The Pharmacology

1

• The Pharmacology
• Of
• Ginexin F
• (Ginkgo biloba)
• And
• Its Clinical Uses
• By
• Professor Kamal Eldin Hussein ElTahir
• Department of Pharmacology,
• College of Pharmacy,
• King Saud University
• Riyadh
• (2005)

2
1

• Introduction
• Ginkgo biloba (Family
• Common Name Maidenhair tree.
• Height 30 40 meters.
• Circumference 4 meters.
• The Leaves Fan shaped
• Green to Golden
  Yellow
• Indigenous to Korea, China Japan.
• Known in China for Over 5000 Years.
• Old Chinese uses Circulation disorders
• Memory
  Disturbance
• Asthma,
  Bronchitis
• Introduction in Europe 1730
• in America 1784
• Start of Interest in it 1965
• In Germany

3
2

• Part of the Plant used Leaves
• Constituents
• a) Flavonoidal Glycosides
• (Mono , bio and tri osides of)
• Quercetin, Kaempferol, Isorhamnetin and
  3-O methyl Myristicin.
• b) Bioflavonoids
• Bilobetin, Amentoflavone, Ginkgetin,
  5-Methyl Bilobtin and
  Isoginkgetin.
• c) Tri Lactonic diterpenes
• Ginkgolides A, B and C
• d) Tri Lactonic Sesquiterpene
• Bilabolide
• e) Anthocyanin

4
3

• Ginkgo Extraction Acetone Water and Spray
  Drying.
• Standardization of Extraction
• Standardized to Contain
• 24 Flavonoid glycosides
• 6 Lactonic di- and
  sesqui-Terpenes
• Lessthan 0.6 mg Ginkgolic Acid per
  100gm
• 1Kg Extract 70 Kg dried
  Leaves
• Pharmaceutical Forms Capsules Tablets, 40 60
  and 120
  mg.
• Trade Names Ginexin F EGB 761
• Ginkgold Ginkoba GBE
  24 Tebonin
• Status Classification
• In USA Dietry Supplement
• In Canada Food Additive
• In France and GermanyAs overthe Counter
  Drugs
• 
  (No Prescription)
• Availability In more than 50 Countries

5
4

• Reported Pharmacological Actions
• 1) Blockade of Platelets-Activating Factor
  (PAF) Receptors due to
  the Ginkgolides and
  bilabolides.
• 2) Stimulation of Release of Nitric oxide
  NO from the endothelia
  due to the anthocyanin.
• 3) As Anti-oxidant to scavenge oxygen free
  radicals due to the flavonoids
  Quercetin, Kaempferol and isorhamntin.
  
• 4) Vasodilator to Blood vessels.
• It increases blood flow to tissues.
• 5) Inhibition of Cyclic Guanisine
  monophospho Diesterase (cGMPD).
  

6
5

• Actions (Contin.)
• 6) Release of prostacyclin from blood
  vessels (PGI2).
• 7) Decrease in blood triglycerides.
• 8) Membrane Stabiliser.
• 9) Stimulation of choline uptake by the
  Hippocampus ? Increase in Ach.
• 10) Neurone protector.
• 11) Inhibition of age-induced decreased in
  brain muscarinic receptors.
  
• 12) Suppression of cerebral cortex and Retina
  Oedemas.
• 13) It increases brain O2 and blood supply.
• 14) It stimulates glucose influx and ATP
  production in cells.
• 15) It helps the brain to record Information,
  communicate ideas and
  recall concepts.

7
6

• Importance of Blockade of PAF Receptors
• 1) PAF is an ether phosphocholine Mixture
• 1-o-hexadecyl-2-acetyl Sn-glycero-3-phosphoch
  oline and 1-o-octadecyl-2-acetyl
  Sn-glycero-3-
  phosphocholine.
• 2) Discovered in 1971. It is Released by
  Lenkocytes and found to aggregate
  Platelets.
• 3) Cells and organs that Synthesize Release PAF
  Platelets, Neutrophils,
  Eosinophils,Monocytes, Mast cells,
  Vascular endothelia, Aminotic sac., Blastocyts,
  Uterus, Liver, Splean.
• 4) Site of Synthesis Endoplasmic Reticulum.
• 5) Storage in cell membranes.

