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Cardiometabolic Disease

Cardiovascular disease accounts for nearly 1 in 3 deaths globally, remaining the primary global cause of mortality. Around 80% of them are due to stroke and heart attacks/hearth failure. This “silent killer”, both chronic and asymptomatic in numerous patients, remains a particular challenge for doctors and the pharmaceutical industry despite the large number of existing drugs.

 

A deficit in circulating hydrogen sulfide (H2S), enzymatically generated by all human organs, is thought to lead to increases in oxidative stress and associated problems contributing to heart failure.

 

Sodium polysuthionate (SG1002), Sulfagenix’sleas H2S prodrug, is the only hydrogen sulfide prodrug converting 100% into H2S. It has been demonstrated in clinically relevant animal models of cardiovascular disease to decrease cardiac fibrosis, reverse the progression of atherosclerosis and heart failure, improve cardiac function and increase angiogenesis through reduction of oxidative stress, as well as decreased inflammation, restore H2S homeostasis, and stimulation of nitric oxide biosynthesis.

  • Obesity

  • Type 2 diabetes

  • Hypertension

  • Hyperlipidemia

  • Hyperhomocysteinemia 

  • Atherosclerosis

  • Heart failure

  • Stroke

  • Nonalcoholic fatty liver disease

Image by jesse orrico

SULFAGENIX FOCUS: 

 Cardiometabolic disease (CMD) may be conceptualized as a single underlying disease state — with oxidative endothelial damage at its foundation — that manifests differently in individual patients and encompasses individuals presenting with highly interrelated obesity, cardiovascular disorders, stroke, type 2 diabetes (T2D), and non-alcoholic fatty liver disease (NAFLD). 

 

At present, one out of every two American adults is living with one or more of these conditions: both T2D and obesity are considered global epidemics. To manage CMD, 40% of adults take five or more medicines daily by age 65 and, as their number grows with age, so does the frequency of experienced side effects and adverse drug-drug interactions.

 

According to the 2018 USA Census, the total national population was 327,167,434 people, with 77.6% over 18 years old. This translates to an adult population of 253,881,929. Therefore, 126,940,964 people live with one or more of the above conditions in the US alone.

 

At this point the question naturally arises as to why, at the present advanced stage of the biomedical sciences, we are suffering a devastating and incredibly costly pandemic of CMD. We at Sulfagenix believe that the main reasons for this are: 

  • Strict adherence to the paradigm of “one target-one drug” while not addressing either the root cause (i.e. oxidative tissue damage mediated by free radicals) or the concomitant endothelial dysfunction ( Citi 2020 );

  • Treating patients with drugs that have the potential to inflict cumulative damage to liver, kidneys, heart and GI tract; 

  • Failure to institute comprehensive behavioral/dietary changes that might curb inflammation/immune dysfunction and even fully reverse organ damage.

 

It is now established, on the basis of a large number of failed single-targeted drug agents in clinical trials/development, that molecularly-targeted therapies are far from being ideally suited for effective treatment of highly complex disease states such as cancer, HIV-AIDS and CMD, since they require modifying integrated biological outcomes rather than targeting single pathways. In the case of CMD, for instance, it is necessary to develop therapies aimed at simultaneously providing cytoprotection and improving endothelial function, energy metabolism, blood pressure, and redox/inflammatory/procoagulant status.

 

Sulfagenix’s solutions to the treatment of complex disease states caused by free radical-mediated oxidative tissue damage address this root cause and rely on the pleiotropic effects of the hydrogen sulfide (H2S) molecule. The plurality of H2S therapeutic targets goes hand in hand with such pleiotropic effects on multiple molecular pathways.

 

The biological profile of H2S, which includes potent antioxidant, antiapoptotic, anti-inflammatory, vasoactive and cytoprotective effects on normal (non-transformed) cells can be harnessed to successfully treat complex biological conditions. (For an account of this new paradigm, please refer to Sestito S. et al.,”Hydrogen Sulfide: A Worthwhile Tool in the Design of New Multitargeted Drugs”, in Frontiers in Chemistry, 27 September 2017, Vol 5.)

 

 Furthermore, exogenous H2S is capable not only of acting as a powerful antioxidant (mainly indirectly, via Nrf2 activation), but also of being used as building block for the synthesis of thiosulfate, sulfate, cysteine, cysteine hydropersulfide, cysteine trisulfide, taurine, hypotaurine, thiotaurine, glutathione, glutathione hydropersulfide and glutathione trisulfide, In other words, exogenous H2S may be used by the organism to synthesize an entire array of sulfur-bearing molecules needed for cytoprotection against free radicals, oxidants, electrophiles, xenobiotics and infectious agents, including viruses. 

 

Moreover, we now know that H2S is used by the human organism to modify numerous important functional proteins, thereby converting them into S-sulfhydrated proteins, and that protein S-sulfhydration probably mediates the promotion of glucose uptake by cells via enhancement of insulin receptor sensitivity, the blood pressure lowering via activation of KATP channels, the inhibition of platelet aggregation, the atherogenesis inhibition via downregulation of Hu R factor and MMP-9 expression, the inhibition of the activation of nuclear transcription factor NF-kB via nuclear translocation, and the upregulation of endothelial NO synthase. 

 

Preservation of mitochondrial function through H2S direct and mainly indirect (via Nrf2 activation) antioxidant effects is at the root of H2S-mediated cytoprotection during myocardial infarction; as such, it is important to point out that nuclear transcription factor Nrf2 is the master regulator of the expression of antioxidant proteins. Inhibition of inflammatory cytokines and reversible inhibition of a cytochrome c-mediated oxidation. In fact, preservation of mitochondrial function is an effective strategy for treating other mitochondrial-driven diseases such as neurodegeneration and aging.

 

H2S therapeutic effects, including those related to inflammation, also depend to a great extent on its capacity to regulate the homeostasis of the cellular immune system, both directly and indirectly, via the H2S-Cysteine-Glutathione connection (see Gojón G. and Morales G.A., 2020. “Antioxidants & Redox Signaling”, in press).

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