Source: http://www.google.com/patents/US6071896?dq=4453763
Timestamp: 2017-10-18 01:25:48
Document Index: 228754073

Matched Legal Cases: ['Application No. 3', 'Application No. 3', 'Application No. 1', 'Application No. 1', 'Application No. 1', 'Application No. 1', 'Application No. 61', 'Application No. 61', 'Application No. 2', 'Application No. 2']

Patent US6071896 - Suppression of thromboxane levels by percutaneous administration of aspirin - Google Patents
A method is disclosed for inducing thromboxane suppression in a mammalian subject by percutaneously administering a pharmaceutical composition containing aspirin. Articles useful for practicing the therapeutic methods of the invention are also disclosed....http://www.google.com/patents/US6071896?utm_source=gb-gplus-sharePatent US6071896 - Suppression of thromboxane levels by percutaneous administration of aspirin
Publication number US6071896 A
Application number US 09/040,901
Publication number 040901, 09040901, US 6071896 A, US 6071896A, US-A-6071896, US6071896 A, US6071896A
Inventors Rudolph M. Keimowitz, Desmond J. Fitzgerald
Original Assignee Gundersen Clinic, Ltd.
Patent Citations (28), Non-Patent Citations (33), Classifications (18), Legal Events (7)
US 6071896 A
1. An article useful for suppressing thromboxane levels in a mammalian subject by contacting the skin of said subject with said article comprising a preparation comprising aspirin and a support or carrier for maintaining said aspirin in a suitable form for topical percutaneous absorption by said skin, wherein said aspirin is present in an amount sufficient to reduce thromboxane levels in said subject by more than 50% without substantially affecting prostacyclin levels or resulting in gastrointestinal toxicity upon application of said article.
2. The article of claim 1 wherein said aspirin is provided in the form of a salt.
3. The article of claim 2 wherein said salt is selected from the group consisting of the lactate salt of aspirin, the sodium salt of aspirin and the lysine salt of aspirin.
4. The article of claim 1, wherein said preparation comprises from about 250 mg to about 750 mg of aspirin.
5. The article of claim 1, wherein said preparation comprises about 250 mg of aspirin.
6. The article of claim 1, wherein said preparation comprises about 750 mg of aspirin.
7. The article of claim 1, wherein said preparation comprises about 9% aspirin.
8. The article of claim 1, wherein said aspirin is present in an amount sufficient to reduce thromboxane levels to from less than about 5% of baseline levels to less than about 50% of baseline levels.
9. The article of claim 1, wherein said article is in continuous contact with said skin for at least 4 successive days.
10. The article of claim 1, wherein said article is in continuous contact with said skin for at least 10 successive days.
11. The article of claim 1, wherein said carrier is selected from the group consisting of suspensions, creams, solutions, patches, gels, ointments, plasters and plaques.
12. The article of claim 1, wherein said carrier is selected from the group consisting of propylene glycol, isopropyl alcohol, and ethyl alcohol.
13. The article of claim 1, wherein said preparation further comprises at least one other active ingredient.
14. The article of claim 1, wherein said preparation further comprises an agent for promoting absorption of said aspirin.
15. The article of claim 1, wherein said preparation further comprises an anticoagulant.
This application is a divisional of U.S. application Ser. No. 08/780,426, filed Jan. 8, 1997, now issued as U.S. Pat. No. 5,763,425, which is a continuation of U.S. application Ser. No. 08/339,646, filed Nov. 14, 1994, now abandoned, which is a continuation of U.S. application Ser. No. 08/047,516, filed Apr. 19, 1993, now abandoned, which is a divisional of U.S. application Ser. No. 07/899,209, filed Jun. 16, 1992, now U.S. Pat. No. 5,240,917, which is a continuation-in-part of U.S. application Ser. No. 07/680,195, filed Apr. 3, 1991, and now abandoned. This application also claims priority from PCT International Application No. PCT/US92/02576, filed Apr. 2, 1992.
The present invention relates to the use of acetyl salicylic acid (aspirin) as an antithrombotic agent and as an agent to treat other medical conditions benefiting from suppression of thromboxane levels. Particularly, the present invention relates to the percutaneous administration of aspirin for inducing such effects and treating such conditions.
With the recognition of the role of antithrombotic agents in clinical medicine, investigators have pursued their efficacy, optimal dose, route of administration and safety. Aspirin has been found to be an effective antithrombotic agent in patients with cerebrovascular disease and ischemic heart disease. Aspirin may also have other antithrombotic applications. Although aspirin has become widely used as an antithrombotic agent, it still exhibits undesirable side effects, including gastrointestinal toxicity which is probably dose related.
