Phase Ib Single- and Multiple-Dose Pharmacokinetic Study of Oral NV-52 in Healthy Volunteers

Drugs R D 2008; 9 (3): 159-166ORIGINAL RESEARCH ARTICLE 1174-5886/08/0003-0159/$48.00/0

© 2008 Adis Data Information BV. All rights reserved.

Phase Ib Single- and Multiple-DosePharmacokinetic Study ofOral NV-52 in Healthy VolunteersLaurence G. Howes,1 Jan B. Howes,2 Jiu Li Huang3 and Catherine Walker3

1 Bond University Medical School, Gold Coast, Queensland, Australia2 ACL Statistics Pty Ltd, Hope Island, Queensland, Australia3 Novogen Pty Ltd, North Ryde, Sydney, New South Wales, Australia

Background and objective: NV-52 is a novel synthetic flavonoid thromboxaneAbstractsynthase (TXS) inhibitor that may be useful for the maintenance of remission ininflammatory bowel disease (IBD). This study was conducted to determine thesingle- and multiple-dose pharmacokinetics of NV-52 in nine healthy volunteers(five men, four women; mean [± SD] age 23 ± 2 years).Methods: NV-52 400 mg was administered once daily for 10 days (excludingday 2) in an open-label study. Plasma was sampled and urine was collected for48 hours after the first and last doses. Plasma and urine unconjugated and total(unconjugated plus glucuronide and sulphate conjugated) NV-52 concentrationswere measured using liquid chromatography-mass spectrometry.Results: No adverse events were observed. Unconjugated and total NV-52appeared and rose rapidly in plasma following the first dose. Time to maximumconcentration values were 1.92 ± 1.17 and 2.72 ± 1.52 hours for unconjugated andtotal NV-52, respectively. Unconjugated and total NV-52 were eliminated withplasma half-lives of 13.12 ± 17.31 and 18.03 ± 19.06 hours, respectively,following the first dose. Pre-dose levels following multiple-dose administrationwere 135.17 ± 120.03 and 751.9 ± 679.74 ng/mL for unconjugated and totalNV-52, respectively. Multiple-dose administration did not significantly alter thepharmacokinetics of NV-52. Renal elimination accounted for about 20–35% ofthe total (largely conjugated) drug but only 1% of unconjugated NV-52.Conclusions: Plasma concentrations of unconjugated NV-52 following single-and multiple-dose administration were well above the range found to be asso-ciated with suppression of colitis in a murine model of IBD.

Introduction Derivatives of 1,2-diphenylpropane (isoflavo-noid) are a potentially important new class of phar-

NV-52 is a novel synthetic flavonoid thrombo- maceutical compounds, with isoflavones from redxane synthase (TXS) inhibitor that may be useful for clover or soy having been reported to have usefulthe maintenance of remission in inflammatory bow- pharmacological effects in preclinical and clinicalel disease (IBD). research. Antioxidant effects, antineoplastic ac-

160 Howes et al.

tivity, tyrosine kinase inhibition (genistein), im- larly successful in the maintenance of remission ofhuman IBD.provements in endothelial function, blood pressure

An initial phase I, single-dose study of NV-52reduction and suppression of inflammation have400 mg in normal volunteers indicated that NV-52been reported for a range of isoflavones orwas well tolerated, rapidly absorbed and underwentisoflavone derivatives.[1-6] NV-52 has been synthe-extensive metabolism to glucuronide or sulphatesized using the structure-function activity of deriva-conjugated forms. The plasma half-life was aroundtives developed from red clover isoflavones and6–8 hours.[10] The present study compared thetheir metabolites. The chemical structure of NV-52pharmacokinetics of NV-52 400 mg once daily fol-is presented in figure 1.lowing single- and multiple- (10 days, excludingIBD comprises two different syndromes: ulcera-day 2) dose administration to determine whether

tive colitis (UC), which involves the rectum andaccumulation of the drug occurs, whether

colon, and Crohn’s disease (CD), in which anypharmacokinetics are altered following repeated ad-

portion of the gastrointestinal tract may be affected.ministration and to assess further the safety of the

