Study Title: Study of Hypertenol on the development of Hypertension in the SHR INTRODUCTION

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1 P.O. No.: HYPERTENOL Pharmacodynamical Study (Efficacy Study) LIIDHATIRY IEPD,RT Test Facilitv: Institut de Cardiologie De Montreal, Canada Sponsor: Hamida Pharma, Inc, USA

2 PHARMACODYNAMICAL STUDY (EFFICACY STUDY) REPORT Study Title: Study of Hypertenol on the development of Hypertension in the SHR Test Article: Hypertenol Identification No.: ESHP-I 002 Test Facility: Physiological Dept. Institut de Cardiologie de Montreal, Canada Sponsor: Hamida Pharma, Inc. Study and Supervisory Personnel: Angelo Calderone, Ph.D. Amine Yacine, Ph.D. INTRODUCTION The spontaneous hypertensive rat (SHR) model has been extensively used to examine the underlying mechanisms implicated in the development of essential hypertension. During the early growth phase (0-30 days following birth) mean arterial pressure ( MAP) was equivalent to its control Wistar- Kyoto (WKY.) However, 40 days following birth, MAP was found to be higher in the SHR as compared to WKY, and continued to increase until it reached a plateau of mm Hg at 80 days of age (WKY= 125 mm Hg.) Although the SHR model represents a genetic model of hypertension, the genetic abnormalities contributing to the disease state remain undetermined. Nonetheless, Numerous studies have identified various abnormalities which are believed to contribute to the progression of hypertension. Circulating angitensin II levels were found significantly increased in the SHR model, and the vasoconstrictor response. Thirdly, left ventricular hypertrophy, and fibrosis represent prominent features in the SHR, and leads to cardiac contractile dysfunction, and subsequent heart failure. Lastly, increased oxidative stress has been documents in the SHR, and it is believed that the interest in free radicals binds to and inactive nitric oxide; an intrinsic cardiprotective mechanism. Based on this latter observation, the administration of anti-oxidants could potentially represent a

3 therapeutic approach to attenuate and/or abrogate established hypertension in the SHR model. The drug Hypertenol has been reported to possess anti-oxidant properties, and in this regard, the efficacy of this drug to alleviate the presence of established hypertension in the SHR model was investigated. METHODS Male SHR rats (Charles River) 9 weeks of age with an average MAP of 176 mm Hg were used in the present study. Hypertenol at a dose of either 20, 40, 100 mg/kg/day was added to the rat chow, changed every three days, and continued for a period of 5 weeks. Each group consisted of 5 rats. At 10, 11, 12, and 13 weeks of age, tail cuff blood pressure readings were made. At 14 weeks, the rats were anesthetized with a ketamine (50 mg/kg/xylazine (10mg/kg) mixtures A microtip pressure transducer (Millar 2F) was inserted into the right carotid artery to obtain mean arterial pressure. The transducer was subsequently advanced into the left ventricle to measure systolic, end- diastolic pressures, and the left ventricular rate of contraction (dp/dt). Lastly, the transducer was inserted into the right jugular vein, and advanced into the right ventricle to measure right ventricular contractile function. Following the assessment of contractile function, blood was withdrawn to measure plasma catecholamine levels, tissues were removed and immediately frozen in liquid nitrogen, and subsequently stored at -80 C. All tissue weight are in grams. RESULTS In the Hypertenol- Morphometric Measurements treated SHR, regardless the doe, an increase in body weight gain was observed during the 5 weeks treatment. Liver and kidney weight was unchanged in the Hypertenol- treated SHR, as compared to untreated SHR, regardless the dose. Interestingly, the lung weight/body weight ratio was decreased in the Hypertenol- treated SHR, regardless the dose, as compared to the untreated SHR ( Figure 1).

4 -.'he effe<.~t of Hyper-tel1ol on Lung '\Veight in the SHR nit o '" :c _= S H R a Figure 1 However, a statistical significance was observed only for the 20 and 100 mg dose regiment. Likewise, right ventricular weight/body weight ratio was decreased in the Hypertenol-treated SHR, regardless the dose, as compared to untreated SHR (Figure 2). However, statistical significance was observed only with the 40 and 100 mg dose of Hypertenol (figure 2). The effect of Ilypertcnul on Right Vl'ntTlcul:u' ''-'eight in the SH R njt I).6 * 1)~ IWt( S p<li.u5 ~'~'I'SIlSSUR: 11=5cnd1 ~rnup,:;,-;: - I) 7 o H S 1-1 R 2 0.-; Figure 2

