Professional Documents
Culture Documents
1 January-March 2009
Contents
R&D Highlights
Cell-based Treatments for Diabetes 72
Diabetes
Diabetes is not a disease but a disorder, affecting 10% of the human population where the body does
not produce insulin or does not properly use insulin due to which the glucose concentration remains high in
the blood stream.
Glucose, Insulin and Diabetes
Like any engine, our body needs fuel to keep it going and this fuel is glucose. Glucose is derived from
all sorts of foods that we consume. After every meal a large part of our food is converted into glucose,
thereby increasing the blood glucose levels. Pancreas, a small gland below the stomach secretes a hormone
called insulin. The insulin released carries the blood glucose present in the blood stream to cells that need
extra energy. The cells do not and can not use glucose without the help of insulin. Once inside the cells, the
glucose produces heat and energy. But if the insulin is not helping, then the glucose is not of use to body
and in fact it is bad for body to have too much of unused glucose. In a normal individual, body manages to
maintain a ideal level of glucose concentration. But in diabetes insulin is either not produced or not utilized
properly, and hence the glucose remains in the blood causing the condition Diabetes.
The problem in people with diabetes is that either they dont produce enough insulin, or the insulin
they do produce does not work properly, or their cells dont respond properly to insulin (insulin resistance).
The net result is that glucose is not cleared from their blood stream and they have high blood glucose
levels which the body tries to clear by various compensatory methods, such as increased urination.
Types of Diabetes
Diabetes due to absence of insulin
This is frequently seen in childhood and hence called, Juvenile Onset or Childhood Diabetes. In this
diabetes which is called Type 1, the patient has failed to produce insulin and the only remedy to overcome
this is to go in for Insulin injections. The problem can happen in any age of the individual, though majority
are from childhood. The injected insulin, the frequency and dose is decided by the medical expert. The
synthesized insulin is injected and it mimics the natural insulin and the individual can lead a normal life.
Diabetes due to ineffective insulin
This is commonly seen in adults and called as Type 2. Though the body produces insulin it has trouble
using it, that is body is resistant to its own insulin. High blood sugar is found in the blood without being
transported to the cells. Routine checkups with dietary restrictions and healthy life style along with regular
affordable physical and mental activities are the only solution. There are medicines available which make
insulin more effective in such individuals and a combination of medicines and calorie control can help the
patients a lot in keeping the disorder under control.
Diabetes Management
Both types of diabetes have different treatment options and in general population the Type 2 diabetes
Views expressed in the journal are those of the authors and the
Editorial Board/Publisher takes no responsibility for the same. We are
a secondary abstracting service and the veracity of information is of
the source quoted and not our primary responsibility.
Editor
S
H 2N S O H 2C CHCH 2S SCH2 CH CH 2
OH O
O Allicin
S-allyl cysteine sulphoxide
Aloe vera (L.) Burm.f. (Family: Aloaceae) and King of bitters in English.
Commonly known as Ghee Kunwar or Andrographolide, a principle present in
Kumar panthu in Hindi. Aloes have long been
O
used all over the world for their various
medicinal properties. Separate experiments on HO O
three groups of rats, namely, non-diabetic
(ND), type I (IDDM) and type II (NIDDM)
diabetic rats were carried out. A. vera leaf pulp
and gel extracts were ineffective on lowering
the blood sugar level of ND rats. Leaf pulp HO
H 3C CH2OH
extract showed hypoglycaemic activity on Andrographolide
IDDM and NIDDM rats. Whereas, leaf gel
extract showed hyperglycaemic activity on Andrographis paniculata is suggested to
NIDDM rats. This study directed that the pulps increase glucose utilization in peripheral tissue
of A. vera leaves devoid of the gel could be via an insulin-dependent mechanism80.
useful in the treatment of non-insulin Annona squamosa L. (Family: Annonaceae)
dependent diabetes mellitus54.
Commonly known as Sharifa or Sitafal in
Andrographis paniculata Nees (Family:
Hindi and Sugar apple or Custard apple in
Acanthaceae) English. Aqueous leaf extract has shown
Commonly known as Kalmegh in Hindi hypoglycemic activity in streptozotocin-
Common name is Tanners Cassia. Extract Coccinia indica Wight & Arn. (Family:
of flowers of C. auriculata suppressed the Cucurbitaceae)
elevated blood glucose and lipid levels in Common name is kundru. It have been
diabetic rats at doses of 0.15, 0.30 and 0.45 used in the traditional treatment of diabetes
g/kg body weight for 30 days. At the dose of mellitus. Toluene, chloroform, ethyl acetate
0.45 g/kg was found to be comparable to and n-butanol fractions of the dried alcoholic
glibenclamide. Extract significantly reduced extract of the aerial part were fed to alloxan
the levels of serum and tissue lipids56. treated diabetic rats orally, twice daily at a
Catharanthus roseus (L.) G. Don. / Vinca dose of 150 mg/kg. The toluene fraction
rosea (Family: Apocynaceae) prevented the elevation of lipid profile
significantly (p<0.001) in comparison to
Commonly called as Sadabahar in Hindi control diabetic rats16. Ethanol extract of C.
and Madagascar periwinkle in English. grandis showed significant triglyceride (TG)
Administration of aqueous extracts of V. rosea and cholesterol-lowering effects in
flower and leaf have been found to regulate the dyslipidemic hamster model. Activity was
blood sugar level in alloxan diabetic male proved to be concentrated in chloroform-
albino rats19. Ethanol extract of V. rosea soluble fraction. Chloroform soluble fraction
promotes significant wound healing and on repeated column chromatography,
closure in diabetic rats compared with furnished a polyprenol characterized as C60-
mupirocin At the dose of 100 mg/kg body polyprenol. It significantly decreased serum
weight, it significantly reduced (p<0.001) TG by 42%, total cholesterol (TC) 25% and
wound size in streptozotocin induced diabetic glycerol (Gly) 12%, accompanied HDL-C/TC
rats53. Alkaloids isolated catharanthine, ratio 26% in highfat diet (HFD)-fed
vindoline and vindolinine lower blood sugar dyslipidemic hamsters at the dose of 50 mg/kg
level48. body weight. Results are comparable to
O
standard drug fenofibrate at the dose of 108
O
N O
HO HO
N
H mg/kg70.