The aetiology of IBD is complex and still poorly drug.understood.[7] Accumulating evidence indicates thatthe IBD is related to inappropriate activation of Subjects and Methodsimmune and inflammatory responses initiated by

The study followed an open-label design withstimulation of luminal flora or their products, andsubjects taking NV-52 400 mg once daily for 10that genetic factors influence the balance betweendays (excluding day 2) [Australian Clinical Trialleukocyte recruitment and down-regulatory mucosalRegistration Number ACTRN12606000240549].repair processes.[8] No management strategy is total-

ly effective, but current therapy is targeted at reduc-Subjectsing inflammation and/or the immune response using

anti-inflammatories (corticosteroids, aminosalicy- Nine healthy volunteers (five men, four women)lates), immunosuppressives, immunotherapies or were enrolled in the study. A full history andsurgery. Improved maintenance therapy remains the medical examination along with baseline laboratorygreatest unmet medical need in treating these disor- testing were performed prior to administration ofders, with the ‘holy grail’ in drug development being study drug. Patients were evaluated to ensure thata nontoxic agent that will maintain remission of they met the inclusion and exclusion criteria for thedisease.[9] study. Healthy male or female volunteers aged

18–40 years who were nonsmokers and able toNV-52 is protective in a murine model of dextranunderstand the risks and benefits of the study andsulphate sodium (DSS)-induced colitis.[10] This ef-provide written informed consent to participationfect was most marked at the lowest dose studiedwere included in the study. Subjects were excluded(0.1 mg/kg). Importantly, protection was maximizedif they were taking a concurrent investigationalwhen NV-52 was administered prior to the inductiondrug; had been treated with any investigationalof colitis, suggesting strongly that it might be simi-agents within 4 weeks of commencing the study;were consuming >40 g of alcohol/day; had a historyof alcohol or drug dependence within the last 3years; had a chronic illness that required regulartherapy; had asthma, previous hypersensitivity orallergy to aspirin or other anti-inflammatory agents;or had taken any prescription medication other thanthe oral contraceptive pill within the precedingweek. Women not using adequate contraception

O

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Fig. 1. Structure of NV-52 (8-bromo-7-hydroxy-3-(4-hydroxy-phenyl)-2,3-dihydrochromen-4-one).

© 2008 Adis Data Information BV. All rights reserved. Drugs R D 2008; 9 (3)

Phase Ib Pharmacokinetic Study of Oral NV-52 161

were also excluded, and a serum pregnancy test was days after the last dose of NV-52) was also conduct-performed on all female participants. ed.

(3) An ECG was performed at screening, and on theNV-52 Administration final dosing day (day 10) [pre-dose and +2 hours

post-dose].Subjects were administered NV-52 2 × 200 mg(4) Any clinically significant, out-of-range labora-oral capsules 2 hours after a standard light breakfasttory parameter or the development of any abnormal-on the first study day; plasma and urine samplesity on clinical examination was recorded as an ad-were collected for 48 hours thereafter. Multiple-verse event.dose administration of NV-52 2 × 200 mg capsules

each morning began on day 3 and continued for 7Assay Methoddays. On day 10 the subjects returned and received

the final dose of NV-52 2 × 200 mg capsules.Plasma and urine samples were assayed using aPlasma and urine samples were collected for 48

fully validated liquid chromatography-electrosprayhours after the last dose.tandem mass spectrometry (LC-ES/MS/MS) tech-nique. For unconjugated NV-52 plasma samples,Collection of Plasma and Urine Samples100 μL was added to 10 μL internal standard

Plasma samples were collected at the following (6-chloro-dihydrodaidzein 2 μg/mL) and 100 μLtimes after the first dose of NV-52: baseline (pre- acetonitrile. After vortex mixing for 30 minutes, thedose), 10, 20, 30, 45 and 60 minutes, and 1.5, 2.5, mixture was centrifuged at 3000 rpm for 15 minutes.3.0, 3.5, 4.0, 5.0, 6.0, 7.0, 8.0, 24 and 48 hours. The supernatant was transferred into an insert vialThese sampling times were repeated on day 10 (after and 10 μL was injected for LC-ES/MS/MS. For7 days of multiple-dose administration). A ‘pre- unconjugated NV-52 urine samples, 10 μL of urinedose’ plasma sample was also collected on days 5 was mixed with 90 μL of blank plasma and theand 7 prior to the morning dose. sample was then treated as a plasma sample. For