To induce its suppressive effects, aspirin irreversibly acetylates the enzyme cyclo-oxygenase found in platelets and vascular wall cells [Burch et al., J. Clin. Invest. 61:314 (1978); Majerus, J. Clin. Invest. 72:1521 (1983); Roth et al., J. Clin. Invest. 56:624 (1975)]. Cyclo-oxygenase converts arachidonic acid to thromboxane-A2 (TXA2) in platelets and to prostaglandin-I2 (PGI2 or prostacyclin) in vascular walls [see for example, FitzGerald et al., J. Clin. Invest. 71:676 (1983); Preston et al., N. Engl. J. Med. 304:76 (1981)]. TXA2 induces platelet aggregation and vasoconstriction, while PGI2 inhibits platelet aggregation and induces vasodilation. In other words, aspirin can have both an antithrombotic effect (by reducing TXA2 production) and a thrombogenic effect (by reducing PGI2 production). As a result, striking an appropriate balance between aspirin's effects on TXA2 and PGI2 production has been a goal of aspirin therapy under these circumstances.
It is generally accepted that when aspirin is administered in doses of approximately 1,000 mg/day, it inhibits both TXA2 and PGI2 synthesis [Weksler et al., N. Engl. J. Med. 308:800 (1983)]. Daily administration of very low doses of aspirin (approximately 40 mg/day) has been reported to inhibit thromboxane-B2 synthesis in vitro and to reduce the urinary excretion of 2,3-dinor-thromboxane-B2 (both of which are metabolites of TXA2), without producing significant changes in the urinary excretion of 6-keto-prostaglandin-F1 a and 2,3-dinor-6-keto-prostaglandin-F1 a (which are both metabolites of PGI2 production) [Patrignani et al., J. Clin. Invest. 69-1366 (1982); FitzGerald et al., supra]. While 40 mg/day has no significant effect on prostacyclin biosynthesis, it does have some measurable effect [FitzGerald et al., supra]. Moreover this dose does not suppress 2,3-dinor-TXB2 very well and it is not known whether it suppresses bradykinin-stimulated prostacyclin formation. Therefore, this dose has not been demonstrated to provide selective inhibition of thromboxane synthesis without also inhibiting prostacyclin formation.
In contrast, others have reported that equally low doses of aspirin reduced PGI2 synthesis by 50% in both arterial and venous tissue [Preston et al., supra], and even lower doses (20 mg/day for 1 week) have been reported to inhibit PGI2 synthesis in both arterial and venous tissue by 50% in atherosclerotic patients [Weksler et al., supra]. It has been proposed that although this differential effect on the inhibition of TXA2 and PGI2 synthesis has been reported when urinary metabolites are measured to assess inhibition, there is no significant evidence for this differential effect when PGI2 synthesis is measured by assay of vascular wall biopsy tissue or when the assays for TXA2 and PGI2 are performed on blood samples [Weksler et al., supra]. However, it is not possible to achieve platelet selectivity with standard oral aspirin. Inhibition of basal PGI2 biosynthesis is similar over doses of 80-2,400 mg/day and bradykinin-stimulated PGI2 formation is abolished on oral aspirin 75 mg/day.
Aspirin has also been found to be an effective treatment for other medical conditions which benefit from lowering of TXA2 levels. For example, it has been reported that daily doses of aspirin given during the third trimester of pregnancy can significantly reduce the incidence of pregnancy-induced hypertension and preeclamptic toxemia in women at high risk for these disorders as a result of reductions in TXA2 levels [Schiff et al., N. Engl J. Med. 321:351 (1989)]. Aspirin has also been reported to provide positive effects in women at risk for pregnancy-induced hypertension. Low doses of aspirin were reported to selectively suppress maternal thromboxane levels, but only partially suppressed neonatal thromboxane, allowing hemostatic competence in the fetus and newborn [Benigni et al., N. Engl. J. Med. 321:357 (1989)]. The use of aspirin for reducing the risk of fatal colon cancer has also been proposed [Thun et al., N. Engl. J. Med. 325:1593 (1991)]. Reduction of thromboxane levels has also been suggested as a means for treating thrombosis in patients having antiphospholipid syndrome associated with lupus [Lellouche et al., Blood 78:2894 (1991)]. Low-dose aspirin has also been suggested as therapy for migraine headache [see for example, Buring et al., JAMA 264(13) (1990)]. The role of arachidonic acid metabolites (e.g., TXA2 and PGI2) in migraine have also been invesitaged [see for example, Parantainen et al., "Prostaglandins in the Pathophysiology of Migraine" in P. B. Curtis--Prior (ed.), Prostaglandins: Biology and Chemistry of Prostaglandins and Related Eicosanoids (new York: Churchill Livingstone 1988), pp. 386-401; Puig-Parellada et al., Headache 31(3):156 (1991); Tuca et al., Headache 29(8):498 (1989); Nattero et al, Headache 29(4):233 (1989)].