N H
N
H N
O H
O H
O N O O
OH
Commonly known as Safeda in Hindi. In
O diabetic rats, the repeated oral administration
O of E. globulus aqueous leaf extract
Ferulic acid significantly increased the basal plasma insulin
Cynodon dactylon (Family: Poaceae) concentrations (p<0.05)27. An aqueous extract
of E. globulus at the dose of 0.5 g/L
Commonly known as Doob in Hindi. At a enhanced 2-deoxy-glucose transport by 50%,
dose of 500 mg/kg, aqueous extract lowered glucose oxidation by 60% and incorporation of
blood glucose level around 31% after 4 hour of glucose into glycogen by 90% in mouse
administration in normal rats. During glucose abdominal muscle. In acute, 20 min
tolerance test (GTT) of mild diabetic rats, the incubations, administration of 0.25-0.5 g
same dose produced a fall of 23% in blood showed stepwise 70-160% enhancement of
glucose level within 1 hour. This dose has insulin secretion from the clonal pancreatic -
almost similar effect as that of standard drug cell line21.
tolbutamide at the dose of 250 mg/kg body
weight. A significant reduction of 59% was Eugenia uniflora L. (Family: Myrtaceae)
observed in fasting blood glucose level of Commonmly known as Surinam Cherry or
severely diabetic rats at same dose given for 14 Brazilian Cherry in English. Ethanolic extract
days. It reduced urine sugar level. In severely of the leaves of E. uniflora inhibited the
diabetic rats total cholesterol (TC), low density increase in plasma glucose level and plasma
lipoprotein (LDL) and triglyceride (TG) levels triglyceride level48.
were decreased by 35, 77 and 29%,
respectively, whereas, cardioprotective, high Ficus bengalensis (Family: Moraceae)
density lipoprotein (HDL) was increased by It is known as bargad in Hindi and Banyan
18%. These results suggested antidiabetic in English. 50 mg/kg of hot water extract of F.
potential of aqueous extract along with bengalensis was given orally to normal rabbits
significant hypoglycemic and hypolipidemic and rabbits with alloxan induced alloxan-
effects70,71. recovered, mildly diabetic and severely
Enicostemma littorale Blume (Family: diabetic states daily for three days. After a gap
of five days, the water extract was
COOH
O
H
HO
H
significantly (p<0.001), (p<0.01) lowered the
18-glycyrrhetinic acid
blood sugar level of hyperglycemic rats
respectively. Barks exhibited better activity
than aerial roots17. Leucodelphinidin, isolated
from the bark of F. bengalensis has been principal aglycone, 18-glycyrrhetinic acid.
reported for its hypoglycemic activity. 18-glycyrrhetinic acid when administered
orally at 100mg/kg of bodyweight, showed
Ficus racemosa (Family: Moraceae) potential antihyperglycemic effect that is
It is commonly known as Gular in India. comparable with glibenclamide34.
-amyrin acetate, isolated from the fruits of F. Gymnema montanum Hook.f. (Family:
racemosa at the dose of 100 mg/kg body Asclepiadaceae)
G. montanum leaf extract possess
antihyperglycemic and antiperoxidative effect.
Oral administration of 200 mg/kg body weight
of the alcoholic extract of the leaf for 3 weeks
resulted in a significant reduction in blood
O glucose and an increase in plasma insulin. The
O
decrease in lipid peroxides and increase in
reduced glutathione (GSH), ascorbic acid
-amyrin acetate (Vitamin C) and -tocopherol (Vitamin E)
showed its antioxidant properties6.
weight, lowered the blood glucose levels by
18.4 and 17.0% at 5 and 24 hour, respectively, Gymnema sylvestre R. Br. (Family:
in sucrose challenged streptozotocin induced Asclepiadaceae)
diabetic rat (STZ-S) model. Its p- G. sylvestre leaf extract lowers the blood
HH
of various disorders. aerial parts of H. O
O O O O
O
OH
OHO HO
auriculata extract possesses significant O
OH
OH OH
HO H O
H O O H O
O O O O OH O O
H H H OH
H OH OH
H H
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O
O O
O
NH
NH O S NH
O NH
S O N N S
O O S
O HO O N O
O
Ciglitazone Troglitazone Rosiglitazone Pioglitazone
O
O
NH N S
N N S O
NH O
N S O N NH
O O O O
O
DRF-2189 BRL-48482 PAT5A
O O O
N NH
NH H
S S
O F3 C O
O O
Englitazone KRP-297
OCH 3
O
COOCH3 O
R NH H3 CO
S NH
O X S
O O
O
Netoglitazone (X=C, R=F) CLX-0921
NC-2100 (X=N, R=H)
O
SB-219994
O N NH2 CO 2H
O OCH N O
N O O
O
O N
SB-213068
Figure 5: Carboxylated Hydroxyurea Derivative
b) -Carbon Substituted -
Phenylpropanoic Acid Based PPAR
Agonists: The thiazolidine-2,4-dione ring can
be replaced by -acyl-, -alkyl- and -
(aralkyl)-carboxylic acids. Inclusion of an Figure 6: -Oxy-acid Based PPAR Agonists
additional lipophilic moiety affords
compounds which are equipotent to BRL The PPAR / dual agonists
48482. These results were surprising since it muraglitazar, tesaglitazar, naveglitazar and
had previously been shown that in the ragaglitazar belong to this class of compounds
heterocyclic series, the thiazolidine-2, 4-dione (figure 7).
