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1. AUTOCOIDS & MEDIATORS OF
INFLAMMATION
1

2. HISTAMINE & SEROTONIN (5-HT)
Dr Sindwa Kanyimba
Lecturer, Pharmacology
2

3. Histamine is produced by decarboxylation of histidine
(catalyzed by L-histidine decarboxylase)
Histamine is found in many tissues, including the brain.
Highest amounts are found in mast cells and basophils
Mast cells store histamine in granules bound in a complex
with heparin, ATP and an acidic protein
There are 4 receptor subtypes that mediate the actions of
histamine (H1, H2, H3 and H4) and all of them are G-protein
coupled
INTRODUCTION
3

4. •
•
The main peripheral pathophysiological roles of histamine
are:
Stimulant of gastric acid secretion
Mediator of type I hypersensitivity reactions such as
urticarial and hay fever
INTRODUCTION …. CONT’D
4

5. Serotonin (5-hydroxytryptamine, 5-HT) is synthesized from
L-tryptophan by hydroxylation and decarboxylation
Location: 90% of 5-HT is found in the enterochromaffin
cells of the GIT. Much of the rest is found in platelets.
Small amounts are found in the brain and other tissues. 5-
HT is stored in granules as a complex with ATP.
There are seven families (5-HT1–7), with further subtypes of
5-HT1 (A–F) and 5-HT2 (A–C). All are G-protein-coupled
receptors, except 5-HT3, which is a ligand-gated ion
channel.
INTRODUCTION …. CONT’D
5

6. LEARNING OBJECTIVES
•
•
•
Describe the biosynthesis and biological effects of
histamine and 5-HT
Describe the pharmacological, clinical uses and
unwanted effects of histamine H1 receptor antagonist
Describe the pharmacology of drugs that act on 5-HT
receptors
6

7. HISTAMINE RELEASE
1.
2.
Release of histamine occurs by two processes:
Energy- and calcium-dependent degranulation – Release
of histamine from mast cells is induced by IgE fixation to
mast cells (sensitization) and subsequent exposure to a
specific antigen. Complement activation (mediated by IgG
or IgM) may also induce degranulation.
Energy- and calcium-independent release (displacement)
– Displacement is induced by drugs such as morphine,
tubocurarine, guanethidine and amine antibiotics.
Damage to mast cells (e.g. by venom, mechanical trauma)
can also release histamine.
7

8. HISTAMINE RECEPTOR SUBTYPES
H1 receptors
Location: brain, heart, bronchi, GI tract, vascular smooth
muscle and leukocytes
Actions: Increase wakefulness, vasodilatation and
increased permeability, and contraction of non-vascular
smooth muscle
H2 receptors
Location: brain, heart, vascular smooth muscle, leukocytes
and parietal cells
Actions: gastric acid production, vasodilatation, smooth
muscle relaxation
8

9. HISTAMINE RECEPTOR SUBTYPES …. CONT’D
H3 receptors
Location: CNS and peripheral nervous system at presynaptic
neurons
Peripheral actions: Stimulation of presynaptic H3 receptors
causes a decrease in histamine release
H4 receptors
Location: haematopoietic cells, spleen, thymus and colon
Actions: Increase chemotaxis of mast cells and leukocytes
toward sites of inflammation
9

10. HISTAMINE H1 ANTAGONISTS (ANTI-HISTAMINES)
•
•
•
•
Competitive inhibitors at the H1 receptor
First generation antihistamines
Include chlorpheniramine, diphenhydramine, cyclizine,
promethazine and cyproheptadine
Have sedative effects (enter the CNS)
Have some anti-muscarinic activity
Some have anti-emetic activity e.g. promethazine,
cyproheptadine, diphenhydramine and cyclizine
10

11. ANTI-HISTAMINES …. CONT’D
•
•
•
•
•
Second generation anti-histamines
Include acrivastine, cetirizine, levocetirizine, loratadine,
desloratadine and fexofenadine
Have higher affinity for and are more selective H1
receptors compared to first generation anti-histamines
Less CNS penetration and therefore less sedating
Very little (cetirizine and levocetirizine) or no anti-
muscarinic activity (the rest)
Have no anti-emetic activity
11