The use of aspirin as a thromboxane suppressant has been hampered by its tendency to cause gastric bleeding upon traditional administration of aspirin in oral dose form. Studies have reported that aspirin produces erythema of the gastric mucosa in approximately 80% of patients with rheumatic diseases, gastric erosions in approximately 40%, and gastric ulcer in 15% [Silvoso et al., Ann. Intern. Med. 91:517 (1979)]. Aspirin applied topically to gastrointestinal tissue damages gastric mucosa and induces occult gastrointestinal bleeding [Croft et al., Br. Med. J. 1:137 (1967)]. Intravenous administration of aspirin may also produce some effects on gastric mucosa which is less pronounced with parenteral than with oral administration [Grossman et al., 40:383 (1961)]. Oral administration of diluted solutions of aspirin cause considerably less bleeding than similar doses in tablet form, and aspirin solutions containing antacids with sufficient buffering capacity cause no measurable blood loss [Leonards et al., Arch. Intern. Med. 129:457 (1972)]. Enteric-coated aspirin use results in less gastric and duodenal mucosal injury than regular aspirin [Graham et al., Ann. Intern. Med. 104:390 (1986)].
In accordance with the present invention, thromboxane suppressing effects are provided without the gastric side effects normally associated with aspirin therapy. Aspirin is applied topically to a patient's skin such that it is percutaneously absorbed. The aspirin is taken into the bloodstream in quantities sufficient to inhibit TXA2 synthesis. The methods of the present invention can be used to treat any medical condition for which suppression of thromboxane levels is beneficial. For example, such methods can be used to produce antithrombotic effects and to treat pregnancy-induced hypertension and preeclamptic toxemia.
The aspirin can be applied by use of a support or carrier which contains the aspirin preparation, including without limitation suspensions, creams, solutions, patches (adhesive and non-adhesive), gels, ointments, plasters, plaques or other known forms for applying topical agents, as long as the aspirin can be delievered in a form which will penetrate the skin (such as, for example, in a solubilized form). Articles can be made which incorporate the aspirin preparation, in some instances with a support or carrier (such as in the form of an adhesive patch), which are useful in practicing the therapeutic methods of the present invention.
The aspirin content of the preparation will vary depending on the form of administration used. In one embodiment, the aspirin is applied at 750 mg/day at a concentration of about 9% aspirin. To achieve the desired suppression effects, aspirin is preferably administered over a period of several days until TXA, levels are reduced to minimal levels, preferably less than 50% of baseline levels, more preferably less than 10% of baseline levels, most preferably less than 5% of baseline levels. Although TXA2 levels will be reduced almost immediately, substantial reductions in those levels are achieved and maintained by daily administration over a course of several days, preferably at least 4 days, most preferably at least 10 days.
Any form of aspirin may be employed in practicing the present invention as long as the active compound can penetrate the skin. The term "aspirin" as used herein and the apended claims is intended to encompass, without limitation, all such forms. Suitable forms may include acetyl salicylate and salts, esters, hydrates, etc. thereof. Particular salts which may be used include without limitation the lactate, sodium and lysine salts of aspirin Compositions and articles of manufacture of the present invention may also include aspirin in a first form (such as for example, an aspririn "prodrug" or another stabilized compound containing acetyl salicylate) which is later converted to a second form which can penetrate the skin.
The preservation of vascular cyclooxygenase is consistent with the low bioavailability of the dermal aspirin. Plasma aspirin and salicylate were determined using a highly sensitive assay that can measure levels of <0.1 ng/ml. Following oral aspirin 325 mg or 162 mg, peak plasma aspirin levels were 2.0 and 1.3 ug/ml, respectively. In contrast, following dermal aspirin, plasma levels peaked at 237±114 ng/ml and plasma salicylate peaked at 788±114 ng/ml.