ring was preferred over the oxazolidine-2, 4- Muraglitazar (N-[(4-methoxyphenoxy)
dione. It was assumed that the role of the carbonyl]-N-{4-[2-(5-methyl-2-phenyl-1,3
acidic thiazolidine-2,4-dione was played by oxazol-4-yl)ethoxy]benzyl}glycine),
carboxylic acid in these compounds and that demonstrated significant glucose lowering,
an appropriate substituent at the -position reduction in triglycerides and increase in HDL-
could alter the chemical environment around C in patients with type 2 diabetes, in early
the carboxylic acid in such a way that the clinical studies[21].
whole group came to mimic the thiazolidine-
2,4-dione ring. Higher binding affinities and Tesaglitazar (2S)-2-Ethoxy-3-[4-[2-(4-
functional activity for PPAR were observed methylsulfonyl oxyphenyl) ethoxy] phenyl]
for the (S)-enantiomers of this series. propanoic acid), is an orally active, potent
PPAR / dual agonist under development
Several -oxy-acids showed activities an for the potential improvement of dyslipidemia
order of magnitude more potent than BRL- and glycemic control in individuals with type 2
48482. In particular the -ethoxyacid SB diabetes [22]. However in 2006, its further
213068 is one of the most potent anti- development was discontinued, after several
hyperglycemic agents yet reported[20](figure phase III clinical trials.
6).
Naveglitazar( -methoxy-4-[3-(phenoxy-
phenoxy)propoxy]phenylpropanoic acid) is
another interesting PPAR / dual agonist in
clinical development. Data from a recent Phase
II clinical
O
H 3C
S
CO 2H O CO2 H
O O
N O
O O
O
Ragaglitazar Tesaglitazar
CO2 H O
N
OCH 3 O
N N
O O CO2 H
O O O
S
Muraglitazar Aleglitazar
trial in patients with type 2 diabetes showed advantages in preclinical models, ragaglitazar
that naveglitazar administration resulted in (DRF2725, NN622), which has a phenoxazinyl
significant reductions in mean fasting serum tail group, was suspended from clinical
glucose levels from baseline compared with development, owing to the development of
placebo at all doses and triglyceride levels urine bladder tumors in rodents.
were also significantly reduced[23]. c) Tyrosine Based PPAR Agonists: A
Aleglitazar ((2S)-2-methoxy-3-[4-[2-(5- series of tyrosine-based PPAR agonists have
methyl-2-phenyl-4-oxazolyl) ethoxy]- 7- also been developed [24] and represent some of
benzothiophenyl]propanoic acid ) is another the most potent agonists reported to date
PPAR / dual agonist. It is currently in (figure 8). The (S)-enantiomers have been
phase II clinical trials. shown to possess greater binding affinity and
The PPAR / dual agonist TAK559 was functional activity at PPAR than the
corresponding (R)-enantiomers [25].
placed on clinical hold owing to findings of
abnormalities in liver enzymes in a small In cell based transactivation assays, these
number of patients during the course of the analogs exhibit up to 1000-fold selectivity for
Phase III studies. Further development of this PPAR over the PPAR and PPAR
compound was discontinued in 2005. subtypes
Despite demonstrating glucose and lipid
CO2 H CO2 H
O
HN N N HN
N O O
O CO2H
O O
HN
N O
H3CO 2C
Farglitazar GW-1929 GW-7845
Food intake 41.29 5.63 44.5 2.20 115 2.88* 82.5 4.33**
(g/day/rat)
Water intake 53.75 5.05 40.0 1.15 118.75 0.72* 87.5 7.21**
(ml/day/rat)
Blood pressure 105.62 10.12 98.23 8.23 146.23 3.75* 82.5 3.22**
(mmHg)
Serum glucose 4.34 0.7 4.58 0.41 14.89 0.6* 6.69 0.9**
(mmol/L)
Serum insulin 514.02 25.08 474.72 81.36 342 29.58* 595.98 62.88**
(pmol/L)
Data is shown as mean S.E.M. (n = 6). *Significantly different than non-diabetic control (p < 0.05), **significantly different than
diabetic control (p <0.05)
As mention earlier, 5-HT levels are high independent of insulin. Hajduch et al (1999)35
in diabetes and 5-HT is one of the stimuli for have reported that rat and human skeletal
the translocation of glucose transporters. Both muscles both express 5-HT2A receptors and
GLUT 1 and GLUT 4 levels were reported to that specific 5-HT2A receptor agonists can
be decreased in cardiomyocytes from STZ- stimulate glucose uptake in skeletal muscles by
diabetic rats15,9.. Insulin was found to prevent a mechanism which does not depend upon
only GLUT 4 in STZ-diabetic rats. However, components that participate in the insulin
sarpogrelate, a specific 5-HT2A receptor signaling pathway. Figure-1 illustrates
antagonist was found to increase both GLUT 1 proposed mechanism of sarpogrelate. tudies
and GLUT 4 levels in diabetic rats. These with extracts and fractions of Z. officinale
results indicate that not only 5-HT2A receptors (ginger) and active isolated compound 6-
are involved in glucose transport mechanisms Gingerol had shown insulin release activity in
but also that increase in glucose transporters in STZ-induced diabetic rats. To correlate in-vivo
cardiomyocytes by sarpogrelate may be and in-vitro actions of these drugs on insulin
Table-3 List of the main peripheral cardiovascular responses caused by 5-HT receptors and their
selective ligands
Receptor Agonist Antagonist Cardiovascular effect
5-HT1B/1D Sumatriptan GR127935 Reduce sympathetic drive (i.e. reduction in
noradrenaline release to the heart and
vasculature)
5-HT1B CP-93129 In Rats GR 55562 Vasoconstriction
Obesity control (OB) (vehicle) 41.6 1.6a 156.7 1.7a 91.3 2.1a
b b
OB+ methanolic extract 32.5 1.1 124.4 2.5 75.0 1.5b
(250mg/kg)
OB+ ethyl acetate extract 35.8 0.8b 128.7 2.1b 88.3 1.8b
(250mg/kg)
N=6, values represent mean S.E.M. a Significantly different from normal control P<0.05. b Significantly different from obesity
control P<0.05.