12. ANTI-HISTAMINES: PHARMACOLOGICAL ACTIVITY
•
•
•
•
•
Relax histamine-induced contraction of bronchial
smooth muscle
Block the vasodilator action of histamine
Inhibit histamine-induced increase in capillary
permeability
Block mucus secretion and sensory nerve stimulation
First generation anti-histamines cause CNS depression
(sedation, decreased alertness). In children and some
adults they may cause CNS excitement.
12

13. ANTI-HISTAMINES …. CONT’D
•
•
•
•
Therapeutic uses
Treatment of allergic rhinitis and conjunctivitis
Treatment of urticaria and atopic dermatitis
For sedation (some first generation antihistamines e.g.
diphenhydramine)
Anti-emesis and prevention of motion sickness (first generation
antihistamines)
Unwanted effects
Sedation, dizziness, and anti-muscarinic effects such as dry mouth,
blurred vision, constipation and urine retention (first generation)
and GI upset
13

14. SEROTONIN (5-HT) RECEPTOR SUBTYPES
•
•
•
5-HT receptors are found in cell membranes of many tissues
5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, 5-HT1E and 5-HT1F: Mediate
vasoconstriction (especially carotid and cranial
vasculature). At presynaptic sites they inhibit neuronal 5-
HT release.
5-HT2A, 5-HT2B and 5-HT2C: Mediate vasoconstriction,
intestinal smooth muscle contraction, microcirculation
and vascular permeability, and platelet aggregation
5-HT3: Stimulation in the chemoreceptor trigger zone
causes nausea and vomiting, and stimulation on
peripheral sensory neurons causes pain
14

15. 5-HT RECEPTOR SUBTYPES …. CONT’D
•
•
5-HT4: They mediate an increase in GIT secretions and
motility
5-HT5a,b, 5-HT6 and 5-HT7 receptors are expressed in the
brain
15

16. EXAMPLES OF DRUGS ACTING ON 5-HT RECEPTORS
•
•
Cyproheptadine
An anti-histamine (H1 antagonist) that also blocks 5-HT1
and 5-HT2 receptors
Used to treat diarrhea and intestinal spasms produced
by serotonin-secreting carcinoid tumours and post-
gastrectomy dumping syndrome
16

17. EXAMPLES OF DRUGS ACTING ON 5-HT RECEPTORS ….
CONT’D
•
•
•
•
5-HT3 antagonists
Include ondansetron and ganisetron
Very effective in treating nausea and vomiting associated
with cancer chemotherapy and radiotherapy
Metoclopramide
5-HT4 agonist
Used as a prokinetic agent for GI hypomotility disorders,
stimulation of gastric emptying and gastro-esophageal
reflux disease
17

18. END
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19. AUTOCOIDS & MEDIATORS OF
INFLAMMATION
19

20. EICOSANOIDS
Dr Sindwa Kanyimba
Lecturer, Pharmacology
20

21. •
•
•
Eicosanoids are a large group of autocoids derived
from eicosanoic acids (20-carbon unsaturated fatty
acids)
Include prostaglandins, thromboxanes, leukotrienes,
hydroperoxyeicosatetranoic acids (HPETEs) and
hydroxyeicosatetranoic acids (HETEs)
The precursor of the eicosanoids is arachidonic acid
(AA)
INTRODUCTION
21

22. 1.
2.
Arachidonic acid is formed from phospholipids by two
pathways:
Phospholipase A2 mediated production (inhibited by
glucocorticoids; glucocorticoids induce the
synthesis of the protein lipocortin-1 (annexin-1),
which inhibits phospholipase A2)
Phospholipase C working with diglyceride lipase
INTRODUCTION …. CONT’D
22

23. 1.
2.
Eicosanoids are synthesized by two pathways:
Prostaglandin G/H synthase (cyclo-oxygenase)
pathway: Produces thromboxane, prostacyclin and
prostaglandins (collectively termed prostanoids)
Lipoxygenase pathway: Produces the HPETEs,
HETEs and the leukotrienes
INTRODUCTION …. CONT’D
23

24. •
•
•
Synthesis of some eicosanoids can be very tissue specific
Prostacyclin is synthesized in endothelial and vascular
smooth muscle cells
Thromboxane synthesis occurs primarily in platelets
HPETEs, HETEs and the leukotrienes are synthesized
predominantly in mast cells, white blood cells, airway
epithelium and platelets
The eicosanoids all have short plasma half-lives (0.5-5
minutes). Most of their metabolism occurs in the lungs.
INTRODUCTION …. CONT’D
24

