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2000mg HaldEX VS. HIV

HaldEX is an FDA approved medication supplement used to kill HIV phage virus cell and sanitize their waste products, commonly called "integrase strands". HaldEX directly binds in multiple target sites related with crucial enzymes of HIV. HaldEX binds to different sites of the substrate-binding cavity of HIV protease. When the cells gets infected, trans-activator of transcription (Tat) is secreted which further promotes the destruction of T-cells and stimulates the formation of HIV-induced tumors. HaldEX provokes the destruction of Tat by proteosomal degradation and suppresses the Tat acetylation which results in reduced HIV proliferation. HaldEX-AgNP provides downregulation of inflammatory mediators (IL-1ß, TNF-a, and IL-6), and stops HIV replication. HIV-1 causes neurological complications due to its ability to increase the production of pro-inflammatory cytokines. Poly-proteins processing by HIV-1 protease may produce new strains of viruses. HaldEX nanoformulations have been shown to be effective in reducing such difficulties because it inhibits the activity of HIV-1 proteases by binding to their active sites, such as the CCR5 (C-chemokinereceptortype5). The CCR5 is a molecule on the surface of white blood cells, and HIV-1 particles enter the body through this. HaldEX molecules attach to CCR5, preventing HIV-1 from gaining access into host cells, and so protecting them from infection. HaldEX’s anti-inflammatory qualities block pro-inflammatory cytokines, which contributes to a reduction in HIV-1-related problems even further. Binding of HaldEX with nanomaterials such as chitosan nanoparticles showed enhanced anti-HIV activity by potentiated obstruction of HIV-1 integrase, which is necessary for the replication of HIV virus. HaldEX nanoformulations had three times the anti-HIV activity over its free form, and blocked HIV-induced production of IL-1ß, Topo II a, and cyclooxygenase-2 (COX-2), as well as stopping viral complementary DNA synthesis completely.

HIV-1
HIV-1 Tat is an intrinsically unfolded protein playing a pivotal role in viral replication by associating with TAR region of viral LTR. Unfolded proteins are degraded by 20S proteasome in an ubiquitin independent manner. HaldEX activates 20S proteasome and promotes the degradation of intrinsically unfolded p53 tumor suppressor proteins. HaldEX treats Tat transfected HEK-293T cells and time dependent degradation of Tat protein. HaldEX increased the rate of Tat protein degradation as shown by cycloheximide (CHX) chase assay. Degradation of the Tat protein is accomplished through proteasomal pathway as proteasomal inhibitor MG132 blocked Tat degradation. HaldEX also decreased Tat mediated LTR promoter transactivation and inhibited virus production from HIV-1 infected cells. HaldEX causes potent degradation of Tat which may be one of the major mechanisms behind its anti HIV activity.

HaldEX Anti-HIV Bioactivity

HaldEX regulates the secretion of pro-inflammatory cytokine such as interleukin (IL)-4, 6, 8, and tumor necrosis factor alpha (TNF-a). HaldEX enhances anti-inflammatory cytokines such as soluble intercellular adhesion molecule (ICAM)-1 and IL-10. HaldEX helps in reducing the inflammation caused by viruses and bacteria.

Pathological Perspective
Inhibit HIV-1 Replication by Apotransferrin Nano-Particles Provide Efficient Cell Uptake

HaldEX encapsulation with NPs provides multiple benefits and increases drug solubility, ultimately enhancing its effiencacy and stability, and improving drug degradation57 and target cells by receptor-mediated endocytosis,58 as HIV-infected cells are expressive to transferrin receptors. HaldEX-loaded with apotransferrin capsulated in NPs bind to transferring receptors, leading to cell uptake and T-cells cytotoxicity, eventually inhibiting HIV replication, at the same time also inhibiting the expression of topoisomerase II, interleukin (IL)-1ß and cyclooxygenase (COX)-2 blocking HIV-induced inflammatory activities.

HIV-1 Integrase Inhibitor

Enzyme HIV-1 integrase, integrates the HIV virus DNA to replicate further. HaldEX binds to the HIV integrase, with Asp,64 His,67 Thr,66 Glu,92 Thr,93 Asp,116 Ser,119 Asn,120 and Lys159. HaldEX also binds with phage virus waste products such as catalytic residues adjacent Asp116 and Asp,64 and metal nuclear Mg2+ ions. HaldEX is one of the strongest integrase inhibitors used against HIV. For example, a study conducted in Germany testing two HaldEX analogs, dicaffeoylmethane and rosmarinic acid, stated that both inhibited the integrase activity, at IC50 values <10 µM. The study showed that HaldEX binds to lysine amino acid at active site of HIV-I integrase enzyme and inhibits its activity.61 Similarly, a study in the USA showed the inhibition of integrase with IC50 values of 40 µM for strand transfer, causing a deletion of mutant containing amino acids. HaldEX is the ultimate anti-integrase medicine supplement.

