O v e r w e i g h t a n d O b e s i t y are becom-ing major health problems worldwide (1). The World Health Organization (WHO) estimated that in 2005, approximately 1.6 billion adults around the globe were overweight and 400 million were obese. WHO projects that by 2015, these numbers will reach 2.3 billion and 700 million, respectively.

The therapeutic benefit of all currently available anti-obesity tools is limited by their marginal effi-cacy and variable tolerability and safety profiles.

A need exists for a product that is able to re-duce stomach volume in a manner compara-ble to bariatric surgery or an intragastric bal-loon, but with a risk-benefit profile acceptable to the entire population of overweight/obese subjects. An intervention that reduces stomach volume, increases elastic response and viscos-ity of the upper gastrointestinal content, and extends gastric emptying time could potential-ly be very beneficial.

Attiva and Gellica are two novel superabsor-bent biodegradable hydrogels that are able to swell in the stomach and the small intestine in the presence of water and gastrointestinal flu-ids. Both can swell approximately 100 times their weight in the gastric and the intestinal environ-ments. Attiva degrades in the colon while Gell-ica degrades in the small intestine. The swelling rate of the two hydrogels in the different parts

of the gastrointestinal tract has been demon-strated in vitro (Figure 1).

By occupying the gastric and the intestinal cavi-ties, increasing the gastric emptying time, and delaying the absorption of glucose in the small intestine, Attiva and Gellica can induce satiety and cause food intake reduction.

A previously unpublished study in rats showed that the administration of 40 mg of Gellica hydrated with 4 mL of water before the administration of 2 mL of liquefied food causes longer gastric emp-tying time (Figure 2). Additional observations of the content of rats’ stomachs after gavage with hydrated Gellica showed that the hydrogel was mixed homogenously with the subsequently con-sumed food (Figure 3c). In fasting rats, the hydrat-ed hydrogel was found in the stomachs for 30 to 60 min (Figures 3a and 3b) while in rats that were fed after the administration of Gellica, the hydro-gel was present in the stomachs for 90 to 120 min.

A study in humans has shown that single admin-istration of 2 g of Attiva significantly increases the post-meal feeling of satiety and decreases the feeling of hunger before the subsequent meal (Figures 4 and 5) (2). This effect on the subsequent meal (second meal effect) sug-gests that the hydrogel could have additional effect on food intake even after leaving the stomach (intestinal effect).

i n t r O d u c t i O n

attiva and gellica, twO nOvelsuperabsOrbent biOdegradable hydrOgels,

decrease FOOd intake in rats

hassan M. heshmati1, Md; eyal s. ron1, phd; yishai Zohar1; nissim bilman1; christian demitri1, phd;gitte hansen2, Md; Jana procházková3; Martin Šlais3, phd; Mircea d. bucevschi4, phd; Monica colt4, phd;

Mendy axlerad4; alessandro sannino5, phd; luigi ambrosio6, phd; luigi nicolais7, phd.

1 gelesis, inc., boston, Ma, usa; 2 gubra, Frederiksberg, denmark; 3 biotest sro., konárovice, czech republic; 4 exotech bio solutions, ltd., kiryat gat, israel; 5 university of salento, lecce, italy;

6 national research council of italy, naples, italy; 7 university of naples, naples, italy.

time in simulated gastric/intestinal/colon Fluids (min)

F i g u r e 1

The aim of this study was to assess and compare the effect of acute administrationof Attiva and Gellica on food intake in rats.

O b J e c t i v e

a n i M a l s

Thirty-two male Sprague-Dawley rats aged 8 weeks were studied.

F i g u r e 2

time after administration (min)

sto

ma

ch

co

nte

nt

(g)

F i g u r e 3 a F i g u r e 3 b F i g u r e 3 c

Excised rat’s stomach 30 min after the gavage with 50 mg Gellica

hydrated with 5 mL of water.

Stomach content of a fasting rat30 min after administration of 50 mg Gellica hydrated with 5 mL of water.

Stomach content of a fed rat 70 min after administration of 50 mg Gellica hydrated with 5 mL of water. Based

on the calculation of consumed food, approximately 80% of the food

bolus was hydrated hydrogel.

in vitro Modeling of swelling capacity of attiva and gellica in the gastrointestinal tract.

(estimated ratio of swelling g/g)

effect of gellica on rats’ stomach content.(40 mg gellica hydrated

with 4 ml of water)

swe

llin

g r

atio

(g

/g)

small intestinestomach colon

4 ml hydrogel + 2 ml food

4 ml water + 2 ml food (control)

attiva

gellica

placebo-adjusted change in satiety scores (%)in humans after administration of 2 g of attiva

at breakfast, lunch, and dinner.

F i g u r e 4 F i g u r e 5

placebo-adjusted change in hunger score (%)in humans before lunch and dinner, after

administration of 2 g of attiva at breakfast and lunch.