Urine was collected for NV-52 assay following total NV-52 plasma or urine samples, a 5-μL samplethe first dose and following multiple-dose adminis- was incubated with 95 μL of blank plasma and 5 μLtration on day 10 at baseline, 0–2 hours, 2–6 hours, of β-glucuronidase (Sigma-Aldrich, Sydney, NSW,6–24 hours and 24–48 hours post-dose. The volume Australia) at 25ºC overnight. After incubation, theof urine was recorded on each occasion. sample was treated as for the unconjugated NV-52

plasma sample as described above. NV-52 in plasmaSafety and Tolerabilitysamples was demonstrated to be stable through three

The safety and tolerability of NV-52 were as- freezing and thawing cycles and at room tempera-sessed as follows: ture for 2 days. The extracted NV-52 was demon-(1) Serum biochemistry and haematology were mea- strated to be stable in the autoinjector at 20ºC for 31sured at screening and at each challenge immediate- days. Analysis of blank plasma samples demonstra-ly prior to and at 6 hours and 24 hours following ted no interference with assay of either NV-52 orNV-52 administration on each of the 2 study days 6-chloro-dihydrodaidzein.and at day 17 (i.e. 7 days after the final dose of The analytical system used a Waters AllianceNV-52) 2795 LC system and Quattro LC triple quadrupore(2) Clinical examination was performed at screen- mass spectrometer (Waters Pty Ltd, Sydney, NSW,ing, immediately prior to drug administration on Australia). A Waters Symmetry Shield™ 1 C18, 5study days 1 and 10, and on day 17 (7 days after the μm, 3.9 × 20 mm column (Waters Pty Ltd, Sydney,last dose of NV-52). A follow-up visit on day 38 (28 NSW, Australia) in a 40°C oven was used for the

1 The use of trade names is for product identification purposes only and does not imply endorsement


162 Howes et al.

chromatograph separation. The gradient elution was • The plasma elimination rate constant calculatedperformed at a flow rate of 0.2 mL/min from an as 0.693/Kel (t1/2).initial condition of 15% mobile phase A (MeOH) • The area under the plasma concentration-timeand 85% mobile phase B (2 mmol/L ammonium curve from time zero to the last measured timeacetate in water) to 100% mobile phase A in 5

point calculated using the trapezoidal ruleminutes. The gradient elution was back to the initial

(AUCt).condition after 11 minutes. A MassLynx 4.0 mass• The AUC from time zero to infinity calculatedspectrometer software program (Waters Pty Ltd,

using the trapezoidal rule (AUC∞). The area fromSydney, NSW, Australia) was used to run the massspectrometer. The lower limit of detection of the the last measured time point to infinity was esti-assay was 2.5 ng/mL and the upper limit of the mated as the concentration at the last measuredstandard curve was 20 000 ng/mL. The assay was time point divided by the elimination rate con-linear over this range (R2 = 0.9999). The within-day stant.and between-day variability of the assay and theaccuracy values were all <8.5% except for at the

Statistical Analysislower limit of quantitation, where these values were<18%. The recovery of both NV-52 and 6-chloro-

Pharmacokinetic parameters were calculated us-dihydrodaidzein was 100%.ing PKF plug-in software for Excel. Verification ofThe level of conjugated NV-52 was calculated by

subtracting the conjugated NV-52 level from the normality was made for each parameter using thetotal NV-52 level. Kolmogorov-Smirnov test. In all cases, the d value

was >0.05, indicating normality of distribution. Re-Pharmacokinetic Analysis Methods sults were expressed as mean ± SD. Comparisons

between single- and multiple-dose administrationThe pharmacokinetic parameters measured and were made using the Student’s paired t-test.

their methods of calculation were as follows:

• The maximum plasma concentration actually re-Participant Consent and Ethical Approvalcorded (Cmax).

