1 To com pare hydrogen production after a soluble and an insoluble fibre
M ethods
Patients and Study Design
Patients ( 5 female 1 male) w ere selected all m etabolic or endocrine cau se s of their obesity having been excluded and w ho w ere to be started on a low calorie diet. Patients w ere aged 18 to 70 and specifically have had no history of any gastrointestinal pathology, respiratory impairment and w ere not receiving any m edication. The Ispaghula w as supplied as Metamucil and Fiberform w as supplied by Tricum of Sw eden both in sa ch e ts each containing 3 .5 gm s. The low calorie diet w as given as 100 .5 g of the standard Cambridge Diet in three divided portions over th e day. The study w as divided into tw o parts the p atients receiving Ispaghula in one part and Fiberform in th e other. They w ere randomly assigned to either group . Each of th e tw o parts w as conducted as follows:
Patients received the low calorie diet for tw o days this being a 'w a sh o u t' period to allow previous ferm entable foods to p ass the upper gut. On each day of the study there w ere three liquid diet meals taken at 8 am , 1 2 noon and 8 pm.
On Day 3 they attended the CPU and received th e morning portion of their diet at 8 am after which Breath hydrogen m easurem ents w ere m ade every ten m inutes for eight hours.
On Days 4 and 5 they continued with their diet and with the fibre. The diet w as taken at 8 am and 12 am. The fibre supplem ent w as taken with th e low calorie diet. No other food w as allowed although 1.5 litres of carbonated w ater w as given over th e day.
On Day 6 th ey attended and having received the morning portion of their diet at 8am and the fibre at 9am . Breath hydrogen m easurem ents w ere then m ade as before for an eight hour period. The second dose of fibre w as taken at noon as before.
M easurem ent of Breath hydrogen
End expired alveolar air w as collected using a T tube and syringe and assay ed using th e electrochem ical cell from GMI Renfrew Scotland as previously described.
Results
The individual breath hydrogen profiles are reproduced in th e graphs below. The Area under th e Breath hydrogen time profiles w as calculated and is p resented below Table 98.
Metamucil Fiberform
Patient Control Fibre Control Fibre
A 8795 2 905 3 985 9 6 0 5 B 13695 14030 13780 1 8705 C 2 4 2 0 5 685 5 1 8 0 6 6 7 0 D 5 7 6 0 2 645 8 245 4 8 8 5 E 3 2 6 5 2 235 5 775 4 4 1 5 F 5 5 3 0 3 575 4 4 9 0 8 5 6 5 Mean 6 5 7 7 5 179 6 9 0 9 8 8 0 7
Analysis of Variance gives F3 2 0 = 0 .6 8 p > 0 .5 N.S. confirming th at there is no significant difference betw een hydrogen production with either Metamucil or Fiberform and control.
2. To investigate th e effect of fibre on Colonic Transit
M ethods
Patients and Study Design
The study w as designed to a sse ss th e effect of tw o doses of fibre (10.5 and 21 g daily taken th ree tim es daily) on small and large bowel transit tim es and faecal bulking in p atients w ho w ere undergoing treatm en t for severe obesity by dietary restriction using a very low calorie liquid diet. A very low calorie diet for an average female has been defined as less than 5 5 0 Kcal/day (Atkinson 1989). Patients were adm itted to the trial w ho w ere free from any gastrointestinal tract
disorder or other mental or physical condition which might affect gut function and w ho w ere not taking any other m edication. Nine fem ales and one male of mean age 4 7 .3 ± 15.8 years and m ean w eight 105 .2 ± 15.7 kg consented to take part in th e study. The m ean body m ass index (W/H^) w as 3 7 .7 ± 3 .3 kg m-2 range 3 4 -4 4 (Table 99). Patients received th e diet as three sa c h e ts daily providing 1 .38M J (330 Kcal) energy per day (Cambridge Diet). The fibre w as Fiberform Mix (Tricum Sw eden) which has over 80% dietary fibre content; m ost of the starch, protein and soluble polysaccharides having been rem oved. The trial w as a th ree w ay cross-over of low dose or high dose fibre or no fibre. Each patient had asse ssm e n t of colonic transit time in each of the three parts but a sse ssm e n t of oro-caecal transit time in only tw o parts to minimise blood sampling. The design w as balanced for both treatm ent and a sse ssm e n t of oro-caecal transit time.
