalance between cytokine and chemokine expression is a potential disease marker for diagnosis of CNO/CRMO
- Affects mostly children and adolescents
- Affects all ethnicities
- Genetics may play a role. Has been associated with other inflammatory conditions i.e. inflammatory bowel disease, acne, ankylosing spondylitis and psoriasis (but no specific gene mutation identified)
- Most frequently involves:
- Metaphysis of long bones
- Pelvic bones
- Vertebral column ( 50 percent adults)
- Shoulder girdle/clavicle
- Inflammasome activation of IL-1B secretion by monocytes from CRMO is reversible by co-culture with recombinant IL-10 or IL-19 suggesting immunomodulatory function of IL-10 and IL-19 on inflammasome activation
- One compound heterozygous mutation in the filamin-binding domain of the FBLIM1 gene (FBLIM1 is believed to act as anti-inflammatory molecule that controls bone remodeling through regulation of RANKL activation via ERK1/2 phosphorylation
- Transcriptional level-FBLIM1 expression regulated by transcription factor STAT3. IL-10 induces STAT3 activation therefore the inhibition of IL10 promoter can be involved
- Host interactions with skin and gut microbiota have significant effects on immune homeostasis. Alterations to microbiomes can result in inflammation and autoimmune/inflammatory conditions. All CRMO-associated disorders are characterized by significant alterations to microbiomes
Treatment Recommendation:
- Right track with TA1 because of the influence it has on IL-10. Ta1 will enhance IL10 ,IL-2 Il-12 .Acts as Agonist of TLR-2 . Reduces production of reactive oxygen Species preventing oxidative Damage improving function of Superoxide Dismutase and catalase and glutathione peroxidase.
- Start TA1 50 IU daily 2 weeks should see pain and swelling improvements then switch to 20 IUs daily for 3 months , then reevaluation.
- Adding TB4 as another immune peptide can add at 2 weeks if no improvement. downregulates inflammation. Tβ4 directly targets the NF‐κB RelA/p65 subunit suppressing TNF‐α‐mediated NF‐κB activation and reducing the levels of a large number of downstream key proinflammatory cytokines like IL-1B and IL‐8.
- Start at TB4 30 IU BID 2 weeks then review and if improving symptoms go to 15 IU’s BID 3 months with TA1 above.
- Pentosan Polysulfate 54 works through some of the inflammatory mechanisms that CRMO affects. Interesting option for further discussion.
- Recommend doing a genetic gut microbiome test called NirvanaBiome . You will more than likely see dysbiosis that needs to be addressed. Short chain fatty acid production and B vitamin production will be deficient. Our belief is microbiome is involved and the NSAID treatment contributed to further dysbiosis. Consider both prebiotics and Butyrate to start.
- Utilizing TA1 improving IL10 and TB4 suppression of TNF‐α‐mediated NF‐κB activation IL1b will promotes deactivation of the IL1 Rankl ligand on the osteoclast inhibiting resorption.
- Always remember diagnostic image of choice whole body MRI, looking for asymptomatic lesions, specifically vertebral body! These lead to fracture.
- With the controversy over bacterial infection., LL-37 is reserved for recalcitrant repose to treatment above. If open biopsy positive would implement LL-37 – 100mcg bid 6 weeks with above treatment plan.
Here is a great review of CRMO. Discussing the Presentation, Pathogenesis and Treatment. Hofmann, Sigrun R., Franz Kapplusch, Hermann J. Girschick, Henner Morbach, Jessica Pablik, Polly J. Ferguson, and Christian M. Hedrich. “Chronic Recurrent Multifocal Osteomyelitis (CRMO): Presentation, Pathogenesis, and Treatment.” Current Osteoporosis Reports 15, no. 6 (2017): 542–54. https://doi.org/10.1007/s11914-017-0405-9.
Other references
Skrabl-Baumgartner, Andrea, Peter Singer, Theresa Greimel, Gregor Gorkiewicz, and Josef Hermann. “Chronic Non-Bacterial Osteomyelitis: A Comparative Study between Children and Adults.” Pediatric Rheumatology Online Journal 17 (July 23, 2019): 49. https://doi.org/10.1186/s12969-019-0353-2.
Schaal, Matthias C., Liya Gendler, Bettina Ammann, Nina Eberhardt, Aleš Janda, Henner Morbach, Kassa Darge, Hermann Girschick, and Meinrad Beer. “Imaging in Non-Bacterial Osteomyelitis in Children and Adolescents: Diagnosis, Differential Diagnosis and Follow-up—an Educational Review Based on a Literature Survey and Own Clinical Experiences.” Insights into Imaging 12 (August 9, 2021): 113. https://doi.org/10.1186/s13244-021-01059-6.
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