Principais doenças da retina
Oral therapy for diabetic retinopathy, in
early trials, appears to be well tolerated.
BOSTON — Inhibition of the beta isoform of the enzyme protein kinase C (PKC)
reduces retinal blood flow abnormalities in patients with diabetes mellitus, as indicated
by study data presented at the American Academy of Ophthalmology meeting.
Additionally, growth hormone and insulin-like growth factor 1 also have been
implicated in ischemia-induced retinal neovascularization. Inhibitors of growth
hormone and its mediators also are entering clinical trials for evaluation in proliferative
diabetic retinopathy.
“The compound [LY333531; Eli Lilly and Company, Indianapolis] appears to be
reaching the retina after oral administration in bioactive concentrations sufficient to
induce pharmacodynamic effects that are consistent with those expected following
inhibition of PKC beta,” said Lloyd P. Aiello, MD, PhD, the presenting author. “This
combined with the fact that the compound, so far, has been well tolerated and not
associated with significant adverse side effects, did not adversely affect immune
function and did not alter glycemic control, justifies continuation of multicenter,
randomized, double-masked trials to test the potential efficacy of the inhibitor in the
treatment of diabetic macular edema and proliferative diabetic retinopathy.”
Hyperglycemia
According to Dr. Aiello, the Diabetes Control and Complications Trial and other
studies have firmly established that hyperglycemia is one of the primary abnormalities
underlying vascular complications of diabetes. In the beginning stages of diabetes,
hyperglycemia results in the activation of PKC. “Protein kinase C activation plays a
critical role in the development of diabetes-associated vascular dysfunction,” Dr.
Aiello said. “The exact mechanisms by which this happens is an area of active
investigation, but it is clear that hyperglycemia increases oxidative stress and advanced
glycosylated end products, all of which can result in activation of PKC in the tissues
predominantly affected by diabetes — namely the retina, nerves, kidney and heart.”
Late stage effects
Dr. Aiello explained that in the later stages of diabetes, vascular dysfunction of the eye
leads to retinal ischemia and the induction of growth factors, particularly vascular
endothelial growth factor (VEGF). A hypoxic induction of VEGF involves the
activation of PKC. According to Dr. Aiello, in order for VEGF to actually cause a
change within the cells, the activation of PKC is a critical step.
“In the pathway from hyperglycemia to retinal vascular complications in diabetes, there
are multiple steps that require not only PKC, but also a particular type of PKC — the
beta isoform of PKC,” Dr. Aiello said. “Inhibition of the PKC beta isoform would
block this pathway in multiple steps, potentially ameliorating the hyperglycemic effects
on retinal vascular complications.”
Trial objectives
The primary objective of the phase 1b, single center, randomized, parallel,
double-masked, placebo-controlled trial was to evaluate the effect of repeated dosing
of the compound in patients with diabetes for safety, pharmacokinetics and
immunology. The secondary objective was to determine pharmacodynamic effects,
particularly on retinal blood flow and circulation time and on retinal vascular leakage
and albumin excretion. The patients included in the trial had type 1 or type 2 diabetes
for less than 10 years of duration, with no or mild proliferative retinopathy, ages 18 to
65 years and with hemoglobin A1c of 11 or less. The trial included four treatment
arms, all receiving four identical pills twice daily. The treatment groups consisted of a
placebo group, two groups receiving 16 mg of drug a day with different types of
dosing and one group at 32 mg a day in two doses. The patients were evaluated every
week and followed for a total of 1 month.
According to Dr. Aiello, there were no clinically significant differences among the
groups in various parameters, including hematology, blood chemistry, ocular safety
parameters, liver function tests and in immunology. Additionally, with regard to blood
glucose, there also was no statistical difference in change of fasting blood glucose,
hemoglobin A1c or insulin, or oral agent use or dosage.
Dr. Aiello reported that the retinal mean circulation times are normally increased by 1
second in diabetes. The changes in mean circulation time and retinal blood flow were
reduced by the study drug. “If one looks at the change along the vertical axis versus
the placebo group, the 16 mg per day group and the 32 mg per day group, we see
what appears to be a dose-dependent normalization of the circulation time,” Dr. Aiello
said. “We saw no patients where blood flow was changed beyond that expected in
the non-diabetic individuals. These changes are very consistent with the observations
observed using this compound in rats.”
In patients with type 1 or type 2 diabetes, oral ingestion of
the compound was well tolerated for 30 days at doses up to 16 mg twice daily. “It
was not associated with significant side effects, did not adversely affect immune
function and did not alter glycemic control,” Dr. Aiello said. “Furthermore, it appeared
to ameliorate diabetes-associated abnormalities in retinal vascular function.”