Mr. Sparks and others arguing the cure subject, pfrenz found an article about a drug that is in the pipeline for XKEM that IS an antisickling drug. I got it mixed up with their approved drug, sorry. But another reason this company has so much to offer it's investors now and in the future.
pfrenz's post:
New antisickling agent by Xechem International, Inc
The antisickling properties of 5- hydroxymethyl-2-furfural (5HMF), a naturally occurring 5-carbon ring aromatic aldehyde, have been investigated by a US research group (Br J Haematol 2005; 128: 552–61). It is present in a variety of foods, including coffee, honey, fruit juices and some alcoholic beverages such as wine and spirits. The group demonstrated that 5HMF forms a stable Schiff base adduct with HbS by binding to the N- terminal amino acid (valine) of the two a-globin subunits.
In a series of in vitro experiments, 5HMF binding of HbS was shown to shift, in a dose-dependent manner, the oxygen dissociation curve of HbS to the left. By this means, the group demonstrated that the affinity of HbS for oxygen is increased by 5HMF and therefore, at a given oxygen tension, relatively less HbS is present in deoxy form and relatively more is in oxy form. As it is only the deoxy form of HbS that polymerises and causes cells to sickle, the theoretical effect of the HbS/5HMF adduct would be to reduce sickling.
Reduced sickling in vitro…
It is possible to induce morphologically normal red cells taken from a patient with SCA to sickle in vitro by incubating them in conditions of reduced oxygen tension, and this is the principle of tests used to screen for sickle cell disease. The US group used such an in vitro system to test the ability of 5HMF to inhibit sickling. Suspensions of red cells from patients with SCA were suspended in buffer containing increasing concentrations of 5HMF (0, 1, 2 and 5 mmol/L) and incubated for a maximum of five hours under reduced oxygen tension (4% O2, 96% N). After five hours, a sample of each mixture was recovered for microscopical examination to determine the percentage of sickled cells present.
As expected, more than 90% of red cells showed morphological signs of sickling in the absence of 5HMF. By contrast, percentage sickling decreased in a dose-dependent manner in the presence of 5HMF. Less than 10% of red cells were found to be sickled after incubation with the highest 5HMF concentration (5 mmol/L) and, for the most part, these cells were sickled before the sample was tested. Thus, the authors were able to conclude that 5 mmol/L 5HMF provided total inhibition of any fresh sickling induced by hypoxia.
…and in vivo
To determine the in vivo effect of 5HMF, the investigators used an established mouse model, the transgenic sickle mouse, of human SCA. Transgenic sickle mice have been genetically manipulated to express the human sickle gene so that their haemoglobin is HbS. When these mice are exposed to hypoxia, a sudden accumulation of sickled red cells in the pulmonary microvasculature causes death within minutes.
The US investigators administered 5HMF at a dose of 100 mg/kg bodyweight to eight of the transgenic mice and an equal volume of saline to eight more (controls). One hour later all mice were exposed to hypoxia (5% O2). All control mice died within 15 minutes, whereas all but one of the eight mice given 5HMF survived the hour of experimental hypoxia.
No adverse effect on erythocytes
In a series of in vitro experiments, the group demonstrated no detectable adverse effect of 5HMF on HbS (no signs of oxidation to MetHb or denaturation) or erythrocyte physiology. It had no effect on the erythrocyte N+/K+ pump (membrane exchange of hydrogen and sodium ions) or hydration of erythrocytes.
Promising results
This study has demonstrated the ability of a naturally occurring substance, 5HMF, to form a stable Schiff adduct with HbS. This adduct results in relatively less HbS in the insoluble (deoxy) form that causes red cells to sickle. In vitro and in vivo inhibition of red cell sickling by 5HMF has been demonstrated and no adverse effects of 5HMF, at a concentration shown to prevent sickling, have been discovered so far. Clearly, much work remains to be done, but these preliminary results suggest that 5HMF is a promising antisickling agent that may be of benefit to those severely affected by SCA. n
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