25. LEARNING OBJECTIVES
•
•
•
•
•
Explain what eicosanoids are
Outline the biosynthetic pathways of prostanoids and
leukotrienes
Describe the biological effects of prostanoids and
leukotrienes
Give examples of clinical applications of prostanoids
Give examples of drugs that reduce the activity of
leukotrienes
25

26. EICOSANOID SYNTHESIS PATHWAYS
26

27. CYCLO-OXYGENASE (PROSTAGLANDIN G/H
SYNTHASE) PATHWAY
•
•
•
There are two isoforms of cyclo-oxygenase (COX): COX
-1 and COX-2
Overall structure and catalytic activity of COX-1 and COX
-2 are similar
COX-1 is a constitutive enzyme involved in homeostatic
functions (including cyto-protection of the gastric
mucosa, haemostasis, renal vasodilatation and
parturition)
27

28. COX PATHWAY …. CONT’D
•
•
•
COX-1 is expressed in all tissues
The expression of COX-1 is regulated by hormonal
signals involved in maintaining physiologic
homeostasis
COX-2 is highly inducible by numerous factors and is
associated with eicosanoid production in
inflammation
28

29. BIOSYNTHESIS OF PROSTANOIDS: SUMMARY
•
•
•
•
AA → PGG/H (Prostaglandin G/H synthase, COX)
PGH → TXA2 (Thromboxane synthase)
PGH → PGI2 (Prostacyclin synthase)
PGH → PGD, PGE & PGF (Prostaglandin synthases)
AA = Arachidonic acid
PG = Prostaglandin
TX = Thromboxane
29

30. ACTIONS OF PROSTANOIDS
•
•
•
Prostacyclin (PGI2) causes vasodilatation, inhibition of
platelet aggregation, renin release and natriuresis
through effects on tubular reabsorption of sodium (IP
receptors)
Thromboxane A2 (TXA2) causes platelet aggregation
and vasoconstriction (TP receptors)
PGF2α causes contraction of the uterine smooth
muscle (FP receptors)
30

31. ACTIONS OF PROSTANOIDS …. CONT’D
•
•
•
•
•
PGD2
Derived from mast cells and its actions include:
Bronchoconstriction
Vasodilatation
Inhibition of platelet aggregation
Relaxation of GIT and uterine muscle
Modulates release of hypothalamic/pituitary hormones
The actions are mediated by DP receptors
31

32. ACTIONS OF PROSTANOIDS …. CONT’D
1.
2.
3.
PGE2
EP1 receptors: contraction of bronchial and GIT smooth
muscle
EP2 receptors: relaxation of bronchial, vascular and GIT
smooth muscle, and increases GIT secretions
EP3 receptors: inhibition of gastric acid secretion,
increased gastric mucus secretion, contraction of
pregnant uterus and of GIT smooth muscle, and inhibition
of lipolysis and of autonomic neurotransmitter release,
and fever (through an action on the hypothalamus)
32

33. THE ROLE OF PROSTANOIDS IN INFLAMMATION
•
•
•
PGE2 and PGI2 are the predominant prostanoids associated
with inflammation. Both markedly enhance edema
formation and leukocyte infiltration by promoting blood
flow in the inflamed region
PGE2 and PGI2, through activation of EP2 and IP,
respectively, increase vascular permeability and leukocyte
infiltration
PGE2, PGI2 and PGD2 synergize with other inflammatory
vasodilators such as histamine and bradykinin
33

34. THE ROLE OF PROSTANOIDS IN INFLAMMATION ….
CONT’D
•
•
Although they do not produce pain by themselves, PGE2
and PGI2 potentiate the effect of bradykinin by sensitizing
nociceptors to the effects of noxious stimuli (lower the
pain threshold)
PGE2 mediates fever by affecting hypothalamic neurons
that regulate thermoregulation
34