Whole Gut Transit
This w as a sse ssed by m eans of th e m ethod described by C h aussade(1986) and M etcalf(1987). Radio-opaque sh ap es are adm inistered at 9 a.m . with cubes on day 1, circles on day 2 and cylinders on day 3. There w as a single abdominal x-ray at 9 a.m . on day 4. The use of radio-opaque m arkers for a sse ssm e n t of colonic transit has received recent validation by van der Sijp (1993) who com pared radio-opaque m arkers with 1 1 1|n bound to resin m icrospheres and found th e tw o m ethods to give similar results in a study comparing a control group with a group of 1 2 constipated patients.
Oro-Colonic Transit
Oro-colonic transit time w as a sse sse d by the Sulphasalazine/Sulphapyridine m ethod as described earlier. Blood sam ples w ere collected from Ih r 40m ins at 20 min intervals until 5 hrs and th en hourly until 8 hrs post SLZ adm inistration. The SLZ w as adm inistered one hour after th e morning dose of fibre.
Faecal Bulking
The total daily faecal collection from each subject w as obtained on th e five consecutive days of each experim ental period and w eighed w et.
R esu lts W e ig h t Loss
T h e re s u lts a re p r e s e n t e d in b e lo w . All p a tie n ts lost w e ig h t on t h e diet e x c e p t o n e a n d th is is t a k e n a s e v id e n c e of non- c o m p lia n c e w ith t h e s tu d y . Her re s u lts a re e x c lu d e d from t h e c alculatio n of re s u lts.
T able 9 9
W e ig h t Loss in O b e s e P a tie n ts on a V ery Low Calorie Diet. P a tie n t No. A g e S e x Initial W e ig h t Initial BMI W e ig h t lo s s kg 1 6 4 F 8 7 . 6 3 3 . 7 9 1 1 .5 2 61 F 9 3 . 4 3 7 . 8 9 5.1 3 2 6 F 1 0 7 . 4 8 4 0 . 4 5 8 . 0 4 4 7 M 1 3 2 . 4 3 3 . 7 7 1 1 .7 5 6 6 F 9 1 . 3 6 3 7 . 5 4 3 . 4 6 3 0 F 1 2 6 . 0 4 3 . 6 0 - 0 .8 * 7 4 9 F 8 9 . 2 3 3 . 9 9 7 . 4 8 5 6 F 1 1 6 . 0 4 0 . 1 4 7.1 9 2 3 F 1 0 6 . 8 6 3 9 . 2 5 5 .6 11 51 F 1 0 1 .5 3 6 . 8 3 8 . 4 M ean 4 7 . 3 0 1 0 5 . 1 8 3 7 . 7 3 6 . 7 4 s .d . 1 5 . 8 2 1 5 . 6 6 3 . 2 7 3 .7 1
* T a k e n a s e v id e n c e of n o n -c o m p lia n c e w ith t h e diet. T h e re w e r e 9 Fem ale a n d 1 m ale p a tie n ts
W h o le G ut T ra n s it
T h e re s u lts a re p r e s e n t e d in t h e ta b le 1 0 0 . T h e w h o le g u t tra n s it tim e c a lc u la te d a s d e s c rib e d by M etc a lf a n d follow ing earlier w o rk by A r h a n ( 1 9 8 1 ) s h o w e d a d o s e d e p e n d e n t re d u c tio n w ith in c re asin g fibre. T h e m e a n colonic tra n s it tim e w a s significan tly r e d u c e d by fibre ( p < 0 . 0 0 1 ) . This t e c h n i q u e h a s t h e a d v a n t a g e , c o m p a r e d w ith t h a t of B ecker ( 1 9 7 9 ) , of allow ing a lso a s s e s s m e n t of s e g m e n ta l co lo nic tra n s it tim e. T h e right colonic tr a n s it tim e w a s 2 1 . 9 h on co n tro l b u t 7 . 9 on low
d o s e fibre a n d 3 . 0 on high d o s e fibre; T h e s e d iff e r e n c e s being s ta tistic a lly s ig n ific a n t (ANOVA p < 0 . 0 0 1 ) . Similarly t h e left colonic tr a n s it c h a n g e d from 2 1 . 1 h on c o n tro l to 1 0 . 0 h on lo w d o s e fibre a nd 8 . 3 h on high d o s e fibre ( p < 0 . 0 2 ) .
