Methods for administration of antilipemic drugs

The present invention concerns methods for reducing cutaneous flushing in a patient to whom niacin is administered. According to the present method, two or more doses of a nonsteroidal anti-inflammatory drug are administered to a patient prior to administering niacin. Alternatively, the nonstcroidal anti-inflammatory drug can be administered concurrently with niacin administration. The nonstcroidal anti-inflammatory drug can be aspirin, ibuprofen, indomethacin, phenylbutazone, or naproxen. The nonsteroidal anti-inflammatory drug is administered in an amount effective to reduce cutaneous flushing caused by the niacin, and is administered in an amount up to 160 mg for aspirin and ibuprofen, 10 mg for indomethacin, and 100 mg for phenylbutazone and naproxen.

I. FIELD OF THE INVENTION 
The invention concerns methods and compositions for administration of 
antihyperlipidemic (ie., hypolipemic or antilipemic) drugs, particularly 
nicotinic acid and its derivatives, while producing decreased flushing 
reaction. 
II. BACKGROUND 
Abnormally high levels of circulating lipids (hyperlipidemias) are a major 
predisposing factor in development of atherosclerosis. Elevated levels of 
serum cholesterol and cholesteryl esters, which are carried by the 
beta-lipoprotein or low density lipoprotein (LDL) and lipoprotein (a) 
(Lp(a)) fractions of serum lipids, are known to be atherogenic. Also 
implicated in cardiovascular disease are elevated levels of triglycerides, 
carried mostly in the very low density lipoprotein (VLDL) fraction. 
Drugs which lower serum lipids (i.e., hypolipemic drugs) frequently are 
prescribed to retard development of atherosclerotic lesions in individuals 
exhibiting hyperlipidemias. Many of these drugs are effective when taken 
regularly, but suffer from poor patient compliance due to unpleasant side 
effects. Examples of effective but underutilized hypolipemic drugs include 
the bile acid binding resins, such as cholestyramine. 
The ability of large doses of nicotinic acid (i.e., niacin) to lower serum 
lipid levels has been recognized for many years. This drug is unusually 
effective because it lowers the levels of several classes of 
morbidity-associated serum lipids, including LDL cholesterol (LDL-C), 
Lp(a), and triglycerides (Tg). In addition to its antilipemic activity, 
niacin is also an essential water-soluble vitamin. Nicotinic acid exhibits 
relatively low toxicity on a molar basis. However, the doses required to 
lower atherogenic serum lipids are quite large, on the order of 1-8 grams 
per day. At these levels, adverse side effects are frequent, and may 
include gastrointestinal disturbances such as nausea, heartburn, and 
diarrhea. However, the most frequent and prominent side effect is intense 
flushing, often accompanied by cutaneous itching, tingling, or warmth, and 
occasionally by headache. Although the flushing side effect is in general 
harmless, it is sufficiently unpleasant that patient compliance is 
markedly reduced. Often, 30-40% of patients cease taking nicotinic acid 
within days after initiating therapy. Consequently, significant efforts 
have been exerted to develop niacin analogs, dosage forms, and treatment 
protocols which minimize the flush reaction. 
Tolerance to the flush reaction develops after a few days or weeks of 
repeated administration of nicotinic acid. One strategy for administration 
is to begin with low doses, i.e., 125 mg twice daily, then to increase the 
daily dose by increments of 30-100% after 1-6 weeks at each dose level; 
see, e.g., McKenney et al., J. Am. Med. Assn. (Mar. 2, 1994) 271:672-710. 
This procedure reduces but does not eliminate the flush reaction. Ibid. A 
further difficulty with relying upon tolerance for suppression of the 
flush reaction is that tolerance is lost rapidly if the drug is 
discontinued for a day or two. Consequently the dose must be reduced again 
when administration is resumed. 
Another method of reducing flush is to administer a sustained release (SR) 
form of nicotinic acid. Sustained release preparations reportedly have a 
lower incidence of flushing and gastrointestinal side effects, and 
concomitantly greater patient compliance and tolerance; see King et al., 
Am. J. Med. (1994) 97:323-331, 329; Knopp et al., Metabolism (1985) 
34:642-650; Alderman et al., Am. J. Cardiol. (989) 64:725-729. However, 
even SR preparations are not tolerated by a significant fraction of the 
patient population; see Luria et al., Arch. Int. Med. (1988) 
148:2493-2495. Moreover, SR dosage forms are prone to induce a much more 
severe side effect, hepatic toxicity; see, e.g., Rader et al., Am. J. Med. 