35. CLINICAL USES OF PROSTANOIDS
•
•
•
Gynaecological and obstetric
Termination of pregnancy: Dinoprostone (a synthetic
preparation of PGE2), gemeprost (PGE1 analogue) and
misoprostol (a metabolically stable PGE1 analogue)
Induction of labour: Dinoprost (PGF2α), dinoprostone,
misoprostol and carboprost (15-methyl-PGF2α; the 15-
methyl group prolongs the duration of action)
Postpartum haemorrhage: Carboprost and misoprostol
35

36. CLINICAL USES OF PROSTANOIDS …. CONT’D
•
•
•
Cardiovascular
To maintain the patency of the ductus arteriosus until
surgical correction of the defect in babies with certain
congenital heart malformations (patency of the fetal
ductus arteriosus depends on COX-2-derived PGE2
acting on the EP4 receptor): Alprostadil (PGE1)
To inhibit platelet aggregation (e.g. during
haemodialysis): Epoprostenol (PGI2), especially if
heparin is contraindicated
Primary pulmonary hypertension: Epoprostenol
36

37. CLINICAL USES OF PROSTANOIDS …. CONT’D
Gastrointestinal
To prevent ulcers associated with non-steroidal anti-inflammatory
drug use: misoprostol
Ophthalmic
Open-angle glaucoma: Latanoprost (a stable long-acting PGF2α
derivative) eye drops (reduces intraocular pressure through
increased outflow of aqueous humor)
Male reproductive system
Treatment of erectile dysfunction: Alprostadil (enhances penile
erection by relaxing the smooth muscle of the corpora cavernosa
(given by intracavernosal injection or transurethral suppositories)
37

38. LIPOXYGENASE PATHWAY


The enzyme 5-lipoxygenase produces 5-HPETEs which are
subsequently converted to 5-HETEs and leukotrienes (LTs)
5-HPETE → 5-HETE
5-HPETE → LTs (LTA4, LTB4, LTC4, LTD4, LTE4, LTF4)
38

39. LIPOXYGENASE PATHWAY …. CONT’D
•
•
•
LTA4 through separate pathways is converted to LTB4 and
to the cysteinyl-containing leukotrienes (LTC4, LTD4, LTE4
and LTF4)
The enzyme 12-lipoxygenase produces 12-HPETEs,
which are converted to 12-HETEs
Other metabolites of HPETEs are hepoxilins and lipoxins
39

40. BIOSYNTHESIS OF LEUKOTRIENES: SUMMARY
1.
2.
AA → 5-HPETE → LTA4
LTA4 → LTB4
LTA4 → LTC4 ↔ LTD4 → LTE4 ↔ LTF4
AA = Arachidonic acid
HPETE = 5-Hydro-peroxy-eicosa-tetranoic acid
LT = Leukotriene
40

41. LEUKOTRIENES: ACTIONS
•
•
LTB4
LTB4 is an important mediator in all types of inflammation
Causes adherence, chemotaxis and activation of
polymorphs and monocytes
Stimulates proliferation and cytokine production from
macrophages and lymphocytes
41

42. LEUKOTRIENES: ACTIONS …. CONT’D
•
•
Cysteinyl-leukotrienes (LTC4, LTD4 and LTE4 )
Contraction of bronchial muscle
Vasodilatation in most vessels, but coronary
vasoconstriction
The cysteinyl-leukotrienes are of particular importance in
asthma
42

43. LEUKOTRIENE INHIBITORS
•
•
•
•
•
Zileuton
Inhibits 5-lipoxygenase the rate-limiting enzyme in
leukotriene biosynthesis
Used in the treatment of bronchial asthma
Effective in relief of exercise-induced
bronchoconstriction
Given orally
Adverse effects: flu-like syndrome, hepatotoxicity
43

44. LEUKOTRIENE INHIBITORS …. CONT’D
•
•
•
•
Zafirlukast and montelukast
Are cysteinyl-leukotriene receptor antagonists
Block the actions of the cysteinyl-leukotrienes
Used in the treatment of bronchial asthma
Given orally
44

45. END
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46. AUTOCOIDS & MEDIATORS OF
INFLAMMATION
46

47. PLATELET ACTIVATING FACTOR (PAF)
BRADYKININ
NEUROPEPTIDES
CYTOKINES
NITRIC OXIDE
Dr Sindwa Kanyimba
Lecturer, Pharmacology
47