• The actual time at which Cmax was observedWritten, informed consent was provided by all(tmax).

participating subjects and the study protocol was• The elimination rate constant calculated as theapproved by the Bond University Human Ethicsslope of the log of plasma concentrations versusReview Committee.time from the Cmax onwards (Kel).

Table I. Pharmacokinetic parameters for unconjugated NV-52 following single- and multiple-dose administration

Unconjugated NV-52 Single dose Multiple dose p-Value

Pre-dose (ng/mL) NA 135.17 ± 120.03 NA

Cmax (ng/mL) 1 850.56 ± 947.90 2 025.47 ± 1546.28 0.74

tmax (h) 1.92 ± 1.17 1.95 ± 1.36 0.96

Kel (ng/mL • h) 0.19 ± 0.22 0.40 ± 0.25 0.13

t1/2 (h) 13.12 ± 17.31 4.32 ± 4.61 0.13

AUCt (ng • h/mL) 10 146.6 ± 4319.7 10 317.7 ± 3551.6 0.90

AUC∞ (ng • h/mL) 17 352.0 ± 18603.5 10 592.7 ± 3604.9 0.31AUC = area under the plasma concentration-time curve; AUCt = AUC from time zero to the last measured time point calculated using thetrapezoidal rule; AUC∞ = AUC from time zero to infinity calculated using the trapezoidal rule; Cmax = maximum plasma concentration;Kel = elimination rate constant calculated as the slope of the log of plasma concentrations vs time from Cmax onwards; NA = not available;t1/2 = plasma elimination rate constant calculated as 0.693/Kel; tmax = time at which Cmax was observed.



subjects with tmax occurring around 2 hours. Therewas a moderate degree of variability in Cmax, whichranged from 941.6 to 3346.5 ng/mL. In severalsubjects there were biphasic peaks of unconjugatedNV-52. Following multiple-dose administration,pre-dose levels of unconjugated NV-52 were low incomparison with Cmax values (98.7 ± 57.8 on day 5,85.5 ± 56.9 on day 7 and 135.2 ± 120.0 on day 10prior to the last dose).

Cmax values following the last dose did not differstatistically from those observed following the first

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Fig. 2. Mean plasma concentration vs time for single-dose unconju-gated NV-52 following administration of a single dose.

dose (multiple dose 2025 ± 1546 vs single dose1851 ± 975 ng/mL; p = 0.74). Values for tmax wereResultsalso similar following single- and multiple-dose ad-ministration (p = 0.96), as were AUCt (p = 0.90) and

Demographic Data AUC∞ (p = 0.31) values. Values for t1/2 of unconju-gated NV-52 tended to be shorter following multi-The nine subjects consisted of five men and fourple-dose administration than following single-dosewomen. There was one Asian and eight Caucasians.administration (4.3 ± 4.6 vs 13.1 ± 17.3 hours), butThe mean age of participants was 23 ± 2 yearsthis was largely a result of particularly high values in(range 19–25 years). The subjects’ mean body masssubjects 5 and 9 following single-dose administra-index (BMI) was 21.37 ± 2.06 kg/m2 (rangetion. Values for t1/2 values for unconjugated NV-5219.58–26.23 kg/m2), their mean heart rate wasdid not differ statistically following single- and mul-65 ± 3 beats/min (range 61–70 beats/min) and theirtiple-dose administration.mean systolic and diastolic blood pressures (BPs)

were 109 ± 14/67 ± 10 mmHg (range 81–127/ Urinary excretion of unconjugated NV-52 was56–71 mmHg), respectively. relatively low following both single- and multiple-

dose administration and the cumulative doses ex-Safety creted in the urine over 48 hours following single-

and multiple-dose administration were 8.23 ±No significant adverse events were reported or10.07 mg and 4.28 ± 2.42 mg, respectivelyobserved. NV-52 therapy was not associated with(p = 0.30). Urinary excretion during the last timeany change in serum biochemistry, haematology,period (24–48 hours) was 1.83 ± 3.25 mg comparedclinical examinations or ECG recordings.