(1992) 92:77-81. 
Recent studies have indicated that the flushing reaction is initiated by 
release of prostaglandin D2. Prostaglandins are known to cause 
vasodilation, as well as a subjective experience of discomfort. Evidence 
supporting the role of prostaglandin D2 in mediating the niacin-induced 
flush includes the observation that a dramatic rise in the concentration 
of prostaglandin F, a metabolite of D2, occurs in the blood coming from 
the skin following administration of niacin. Furthermore, the level of 
prostaglandin F2 decreases markedly after 6 days of continuous twice-daily 
administration of nicotinic acid. This decrease in nicotinic acid-induced 
prostaglandin F2 correlates with the development of tolerance to the flush 
reaction which usually develops upon prolonged administration. Therefore 
tolerance appears to reflect a decline in prostaglandin D2 release, rather 
than an increase in metabolic inactivation of nicotinic acid. 
The putative role of prostaglandins in mediating the flush reaction 
suggests that inhibitors of prostaglandin synthesis might be useful in 
preventing the flush reaction. Several nonsteroidal antiinflammatory drugs 
(NSAIDs) have been shown to inhibit the synthesis of one or more 
prostaglandins (PGs) by blocking the enzyme prostaglandin synthetase, also 
referred to as cyclooxygenase. Among the NSAIDs in clinical use are 
aspirin, ibuprofen, naproxen, phenylbutazone, indomethacin, and flufenamic 
acid and its congeners. These NSAIDs inhibit the synthesis of PGs such as 
E2 and F2, but typically at high micromolar (uM) concentrations; see, 
e.g., Flower, Pharmacol. Rev. (1974) 26:33 (Table 1 therein). 
The prostaglandin synthetase inhibitors aspirin and indomethacin have been 
shown to reduce the cutaneous flush induced by nicotinic acid. Anderson et 
al. (1977) Acta Pharmacol. Toxicol. 41:1-10, demonstrated that nicotinic 
acid-induced flush in guinea pigs, as measured by an increase in ear 
temperature, was inhibited by pretreatment at 4.5 and 0.5 hr with 
indomethacin (25 or 50 mg/kg) or aspirin (50, 100, or 200 mg/kg). An 
aspirin total dose of 975 mg, administered to human subjects in a divided 
dose of 650 mg at 1 hr and 325 mg at 0.5 hr prior to high dose nicotinic 
acid challenge, was shown to significantly reduce cutaneous flush; see 
Wilken et al. (1982) Clin. Pharmacol. Ther. 31:478-482. 
A nicotinic acid ester derivative, methyl nicotinate, which causes local 
cutaneous erythema when administered topically, was used to study the 
flush-inhibiting effects of aspirin. 
III. SUMMARY OF THE INVENTION 
The present invention provides methods for administration of hypolipemic 
amounts of nicotinic acid or its congeners whereby the flush reaction is 
lessened or suppressed. The method involves pretreatment of a subject with 
a nonsteroidal antiinflammatory drug (NSAID) for a period of 1-6 days 
prior to beginning administration of nicotinic acid. Administration of the 
NSAID is continued during the period of administration of nicotinic acid. 
NSAIDs of particular interest include salicylates such as aspirin and 
salicylate salts; propionic acids such as ibuprofen, fenoprofen, suprofen, 
benoxaprofen, flurbiprofen, ketoprofen, carprofen, naproxen, and sodium 
naproxen; indoleacetic acid derivatives such as indomethacin, sulindac, 
and etodolac; benzeneacetic acids such as aclofenac, diclofenac, and 
fenclofenac; pyrroleacetic acids such as tolmectin and zomepirac; 
anthranilic acids such as meclofenamate and mefenamic acid; pyrazoles such 
as oxyphenbutazone and phenylbutazone; and oxicams such as piroxicam. In 
certain preferred embodiments, the NSAID may be administered in dosages 
which are less than 25%, often less than 15%, frequently less than 10%, 
sometimes less than 5%, and even as little as 1-0.1%, of the usual 
antiinflammatory or analgesic dosage. For example, with respect to 
aspirin, the total daily dosage optionally may be as low as 10-160 mg, and 
commonly may be 20-100 mg, often 40-80 mg. Administration of the daily 
total dosage in multiple doses of an immediate release (IR) formulation or 
in sustained release (SR) formulations is preferred.