8
7

• Biosynthesis PAF
• 1) 1-o-Hexadecyl-2-acyl-glycerophosphcholine
• PLA2 Ca 2
• 1-o-Hexadecyl-2-Lyso-glycerophosphocholine
• 
  (Lyso PAF)
• Ca2 Acetyl
  CoA
• 
  Acetyl Transferase
• PAF
• 2) Stimulators of Acetyl transferase
• Antigen-Antibody Reactions Thrombin,
  Collagen Chemotactic Peptides,
  Endotoxin, stress
• 3)Another SourceOxidation of membrane
  Phospholipids
• Mediated via oxidants

9
8

• Known Pharmacological Actions of PAF
• 1) Aggregation of both plateletes and
  PMNL(Neutrophil, Eosinophils, Monocytes).
• 2) Release of TXA2 from platelets.
• 3) Release of PMNL contents. i.e. Degranulation
  e.g Release of Lysosomal enzymes
  Eicosanoids (PGs LTs) oxygen
  free radicals.
• 4) Vasodilation leading to decrease in arteial
  blood pressure.
• 5) But decreases Coronary blood flow due to its
  induced aggregation and release of TXA2 .
• 6) Decrease in Pulmonary blood flow due to
  platelets aggregation and Release of
  TXA2 .

10
9

• Action of PAF (Contin.)
• 7) Increase in Capillary permeability leading to
  Oedemas.
• 8) Chemotaxis of Leukocytes.
• 9) Stimulation of Adherence of neutrophils to
  endothelial cells leading to
  Leukocytopenia.
• 10) Bronchoconstriction and induction of
  pulmonary oedemas.Its
  Bronchoconstriction is direct via release of
  intracellular Ca2 via IP3. and due to Release
  of Histamine Eicosanoids.
• 11) Induction of Hyper-responsiveness
  (Reactivity) of Pulmonary relaxant
  epithelia and the Non-Adrenergic
  Non-cholinergic autonomic innervation via its
  induced release of Basic and Cationic
  Proteins from
  Eosinophils.

11
10

• Actions of PAF (Contin)
• 12) Release of Histamine from Mast cells
  ?Allergy.
• 13) It stimulates gastric Acid secretion and
  peroxides formation and inhibition of
  mucus secretion. ? Ulcers
• 14) It stimulates the intestine and stomach.
• 15) It decreases the renal blood flow, glomerular
  filtration Rate and decreases urine
  production.
• 16) It inhibits (Decreases) Excretion of Na.
• 17) It activates and stimulates the uterus
  directly and via Release of PGs from the
  Amnion.
• 18) It facilitates Ovulation, implantation and
  parturition.

12
11

• PAF-induced Diseases Disorders It is involved
  in
• 1) Inflammation 2) Asthma
• 3) Anginas 4)
  Atherosclerosis
• 5) Rejection of transplanted organs.
• 6) Anuria 7)
  Gastric ulcers
• 8) Anaphylactic and Endotoxin shocks (It
  decreases blood pressure, cardiac
  output, heart rate, plasma volume,
  coronary blood flow and the haematocrit)
• 9) Pulmonary Hypertension.

13
12

• PAF Receptor Blockers
• 1) Ginkgolide B contained in Ginexin-F.
• 2) Triazolam 3) Alprazolam
• 4) TCV-309 5) BN 52501
• Metabolism of PAF
• PAF is metabolized initially by PAF
  acetylhydrolase in cells and Plasma to produce
  Lyso PAF which is acted on by Alylltransforare
  enzyme to produce its precursor 1-alkyl-2-acyl
  glycerophosphocholine to start PAF Biosynthesis
  again.

14
13

• Importance of Release of NO
• 1) Nitric Oxide is a vasodilator substance
  Released from various endothelia and was
  first known in 1980 by the name
  Endothelium-derived factor (EDRF).
• 2) It is now known to be released from endothelia
  of all blood vessels of the brain and
  periphera. It acts as a neurotransmitter in
  the brain with high concentrations in the
  cerebellum, Hypothalamus, mid brain and
  Medulla Oblongata.
• 3)It is also the neurotransmitter of the
  non-adrenergic- non-cholinergic autonomic
  nervous system in the lungs, bronchi,
  bronchioles, trachea, intestine, colon,
  stomach, anococcygeus muscle, platelets,
  macrophages.etc.
• 4) It is identified as NO in 1987.