5 91 5 D I, Tail Cuff Blood Pressure Measurements (Figure 3) Th~ ~rrcct of 1-I)'p. '-tl.. [l1i1on T.,if Cuff Blood Pressure in the SIIR n'l :7 0 (1.- SHR~20 SHR~40 ~//. I 9 0 l "" 1, es, 0e - H 1 k1 R0s ",. /"" ""A _._-" --2f Figure 3 1.A. 7 0 I I> 0 I- f- ','01 The average MAP of the SHR rats prior to Hypertenol treatment was 176 mm Hg. Following the first week of Hypertenol treatment, a marked reduction in tail cuff MAP was observed. In the 20 mg treated SHR, a reduction of 23 mm Hg was observed, whereas the 40 and 100 mg treated SHR, a reduction of 11 and 17 mm Hg was observed, respectively. Following the second to fourth week of treatment, MAP slowly returned to baseline levels observed prior to the administration of Hypertenol, regardless the dose. By contrast, in the untreated SHR, MAP remained unchanged, and markedly increased during the 13th week. In Vivo Hemodynamic Measurements & Plasma Catecholamine Levels Following 5 weeks of Hypertenol treatment, the rats were anesthetized cardiac contractile function were assessed. Hg, and Hypertenol treatment reduced MAP (Figure 4). and MAP, and In the untreated SHR rat, MAP was 165 mm The cfft'ct of Hypcrtcnol on j\. lcan A,'tcria! P"CSSlII'C in the SHR rat = ',\::Den"tl'" r.<n.ns versus SHR: n=::; 1 :I<.'h~rC1U(J E -E <r: I a.. 1 ~ S H R Figure 4

6 A significant reduction of35 and 47 mm Hg was observed in the 20 and 40 mg treated SHR (Figure 4), Likewise, the 100 mg dose of Hypertenol resulted in a 24 mm Hg reduction of MAP, but was not statistically significant, as compared to untreated SHR (Figure 4). Left ventricular systolic function was elevated in the untreated SHR, and a significant decrease was observed in the Hypertenol-treated (Figure 5). rat, regardless the dose Thl' effect of Hypcr"lennl 011 Ll'fI Vcntricular Syslolic PI'I~ssurl' in the SHR nil :r; E 'k DC'n"I ~ p<ii,u:- \'cn"~ SIIR: 11=::; :lch ~rol1l) CL (/) > -' S H R Figure 5 Consistent with theses data, the rate of left ventricular contraction (dp/dt) was increased in the SHR, and Hypertenol treatment markedly improved dp/dt (Figure 6). Thl' efft,cc of Hypcr'lennl on Left Vcntricul:lr Systolic I'r'csSlIl'l' ill the SHR nit :r; E E "" 2? 50 0 k nchu.c~ p<o..05 \-cr.'li~ SIIR: 11=:' c:ach }..:r"oup a > -' 1" 0 S H R 2 0 < Figure 6 A significant reduction of dp/dt was observed with 20 and 40 mg Hypertenol, whereas a non-significant decease was observed with 100 mg (Figure 6). Left ventricular relaxation, as measured by left ventricular end-diastolic pressure (LVEPD) was elevated in the SHR, and a reduction was observed following Hypertenol treatment (Figure7).

7 The effect o!" Hypcr'tcllol on Left Ventr'icu!:u' End-Diastolic Pn'ssurc in the SHR I'a' 0) I E E i 2 I 0 II ~t Dl'IIU[e~ p<ilu5 \erc~ljs SIIR; n=:- each gnlllp (L o 4 u.j > 2 SHR Figure 7 The 20 and 49 mg dose normalized LVEDP in the SHR, whereas the 100 mg nonsignificantly decreased LVEDP (Figure 7). Right ventricular systolic pressure was modestly increased in the SHR, and Hypertenol caused a non-significant reduction, regardless the dose. Lastly, plasma catecholamine levels were unchanged in the Hypertenol treated SHR, regardless he dose, as compared to untreated SHR (data not shown). DISCUSSION One week following Hypertenol treatment, a marked reduction of MAP via the tail cuff method was observed, regardless the dose. However, during the following three weeks of treatment with Hypertenol, MAP returned to baseline levels, prior to drug administration. These latter observations suggests that Hypertenol can indeed reduce MAP. Albeit, during the latter weeks, an increased stress level was observed in the rats, and this may have masked the beneficial effect of Hypertenol. Indeed, this latter conclusion is valid since in the anesthetized animal, MAP was markedly reduced in the Hypertenol treated SHR, regardless the dose. Secondly, left ventricular systolic pressure (LVSP), an index of contractility was elevated in the SHR, and Hypertenol treatment significantly improved LVSP, regardless the dose. Moreover, the rate of left ventricular contraction dp/dt was also improved with Hypertenol treatment, thereby supporting the premise that Hypertenol alleviation of MAP was associated with improved left ventricular function. Thirdly, left ventricular relaxation as assessed by left ventricular