V. DETAILED DESCRIPTION OF THE INVENTION 
The present invention provides methods for administration of 
antihyperlipidemic amounts of nicotinic acid and its antihyperlipidemic 
congeners (herein collectively referred to as nicotinates) so that the 
flush reaction is lessened or prevented. The methods involve pretreatment 
of a subject with a nonsteroidal antiinflammatory drug agent (NSAID) in an 
amount sufficient to inhibit synthesis of prostaglandin D2 (PGD2) by 
monocyte-derived skin cells, especially macrophage-like cells such as 
Langerhans cells. The pretreatment is continued for a period of 1-6 days 
prior to administration of the nicotinate, preferably for at least 2 days, 
more preferably at least 3 days, and typically within the range of 2-4 
days. Pretreatment beyond 3-4 days generally does not provide additional 
enhancement of the protection against flushing, but does preserve the 
protective effect and may be practiced within the scope of the invention. 
During pretreatment the NSAID is administered in at least one dose daily, 
preferably 2 or more doses daily. In most cases, 4 or fewer doses are 
preferred, for the convenience and concomitantly improved compliance of 
the patient or subject. The dosage form may provide immediate release (IR) 
or sustained release (SR) of the NSAID. An SR dosage form may be 
administered fewer times daily than a comparable IR form, while providing 
similar protective serum concentrations of the NSAID. 
The methods further provide for continued administration of the NSAID while 
the nicotinate is being taken. The nicotinate may be taken initially at a 
dosage level which is sufficient to produce hypolipemic effects in the 
subject, or may be taken initially at a lower level and raised 
progressively to hypolipemic dosage levels. This latter procedure allows 
induction of nicotinate tolerance to occur simultaneously with inhibition 
of flush by a NSAID. 
A preferred nicotinate is nicotinic acid itself, which optionally may be 
provided as a salt. Other hypolipemic nicotinates include esters of 
nicotinic acid, such as lower alcohol esters (e.g., methyl, ethyl, or 
propyl esters). 
When the nicotinate is an IR form of nicotinic acid itself, a hypolipemic 
dose level typically is at least 500 mg per day, often at least 500-750 mg 
or 750 mg-1 g, 1-1.5 g, or even up to 1.5-2 g daily. SR forms of 
nicotinate may be administered in lower dosages, often one-half the IR 
dosage. The daily dosage of nicotinate frequently is divided into multiple 
doses taken, e.g., 2-4 times daily. For purposes of defining the 
invention, a "hypolipemic amount" of nicotinate includes an amount which 
initially may be less than the amount which produces clinically 
significant hypolipemia, e.g., less than 500 mg for an IR form, provided 
that the daily dose is increased over time to a clinically effective 
hypolipemic amount. This allows for development of tolerance in 
conjunction with use of NSAIDs to lessen flush. An initial dosage of a 
subtherapeutic but tolerance-inducing amount of nicotinate typically will 
be capable of provoking at least some flushing reaction, e.g., 50-200 mg. 
This dosage may be increased gradually until dosages of 500 mg or greater 
are achieved. 
Particularly preferred NSAIDs include aspirin, phenylbutazone, ibuprofen, 
naproxen, and indomethacin. These may be administered in the usual dosage 
ranges for treatment of pain and inflammation. In preferred embodiments, 
the NSAID is administered in dosage ranges less than 25%, often less than 
15%, 10%, 5%, 1% or even 0.1%, of the usual antiinflammatory or analgesic 
dosage. 
An especially preferred NSAID is aspirin. Aspirin preferably may be 
administered in daily dosages of at least 10 mg, more preferably at least 
20, 40, 60, or 80 mg, but alternatively may be administered at levels of 
100, 120, 140, 160, or up to 325 or 650 mg daily. Even higher daily 
dosages of aspirin may be consumed and will tend to suppress flushing in 
accordance with the invention, but these dosages run some risk of 
provoking undesirable side effects such as gastrointestinal (GI) upset or 
even ulceration. Moreover, these higher dosages are not more effective 
than the preferred lower dosages; indeed, because they tend to interfere 
with the metabolism of niacin in the liver, higher doses of aspirin tend 
to increase the serum concentration of niacin and thereby exacerbate the 
flushing reaction. An especially preferred daily dose range of aspirin is 
40-80 mg, which is sufficient for extensive inhibition of synthesis of 
PGD2 in Langerhans cells, but low enough to have little capacity to 
provoke untoward side effects. Dosages at the low end of the range, e.g., 
10-80 or 10-40 mg daily, may be administered even to many patients who are 
sensitive to aspirin and who readily develop GI ulcers, etc. IR aspirin 
preferably is administered at least twice daily (i.e., bid), optionally 
three (tid) or four (qid) times daily. In particular preferred 
embodiments, an aspirin dose of 10-40 mg is administered twice a day. 