These data suggest that aspirin applied to the skin is absorbed very slowly, resulting in a delayed onset and offset of activity. Platelets passing through the site of application are inhibited by relatively high concentrations of aspirin. A similar localized platelet effect has been reported with oral aspirin, where inhibition of serum TXB2 occurs prior to the appearance of aspirin systematically. As platelet cyclooxygenase cannot recover, cumulative inhibition of all platelets occurs over time. In contrast, little aspirin reaches the systemic circulation, so that vascular cyclooxygenase is protected. The poor systemic bioavailability of dermal aspirin presumably reflects low skin permeability and dilution and inactivation in the venous and pulmonary circulations.
FIG. 1 is a graph of serum TXB2 (ng/ml) levels during administration of dermal aspirin 250 mg/day and 750 mg/day vs. vehicle for 10 days and following withdrawal of therapy.
FIG. 2 is a graph of urinary excretion of 2,3-dinor TXB2 (TX-M), expressed as a percent of baseline, during the administration of dermal aspirin or vehicle for 10 days and following withdrawal of therapy. Note that the baseline levels were 381±48, 440±56 and 498±76 pg/mg creatinine for vehicle, aspirin 250 mg and aspirin 750 mg groups, respectively.
FIG. 3 is a graph of urinary excretion of 2,3-dinor-6-keto PGF12 (PGI-M), expressed as a percent of baseline, during the administration of dermal aspirin or vehicle for 10 days and following withdrawal of therapy. Note that the baseline levels were 244±68, 402±139 and 248±73 pg/mg creatinine for vehicle, aspirin 250 mg and aspirin 750 mg groups, respectively.
The advantages of the present invention can be appreciated by reference to the following example which is meant to illustrate, but not limit, the present invention.
Five healthy adult volunteers (3 male, 2 female) were studied. Each refrained from ingesting oral aspirin for two weeks prior to study. Prior to treatment in accordance with the present invention, baseline thromboxane levels and hemoccults were obtained.
0.2 ml of serum or heparinized plasma were used as sample specimens. 0.2 ml of each standard and each sample was pipetted into respectively labeled disposable polystyrene tubes. Into another polystyrene tube, 0.2 ml of deionized water was pipetted to be used as a reagent blank. 1.0 ml of deionized water was added to all tubes. 1.0 ml of Trinder's reagent was then added to all tubes, which were mixed and let stand tubes for 5 minutes. The tubes were then centrifuged for 10 minutes. The clear supernatant (minimum of 1.0 ml) was placed into respectively labeled 10×75 nm cuvettes. Samples were analyzed by reading % T at 540 nm against the reagent blank set at 100% T. Sample values were compared with standard values to determine levels. Results over 75 mg percent were diluted and re-analyzed.
A preparation of aspirin in isopropyl alcohol and propylene glycol was prepared by mixing "Aspirsol"™ topical aspirin (NDC54102-001-01; commercially available from TERRI Pharmaceuticals, Inc., PO Box 6454, Kingwood, Tex. 77325) in accordance with the package instructions except that 8 ml instead of 10 ml of the suspending solution was used. The resulting solution contained approximately 9% aspirin rather than the 7-8% indicated on the package label.
Two of the subjects continued daily application for another five days (total ten days). For Days 6 and 7, aspirin solutions freshly prepared as described above were used. Beginning with Day 8, a different aspirin preparation was used. This second preparation was prepared by crushing aspirin tablets containing approximately 975 mg aspirin to form a powder. The powder was then formed into a paste with approximately 2 ml of distilled water. This paste was then mixed with 4 ml propylene glycol and 4 ml ethanol to produce approximately 10 ml of a cloudy solution. This cloudy solution was then filtered to remove excipients and other insoluble material found in the crushed aspirin tablets. After filtering, approximately 10 ml of a clear solution was obtained which contained approximately 9% aspirin. 8 ml of the resulting solution was used in each application. This second solution was applied to the two continuing subjects as previously described. Salicylate and thromboxane levels were checked after the tenth day.
Thromboxane levels are summarized in Table 1.
TABLE 1______________________________________Thromboxane Levels  (ng/cc)  Subject  Baseline Day 2 Day 3 Day 4  Day 5 Day 10______________________________________1      401      311     250   199    105/351                                      18  2 372    105 12  3 .sup. 1072    124  4 402    152  5 394     25______________________________________ 1 The first number is the level measured in the morning of Day 5 prior to administration of the new Day 5 dose. The second number is the level measured eight hours after the Day 5 application. 2 Subject 3 had a very low measured baseline thromboxane level which is believed to have been a sampling error.