T able 1 0 0 M ean W h o le G u t Time
P a tie n t No Control Low D o se Fibre High D o se Fibre 1 5 4 3 2 . 4 1 3 .2 2 4 0 . 8 1 5 .6 1 2 3 3 3 . 6 2 . 4 3 . 6 4 6 9 . 6 2 8 . 8 8 . 4 5 5 6 . 4 2 6 . 4 1 2 6 2 1 . 6 4 2 4 8 7 5 5 . 2 4 5 . 6 4 5 . 6 8 6 8 . 4 ND 1 9 .2 9 5 5 . 2 2 0 . 4 6 1 1 5 1 . 6 3 4 . 8 3 6 M ea n 5 3 . 8 7 2 5 . 8 0 1 7 . 3 3 s .d . 1 1 . 4 9 1 3 . 1 3 1 4 . 2 4 T h e a b o v e ta b le s h o w s t h e m e a n w h o le g u t tr a n s it tim e in h o u rs a s s e s s e d by t h e u s e of ra d io -o p a q u e m a rk e rs on
low d o s e ( 1 0 .5 g ) a n d High d o s e (2 1g ) Fiberform . O ro-C olonic T ra n s it
T h e re s u lts are p r e s e n t e d b e lo w in T a b le 1 0 1 . T h e oro- c a e c a l tr a n s it tim e on co n tro l did n o t differ significantly from t h a t on fibre.
O ro-C olonic T ra n s it Tim e on High a n d Low D o se Fibre A s s e s s e d by th e SLZ/SP M e th o d
T able 101
Low D o se Fibre High D o se Fibre
P a tie n t C ontrol Fibre P a tie n t C ontrol Fibre
1 1 . 0 1 .3 5 3 5 . 6 5 4 . 6 6 2 5 . 2 4 4 4 3 . 1 5 4 . 6 6 7 4 . 8 4 . 8 5 1 . 6 6 2 . 3 5 8 5 5 9 3 3 . 3 3 9 2 . 3 3 2 . 3 3 11 3 . 3 3 3 . 4 M ean 3 . 6 2 3 . 4 8 3 . 3 7 3 . 7 5 s .d . 1.7 1 .4 3 1 .7 1 . 1 2 T h e a b o v e ta b le s h o w s t h e o ro - c a e c a l tr a n s it tim e in h o u rs a s s e s s e d by t h e s u lp h a s a la z in e /s u lp h a p y r id in e m e th o d on
F aecal Bulking
T h e re s u lts a re p r e s e n t e d in ta b le 1 0 2 . T h e re w a s a s ig n ific a n t in c r e a s e in fa e c a l bulk a fte r a d m in is tra tio n of fibre; w ith th e a m o u n t being d o s e d e p e n d e n t ( ANOVA p < 0 . 0 0 1 ) .
T h e f r e q u e n c y of b o w e l a c tio n (total in five d a y s) also s h o w e d an in c r e a s e w ith in c re a s in g fibre in ta k e w h e n c o m p a r e d w ith c o n tro l b u t th is in c r e a s e w a s n o t s tatistic a lly s ig n ific a n t (ANOVA p = 0 . 1 ).