48. •
•
•
Platelet activating factor, bradykinin, some
neuropeptides (substance P, neurokinin A and
calcitonin gene related peptide) and nitric oxide are
autocoids (local hormones) that are involved in
various inflammatory processes
Some of these autocoids have potential clinical
applications e.g. cytokines and nitric oxide
There are very few clinically useful drugs available to
inhibit the activity of these autocoids
INTRODUCTION
48

49. LEARNING OBJECTIVES
•
•
•
To describe the biological actions of platelet activating
factor, bradykinin, substance P, neurokinin A, cytokines and
nitric oxide, and
Explain the role they play in inflammatory processes
Give examples of their clinical applications
Give examples of drugs that reduce their activity
49

50. PLATELET ACTIVATING FACTOR (PAF)
•
•
•
•
PAF precursors are released from activated inflammatory
cells by phospholipase A2. After acetylation, the resultant
PAF is released and acts on specific receptors in target
cells
Actions include vasodilatation, increased vascular
permeability, chemotaxis and activation of leukocytes
(especially eosinophils), activation and aggregation of
platelets, and non-vascular smooth muscle contraction
PAF is implicated in bronchial hyper-responsiveness and in
the delayed phase of asthma
A PAF antagonist, lexipafant, is undergoing clinical trial in
pancreatitis
50

51. BRADYKININ
•
•
•
Bradykinin (BK) is a nonapeptide cleaved from a plasma
α-globulin, kininogen, by kallikrein
It is converted by kininase I to an octapeptide and
inactivated by the removal of an additional amino acid by
kininase II (angiotensin converting enzyme) in the lung
There are two main subtypes of bradykinin receptors: B2,
which is constitutively present, and B1, which is induced
in inflammation
51

52. BRADYKININ …. CONT’D
•
•
Actions: Vasodilatation (dependent on endothelial cell
nitric oxide and PGI2), increased vascular permeability,
stimulation of pain nerve endings, stimulation of
epithelial ion transport and fluid secretion in airways and
GIT, and contraction of intestinal, bronchial and uterine
smooth muscle
Icatibant, a peptide analogue of bradykinin, is a selective
competitive antagonist for B2 receptors and is used to
treat acute attacks of hereditary angioedema
52

53. NEUROPEPTIDES
•
•
•
The neuropeptides are a large and diverse family of
small to medium-sized peptides
A large number are found in the CNS, the autonomic
nervous system, and peripheral sensory neurons, and in
many peripheral tissues. They are often released as co-
transmitters along with non-peptide neurotransmitters.
When released from peripheral endings of nociceptive
sensory neurons, neuropeptides can cause neurogenic
inflammation
53

54. NEUROPEPTIDES …. CONT’D
The main peptides involved in inflammation are
substance P, neurokinin A and calcitonin gene related
peptide (CGRP)
Other important members of the neuropeptide family
include enkephalins/endorphins
Tachykinins
Substance P and neurokinin A are members of the
tachykinin family
54

55. TACHYKININS
•
•
•
Tachykinins act on mast cells, releasing histamine and
other mediators, and producing non-vascular smooth
muscle contraction, neuronal activation, mucus secretion
and vasodilatation
Tachykinins released from the central endings of
nociceptive neurons are involved in pain transmission in
the spinal cord
CGRP, a member of the calcitonin family shares properties
with the tachykinins and is a potent vasodilator
55

56. NEUROPEPTIDES …. CONT’D
Neurogenic inflammation is implicated in the
pathogenesis of several inflammatory conditions,
including the delayed phase of asthma, allergic rhinitis,
inflammatory bowel disease, some types of arthritis and
migraine
Substance P receptor antagonist: Aprepitant
Aprepitant is a drug used to treat emesis, particularly that
associated with cancer chemotherapy. It’s anti-emetic
effects are due to blockade of the actions of substance P
on neurokinin NK1 receptors in the vomiting centre.
56

57. CYTOKINES
•
•
•
Cytokines are polypeptides that are rapidly induced and
released during inflammation
The cytokine superfamily includes the interferons,
interleukins, chemokines and colony-stimulating factors
Cytokines regulate the action of inflammatory and
immune system cells. They have complex effects on
leukocytes, vascular endothelial cells, mast cells,
fibroblasts, haemopoietic stem cells and osteoclasts,
controlling proliferation, differentiation and/or
activation.
57