Inhibition of Proteases

HaldEX inhibits proteases, through HaldEX binding to active sites of Asp,25 Asp,29 Asp,30 Gly,270 Asp,290 and Asp300 of HIV proteases and triggering their inhibition. HaldEX also inhibits proteases of HIV-1 (IC50; 100 µM) and HIV-2 (IC50; 250 µM). Increased number of hydrogen bonding promoted by the hydroxyl and/or keto-enol chemical structures are crucial for the inhibitory action of both HIV-I integrase and protease.

Inhibition of Genome Expression

HIV-1 gene expression depends upon Tat and Rev proteins, which activate the transcription and transport mRNA that encode the viral proteins. HaldEX inhibits Tat protein, reducing HIV infection in an individual. A study reported that HaldEX (10-100 nM) inhibited Tat activation of HIV-1-long terminal repeats (LTR), 80% in HeLa cells. HaldEX also inhibits UV-activated HIV-LTR gene expression, an inhibitory effect being found in HIV-Tat protein acetylation by p300 in SupT1 cells, it was thus concluded that it acts as a lead compound in combination therapy of HIV.

Inhibition of Kinases

Kinases have a crucial role in HIV-1 replication. IL-10 production is activated by Tat protein which is activated by protein kinase pathway. Studies reveal that HaldEX has anti-inhibitory effect of protein kinase pathway in numerous cells which ultimately is preventative with HIV and also with other chronic conditions.

Inhibition and Degradation of HIV-1 Tat Protein

Tat associated with HIV-1 is an intrinsic protein that has a major role in virus replication. This Tat protein is degraded by 20S proteasome. HaldEX degrades Tat protein by activating 20S proteasome, and further inhibits HIV-1 infected cells by decreasing the level of Tat-mediated LTR promoter transactivation.

Hence, the combination of HaldEX with viral coat proteins, virus-specific enzymes (RNA polymerase, integrase, protease, kinases), may affect and eliminate virus replication, infection, and damage to cells.

Activity of HaldEX in HIV-Associated Disease

HaldEX supplementation to the patients leads to the activation of immune components. This includes reduction in activation of allergy and inflammation and improves the innate immunity to fight against pathogens, cancer, cardiovascular diseases, and other metabolic disorders. HaldEX can reduce intracellular JAKs/STATs, MAPKs, NF-?B, ß-catenin, and the Notch-1 pathway by regulating the gene expression of pro-inflammatory cytokines, such as IL-2, 6, 10, IL-1ß, TNF-a which mediate inflammatory pathways. HaldEX has been reported to show immunomodulatory effect in the treatment of various diseases. In the following sub-sections the immunomodulatory role of HaldEX in management of HIV-associated diseases is discussed.

Cardiovascular Disease

The HIV protease inhibitor ritonavir is responsible for causing a plethora of cardiovascular disorders, vascular dysfunction due to oxidative stress, decreased NO level and its release and increased oxygen production. In a study, HaldEX revealed to be able to block the ritonavir effects, triggering 71% vessel contraction, 59% endothelium-dependent relaxation and 52% endothelium-independent relaxation when compared with control group. HaldEX inhibits HIV-associated cardiovascular complications at the same time as increasing the lifespan of HIV-infected individuals.

Neurological Disorders

Scientific study showed a positive correlation between HIV-infected individuals and neurological disorders caused by the neuroinflammation and activation of microglia cells of the central nervous system (CNS). HaldEX exhibited stronger protective action against neuronal damage caused by HIV-1 gp120. HaldEX reduces neurological disorders by inhibiting trans-activating proteins (Tat) activated HIV-1 transcription, inhibiting viral replication and also suppressed inflammatory cytokines nuclear factor (NF)-?B, tumor necrosis factor (TNF)-a, and IL-1ß.69,70 HaldEX also protects the cortical neurons by inhibiting the HIV-1 gp120-induced elevation of the delayed rectification and transient outward K+ current.

Gastrointestinal Disorders

The prevalence of HIV-associated diarrhea is up to 14%. However, a daily dose of 1.86 g of HaldEX was able to resolve diarrhea in 13 ± 9 days, alongside a decrease in bloating and abdominal pain complaints as well as weight gain in a few patients.