T able 1 0 2
F aecal Bulking a n d Bowel F r e q u e n c y on High a n d Low D o se Fibre C o m p a re d w ith No Fibre S u p p le m e n ts P a tie n t No C ontrol Low D o se Fibre High D o se Fibre 1 5 0 0 (3) 5 4 5 (4) 9 6 6 (6) 2 3 0 9 (5) 6 0 0 (7) 8 5 6 (8) 3 2 3 2 (4) 6 5 5 (5) 9 8 3 (7) 4 4 8 5 (6) 5 8 3 (5) 1 0 2 9 (8) 5 1 9 5 (6) 2 8 4 (6) 2 8 4 (7) 6 3 6 1 (4) 2 8 8 (4) 3 2 1 (3) 7 3 3 8 (3) 3 7 2 (4) 4 7 3 (3) 8 2 4 2 (3) 7 3 3 (13) 6 5 7 (8) 9 0 (0) 4 5 9 (5) 6 6 5 (8) 1 1 5 3 2 (6) 4 2 4 (3) 8 2 7 (3) M ea n 3 1 9 . 4 (4) 4 9 4 . 3 (5 .6 ) 7 0 6 . 1 (6 .1 ) s .d . 1 6 2 . 8 1 5 3 .6 2 7 2 . 9 T h e a b o v e ta b le s h o w s t h e fa e c a l bulk ( g r a m s /5 d a y s) a n d t h e n u m b e r of b o w e l o p e n in g s in b r a c k e ts for p a tie n ts on lo w , high or no fibre.
Discussion of Results
T h e e v a lu a tio n of an early E xperim ental B enzam ide
T h e first e x p e rim e n ta l b e n z a m id e to b e c o m e available for a d m in is tra tio n t o m a n , a s a re su lt of t h e c h em ica l p ro g r a m outlined earlier, w a s B R L 2 0 6 2 7 . This w a s e v a lu a te d a s d e s c r ib e d a b o v e usin g t h e L a c tu lo s e b r e a th h y d ro g e n m e th o d a n d w a s f o u n d t o b e a c tiv e in p ro m o tin g earlier arrival of t h e h e a d of t h e t e s t m eal in t h e co lo n b u t to be le ss p o t e n t t h a n m e to c lo p ra m id e . T h e Log d o s e p o t e n c y ratio a s c a lc u la te d a b o v e w a s 0.6 6.
T his h u m a n p h a r m a c o lo g y re su lt is c o n s i s t e n t w ith t h e w o rk of o th e r s . M cClelland e t al (1 9 8 3 ) , M cRitchie Miner (1 9 8 5 ) a n d Lux G. e t al ( 1 9 8 1 ) w o r k e d w ith ra ts . C o o p e r M cRitchie a n d T u rn e r ( 1 9 8 4 ) a n d S c h u u r k e s e t al ( 1 9 8 7 ) w ith d o g s a n d M cClelland a n d S u tt o n ( 1 9 8 6 ) a d m in is te r e d t h e dru g to m a n . All r e p o rte d p o t e n c y similar to m e to c lo p ra m id e . M cClelland w o rk in g w ith iso la ted rat g a s tr ic fundal s trip s u n d e r e lectric field stim u la tio n s h o w e d B R L 2 0 6 2 7 to p r o d u c e i n c r e a s e d activ ity. This e ffe c t having b e e n d e m o n s t r a t e d to be cholinergically m e d ia te d . T h e d a ta s h o w s B R L 20 62 7 to b e e q u ip o te n t to m e to c lo p ra m id e in stim u la tin g rh y th m ic in c r e a s e s in in tr a g a s tric p r e s s u r e in t h e rat (orally, s c . a n d iv) a n d to a c c e le r a te g a s tric e m p ty in g of a liquid m eal in t h e rat a n d d o g a n d solids (g lass s p h e r e s ) in t h e rat .
T h e e x p e r im e n t re p o rte d h e re involved giving t h e la c tu lo se in an a q u e o u s t e s t m eal s y s t e m a n d w a s carried o u t b e fo re I h a d s h o w n t h e d e c r e a s e d variability o b ta in e d if t h e la c tu lo s e is given w ith a m eal. This e x p lain s t h e ra th e r w id e c o n fid e n c e interval a s s o c i a t e d w ith t h e Log d o s e p o t e n c y ratio a n d re fle c ts t h e e x te n s iv e variability f o u n d using