Pharmacokinetics

Unconjugated NV-52Pharmacokinetic measurements derived from

plasma concentration of unconjugated NV-52 ver-sus time plots for single- and multiple-dose adminis-tration of NV-52 are presented in table I. Graphicsof plasma concentration versus time plots followingsingle- and multiple-dose administration of NV-52are presented in figure 2 and figure 3.

Plasma levels of unconjugated NV-52 rose rapid-ly following administration of the first dose in most

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Fig. 3. Mean plasma concentration vs time for unconjugated NV-52following multiple-dose (10-day) administration.


164 Howes et al.

Table II. Pharmacokinetic parameters for total NV-52 following single- and multiple-dose administration

Total NV-52 Single dose Multiple dose p-Value

Pre-dose (ng/mL) NA 751.9 ± 679.74 NA

Cmax (ng/mL) 4 191.94 ± 1417.97 5 716.24 ± 2792.54 0.11

tmax (h) 2.72 ± 1.52 2.50 ± 1.47 0.78

Kel (ng/mL • h) 0.07 ± 0.04 0.08 ± 0.02 0.59

t1/2 (h) 18.03 ± 19.06 9.15 ± 2.39 0.21

AUCt (ng • h/mL) 42 442.0 ± 9015.2 48 206.8 ± 13663.3 0.34

AUC∞ (ng • h/mL) 45 781.3 ± 9616.8 50 309.6 ± 15727.3 0.42AUC = area under the plasma concentration-time curve; AUCt = AUC from time zero to the last measured time point calculated using thetrapezoidal rule; AUC∞ = AUC from time zero to infinity calculated using the trapezoidal rule; Cmax = maximum plasma concentration;Kel = elimination rate constant calculated as the slope of the log of plasma concentrations vs time from Cmax onwards; NA = not available;t1/2 = plasma elimination rate constant calculated as 0.693/Kel; tmax = time at which Cmax was observed.

with 0.90 ± 0.69, 24–48 hours after single- and peaks for unconjugated NV-52. Following multiple-multiple-dose administration, respectively, and most dose administration, pre-dose levels of unconjugat-of the unconjugated drug was excreted between ed NV-52 were relatively low in comparison with6–24 hours post-dose. The cumulative dose of un- the Cmax values (750 ± 256.2 on day 5,conjugated NV-52 excreted in urine up to 48 hours 486.7 ± 283.1 on day 7 and 751.9 ± 679.7 on day 10was 2.05% and 1.07% of the oral dose following prior to the last dose).single- and multiple-dose administration, respec-

Cmax values following the last dose did not differtively. The renal clearance of unconjugated NV-52statistically from those observed following thewas 0.18 ± 0.21 L/h following single-dose adminis-first dose (multiple dose 5716.2 ± 2792.5 vs singletration and 0.25 ± 0.22 L/h following multiple-dose

administration (p = 0.47). dose 4191.9 ± 1418.0 ng/mL; p = 0.11) althoughthey tended to be higher. Values for tmax weresimilar following single- and multiple-dose admin-Total NV-52istration (p = 0.78), as were AUCt (p = 0.34) and

Pharmacokinetic measurements derived from AUC∞ (p = 0.42) values. Values for t1/2 for unconju-plasma concentration versus time plots for total (un- gated NV-52 tended to be shorter following multi-conjugated plus glucuronide- and sulphate-conju- ple-dose administration than following single-dosegated) NV-52 following single- and multiple-dose administration (9.15 ± 2.39 vs 18.03 ± 19.06 hours),administration of NV-52 are presented in table II. and were considerably longer than t1/2 values forGraphics of plasma concentration versus time plots unconjugated NV-52. Nonetheless, t1/2 values forfollowing single- and multiple-dose administrationof NV-52 are presented in figure 4 and figure 5.

