Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-16
2002-07-23
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S408000
Reexamination Certificate
active
06423744
ABSTRACT:
INTRODUCTION
1. Technical Field
This invention relates to mitigating adverse effects induced by interleukin-2 through the administration of an effective amount of a leukotriene B
4
antagonist.
2. Background
Recombinant interleukin-2 (PROLEUKIN® or “IL-2”) is an analogue of human native interleukin-2. While human native interleukin-2 is present in a human in small amounts, under certain conditions, i.e., the administration of IL-2 to treat certain conditions, excess levels (i.e., higher than normal levels) of IL-2 will be present in a subject's system. IL-2 is approved for the treatment of certain human malignancies including melanoma and renal cell carcinoma and is useful in treating certain viral conditions. IL-2 is thought to work by stimulating the immune system to work as an antitumor or antiviral agent. It can be viewed as having antitumor, antiviral, and immunostimulating activity. The administration of IL-2 has been associated with “vascular leak syndrome” (VLS), which results from extravasation of plasma proteins and fluid into the extravascular space. It is known that, among other adverse signs or symptoms, VLS can cause generalized edema, systemic hypotension, reduced organ perfusion, and subsequent dysfunction of one or more organs. When sufficiently severe, VLS may cause significant disability or even death. The adverse effects of IL-2 may necessitate using a lower dose of IL-2, thereby diminishing the potential for therapeutic benefit from IL-2. An effective means of mitigating IL-2 toxicity would be beneficial.
Empirical approaches to treating VLS have included the use of corticosteroids, which, unfortunately, can reduce the antitumor effects of IL-2. The pluripotent filaricide diethylcarbamazine (DEC) has also been studied experimentally, but because of its diverse pharmacological effects, the specific role of DEC in VLS is unclear. DEC is known to be a 5-lipoxygenase inhibitor. The antifolate methotrexate has also been suggested as a means of mitigating VLS. Unfortunately, methotrexate itself is quite toxic.
However, blocking the adverse effects of any substance, e.g. IL-2, may also block the beneficial effects. It is a deficiency of prior art that no intervention to prevent or mitigate VLS has been shown not to interfere with the antitumor activity or, more preferably, to enhance the antitumor activity of interleukin-2.
It is generally known that 5-lipoxygenase is instrumental in initiating production of 5-hydroperoxyeicosatetraenoic acid (HPETE) and leading to the production of 5-HETE, LTA
4
, LTB
4
, LTC
4
, LTD
4
, and LTE
4
. See Figure 3-18 at page 71 of Robbins,
Pathologic Basis of Disease,
6th Ed. By Ramzi S. Kotran, M.D.; Vinay Kumar, M.D., FRC Path.; and Tucker Collins, M.D., Ph.D., W. B. Saunders & Co. (1999). This Chapter also establishes that LTC
4
, LTD4, and LTE
4
have an action of elevating vascular permeability, but not LTB
4
. (See Table 3-4). See Goodman & Gilman's,
The Pharmacological Basis of Therapeutics,
9th Ed., McGraw Hill (1996), pp. 601-616. On cell activation and intracellular Ca
2+
increases, 5-lipoxygenase binds to a 5-lipoxygenase activating protein (FLAP). This binding activates the 5-lipoxygenase which results in its association with the cell membrane and increased synthesis of 5-HPETE. The 5-HPETE is rearranged by LTA synthase to an unstable 5,6-epoxide, known as LTA
4
. LTA
4
may be transformed by LTA hydrolase to LTB
4
. Alternatively, it may be conjugated with glutathione by LTC
4
synthase to form LTC
4
. LTC
4
may be transformed to LTD
4
by the removal of glutamic acid. LTD
4
may in turn be converted to LTE
4
by the cleavage of glycine. The reincorporation of glutamic acid to LTE
4
yields a &ggr;-glutamylcysteinyl derivative called LTF
4
.
Thus, a 5-lipoxygenase inhibitor would be expected to decrease production of 5-HPETE (and 5-HETE), LTA
4
, LTB
4
, LTC
4
, LTD
4
, and LTE
4
.