15
14

• Biosynthesis and Release of NO
• 1) L-Arginine is acted on by the cytosolic enzyme
  Nitric oxide Synthase in presence of
  Nicotinamide dinucleotide
  Phosphate (NADPH), Ca2 and
  tetrahydrobiopterin to produce hydroxy arginine
  that produces Citrulline and NO.
• 2) In the Endothelial cells it is released mainly
  abluminally i.e towards the
  underlying smooth muscles. Small
  quantities are released luminally
  towards the Blood stream.
• 3) t ½ 6 to 60 seconds.

16
15

• NO Synthases NO
• 1) Types a) Constitutive Enzyme always present
  in its synthesizing
  organs.
• b) Inducible Enzyme Induced
  by Bacterial
  endotoxins (Lipopolysaccherides), the
  Cytokines TNF, IL-1, INF-? in
  
  Macrophages, Liver, Tumor cells.
• 2) Brain NO Synthase is Identical to Cytochrome
  P450 Reductase.
• 3) The Inducible NOS is independent of Ca2 but
  for its activity it requires both NADPH
  Tetrahydrobiopterin.
• 4) The Inducible NOS is present both in the
  Cytoplasm and attached to cell membranes.

17
16

• NO Synthesis Inhibitors
• 1) L-N-Nitromethyl arginine (LNMA).
• 2) GN- Nitoarginine.
• 3) L-GN-Nitroarginine Methyl ester (L-NAME).
• 4) L- Canavanine (In neutrophils only).
• NO Synthesis Stimulators
• 1)Ginexin-F 2) Arginine 3) ACh
  4) BK
• 5) Histamine 6)Substance 7)Kainic
  Acid (Brain)
• 8)N-Methyl D-aspartate (NMDA) in Brain.
• 9)IP3 (Inositol tri Phosphate) 10)Cromakalin
  11)ADP
• 12)ATP 13)5-HT 14)VIP (Vaso Active
  intestinal
  peptide)
• 15)Endothelin 16)Thrombin
  17)Blood flow 18)UV Rays.

18
17

• Known NO Pharmacological Actions
• 1) It mediates all inhibitory neurotransmission
  in Respiratory system,
  Gastrointestinal tract, .etc.
• 2) Potent Vasodilator in all blood vessels.
• 3) Potent Inhibitor of platelet aggregation
  induced by ADP,AA, Collagen etc.
• 4) It inhibits adhesion of platelets to vascular
  endothelial cells.
• 5) Cytotoxicity Towards Tumor cells, bacteria,
  viruses etc. (It is released by
  Macrophages during their attack to
  foreign bodies).
• 6) It is a cytotoxic tool released by T-Killer
  lymphocytes (CD8).

19
18

• NO Actions (Contin.)
• 7) Decreases Pulmonary Vascular Resistance.
• 8) Enhances Blood flow to the penis leading to
  erection.
• 9) It is involved in pain transmission within the
  spinal cord. It enhances transmission.
• 10)It is involved in inflammation via its
  vasodilation.
• 11)It increases the bleeding time.

20
19

• NO Antagonists or Inhibitors
• 1) Oxy haemoglobin
• 2) Methylene Blue.
• 3) Mepacrine.
• 4) Nordihydroguiaretic Acid
• Mechanism of Action
• NO Activates the enzyme Guanylyl Cyclase leading
  to stimulation of production of Cyclic guanisine
  mono-phosphate. The latter activates protein
  Kinases that act in presence of ATP to
  phosphorylate cellular proteins that bind
  intracellular Ca2 and inhibit influx of
  extracellular Ca2 together with stimulation of
  K eflux resulting in hyperpolarization of the
  cells.

21
20

• Metabolism
• It is inactivated by Superoxide Anions
• (O2 . -). This is protected by super oxide
  dismutase.
• Diseases Associated with Deficiency of NO
• 1) Hypertension 2) Atherosclerosis
• 3)Cerebral spasms 4)Angina
• 5) Pulmonary Hypertension 6) Erectile
  Dysfunction

22
21

• Importance of Scavenging Free Radicals
• 1) Definition A free radical is any atom or
  molecule that contains one or more unpaired
  (unshared) electron. They are very
  unstable and reactive.
• 2) Examples are the oxygen free Radicals The
  superoxide anion O2. -( - . OH)(-
  . O-O-H) and (NO . )
• 3)The superoxide anion interacts with NO to give
  the more toxic peroxynitrite radical
  N-O-O .
• 4) Sites of production
• a) In Mitochondria during ATP
  production.
• b) In the Endoplasmic Reticulum.