Plasma levels of total NV-52 rose rapidly follow-ing administration of the first dose in most subjectswith tmax occurring around 2.7 hours. Thus, themaximum plasma concentration for total NV-52tended to lag behind that of unconjugated NV-52 byabout 0.8 hours. There was a moderate degree ofvariability in Cmax, which ranged from 2780.8 to6933.1 ng/mL. In several subjects there werebiphasic peaks of total NV-52. The presence ofbiphasic plasma peaks for total NV-52 did not nec-essarily occur in the same subjects who had biphasic

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Fig. 4. Mean plasma concentration vs time for total NV-52 followingadministration of a single dose.



the method used to calculate t1/2 and the presence ofan apparent second plasma peak of NV-52 in somesubjects. This second plasma peak may have repre-sented enterohepatic circulation of the drug and hasbeen noted in a previous study.[10] The plasma t1/2

values of total NV-52 were longer than for unconju-gated NV-52, most likely reflecting the fact thatconjugated NV-52 relies upon renal or gastrointesti-nal excretion for elimination while unconjugatedNV-52 is most likely metabolized by conjugation.

While Cmax and AUC values appeared to be

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Fig. 5. Mean plasma concentration vs time for total NV-52 followingmultiple-dose (10-day) administration.

higher following multiple-dose administration, andplasma levels of unconjugated and total NV-52 weretotal NV-52 did not differ statistically followingmeasurable prior to the last dose, multiple-dose ad-single- and multiple-dose administration (p = 0.21)ministration did alter the pharmacokinetic para-Urinary excretion of total NV-52 was substantialmeters of unconjugated and total NV-52 to a statisti-following both single- and multiple-dose adminis-cally significant extent. This suggests that multiple-tration and the cumulative doses excreted in thedose administration of NV-52 does not alter theurine over 48 hours following single- and multiple-pharmacokinetics of the drug to a clinically mean-dose administration were 131.94 ± 64.59 mg andingful extent, but the presence of measurable pre-132.49 ± 27.60 mg, respectively (p = 0.98). Urinarydose levels and a trend towards higher Cmax andexcretion during the last time period (24–48 hours)AUC values is consistent with the mean plasma t1/2was 30.00 ± 51.53 mg compared with 19.61 ± 15.52values of approximately 13 hours for unconjugatedmg, respectively, and most of the unconjugated drugand 18 hours for total NV-52 calculated followingwas excreted between 6 and 24 hours post-dose. Thethe first dose. The considerable variation observedcumulative dose of unconjugated NV-52 excreted infor Cmax values most likely reflected interindividualthe urine up to 48 hours was 32.98% and 33.12% ofvariability in first-pass metabolism (hepatic conju-the oral dose for single- and multiple-dose adminis-gation) rather than variation in intestinal absorption,tration, respectively. The renal clearance of totalas NV-52 is likely to be lipophilic and readily ab-NV-52 was 3.20 ± 2.12 L/h following single-dosesorbed from the gut. In addition, no known intestinaladministration and 2.99 ± 1.14 L/h following multi-transport mechanisms exist for isoflavone deriva-ple-dose administration (p = 0.79).tives and none are suspected.

Discussion Plasma t1/2 values for unconjugated and conjugat-ed NV-52 varied considerably between subjects andbetween study days. Furthermore, they appearedThe present study has confirmed[10] that NV-52 isconsiderably longer than values previously reportedabsorbed rapidly and extensively, with tmax valuesfor a small group of men in a phase 1a study.[10]for unconjugated NV-52 of around 2 hours beingConsequently, it is possible that there were signif-observed. Total NV-52 reaches a tmax about 50icant differences in plasma half-lives between sin-minutes later, reflecting the time taken for glucur-gle- and multiple-dose administration that the studyonide or sulphate conjugation to occur. Unconjugat-lacked sufficient statistical power to detect. Vari-ed NV-52 in plasma represented about 20–35% ofability in t1/2 within this study and between this andtotal drug following multiple-dose administration.the previous study are likely to reflect different ratesThe elimination half-lives of unconjugated and totalof hepatic conjugation, gastrointestinal excretion,NV-52 varied considerably among the subjects, al-enterohepatic circulation and renal excretion be-though some of this variability may have reflected


166 Howes et al.

tween individuals. The plasma t1/2 values and the pre- ple-dose administration of NV-52 is effective indose plasma concentrations of unconjugated NV-52 maintaining remission in IBD patients.(believed to be the active form) following multiple-dose administration may be interpreted as sug-

Acknowledgementsgesting that twice-daily rather than once-daily ad-ministration of the drug would be preferable in the