N
In the light of the robustness and fragility HO OH
HO
O OH
failure leads to diabetes. This opens new vistas O
HO OH
Acarbose Voglibose
description of these categories and treatment
available and the targets currently being glucose levels and the long term effect of these
pursued in-view of the recent advancements in drugs is only a small reduction in blood. Since
molecular biology of the disease. alpha-glucosidase inhibitors prevent the
A. Food Intake, Absorption and Control degradation of complex carbohydrates into
Mechanism glucose, the undigested complex carbohydrates
The process of food intake can be move to the colon, where bacteria digests them
categorized under positive feed back in process causing gastrointestinal side effects such as
of energy intake, whereas negative feed back flatulence and diarrhoea.
loops regulate appetite by hormonal The appetite control mechanisms
messengers. The hormonal messengers however, may be exploited for the
controlling the food intake (appetite) are management of obesity. To control
leptin, secreted by adipocytes and ghrelin by hyperglycemic condition, the peptide
the stomach are controlled at the level of hormones called incretins have been targeted.
hypothalamus. The arrival of food in the duodenum stimulates
the release of polypeptides called glucagon-
After the ingestion of food, the
carbohydrate constituents are absorbed into the like peptide-1 (incretin) and glucose-dependent
system through their conversion to mono insulinotropic polypeptide (GLP). They
saccharides. Pancreatic amylase in the intestine enhance the ability of glucose to stimulate
degrades complex carbohydrates to oligo and insulin secretion by the pancreas and stimulate
disaccharides. Within the brush border of the the ability of the tissues to take up glucose
intestinal villi of small intestine, -glucosidase from the blood. GLP-1 is rapidly degraded in
enzymes break down the oligo- and vivo through the action of dipeptidyl peptidase
disaccharides to monosaccharides, which are IV (DPP-IV), which cleaves the N-terminal
absorbed through the mucosal border. two amino acids to give the inactive GLP-1
Competitive inhibition of these enzymes amide.
reduces the rate of absorption and hence A cell surface serine protease, DPP-IV is
postprandial hyperglycemia. -1, 4- ubiquitously expressed, with highest levels
glucosidase inhibitors such as acarbose, found in the kidney and the lower levels in
voglibose and miglitol are therefore used for liver and pancreas, where it rapidly terminates
the treatment of patients with diabetes the activity of GLP-1 by cleaving the N-
mellitus. terminal dipeptide (His-Ala) of GLP-1. DPP-
In diabetic patients, the short-term effect IV inhibitors, therefore stabilize endogenous
of these drugs is to decrease current blood GLP-1 at the physiological concentrations, and
NH2
postprandial disposition of glucose via its
BMS-477118 (Saxagliptin)
F
F
actions on three key target tissues: suppression
O GSK 832093C (Denagliptin)
of glucose output from the liver and
stimulation of glucose uptake and metabolism
O
NH
H
CN
in skeletal muscle and adipose tissue. Defects
H2N N
N N O N in insulin secretion and action on its target
HO
tissues manifest diabetes. Reduced insulin
action and its resistance for glucose transport
NC
in skeletal muscle and adipose tissue have
SYR-322 (Alogliptin) LAF 237 (Vildagliptin) therefore been targets of drug design for type 2
F
F diabetes.
F
H3 C H2 H H O H 2 H
CH C C N C C COOH H3 C O O H
H H H2 2 H H2
H3 C N CH C N C C N C C C C
CH 3
O H3 C COOH COOH
H
Repaglinide Nateglinide KAD-1229 (Meglitinide)
iii) KATP channel opener stimulated effect on the exocytotic machinery of -cells.
secretion: These compounds are at different phases of
MCC 134 opens potassium channels, development as novel oral insulinotropic
activates KATP channel on smooth muscle cells agents.
and inhibits SUR1 resulting in reduced insulin The imidazoline compounds such as KU
secretion. Therefore it is effective in 14R act via another putative imidazoline
hypertensive diabetic patients. NN 414 opens receptors on pancreatic islet. The classical
KATP channels on pancreatic -cells, thereby imidazoline receptors (I1 and I2) occur on
reduces insulin secretion. It also prevents smooth muscle cells. The imidazoline
glucose induced apoptosis of human islets. compound KU 14R causing insulin secretion
from pancreatic islet acts through another
O unknown imidazoline receptor on -cells,
O S
S
O
S
O N
NH 2
termed as I3.