23
22

• Initiation of Production of free - . OH Radicals
• a) Interaction of Fe3 (iron) with
  superoxide anion
• O2. - Fe3
  Fe2 O2
• Then Fe2 H2O2
  Fe3 OH - . OH
• b) Interaction of superoxide anion with
  H2O2
• O2. - H2O2
  O2 OH - . OH
• c) Acceptance of a proton by H2O2
  
  
• H2O2 e H O2
  OH - . OH
• d) Interaction of O2. - or - . O-O-H
  with Cuprous Cu2 Or Ferrous
  Fe2

24
23

• Factors that Increase Free Radicals Production
• 1) Ischaemia
• 2) Excessive metabolism of Arachidonic acid via
  COXes Enzymes to produce Prostoglandins and
  via Lipoxygenases
  (5-Lipoxygenase and 12-
  Lipoxygenase) to produce Leukotrienes

25
24

• Actions of Free Radicals
• 1) They are the weapons of Macrophages during
  Phagocytosis and T-killer
  Lymphocytes in attacking transplanted
  foreign organs.
• 2) However, they attack unsaturated fatty acids,
  Proteins and DNA resulting in necrosis of
  various cells and damage to the
  neurones.

26
25

• Actions of free Radicals (Contin.)
• 3) Attack of Polyunsaturated fatty acids e.g.
  Linolenic or Linoleic to produce peroxy
  acids (Fatty acid radicals) which are also
  damaging to enzymes, proteins, ion
  channel, receptors and even DNA. They inhibit
  prostacyclin synthesis.
• O2. - R C C C ? R O O .
• 
  Fatty Acid Radical
• 4)The fatty acid Radical then interacts with O2
  to produce a Peroxide Radical
  
• R O O . - O2 ? Fatty Acid . O O
  H
• 5) The peroxyl Radical then attacks a new
  unsaturated fatty acid to produce a fatty
  acid radical the cycle goes on.
  

27
26

• Actions of free Radicals (Contin.)
• 6) Free O2 radicals interact with various amino
  acids containing unsaturated carbons
  e.g Tryptophan, histidine .etc. and
  those containing S groups e.g Cysteine
  to result in protein damages (Denaturation).
• 7) The . OH Radical but not other radicals
  interact with Deoxyribonucleic acid (DNA) at
  the Deoxyribose part to release free bases
  from DNA. It also attacks the CC (at
  positions 4 and5) of Pyrimidine and purine
  bases. This results in inhibition of DNA
  replication, mutagenicity and death of
  cells.

28
27

• Anti Oxidants
• 1) These are substances which prevent the
  damaging actions of free radicals.
  They may be enzymes, sequestering
  agents or scavenging substances.
• 2) Enzymatic Anti-oxidants act intracellularly
  and convert the reactive radicals to less
  harmful products.
• Examples are (i) Superoxide dismutase (S.D.)
  
• O2. - S.D. H2O2
  
• (ii)
  Catalase
• H2O2 H2O
  O2
• (iii)
  Glutathione peroxidase
• H2O2 Glutathione H2O
  oxidized
  glutathione
• 
  disulphide.

29
28

• Anti Oxidants (Contin.)
• 3) The scavenging Agents interact with the free
  radicals perferentially. They are oxidized
  in preference to endogenous
  unsaturated fatty acids, proteins DNA.
• Examples ? - tocopherol, ß carotene,glutathion
  e, Melatonin, the flavonoid
  glycosides of Ginexin F.
• 4) Sequestring Agents that interact with Fe and
  Cu which contain unpaired electrons e.g
  Transferrin (Fe), Ceruloplasmin
  (Cu).

30
29

• Claimed Clinical Uses of Ginexin F
• 1) Vascular Dementia associated or non-associated
  with early Alzheimers Disease.
• 2) Peripheral Intermittent Claudication.
• 3) Stroke.
• 4) Tinnitus.
• 5) Retinopathy.
• 6) Shock.
• 7) Sexual erectile Dysfunction.
• 8) Glaucoma.

31
30

• Potential Future Clinical Uses
• 1) Spontaneous Abortion.
• 2) Pre-menstrual Syndrome.
• 3) Suppression of Rejection of transplants.
• 4) Enhancement of hair-growth.