58. CYTOKINES …. CONT’D
•
•
•
•
IL-1 and TNF-α are important primary inflammatory
cytokines, inducing the formation of other cytokines
Chemokines, such as IL-8, are mainly involved in the
regulation of cell trafficking
Interferons IFN-α IFN-β have antiviral activity. IFN-α is
used as an adjunct in the treatment of viral infections.
IFN-γ has significant immune-regulatory function and is
used in the treatment of multiple sclerosis
58

59. NITRIC OXIDE (NO)
•
•
•
•
•
NO is synthesized from L-arginine and molecular O2 by
nitric oxide synthase (NOS)
NOS exists in three isoforms: neuronal (NOS-1), inducible
(NOS-2) and constitutive (NOS-3)
NOS-1 is present in the CNS and in autonomic nerves
NOS-2 is induced in macrophages and other cells by
interferon-γ. Glucocorticoids inhibit biosynthesis of NOS
-2.
NOS-3 is present in endothelial cells, platelets and other
cells
59

60. NITRIC OXIDE …. CONT’D
•
•
NO diffuses to sites of action in neighbouring cells
NO is inactivated by combination with the haem of
haemoglobin or by oxidation to nitrite and nitrate, which
are excreted in urine
60

61. ACTIONS OF NITRIC OXIDE
•
•
•
•
Nitric oxide acts by:
Combining with haem in guanylyl cyclase activating the
enzyme, increasing cGMP and thereby lowering
intracellular Ca2+
Combining with haem groups in other proteins (e.g.
cytochrome C oxidase)
Combining with superoxide anion to yield the cytotoxic
peroxynitrite anion
Nitrosation of proteins, lipids and nucleic acids
61

62. ACTIONS OF NITRIC OXIDE
•
•
•
•
•
•
•
Vasodilatation
Inhibition of platelet and monocyte adhesion and
aggregation
Inhibition of smooth muscle proliferation
Protection against atheroma
Neurotransmission in the peripheral and CNS
Host defence and cytotoxic effects on pathogens
Cytoprotection
62

63. PHYSIOLOGICAL ROLES OF NITRIC OXIDE
•
•
•
•
•
Control of blood pressure and regional blood flow
Limitation of platelet adhesion/aggregation
Defence against viruses, bacteria, fungi, protozoa,
parasites
Neurotransmission, long-term potentiation, plasticity
(memory, appetite, nociception)
Neurotransmission (e.g. gastric emptying, penile
erection)
63

64. PATHOLOGICAL ROLES OF NITRIC OXIDE
•
•
•
•
•
Excess production
Hypotension (septic shock)
Excitotoxicity (e.g. ischaemic stroke, Huntington’s disease,
AIDS dementia)
Inadequate production or action
Atherogenesis and thrombosis (e.g. in
hypercholesterolaemia and diabetes mellitus)
Hypertrophic pyloric stenosis
Erectile dysfunction
64

65. NITRIC OXIDE IN DISEASE
•
•
•
NO is synthesized under physiological and
pathological circumstances. Either reduced or increased
NO production can contribute to disease.
Hypertrophic pyloric stenosis in babies is associated with
underproduction of neuronal NO
Endothelial NO production is reduced in patients with
hypercholesterolaemia and some other risk factors for
atherosclerosis, and this may contribute to atherogenesis
Overproduction of NO may be important in
neurodegenerative diseases and in septic shock
65

66. CLINICAL APPLICATIONS OF NITRIC OXIDE
•
•
Therapeutic applications
Drugs that release NO (NO donors) e.g. nitroprusside and
organic nitrates are vasodilators and are used in
cardiovascular conditions such as angina pectoris and
hypertension
Drugs that inhibit the phosphodiesterases (cyclic GMP is
metabolized by phosphodiesterases) such as sildenafil
potentiate the action of NO. They are used to treat
conditions such as erectile dysfunction and pulmonary
hypertension.
66

67. CLINICAL APPLICATIONS OF NO …. CONT’D
Therapeutic applications
Inhaled NO is used in adult and neonatal respiratory
distress syndrome to reduce pulmonary hypertension and
improve oxygen delivery
NO inhibition
Inhibition of NO biosynthesis is being investigated in
disorders where there is overproduction of NO (e.g.
inflammation and neurodegenerative disease)
67

68. END
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