The conduct of this study was funded by the drug sponsor,maintenance of remission in IBD. However, studiesNovogen Pty Ltd. Prof. Laurence G. Howes has previouslyconducted in a murine model of IBD suggest thatacted as a paid consultant to Novogen Pty Ltd. The otheronce-daily administration is effective despite a short authors have no conflicts of interest that are directly relevant

half-life of NV-52 in mice.[10] Importantly, NV-52 to the content of this study.was active at very low doses (0.1–1 mg/kg) in thosestudies. Plasma concentrations may therefore not beclosely related to concentrations of the drug at its References

1. Middleton Jr E, Kandaswami C, Theoharides TC. The effects ofsite of action in inflammatory or gastrointestinalplant flavonoids on mammalian cells: implications for inflam-epithelial cells. mation, heart disease, and cancer. Pharmacol Rev 2000; 52 (4):673-751The renal excretion of unconjugated NV-52 was

2. Howes JB, Tran D, Howes LG. Effects of dietary supplementa-very low, at about 1% of the total daily dose, where-tion with isoflavones from red clover on ambulatory blood

as for total NV-52 it was much higher, at around pressure and endothelial function in postmenopausal type 2diabetics. Diab Obes Metab 2003; 5: 325-3233%. These results are consistent with unconjugated

3. Lam AN, Demasi M, James MJ, et al. Effect of red cloverNV-52 being extensively metabolized in the liver isoflavones on COX-2 activity in murine and human mono-(by glucuronide and sulphate conjugation), whereas cyte/macrophage cells Nutr Cancer 2004; 49 (1): 89-93

4. Huang Y, Cao S, Nagamani M, et al. Decreased circulatingtotal (largely conjugated) NV-52 most likely under-levels of tumor necrosis factor-alpha in postmenopausal

goes both renal and gastrointestinal excretion. No women during consumption of soy-containing isoflavones. JClin Endocrinol Metab 2005; 90 (7): 3956-62enzymes other than those involved in hepatic and

5. Verdrengh M, Jonsson IM, Holmdahl R, et al. Genistein as anintestinal conjugation are known to be involved in anti-inflammatory agent. Inflamm Res 2003; 52 (8): 341-6the metabolism of NV-52. 6. Duan W, Kuo IC, Selvarajan S, et al. Antiinflammatory effects

of genistein, a tyrosine kinase inhibitor, on a guinea pig modelof asthma. Am J Resp Crit Care Med 2003; 167 (2): 185-92

7. Strober W, Fuss I, Mannon P. The fundamental basis of in-Conclusionflammatory bowel disease. J Clin Invest 2007; 117 (3): 514-21

8. Podolsky DK. The current future understanding of inflamma-tory bowel disease. Best Pract Res Clin Gastroenterol 2002;

The results of the present study demonstrated that 16: 933-439. Feagan BG. Maintenance therapy for inflammatory bowel dis-single- and multiple-dose administration of NV-52

ease. Am J Gastroenterol 2003; 98 (12 Suppl.): S6-S17400 mg once daily produces plasma concentrations10. Howes LG, James MJ, Florin T, et al. NV-52: a novel flavonoid

well above the range (15–35 ng/mL) consistent with anti-inflammatory thromboxane synthase inhibitor for thetreatment of inflammatory bowel disease. Curr Opin Investconcentrations that have been shown to suppress theDrugs 2007; 16: 1255-66

development of colitis in a murine model[10] and tohave anti-inflammatory action in vitro.[10] Further-

Correspondence: Dr Laurence G. Howes, Department ofmore, administration of NV-52 400 mg once daily to Pharmacology and Therapeutics, Level 9, Gold Coast Hos-healthy volunteers appeared to be safe. Further stud- pital, Nerang St, Southport, QLD 4215, Australia.ies are now appropriate to determine whether multi- E-mail: [email protected]


Phase Ib Single- and Multiple-Dose Pharmacokinetic Study of Oral NV-52 in Healthy Volunteers

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Transcript of Phase Ib Single- and Multiple-Dose Pharmacokinetic Study of Oral NV-52 in Healthy Volunteers