32
31

• Ginexin F in Dementia
• 1)Dementia is considered a group of disorders
  embracing multiple cognitive deficits and memory
  impairment. The cognitive disorders include
  aphasia, apraxia and agnosia. In this disease
  there is impairment of social and occupational
  functions. It may be due to vascular disorders or
  insufficiencies or as a part of the symptoms
  which characterize Alzheimers disease such as
  Memory loss, disorientation, insomnia,
  depression, anxiety and cognitive decline.

33
32

• Memory
• 1) Memory Function depends upon
• a) The cholinergic system (M1 and M3
  Receptors)
• b) The N-Methyl-D-Aspartate receptor
  density in the hippocampus.
• c) Regulation of Blood supply to the brain
• d) Presence of break down products of the
  Amyloid Precursor protein via ?-
  secretase enzyme within the brain
  neurones.
• e) Neuronal Glucose metabolism and its
  control by insulin.

34
33

• Memory and Acetylcholine
• 1) Within the cholinergic hippocampal neurones,
  Ach is synthesized from
• Acetyl CoA Choline Choline Ach
• 
  Transferase
• 2) Acetyl CoA is provided via Glycolysis.
• Glucose Pyruvate
  Acetyl CoA
• 3) The Activity of the enzyme choline transferase
  is regulated by insulin.
• 4) Together with NA, Ach regulates the blood
  supply to the Brain.
• 5) The most important role of Ach in the
  hippocampal neurones is stimulation of
  formation of the secretable forms of an
  Amyloid precursor protein (APP) from
  within the hippocampal neurones into the synapses.

35
34

• Memory and Ach (Contin.)
• 6) An Amyloid Precursor protein (APP) is present
  inside the hippocampal neurones in the
  endoplasmic Reticulum and Golgi
  apparatus.
• 7) APP is acted on by ? - secretase to Release
• ß A40 ß A 42 (Amyloids).
• 8) When these are secreted outside the
  hippocampal neurones they act to enhance
  memory capacity via
• a) promotion of Dendritic outgrowth.
• b) Increase in the synaptic Density (An
  increase in number of synapses ? Increase in
  Memory Retention.

36
35

• Memory and Insulin
• 1) Insulin acts to stimulate secretion of the two
  Amyloids ß A 40 ß A 42 outside the hippocampal
  neurones.
• 2) Deficiency of insulin prevents this release
  and leads to impairment in memory.
• 3) Similary, decrease in insulin Receptors
  sensitivity leads to accumulation of the
  releasable Amyloids inside the endoplasmic
  reticulum and Golgi Apparatus inside hippocampal
  neurones and hence Decrease in memory.
• 4) Accumulation of ß A 42 Amyloid intracellularly
  in the hippocampal and cortical neurones is
  involved in Alzheimers disease dementia.

37
36

• Thus, Disturbance and insufficiency of
  insulin or decrease in the sensitivity of its
  Receptor in both the hippocampus and the cortex
  leads to Disturbance in glucose metabolism
  (Glycolysis) with decrease in production of ATP
  and Acetyl CoA and hence a) No
  stimulation of production of the Amyloids ß A 40
  and ß A 42 via ? secretase enzyme due to
  deficiency of Ach and
• b) No release of the Amyloids outside the
  neurones due to deficiency of insulin.
• ? Decrease in neuromal Activity at the
  synapses leading to decrease in memory
  Dementia.

38
37

• Drugs in use for Dementia
• 1) Levacecarnine
• 2.5 3 gm per day.
• It enhances Ach synthesis.
• 2) Anti-oxidant Vitamin E C.
• 3) Cholinesterase Inhibitors
• a) Donepezil Arisept
• 5 10 mg /
  day
• b) Rivastingmine Exelon Capsules.
• 1.5 mg 2x daily up to 12 mg
  / day
• c) Galantamine Reminyl
• 24 mg / day
• d) Huperzine A
• 50 100 µg 2
  x daily.
• This is an alkaloid obtained from Club
  Moss Huperzia serrata
• Rate of success of Anti-Choline esterases
• 45
  50
• 4) Memantine (NMDA Blocker) 5) Piracetam
  Nootropil

39
38

• Ginexin-F in Dementia
• A) Doses used in Double blind placebo studies
• 1)12o 160mg /day for 24 wks (2 3 doses)
• Types of Dementia Mild Moderate senile
  and primary degenerative
  Alzheimers.
• Effectiveness 32
• 2) 240 mg / day for 24 wks.
• Type of Dementia Mild to moderate
  Alzheimers.
• Effectiveness Modest as in case of Anti
  cholinestreses.
  (Donepezil).
• 3) 120 160 mg / day for 6 months.
• Type of Dementia Progressive Degenerative
• Effectiveness 63.