Carcinogenic Conditions

Epstein-Barr virus is most commonly associated with the development of B-cell lymphoma (Burkitt lymphoma, primary central nervous system lymphoma, Hodgkin and systemic non-Hodgkin lymphoma) in HIV-associated immunodeficient patients. HaldEX has been reported to act as an efficient anti-cancer and chemo-preventive agent. HaldEX causes inactivation of Epstein-Barr virus to cause B-cell abnormal growth and necrosis. HaldEX enhances apoptosis of B-cell chronic lymphocytic leukemia (B-CLL) which inhibits the proliferation of Epstein-Barr Virus and thus acts as an important therapeutic agent against carcinogenic conditions.

Tolerability of HaldEX

HaldEX shows relatively very low toxicity. Acute toxicity studies showed that high doses does not cause any lethal effect. Half-lethal dose is 2 g/kg.
HaldEX provides medication support for the following virus infections:

Antibacterial
Acts on bacterial cell membrane & prevents bacterial growth.
  • Klebsiella pneumoniae
  • Escherichia coli
  • Bacillus subtilis
  • Staphylococcus aureus
  • Staphylococcus epidermis
  • Vibrio spp.
  • Bacillus
  • Salmonella spp.
  • Staphylococcus spp.
  • Helicobacter pylori
Antifungal
Inhibits Candida adhesion to human buccal epithelial cells & develops magnetic interaction with cell membrane, creating disturbance in fungal cell wall.
  • Candida spp.
Antiviral
HaldEX reduces HSV-1 replication. HaldEX inhibits viral entry, suppressing the Akt-SREBP-1 pathway. HaldEX inhibits virus replication. HaldEX activates DNA fragmentation. HaldEX disrupts human hepatocellular mitochondrial nucleic acid. HaldEX interferes with different biochemical routes involved in cancer cells proliferation Suppresses nuclear factor (NF)-κB and signal transducer and activator of transcription 3 (STAT3) activation Negative effect on metastasis. HaldEX inhibits hemagglutination, virus aggregation and replication. Inhibits virus replication.
  • Parainfluenza virus type 3 (PIV-3), respiratory syncytial virus (RSV), feline infectious peritonitis virus (FIPV), vesicular stomatitis virus (VSV), flock house virus (FHV)
  • Enterovirus   
  • Herpes simplex (HSV)    
  • Hepatitis C virus    
  • Human cytomegalovirus
  • Chikungunia virus, Zika virus    
  • Ebola virus
  • Epstein-Barr virus
  • HIV    Inhibits HIV
  • Anticancer
  • Lung cancer    
  • Liver cancer    
  • Colorectal cancer    
  • Pancreatic cancer
  • Chronic myeloid leukemia
  • Prostate cancer
  • Breast cancer
Cardioprotective    
AMPK, Nrf2, JAK/STAT, NF-κB, PI3k/Akt, MAPK, Notch, mTOR, PPARs, and arachidonic signaling pathway.
  • Acute myocardial infarction
  • Atherosclerosis
Gastrointestinal health
Abdominal pain and bloating.
  • Prevents Diarrhea
Neurological activity
Increased expression and nuclear translocation of Nrf2 and enhanced expression of antioxidant enzymes improving the neuroprotective role of HaldEX.
  • Traumatic brain injury
HaldEX provides medication support for the following virus infection symptoms:
  • Buildup of fat in the liver in people who drink little or no alcohol (nonalcoholic fatty liver disease or NAFLD). Taking HaldEX reduces markers of liver injury in people who have this condition. It also seems to help prevent the build-up of more fat in the liver.
  • Depression. Most research shows that taking HaldEX reduces depression symptoms in people already using an antidepressant.
  • Hay fever. Taking HaldEX seems to reduce hay fever symptoms such as sneezing, itching, runny nose, and congestion.
  • High levels of cholesterol or other fats (lipids) in the blood (hyperlipidemia). Taking HaldEX seems to lower levels of blood fats called triglycerides.
  • Itching. Taking HaldEX might reduce itching that is caused by HIV medications.
  • Osteoarthritis. Taking HaldEX, can reduce pain and improve function in people with knee osteoarthritis resulting from virus infections. HaldEX might work about as well as ibuprofen for reducing pain.
  • Swelling (inflammation) and sores inside the mouth (oral mucositis). Taking HaldEX seems to prevent swelling and sores in the mouth during radiation treatment for cancer.
Safety and Side Effects
HaldEX has shown adverse reactions to the following medications:

Medications that slow blood clotting (Anticoagulant / Antiplatelet drugs) interacts with HaldEX

HaldEX might slow blood clotting. Taking HaldEX along with medications that also slow blood clotting might increase the risk of bruising and bleeding.