CH 3 N
N N
H N CH
N N 3
N H H CH 3
N CH 3
N
The three PPARs (alpha, beta/delta, and O
S
NH O O O
As part lisproglulisine 10-20 minutes15-30 1-3 hours.5-2.5 hours1-1.5 3-5 hours3-6.5 hours3-
minutes10-15 minutes hours 5 hours
Short-acting (human)
Intermediate (human)
Long-acting (analog)
Premixed (analog)
Premixed (human)
70% NPH/30% regular50% 30-60 minutes30-60 1.5-16 (4.4) hours2-5.5 Up to 18-24 hoursUp
NPH/50% regular minutes (3.3) hours to 18-24 hours
Range (mean)NPH = neutral protamine Hagedorn; APS = aspart protamine suspension; NPL = neutral protamine
lispro
Prefilled pen, eg, FlexPen Less wastage of pen contents vs Initially can be more expensive than
(Novo Nordisk, Bagsvaerd, vial/syringe Discreet Appears less vial/ syringe Cannot mix insulins
Denmark), Humalog Pen (Eli ''medical''Injection may be more Possibility of air bubbles
Lilly and Co, Indianapolis, comfortable than vial and syringe
Indiana), SoloSTAR (Aventis Less time consuming Refrigeration
Pharma Holding GmbH, not required Easy to use Accurate
Frankfurt, Germany) dosing Disposable
Reusable pen, eg, NovoPen Discreet Sturdier than prefilled pens As above Need to change cartridges
Dosers, eg, InnoLet (Novo Easy to use Accurate dosing Suitable As above Not currently available with
Nordisk) for patients with visual/ dexterity insulin analogs
problems Disposable
Insulin pump Uses only rapid-acting insulin (most Pump and supplies expensive
consistent profile) Most accurate Undetected interruptions in insulin
dosing Allows very flexible lifestyle delivery may occur, with possible
Closest to replacing body's own increased risk of ketoacidosisMay
insulin cause discomfort as worn
continuously Needs high patient
motivation, involvement, and
commitment to use
Jet injectors Needle-free Single component May May cause bruising Potential for
benefit patients with severe insulin- decreased amount of absorbed insulin
induced lipoatrophy Requires weekly cleaningRisk of
infection May be less comfortable
than needle-based devices Not suited
to intermediate- or long-acting
insulins
Lilly Prefilled Humalog, Humalog Mix 70/30, Humalog Mix 75/25, Humalog Mix Eli Lilly
Pen 50/50, Humulin N
Dosers
For example, a patient may take an insulin. The cartridges and needles are
injection of Lantus in the morning and evening disposed of when finished and new ones
to provide a baseline of insulin throughout a simply are inserted. In many cases, the entire
24-hour period. In addition, the same patient pen is disposed of. These insulin delivery
may take an injection of Humalog just before devices are less cumbersome than traditional
meals to cover the increase in carbohydrate methods.
load after eating. Insulin pump: The most recently
Different Methods of Delivering Insulin available advance in insulin delivery is the
There are now a variety of insulin insulin pump. In the U. S., MiniMed, Deltec
preparations and also there are various and Disetronic market the insulin pump. An
methods for administering insulin. insulin pump is composed of a pump reservoir
similar to that of an insulin cartridge, a battery-
Pre-filled insulin pens: In the past, insulin operated pump, and a computer chip that
was available only in an injectable form that allows the user to control the exact amount of
involved carrying syringes (which a few insulin being delivered. Currently, pumps on
decades ago were made of glass and required the market are about the size of a pager or
sterilization), needles, vials of insulin, and beeper. The pump is attached to a thin plastic
alcohol swabs. Needless to say, patients often tube (an infusion set) that has a cannula (like a
found it difficult to take multiple shots each needle but soft) at the end through which
day, and, as a result, good blood sugar control insulin passes. This cannula is inserted under
was often compromised. Many pharmaceutical the skin, usually on the abdomen. The cannula
companies are now offering discreet and is changed every two days. The tubing can be
convenient methods of delivering insulin. disconnected from the pump while showering
Both Novo Nordisk and Lilly have an or swimming. The pump is used for continuous
insulin pen delivery system. This system is insulin delivery, 24 hours a day. The amount
similar to an ink cartridge in a fountain pen. A of insulin is programmed and is administered
small pen-sized device holds an insulin at a constant rate (basal rate). Often, the
cartridge (usually containing 300 units). amount of insulin needed over the course of 24
Cartridges are available in the most widely hours varies depending on factors like
used insulin formulations, such as those listed exercise, activity level, and sleep. The insulin
in the table above. The amount of insulin to be pump allows for the user to program many
injected is dialed in by turning the bottom of different basal rates to allow for this variation
the pen until the required number of units is in lifestyle. In addition, the user can program
seen in the dose-viewing window. The tip of the pump to deliver additional insulin during
the pen consists of a needle that is replaced meals to cover the excess demands for insulin
with each injection. A release mechanism caused by the ingestion of carbohydrates with
allows the needle to penetrate just under the the meal.
skin and deliver the required amount of Over 50,000 people worldwide are using
Before being absorbed into the New Medications that Affect Glycemic
bloodstream, carbohydrates must be broken Control
down into smaller sugar particles, such as Symlin (pramlintide): Symlin is the first in
glucose, by enzymes in the small intestine. a new class of injectable, anti-hyperglycemic
One of the enzymes involved in breaking medications for use in patients with type 2 or
down carbohydrates is called alpha type 1 diabetes treated with insulin.
glucosidase. By inhibiting this enzyme, Pramlintide, the active ingredient in Symlin, is
carbohydrates are not broken down as a synthetic analog of human amylin, a
efficiently and glucose absorption is delayed. naturally occurring neuroendocrine hormone
Acarbose: The alpha glucosidase inhibitor synthesized by pancreatic beta cells that helps
available in the India. is arcabose (Multibay). control glucose control after meals. Amylin,
In clinical trials with over 700 patients, the use similar to insulin, is absent or deficient in
of arcabose was associated with a reduction in patients with diabetes. When used with insulin,
hemoglobin Alc values (a well known this compound can improve glycemic control
measurement of average blood sugars over the and has additional benefits that cannot be
preceding three months) that was significantly realized with insulin alone.
greater than the use of placebo (no treatment). According to published data, Symlin
However, as a single agent, arcabose is not as reduces post meal blood sugar peaks, reduces
effective as the other medications for diabetes. glucose fluctuations throughout the day,
Since arcabose works in the intestine, its enhances satiety (the sensation of fullness)
effects are additive to diabetic medications that leading to potential weight loss, and lowers
Dear Readers
We are happy to receive your encouraging response to our
journal. We shall, however, appreciate receiving your critical
comments and suggestions for further improvements. We are
always looking forward to your specific contributions on
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approximately 106 islets (~2 x 109 -cells), but o insulin-secreting cell lines
these comprise only a minor part of total o engineered non--cells/gene therapy
o islets/l3-cells from other species
pancreatic tissue (2-3%) so islets for o tissue stem cells
transplantation must be isolated from whole pancreas
bone marrow
pancreas by enzymatic digestion, which is an liver
inefficient process. The clinical symptoms of neural
o embryonic stem cells
diabetes do not usually become apparent until
and some of these are shown in Box 1. The
60-80% of the -cell mass is lost, suggesting
physiological properties required of substit'!te
that glycaemic control can be maintained on
-cells have been considered in detail
20-40% of normal -cell mass. Current
elsewhere but it is worth considering briefly
evidence suggests that a significant fraction of
two essential attributes of such cells. First,
transplanted islets are lost in the immediate
they must be able to synthesise and store
Views expressed in the journal are those of the authors and the
Editorial Board/Publisher takes no responsibility for the same. We are
a secondary abstracting service and the veracity of information is of
the source quoted and not our primary responsibility.