Other preferred NSAIDs include ibuprofen, naproxen, phenylbutazone, and 
indomethacin. Dosages of these NSAIDs are sufficient to inhibit synthesis 
of PGD2 in skin macrophages (Langerhans cells), thereby decreasing the 
flush reaction. As with aspirin, these NSAIDs inhibit PGD2 synthesis in 
the skin at lower concentrations than are required for inhibition of 
synthesis of other PGs in nonskin. tissue. For example, indomethacin is 
effective in reducing flush reaction at doses only 0.1%-10% as great as 
those used for general antiinflammatory effects. 
Indomethacin is active in inhibiting flush in daily dosages as low as 2-25 
mg, although up to 50, 100, 150, or even 200 mg daily may be taken. As 
with other NSAIDs, the daily dosage preferably is divided among 2, 3, 4, 
or more doses, or may be taken as one or more doses of an SR formulation. 
A preferred dosage range is 2-10 mg, including 2, 4, 5, 6, or 8 mg, 
preferably administered bid. 
Ibuprofen is effective in inhibiting flush in a daily dosage range similar 
to that for aspirin, e.g., 5-160 mg, although higher doses are effective 
also. In certain embodiments, preferred daily dosages are 5-80 mg, often 
10-50 mg, commonly 20-40 mg. The dosage usually is taken in a divided dose 
bid, tid, or qid. 
Naproxen is active in suppressing flush at a daily dosage of as little as 
5-100 mg, often within the range 10-80 mg, commonly 15-50 mg, typically 
20-40 mg. As with other NSAIDs, multiple doses, e.g., bid, tid, or qid, 
are preferred. Alternatively, an SR dosage form may be administered. 
Higher dosages, e.g., within the usual antiinflammatory dosage range of 
500-1500 mg, are also effective but not required. 
Phenylbutazone is active in suppressing flush at a daily dosage of 1-100 
mg, often 5-50 mg, commonly 10-25 mg. As with other NSAIDs, multiple 
doses, e.g., bid, tid, or qid, are preferred. Alternatively, an SR dosage 
form may be administered. Higher dosages, e.g., within the usual 
antiinflammatory dosage range of 300-600 mg, are also effective but not 
required. Dosages at the low end of the active range, e.g., 1-10 mg, are 
advantageous because of the incidence of side effects such as blood 
dyscrasias (e.g., granulocytosis, aplastic anemia). 
SR dosage forms are commercially available for some NSAIDs. For example, a 
timed-release form of aspirin is available in tablet form from Glenbrook 
Laboratories; see, e.g., Physician's Desk Reference. The tablets contain 
aspirin in a microencapsulated formulation with guar gum, microcrystalline 
cellulose, and starch. 
Other SR formulations may be prepared by conventional methods. Solid dosage 
forms such as tablets and capsules may be prepared by incorporating 
hydrophilic gums such as cellulose ethers, exemplified by methylcellulose, 
hydroxypropyl-methylcellulose, and sodium carboxymethylcellulose. These 
polymers control the release of a NSAID by diffusion out of and erosion of 
the gelatinous layer formed by hydration of the gum within the gut after 
oral administration. Sustained release tablets may be manufactured by 
direct compression of the mixture following blending or by conventional 
wet granulation methods. A blend comprising a polymeric gum, a diluent 
such as lactose, a NSAID, and a lubricant such as magnesium stearate may 
be mixed thoroughly (e.g., 30 min in a Hobart mixer) and compressed with a 
hydrulic press at pressures between 1,000-5,000 psi, resulting in a tablet 
having a hardness of 3-8 Kp. Capsules may be manufactured by filling 
shells with a similar blend. In general, the percentage of polymer may be 
varied between 20-80% (w/w). 