As the variety of potential interventions suggests, the pathogenesis of VLS is unknown. It has been demonstrated, however, that IL-2 increases plasma levels of leukotriene B
4
. I have found that using a leukotriene B
4
receptor antagonist (LA), preferably a leukotriene B
4
antagonist, during IL-2 therapy mitigates VLS and lessens the adverse effects of IL-2 while preserving or enhancing the beneficial effect of IL-2.
Thus, evidence shows that specific blockade of the leukotriene B
4
receptor not only mitigates VLS and lessens the adverse effects of IL-2 but it also preserves or enhances antitumor, antiviral, or immunostimulatory activity, thereby improving the therapeutic index of IL-2. The improved therapeutic index of IL-2 leads to several advantages. These include
reducing diagnostic testing required to
i. enhance tumor response to IL-2 by permitting a higher number of doses or a larger dosing amount of IL-2 with no significant increase in adverse effects induced by IL-2
ii. monitor patient responses to IL-2
iii. determine the success of therapeutic interventions required to mitigate IL-2 related adverse events
iv. demonstrate that certain events are caused by IL-2 rather than another agent
obviating or reducing the need to place patients into intensive care units or onto respirators in the case of severe pulmonary edema,
obviating or reducing the need to place patients into cardiac or coronary care units in the case of severe arrhythmia or congestive heart failure,
obviating the need for placing patients onto dialysis protocols the case of renal compromise,
reducing the need for intensive nursing or support care.
reducing or obviating the use of medications or other devices for prevention or treatment of adverse effects expected or caused by IL-2
All of these advantages should then lead to better tolerated treatment, reduced overall cost of treatment and better response to treatment.
SUMMARY OF THE INVENTION
One aspect of this invention is a method of mitigating an adverse pharmacological effect of IL-2 in a subject. The method comprises administering to a subject receiving exogenous IL-2 an amount of a leukotriene B
4
inhibitor or antagonist (preferably a leukotriene B
4
receptor antagonist) that is sufficient to mitigate the adverse effects. Another aspect is treating a malignancy or viral infection in a mammal by administering a therapeutically effective amount of IL-2 in combination with a leukotriene B
4
antagonist in an amount sufficient to reduce IL-2-induced adverse pharmacological effects, e.g., increased vascular permeability. Another aspect is simultaneously preserving or enhancing the antitumor, antiviral, or immunostimulatory activity of IL-2.
The preferred leukotriene B
4
receptor antagonist is represented by the Formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
R
1
represents alkyl having 2 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms, alkynyl having 2 to 6 carbon atoms, or (CH
2
)
n
R wherein R represents cycloalkyl of 3 to 5 carbon atoms and n is 1 or 2;
R
2
represents hydrogen, methyl or ethyl;
R
3
represents alkyl having 1 to 5 carbon atoms;
W represents a bridging group such as (CH
2
)
x
where x is 2 to 7, alkenylene having 3 to 7 carbon atoms, alkynylene having 3 to 7 carbon atoms or cyclopentyl;
R
4
represents hydrogen, alkyl having 2 to 5 carbon atoms, alkynyl having 2 to 5 carbon atoms, alkenyl having 2 to 5 carbon atoms, alkanoyl of 2 to 5 carbon atoms, or aralkanoyl of 7 to 9 carbon atoms;
R
5
represents hydrogen, alkyl having 1 to 6 carbon atoms, or R
5
represents alkanoyl having 2 to 4 carbon atoms, or (CH
2
)
y
—CO
2
R
8
wherein y is 0 to 4 and R
8
is hydrogen or alkyl having 1 to 6 carbon atoms;
R
6
represents hydrogen or together with R
5
represents a carbon to carbon bond; and
A represents —Z—CO
2
R
7
wherein R
7
represents hydrogen or alkyl having 1 to 6 carbon atoms, and wherein Z is absent or represents straight or branched chain alkylene or alkenylene having up to 6 carbon atoms.
Other leukotriene B
4
receptor antagonists include those set forth in U.S. Pat. No. 4,788,214 (which is incorporated herein by reference)
Biomedicines, Inc.
Cooley & Godward LLP
Solola T. A.
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