Editor
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To,
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Dear Sir,
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CH3
CH3
H3C CH3 H3 C CH2 OH
H 3C HO
HO O
H 3C H
O HO
CH 3 H O O
O CH 3 H
O
H
H
OH HO
OH 12: Coagulin J
11 : Coagulin I
CH 3 CH 3
H 3C CH 3 H 3 C OH CH 3
H3C H H 3C H O
H O O
O O O O OH
CH3 H HO CH 3 H
HO
O H O H OH
HO HO
HO O HO O
OH OH
13: Coagulin K 14: Coagulin L
CH3 CH 3
H3 C CH 2OH H 3C CH3
H3 C H H 3C HO
HO HO
O O O O
CH 3 H CH 3 H
O HO O
H O H
HO OH
OH HO O
OH OH
CH3 CH3
H3 C OH CH 3 H 3C OH CH 2OH
H 3C H H3 C
HO HO
O O O O
CH 3 H H
CH 3 H HO
HO
O H OH O H
HO HO
HO O HO O
OH OH
CH3 CH3
H3C OH CH3 H3C OH CH2OH
H3C H3 C
HO HO
O H O O H O
CH3 H CH3 H
H H H
21 22: Withacoagulin
CH3 CH3
23 24:Coagulin S
OCH3
OH
H3CO OCH3
O
HO O
HO
OH O
O O O
O O O
O HO
O
OH
O OH
H3CO OCH3
OCH3 HO
HO
H OH
HO extract of roots of Withania coagulans have
resulted in the isolation of withanolides,
26:3Hydroxy-2,3-dihydro-withanolide F 27:Ergosta-5,25-diene-3,24-diol
CH 3
5,20(R)-dihydroxy-6,7-epoxy-1-oxo-(5)-
H 3C OH
CH3
witha-2,24-dienolide (32) and withaferin A
(33) [16, 17, 18]. 5,27-Dihydroxy-6,7-epoxy-1-
H3C OH
HO O CH3 H
O HO
CH3 H [19]
H OH
HO
HO
O
O
H
oxo-(5)-witha-2,24-dienolide (34) .
HO
OH
Defatted methanolic extract of roots of
28: 3-hydroxy-2,3-dihydrowithanolide H 29: Sitosterol--D-glucoside
Withania coagulans have afforded withacoagin
CH3 CH3
(20R,22R)-5,20-dihydroxy-1-oxowitha-
H3 C OH CH 3 H 3C OH CH 3 2,6,24-trienolide (35), (20R,22R)-6,7-
CH 3 H O CH 3 H O
O
CH 3 H OH
O O
CH 3 H OH
O epoxy-5-20-hydroxy-1-oxowitha-2,24-
H OH
OH H OH dienolide (36) and (20S,22R)-6,7-epoxy-
30: coagulanolide 31:Withanolide F 5-dihydroxy-1-oxowitha-2,24-dienolide (37)
[20]
.
Fig 2: Compounds isolated from the fruits of Withania coagulans Dunal possess interesting
Withania coagulans biological activities. The fruits of the plant are
CH 3 CH 3
H 3C OH CH3 H 3C H CH2OH
sweet and are reported to be sedative, emetic,
CH 3
HO
O O
CH 3
H
HO
O
alterative and diuretic. They are useful in the
O
CH3 H CH3 H
chronic complaints of liver. In some places
H H H H
OH O O
they are used as blood purifier. It is also used
OH
in dyspepsia, flatulent colic and other intestinal
32 33: Withaferin A
infections. These are used for the treatment of
CH3 CH 3 asthma, biliousness and stranguary [21]. In the
H 3C H
CH3
CH 2OH H 3C OH
CH 3
CH3 Unani system of medicine, they are used for
HO HO
O
CH 3 H
H O
O
CH 3 H
H O the treatment of wounds and ulcers. In the
H H H H fruits of Withania coagulans high degree of
OH O OH proteolytic activity has been reported. Acetone
34 35: Withacoagin
and alcohol precipitated fractions of the plant
CH 3 CH 3 showed 50.0 and 33.0 units of activity per
H 3C OH
CH3
CH 3 H 3C H CH3 gram respectively, which is about half of that
CH3
O
CH3 H
HO O
O
CH3 H
HO O found for papain [22]. This plant is reported to
H H H H possess hepatoprotective, anti-inflammatory,
OH O OH O
antihyperglycemic, hypolipidemic, free radical
36
scavenging, antimicrobial, cardiovascular,
37
central nervous system depressant,
Fig 3: Compounds isolated from the root of immunomodulating, antitumor and cytotoxic
Withania coagulans. activities.
Pharmacology Antihyperglycemic activity
It has a prominent place in Ayurvedic, Administration of an aqueous extract of
Unani, and ancient Indian systems of fruits of W. coagulans (1 g/kg; p.o.)
medicine. The berries of the plant are used for significantly lowered the blood sugar, serum
milk coagulation [3]. A number of reports cholesterol, serum LPO and hepatic LPO
reveal that the withanolides isolated from
[2] Maurya, R., Akanksha, Jayendra, Singh, A.B., [13] Alam, Nur-e., Yousaf, M., Qureshi, S., Baig, I.,
Srivastava, A.K., 2008; Bioorganic & Medicinal Nasim, S., Rahman, Atta-Ur., Choudhary, M.I., 2003;
Chemistry Letters; 18; 65346537. Helvetica Chimica Acta; 86; 607-614.