8 end diastolic pressure (L VEDP) was significantly reduced by Hypertenol treatment. This latter therapeutic action of Hypertenol is important since an increase in LVEDP leads to impaired ventricular relaxation, resulting in ventricular dilation, and subsequent heart failure. Moreover, elevated LVEDP can result in pulmonary hypertension, and in the present study, Hypertenol reduction of LVEDP was associated with a decrease in lung weight/body weight ratio. Consistent with this latter result, right ventricular hypertrophy was also reduced wit Hypertenol therapy. Thus, Hypertenol may be beneficial in the treatment of pulmonary hypertension via its therapeutic action on LVEDP. In conclusion, the treatment of SHR with established essential hypertension with Hypertenol significantly improved MAP, and left ventricular contractile function. Based on the antioxidant property of Hypertenol, the reduction of free radicals in the SHR may result in a secondary increase in nitric oxide, thereby recruiting the intrinsic cardioprotective mechanism. Moreover, the growing evidence supporting a nefarious role of increased oxidative stress in other cardiovascular disease states warrants further investigation regarding the potential therapeutic effect of Hypertenol.

9 A pilot trial of oral administration of Hypertenol in the treatment of High blood pressure OBJECTIVE: To evaluate the efficacy of oral administration pressure. of Hypertenol in treatment of high blood METHODS: After initial screening, 29 patients with high blood pressure (Systolic> l30mmhg or Diastolic >85mmHg) were selected to join this pilot study. The patients were treated with Hypertenol by chewing 1-3 tablets each time, 1-2 time during 24 hours. The blood pressure was measured before taking Hypertenol and in some time after taking Hypertenol. Efficacy parameters including Systolic, Diastolic, Pulse, Pulse Press and Arterial Stiffness Index (ASI), were assessed by Cardiovision Machine. RESULTS: All 29 patients have completed the full course of therapy and observation and had reductions in Systolic after taking Hypertenol in at least 4 minutes. The Diastolic tends to normal range. Mean values for other efficacy parameters also showed improvement. There were no adverse events that were considered to be treatment related. (See enclosed Table and Figure) CONCLUSION: Oral administration of Hypertenol may be an effective therapy for hypertension.

10 Page Sex Patients 6. L'1SP 6.SP 45 9/23/ /15/ /15/ /17/ /17/ /18/ /15/ /24/00 3/17/ /13/00 7/15/ Age 3/25/00 6/15/00 3/16/00 7/16/ /2/00 7/14/ /1/ /4/00 M F Start First L'1Time Time K.AHN 32 D.GS1 75 Last T.NHN K.DS /16/00 7/15/ J.AHN L.DHN K.LS1 G.IS1 W.AS2 93 6/16/ /23/00 3/24/00 7/1100 7/15/ /17/ /13/00 L.LS1 M.CS1 R.GS2 8/2/ /4/ /25/00 6/15/00 7/15/ /18/00 7/14/ /15/ M.S1 RayS1 L'1DP G.RS2 K.M End P.CS1 S.BS1 C.LS2 E.BS2 H.BS2 7/16/ :06 0:12 2:47 0:11 0:09 0:05 0:08 0:27 0:07 2:19 0:15 5:40 0:25 0:04 S2/L Hypertenol After name Time Stage takingbefore Sex taking Diastolic Period (mmhg) Before Hypertenol taking Hypertenol Blood Pressure before/after taking Hypertenol Systolic (mmhg)

11 Page 22 Total 80 7/27/ /23/ /26/00 6/16/ /20/00 9/9/2000 9/9/00 7/15/ M7/8/00 F ± ± /10/ ± ± ± ± ± /23/ /16/ /20/00 7/27/00 5/29/00 7/8/00 9/9/ /15/ V.MS4 0:00 4:52 C.RS3 157± ±7.09 E.BS2 K.BS2 P.HS3 V.LS3 B.RS3 0:10 K.AS3 R.LL 0:54 136± :18 S.IL 0:14 0:06 148±6.26 0:12 1:12 0:34 144± ± ± ± ± :56 106± :58 S2

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