0

5

10

15

20

Breakfast Lunch Dinner

30 min

60 min

* **

**

**

Figure 4. Placebo-adjusted change in satiety scores (%) in

humans after administration of 2 g of Attiva at breakfast,

lunch, and dinner.

Perc

en

t

*P < 0.05

**P < 0.01

-20

-15

-10

-5

0

5

Lunch Dinner

Pre-meal

*

Figure 5. Placebo-adjusted change in hunger score (%) in

humans before lunch and dinner, after administration of 2

g of Attiva at breakfast and lunch.

Perc

en

t

*P < 0.02

F i g u r e 6 F i g u r e 7

time (min) time (h)

M e t h O d s

Twenty to 100 mg of Attiva and Gellica were hydrated in a ratio of 1:100 (polymer to tap wa-ter). Rats were gavaged with the resulting mix-ture or an equal volume of water. Animals were randomized into 3 weight-matched groups, each receiving either hydrated Attiva, hydrat-ed Gellica, or water alone (control or vehicle).

The rats were housed individually in MANI Feed-win cages. The room environment was con-trolled (temperature: 22 ± 2°C; humidity: 50 ± 10%; light/dark cycle: 12 h light, from 3 am to

3 pm, 12 h dark). Animals had ad libitum ac-cess to Altromin 1321 powdered diet (20 h/day, from 3 pm to 11 am) and tap water (24 h/day). Food intake was recorded every 5 min for 18 h following the administration of Attiva/Gellica/vehicle. A 7-day habituation to the system was allowed before the first administration of the test agents.

Statistical evaluation was performed with anal-ysis of variance (ANOVA).

cumulative Food intake (% of vehicle) in rats within 4 h after administration of 80 mg ofhydrogels hydrated with 8 ml of water.

cumulative Food intake (% of vehicle) in rats within 18 h after administration of 80 mg of

hydrogels hydrated with 8 ml of water.

perc

en

t

breakfast lunch dinner

30 min

60 min

**P < 0.05**P < 0.01 lunch dinner

perc

en

t

pre-meal

**P < 0.02

cu

mu

lativ

e F

oo

d i

nta

ke(%

of

veh

icle

)

cu

mu

lativ

e F

oo

d i

nta

ke(%

of

veh

icle

)

anOva factorial, Fisher’s post-hoc test

a. P < 0.05 (Gellica vs. vehicle)b. P < 0.05 (Attiva vs. vehicle)

anOva factorial, Fisher’s post-hoc test

a. P < 0.05 (Gellica vs. vehicle)b. P < 0.05 (Attiva vs. vehicle)

vehicle (water) gellica

attiva

vehicle (water) gellica

attiva

r e s u l t s

d i s c u s s i O n

c O n c l u s i O n

r e F e r e n c e s

Administration of 80 and 100 mg of Attiva and Gellica hydrated with 8 and 10 mL of water, re-spectively, significantly decreased food intake for up to 18 h (Figures 6 and 7) compared to ad-ministration of the same amounts of water alone. Administration of 60 mg hydrated with 6 mL of

water had a significant effect for a shorter period of time (up to 4 h) while administration of lower amounts (20 and 40 mg) showed a trend for re-duction of food intake without statistical signifi-cance. In most cases, the pattern of food intake reduction was similar with the two hydrogels.

The results of this study demonstrate a significant decrease in food intake in rats with Attiva and Gellica and are in agreement with the hydrogel properties observed in the in vitro gastrointes-tinal simulations (Figure 1) and observations of the effects on gastric emptying in rats (Figures 2, 3a, 3b, and 3c).

Some heterogeneities in the results (dose-response patterns) are probably due to the fact that the

rats were in their active growing period and the amounts of hydrogels were not adjusted to their new weight during the study.

While previous observations showed that hydrat-ed Gellica lasts in the rat’s stomach for up to ap-proximately 60 min in fasting animals and 120 min in fed animals, the observed reduction in food in-take for up to 18 h in the present study supports the hypothesis of an effect on the small intestine.

Acute oral administration of Attiva and Gellica, novel superabsorbent biodegradable hydro-gels, significantly decreases food intake in rats when compared to administration of a similar amount of water.

This effect on food intake is probably due to a combination of transient reduction of the avail-able stomach volume and delayed gastric emptying. Additional mechanisms involving the

small intestine could also be present.

This animal data is consistent with the previously reported human data with Attiva (2).

The observed effects in rats, if confirmed by chronic administration in humans, will provide a promising new approach in the treatment of overweight and obesity.

1. bessesen dh. Update on obesity. J Clin Endocrinol Metab, 2008, 93, 2027-2034.2. heshmati hM, tacchino r, ron e, sannino a, Zohar y. Attiva, a novel superabsorbent biodegradable

hydrogel, increases the feeling of satiety in humans. In: Program of the 19th Annual Meeting and Clinical Congress of the American Association of Clinical Endocrinologists, April 21–25, 2010; Boston, MA, USA. Abstract #605.

the content of this document was presented in a poster at Obesity 2010,

28th annual scientific Meeting, san diego, california, October 8–12, 2010.