[3] Chadha, Y.R., 1976; The Wealth of India, Raw [14] Velde, V.V., Lavie, D., Budhiraja, R.D., Sudhir, S.,
Materials; CSIR, New Delhi; 10; 580-581. Garg, K.N.; 1983; Phytochemistry; 22(10); 2253-2257.
[4] Rahman, Atta-Ur., Abbas, S., Shahwar, Dur-E., [15] Ramaiah, P.A., David, L., Budhiraja, R.D., Sharan,
Jamal, S.A., Choudhary, M.I., 1993; Journal of Natural S., Garg K.N., 1984; Phytochemistry; 23; 143-149.
Product; 56; 1000-1006.
[16] Subramanian, S.S., Sethi, P.D., 1969; Current
[5] Choudhary, M.I., Shahwar, Dur-E., Zeba, P., Jabbar, Science; 38; 267-68.
A., Ali, I., Rahman, Atta-Ur., 1995; Phytochemistry; 40;
[17] Kupchan, S.M., Anderson, W.K., Bollinger, P.,
1243-1246.
Doskotch, R.W., Smith, R.M., Renauld, J.A.S., Schnoes,
[6] Rahman, Atta-Ur., Choudhary, M.I.; 1998; Pure & H.K., Burlingame, A.L., Smith, D.H.; 1969; Journal of
Applied Chemistry; 70; 385-389. Organic Chemistry; 34; 3858-3866.
[7] Rahman, Atta-Ur., Shabbir, M., Shahwar, Dur-e., [18] Subramanian S.S., Sethi, P.D., Glotter, E., Kirson,
Choudhary. M. I., Voelter, W., Hohnholz, D., 1998a; I., Lavie, D., 1971; Phytochemistry; 10; 685-688.
Heterocycles; 47; 1005-1011.
[19] Sethi, P.D., Subramanian, S.S., 1976; 38; 22-23.
[8] Rahman, Atta-Ur., Choudhary, M.I., Qureshi, S.,
[20] Neogi, P., Kawai, M., Butsugan, Y., Mori, Y.,
Gul, W., Yousaf, M., 1998b; Journal of Natural
Suzuki, M., 1988; Bulletin of the Chemical Society of
Product; 61; 812-814.
Japan; 61; 4479-4481.
[9] Rahman, Atta-Ur., Yousaf, M., Gul, W., Qureshi, S.,
[21] Kirtikar, K.R., Basu, B.D., 1933; Indian Medicinal
Choudhary, M.I., Voelter, W., Hoff, A., Jens, F., Naz,
Plants; vol. 3; Ed. By Basu, L. M., Allahabad; 1777-
A., 1998c; Heterocycles; 48; 1801-1811.
1779.
[10] Rahman, Att-Ur., Choudhary, M.I., Yousaf, M.,
[22] Atal, C.K., Sethi, P.D., 1961; Indian Journal of
Gul, W., Qureshi, S., 1998d; Chemical &
Pharmacy; 23; 7-9.
Pharmaceutical Bulletin; 46; 1853-1856.
[23] Hemalatha, S., Wahi, A.K., Singh, P.N.,
[11] Choudhary, M.I., 1999; Phytochemistry; 52; 1361-
Chansouria, J.P.N., 2004; Journal of
1364.
Ethnopharmacology; 93; 261-264.
Hwang, C. G. Marshall, W. S.
System and method for modifying a fluid for oral IgG Fc-domain peptide conjugates as glucagon
administration. antagonists.
ed. (Remote Clinical Solutions, I. U. 2005-US30146 ed. (Amgen Inc., U. 2001-US14321[2001083527], 54-
[2006023985], 41-20060302. WO. 8-23-2005. 20011108. WO. 5-3-2001.
Urakami, T. et al.
Negreanu-Pirjol, T., Sirbu, R., & Guran, C. Process for producing oxazopyrroloquinolines, novel
New transitional metal complexes of biguanide oxazopyrroloquinolines, and use of oxazopyrro-
derivatives - biological activity on marine organisms. loquinolines.
J.Environ.Prot.Ecol. 6[4], 827-837. 2005. ed. (Mitsubishi Gas Chemical Co., I. J. 90-403176
[429333], 59-19910529. EP. 11-8-1990.
Sato, N.
Health food compositions for prevention and Van Kaer, L.
treatment of obesity. Drugs from the sea: A marine sponge-derived
eds. (Someya, H. J. & Tangolwood K.K.). 2004- compound prevents type 1 diabetes.
203833[2006020606], 12-20060126. JP. 7-9-2004. The Scientific World 1, 630-632. 2001
(Compiled byDr. RK Sharma,Botany Division, Central Drug
Research Institute, Lucknow)
Ueno, Y., Tsuda, T., Takanori, H., Yoshikawa, T., &
Osawa, T.
glutathione-S-transferase (GST), superoxide
Antidiabetic effect of Punica granatum dismutase (SOD) and catalase (CAT) were the
flowers: Effect on hyperlipidemia, salient features observed in diabetic rats. On
pancreatic cells lipid peroxidation and the other hand, oral administration of PgAq at
antioxidant enzymes in experimental doses of 250 mg/kg and 500 mg/kg for 21 days
diabetes. resulted in a significant reduction in fasting
Bagri, Priyanka et al. blood glucose, TC, TG, LDL-C, VLDL-C and
Food and Chemical Toxicology, 47(1), 50 tissue LPO levels coupled with elevation of
(Jan., 2009) HDL-C, GSH content and antioxidant enzymes
The study investigated the effects of in comparison with diabetic control group. The
Punica granatum aqueous extract (PgAq) on results suggest that PG could be used, as a
streptozotocin (STZ) induced diabetic rats by dietary supplement, in the treatment of chronic
diseases characterized by atherogenous
measuring fasting blood glucose, lipid profiles
(atherogenic index), lipid peroxidation (LPO) lipoprotein profile, aggravated antioxidant
and activities of both non-enzymatic and status and impaired glucose metabolism and
enzymatic antioxidants. Diabetes was induced also in their prevention.