As summarized in the table, baseline thromboxane levels were found to range from 372-402 ng/cc in four out of five subjects. The low baseline for Subject 3 is believed to be erroneous and, as a result, the data for Subject 3 was not considered relevant. After five daily applications of aspirin in accordance with the present invention, caused a decrease in thromboxane levels of at least 50%. The two subjects that continued therapy in accordance with the present invention for another five days had marked suppression by Day 10 of 95 and 97% to levels of 18 and 12 ng/cc. Salicylate levels in four of five patients on day five were measured as 1 mg percent or less (approx. 1 mg percent being the lower limit of sensitivity of the assay). All hemoccults taken were negative. No gastrointestinal symptoms or other side effects were noted or reported by the subjects.
Only healthy male and female volunteers were studied. The subjects were asked to avoid aspirin and any other cyclooxygenase inhibitors for the 10 days before and throughout the period of investigation. Aspirin (acetyl salicylic acid, USP) powder was dissolved in propylene glycol and either isopropyl alcohol or ethanol (1.7:1 v/v) to a final concentration of 94 mg/ml. Preliminary studies demonstrated that aspirin was stable in this vehicle, with less than 1% salicylate detected after 24 hr at room temperature. The aspirin preparation was made daily immediately prior to its application Volunteers attended the clinic where the preparation was applied and were asked not to wash the area for at least 12 hours. The aspirin solution was applied to the forearm and upper arm over a 15 min interval. Volunteers received aspirin 250 mg (n=4), aspirin 750 mg (n=6) or vehicle (n=6) for 10 days and were followed for 8 days following drug withdrawal. The volunteers were aged 31-56 years, with equal numbers of male and females in each treatment group.
Blood without anticoagulant was obtained for serum TXB2, the stable metabolite of TXA2, prior to and at intervals during and following aspirin administration. The blood was allowed to clot in glass at 37° C. for 60 min and the serum removed and stored at -20° C. until analyzed. Urine was collected over 24 hours at corresponding times for measurement of 2,3-dinor-TXB2 (TX-M) and 2,3-dinor-6-keto-PGF1a (PGI-M), major enzymatic metabolites of TXA2 and PGI2, respectively [Lawson et al., Analyt. Biochem. 150:463 (1985); FitzGerald et al., N. Engl. J. Med. 310: 1065 (1984)]. Excretion of these products is an index of the in vivo formation of their parent compounds [FitzGerald et al., supra; Reilly and Fitzgerald, Blood 69: 180 (1987)]. Serum TXB2 and urinary metabolites were determined by negative ion-chemical ionization, gas chromatography-mass spectrometry (NICI-GCMS) using authentic deuterated standards, as previously described [Braden et al., supra].
Serum TXB2, an index of the capacity of platelets to generate TXA2, was within the normal range in all subjects prior to study, demonstrating that none had been exposed to a cyclooxygenase inhibitor. Application of the vehicle alone had no effect on serum TXB2 in 6 subjects (FIG. 1). With aspirin 750 mg/day (n=6), there was a progressive reduction in serum TXB2 in all but one of the volunteers. In the remaining subjects, serum TXB2 was 5±3% of baseline by day 10 of application (n=5, p=0.003; FIG. 1). Aspirin 250 mg/day induced a smaller fall in serum TXB2, which was 55±11% by day 10 (n=4; p<0.01). Following the withdrawal of aspirin, serum TXB2 increased gradually and by day 8 was 93±7 and 65±9% of baseline for aspirin 250 mg and 750 mg, respectively.