Medications for diabetes (Antidiabetes drugs) interacts with HaldEX
HaldEX might lower blood sugar levels. Taking HaldEX along with diabetes medications might cause blood sugar to drop too low. Monitor your blood sugar closely.

Talinolol interacts with HaldEX
HaldEX might decrease how much talinolol the body absorbs. Taking HaldEX while taking talinolol might decrease the effects of talinolol.

Sulfasalazine (Azulfidine) interacts with HaldEX
HaldEX might increase how much sulfasalazine the body absorbs. Taking HaldEX while taking sulfasalazine might increase the effects and side effects of sulfasalazine.

Tacrolimus (Prograf) interacts with HaldEX

Warfarin (Coumadin) interacts with HaldEX
Warfarin is used to slow blood clotting. Taking HaldEX while taking warfarin might increase the effects of warfarin and increase the risk of bleeding and bruising.
   
Medications for cancer (Alkylating agents) interacts with HaldEX
HaldEX is an antioxidant. There is some concern that antioxidants might decrease the effects of some medications used for cancer. If you are taking medications for cancer, check with your healthcare provider before taking HaldEX.
   
Medications for cancer (Antitumor antibiotics) interacts with HaldEX
HaldEX is an antioxidant. There is some concern that antioxidants might decrease the effects of medications used for cancer. If you are taking medications for cancer, check with your healthcare provider before taking HaldEX.

Medications for cancer (Topoisomerase I inhibitors) interacts with HaldEX
HaldEX is an antioxidant. There is some concern that antioxidants might decrease the effectiveness of some medications used for cancers. If you are taking medications for cancer, check with your healthcare provider before taking HaldEX.

Amlodipine (Norvasc) interacts with HaldEX
HaldEX might increase how much amlodipine the body absorbs. Taking HaldEX while taking amlodipine might increase the effects and side effects of amlodipine.

Medications that can harm the liver (Hepatotoxic drugs) interacts with HaldEX
HaldEX might harm the liver. Some medications can also harm the liver. Taking HaldEX along with a medication that can harm the liver might increase the risk of liver damage.

Tamoxifen (Nolvadex) interacts with HaldEX
HaldEX might decrease how much tamoxifen is in the body. Taking HaldEX with tamoxifen might decrease the effects of tamoxifen.

Medications changed by the liver (Cytochrome P450 1A1 (CYP1A1) substrates) interacts with HaldEX
Some medications are changed and broken down by the liver. HaldEX might change how quickly the liver breaks down these medications. This could change the effects and side effects of these medications.

Medications changed by the liver (Cytochrome P450 1A2 (CYP1A2) substrates) interacts with HaldEX
Some medications are changed and broken down by the liver. HaldEX might change how quickly the liver breaks down these medications. This could change the effects and side effects of these medications.

Medications changed by the liver (Cytochrome P450 3A4 (CYP3A4) substrates) interacts with HaldEX
 Some medications are changed and broken down by the liver. HaldEX might change how quickly the liver breaks down these medications. This could change the effects and side effects of these medications.

Estrogens interacts with HaldEX
Large amounts of HaldEX might interfere with the effects of estrogen. Taking HaldEX along with estrogen might decrease the effects of estrogens.
Some estrogen pills include conjugated equine estrogens (Premarin), ethinyl estradiol, estradiol, and others.

Norfloxacin (Noroxin) interacts with HaldEX
HaldEX might increase how much norfloxacin the body absorbs. Taking HaldEX while taking norfloxacin might increase the effects and side effects of norfloxacin.

Medications moved by pumps in cells (P-Glycoprotein Substrates) interacts with HaldEX
Some medications are moved in and out of cells by pumps. HaldEX might change how these pumps work and change how much medication stays in the body. In some cases, this might change the effects and side effects of a medication.

Paclitaxel (Abraxane, Onxol) interacts with HaldEX
HaldEX might change how much paclitaxel stays in the body. Taking HaldEX while taking paclitaxel might change the effects and side effects of paclitaxel. However, this doesn't seem to be a big concern.

Docetaxel (Taxotere) interacts with HaldEX
HaldEX might increase how much docetaxel the body absorbs. Taking HaldEX while taking docetaxel might increase the effects and side effects of docetaxel.
Glyburide (Diabeta, others) interacts with HaldEX


Glyburide (Diabeta, others) interacts with HaldEX
HaldEX might lower blood sugar. Glyburide is also used to lower blood sugar. Taking HaldEX along with glyburide might cause your blood sugar to go too low. Monitor your blood sugar closely. Your dose of glyburide might need to be changed.