VI. EXAMPLES 
The following examples are illustrative of certain aspects of the 
invention; they are not to be construed as limiting the scope of the 
invention as a whole. 
A. Example 1: Pretreatment with Single Dose Aspirin 
Three subjects were administered 40 mg aspirin 1 hr prior to a single 500 
mg dose of IR nicotinic acid (Squibb). All three experienced severe 
flushing with a sunburned appearance on the face and ears, and blotches on 
the palms. All reported a subjective sensation of cutaneous warmth. Urine 
samples obtained at intervals after niacin administration demonstrated 
excretion of significant amounts of PGD-M, the major urinary metabolite of 
PGD2, over the next 7 hr (FIG. 1), confirming the association between PGD2 
release and flushing symptoms. 
Two weeks later the same subjects were administered 40 mg aspirin for each 
of four days. On the fourth day, a single 500 mg dose of IR nicotinic acid 
(Squibb) was administered 1 hr after the aspirin. Two of the subjects 
experienced virtually no flushing. The third subject experienced some 
flushing, but less than that encountered previously without multiday 
aspirin pretreatment. Urinary excretion of PGD-M was much lower (FIG. 2), 
confirming the suppressive activity of aspirin on PGD2 release. Release of 
PGF2 after aspirin pretreatment (40 mg) was approximately 10% of baseline 
(FIG. 3). 
B. Example 2: Pretreatment with bid Aspirin 
Three subjects were administered 40 mg aspirin twice daily (i.e., bid) in 
the morning and evening for three days. On the fourth day, a 500 mg dose 
of IR nicotinic acid was taken with 40 mg aspirin. None of the subjects 
experienced any appreciable flushing. 
Two weeks later the same subjects were administered a single dose of 500 mg 
nicotinic acid without aspirin. All three experienced severe flushing. 
C. Example 3: Inhibition of PG Release in vitro 
Niacin was shown to stimulate in vitro release of PGs from human 
circulating monocytes, which are precursors of macrophages, and from the 
human macrophage cell line THP-1 (FIG. 4). Aspirin in vitro inhibited 
niacin-stimulated release of PG from THP-1 cells with an IC50 of circa 
0.38 micromolar (0.07 ug/ml) (FIG. 5). For comparison, a dose of 40 mg 
aspirin in an adult causes a peak plasma concentration of about 0.6 ug/ml. 
Thus the in vitro results are consistent with the clinical observation of 
inhibition of flushing with 40 mg aspirin. 
D. Example 4: Inhibition of PG Release from Kupfer Cells in vitro 
Kupfer cells, a type of macrophage found in the liver, were obtained from 
guinea pigs. Niacin stimulated release of PGD2 from Kupfer cells in vitro 
in a dose dependent manner (FIG. 6). This further supports the conclusion 
that macrophages are the source of PGs released by niacin administration 
in vivo. 
E. Example 5: Niacin-stimulated Release of PG from Skin 
As further evidence that niacin -induced skin flushing is mediated by 
release of PGs, skin was treated with topical niacin, and release of 
eicosanoids into the efferent circulation was measured. Niacin increased 
the release of 9a, 11b-PGF2, a metabolite of PGD2, but did not release 
another eicosanoid, thromboxane (TxB2), which is also found in macrophages 
(FIG. 7). However, oral administration did result in increased amounts of 
metabolites of thromboxane and leukotriene as well as PGD2 in urine (FIG. 
8). Langerhans cells, the macrophages of skin, may differ from other 
macrophages in releasing lesser amounts of eicosanoids other than PGD2. 
F. Example 6: Pretreatment with Indomethacin in vitro 
Indomethacin was used in place of aspirin to inhibit PG production in THP-1 
cells in vitro as in Example 3. The IC50 was calculated to be 
approximately 1 nm. By contrast, inhibitory concentrations of indomethacin 
on PG production in other cell types are in the micromolar range. Thus 
THP-1 cells are approximately 1000 times more sensitive to indomethacin 
than are other cells. The dose of indomethacin required for in vivo 
inhibition of flushing is expected to be quite low as well. This confirms 
that low doses of NSAIDS other than aspirin are also effective in 
alleviating niacin-induced flushing. 
VlI. INCORPORATION BY REFERENCE 
All publications and patent applications mentioned herein are explicitly 
incorporated by reference.