TXA2 biosynthesis demonstrated a similar response. Thus, there was a dose dependent reduction in the urinary excretion of TX-M. At 750 mg/day of dermal aspirin. TX-M declined gradually and was 32±7% of baseline by day 10 (n=5; p=0.002) of drug application. By 8 days following drug withdrawal, excretion of the metabolite had recovered to 65±9% of the pretreatment value (FIG. 2). Despite the evidence of marked inhibition of platelet cyclooxygenase, there was only a small fall in PGI2 biosynthesis, based on urinary PGI-M determinations (FIG. 3). Although the changes did not achieve statistical significance (p=0.074 by ANOVA), there was an apparent dose response relationship. Thus, urinary excretion of PGI-M fell to 84±4% and 76±7% of baseline on aspirin 250 mg/day and 750 mg/day, respectively (FIG. 3). The peak decrease in PGI-M excretion occurred by day 4 on both doses, in contrast to TX-M excretion
In an additional 4 subjects, we examined the increase in PGI2 formation in response to intravenous bradykinin prior to and following oral aspirin 75 mg or dermal aspirin 750 mg daily for 14 days. The protocol for bradykinin has been described previously [Clark, N.Engl.J.Med 325:1137 (1991)]. Volunteers were admitted after an overnight fast to the Clinical Research Center. Blood samples were obtained for serum TXB2 and the subject asked to void. Through a peripheral vein, 1 liter of normal saline was infused over 1 hour. After a further hour, bradykinin was infused in incremental doses of 100-800 ng/kg/min, each over 15 mm. The infusion was continued at the maximum tolerated dose for a total period of 2 hr. Blood pressure and heart rate were monitored continuously. Urine was collected in separate 2 hr aliquots prior to, during and following the bradykinin infusion.
Previous studies have demonstrated that bradykinin increases PGI2 biosynthesis by on average 2-6 fold. In the 4 subjects studied, bradykinin induced a 5.1±6 fold increase in PGI-M excretion. Two subjects were treated with oral aspirin 75 mg/day for 14 days and two with dermal aspirin 750 mg/day. Both preparations caused a marked fall in urinary TX-M (TABLE 2). Oral aspirin resulted in a decrease in urinary PGI-M at rest and following stimulation with bradykinin. In contrast, resting and stimulated PGI-M excretion was largely unaltered by dermal aspirin.
TABLE 21______________________________________        Dermal Aspirin                    Oral Aspirin  (750 mg/day) (75 mg/day)        PT 1  PT 2      PT 1   PT 2______________________________________TX-M     pre ASA   220     121     136  111   post ASA  46  29  26  43  PGI-M pre ASA 163 105 104 200  (rest)   post ASA 138 149  63  96  PGI-M pre ASA 1520  559 433 340  (stim)   post ASA 1553  601 173 132______________________________________ 1 The excretion of TXM and PGIM before and following dermal aspirin 750 mg/day or oral aspirin 75 mg/day for 10 days. Urine samples were collected over 2 hr before (rest) and following the administration of bradykinin (stim). Dermal aspirin suppressed TXM, but had not effect on PGIM.
In 4 subjects (2 male, 2 female) demonstrating a marked (>90%) decrease in serum TXB2, plasma aspirin and salicylate were determined at timed intervals (0, 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 12 and 24 hr) following the application of aspirin on days 1 and 14. Aspirin was applied in a dose of 750 mg on one limb over a 15 min interval. Samples were drawn from the opposite arm. Blood was withdrawn into heparin (10 U/ml final concentration) and potassium fluoride (5% final concentration), the latter to prevent ex vivo metabolism of aspirin by plasma esterases. The plasma was separated immediately and stored at -700° C. until analyzed. Aspirin and its metabolite, salicylic acid, were measured by NICI-GCMS using deuterium-labelled analogues as internal standards, as previously described [Clark, supra].
Plasma aspirin and salicylate levels were determined following the single application of dermal aspirin in five subjects who demonstrated a marked (>90%) reduction in serum TXB2. Plasma aspirin was barely detectable up to three hours following application when it rose to 237±114 ng/ml. At six hours, it fell to 52±14 ng/ml and by 24 hours it decreased to 4±3 ng/ml. Plasma salicylate demonstrated a similar pattern. At two hours, it was 69±20 ng/ml rising to 250±77 ng/ml at three hours. At six hours, plasma salicylate was 774±296 ng/ml. By twenty-four hours, the levels had fallen to 329±84 ng/ml. The later peak in salicylate levels is consistent with its being derived from aspirin. Moreover, this prolonged elevation of plasma salicylate is to be expected, given its longer plasma half-life. Note that levels following oral aspirin (75 mg) are 1-2 ug/ml.
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U.S. Classification 514/165, 424/449, 514/947
International Classification A61K47/10, A61K31/60, A61K9/00, A61K45/06
Cooperative Classification Y10S514/947, A61K31/60, A61K9/0014, A61K45/06, A61K31/616, A61K47/10
European Classification A61K31/60, A61K45/06, A61K47/10, A61K9/00M3, A61K31/616
Owner name: KEIMOWITZ, RUDOLPH M.D., MINNESOTA
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