by single intraperitoneal injection of STZ Effect of bitter gourd and spent
(60 mg/kg) to albino Wistar rats. The increase turmeric on glycoconjugate metabolism in
in blood glucose level, total cholesterol (TC), streptozotocin-induced diabetic rats.
triglycerides (TG), low-density lipoprotein Vijayalakshmi, B. et al.
cholesterol (LDL-C), very low density Journal of Diabetes and its
lipoprotein (VLDL), LPO level with decrease Complications, 23(1), 71 (2009)
in high density lipoprotein cholesterol (HDL- Changes in glycoconjugate metabolism
C), reduced glutathione (GSH) content and during the development of diabetic
antioxidant enzymes namely, glutathione complications and their modulation by feeding
peroxidase (GPx), glutathione reductase (GR), bitter gourd and spent turmeric as fiber-rich
Current R&D Highlights, Jan.-Mar. 2009 115
Natural Products
source. This was studied by measuring the model). We observed that STZ administration
contents of total sugar, uronic acid, amino (at a dose of 65 mg/kg body weight, injected in
sugar, and sulfate in the streptozotocin-induced the tail vain) caused increased production of
diabetic rats. Total sugar content decreased in both ROS and RNS in the pancreas tissue of
liver, spleen, and brain, while an increase was experimental animals. Formation of these
observed in heart and lungs. Uronic acid reactive intermediates decreased the
content in liver, spleen, and brain decreased, intracellular antioxidant defense, increased the
and marginal increase was observed in testis. levels of lipid peroxidation, protein
Amino sugar content decreased in liver, carbonylation, serum glucose and TNF-
spleen, lungs and heart during diabetes, and [alpha]. Investigating the signaling pathways,
augmentation was observed to different we found that STZ administration caused the
extents. Decrease in sulfation of activation of phospho-ERK1/2, phospho-p38,
glycoconjugates was observed in liver, spleen, NF-[kappa]B and destruction of mitochondrial
lungs and heart during diabetes and was transmembrane potential, release of
significantly ameliorated by bitter gourd and cytochrome c as well as activation of caspase 3
spent turmeric, except brain. Protein content in the pancreas tissue keeping the levels of
decreased in liver, while an increase was total ERK1/2 and p38 significantly unchanged.
observed in brain. The studies clearly showed Treatment of animals with AA (at a dose of
alteration in glycoconjugate metabolism during 20 mg/kg body weight, orally) both prior and
diabetes and amelioration to different extents post to the STZ administration effectively
by feeding bitter gourd and spent turmeric. reduced these adverse effects by inhibiting the
Improvement is due to slow release of glucose excessive ROS and RNS formation as well as
by fiber in the gastrointestinal track and short- by down-regulating the activation of phospho-
chain fatty acid production from fiber by colon ERK1/2, phospho-p38, NF-[kappa]B and
microbes. mitochondrial dependent signal transduction
Protective role of arjunolic acid in pathways leading to apoptotic cell death.
response to streptozotocin-induced type-I Combining all, these results suggest that AA
diabetes via the mitochondrial dependent plays some beneficial roles against STZ-
and independent pathways. induced diabetes.
Manna, Prasenjit et al. Modification of psyllium poly-
Toxicology (In Press) saccharides for use in oral insulin delivery.
Increasing evidences in both experimental Singh, Baljit et al.
and clinical studies suggest that oxidative Food Hydrocolloids, 23(3), 928 (May
stress is involved in the pathogenesis of 2009)
diabetic tissue damage. Pancreatic [beta]-cell There is no doubt that fibers, in particular
death is the cause of decreased insulin viscous dietary fibers, have positive effects on
production in diabetes. Streptozotocin (STZ) is human health, both in the prevention and in
widely used to induce experimental diabetes treatment of chronic diseases. Psyllium, a
due to its ability to selectively target and medicinally important serum glucose reducing
destroy insulin producing pancreatic [beta]- natural polysaccharide, if suitably tailored to
cells via the formation of both reactive oxygen prepare the hydrogels for controlled release of
species (ROS) and RNS (reactive nitrogen insulin; it can act as double potential candidate
species). This study investigated the for cure of diabetes mellitus. Keeping in view
prophylactic role of arjunolic acid (AA) the therapeutic importance of psyllium and its
against STZ-induced diabetes in the pancreas gel-forming nature we have prepared psyllium
tissue of the Swiss albino rats (as a working and methacrylamide based hydrogels by using
Randomized
Human recombinant 47 This randomized, double-blind, dose-
Double-blind
GAD65 , 20 Ilg s.c. escalation trial of Diamyd@ showed
at wks 1 and 4 increased C-peptide levels at 24 weeks at a
Placebo dose of 20 Ilg in LADA patients. No safety
issues were reported.
(Based on the article written by E. Ferrer, C. Dulsat and published in Drugs of the Future 2008, 33(11): 963-967)
1. Ahamad R, Srivastava SP, Maurya R, Rajendran SM, Arya KR and Srivastava A - Mild
antihyperglycaemic activity in Eclipta alba, Berberis aristata, Betula utilis, Cedrus deodara, Myristica
fragrans, Terminalia chebula (2008) - Ind. J. Sci. & Technology 1,1-6
2. Maurya, R., Akanksha, Jayendra, Singh, A.B., Srivastava, A.K., 2008; Bioorganic & Medicinal
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chromatography/tandem mass spectrometric study and analysis of xanthone and secoiridoid glycoside
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