40
39

• Dementia (Contin.)
• 4) 120 240 mg/day for 6 months
• Type of Dementia Multi-infarct dementia.
  
• Effectiveness 27.
• 5) 120mg/day for 24wks.
• Type of Dementia Mild to Moderate.
• Effectiveness 52

41
40

• Actions Observed After Ginexin-F
• 1) Increase in Attention (Vigilance).
• 2) Enhancement of Mental concentration.
• 3) Enhancement of communication of idea.
• 4) Enhancement of re-call of concepts.
• 5) Enhancement of information processing
• 6) Increase in ?- waves in EEG
• (indication of wakefulness attention)
• (Normal waves 7.5 13 Hz)
• 7) Decrease in slow delta waves activity in EEG.
• (Normal waves 1.3 7.5 Hz)

42
41

• Probable Mechanisms of Action
• 1) Enhancement of cerebal blood flow via a)
  direct action b) Blockade of ?1 Receptors.
  
• c) Antagonism of PAF-induced platelets
  aggregation.
• d) Release of NO which vasodilates blood
  vessels and inhibits platelets
  aggregation.
• e) Anti-oxidant effect against
  vasoconstricting O2
  radicals.
  
• f) Inhibition of cerebral oedema.
  
• The increase in blood supply ensures
  excellent supply of O2 and glucose and insulin
  resulting in elevation of ATP and creatine
  phosphate.

43
42

• Mechanisms (Contin.)
• 2) Enhancement of insulin binding to its cortical
  and hippocampal receptors. It probably
  regulates the function of insulin Receptors
  disturbed during Dementia.
• 3) Enhancement of utilization of both Glucose and
  O2 in the hippocampus and the cortex.
• 4) Stimulation of choline uptake by the
  hippocampus cholinergic neurones
  resulting in an increase in synthesis of Ach.
• 5) Increase in cortex and Hippocampus Muscarinic
  M1 and M3 receptors.

44
43

• Parameters Assessed in Dementia
• 1) Absent mindedness.
• 2) Difficulties in concentration.
• 3) Loss of short-term Memory.
• 4) Lack of Energy.
• 5) Decrease in Physical performance.
• 6) Number-Connection tests.
• 7) Reaction Time.
• 8) Electroencephalogram (EEG).
• 9) Via Syndorm-Kuvz Test (Attention and memory).
• 10) Social Behavior.

45
44

• Effect on Healthy Subjects
• 1) 120, 240 or 600 mg single doses one hour
  before testing the speed of information
  processing in healthy subjects (25 40
  years of age) did not enhance memory.
• 2) 320 or 600 mg single dose one hour before or
  daily for several weeks then testing the
  speed of information processing
  in elderly with slight age- related
  memory impairment improved performance.
• 3) 120 mg/day in healthy subjects for 6 weeks did
  not improve memory. However 180 mg/day
  for 6weeks enhanced memory.

46
45

• General Notes Regarding Use in Dementia
• 1) The effectiveness is Moderate. It depends upon
  the severity of the disease.
• 2) Also, moderate effectiveness (50) in primary
  Degenerative Alzheimers Dementia.
• 3) Its rate of success (or efficiency) is similar
  to the available anticholine esterases.
• 4) Duration of treatment depends upon the
  condition of the patient.

47
46

• Intermittent Claudication
• 1) Definition Intermittent Claudication (I.C.)
  is defined as occurrence of pain, cramping
  and fatigue of the legs muscles during
  exercise. Generally, the pains are relieved
  by rest except in advanced cases of the
  disease.
• 2) It results from inadequate blood flow to
  peripheral vascular organs disease.
  
• 3) It is common in elderly 50 70 years of age
  ranging from 6 20.

48
47

• I.C. (Contin.)
• 4) It is associated with atherosclerotic
  narrowing in iliac or femoral arteries or a
  distal leg artery.
• 5) Blood perfusion of the post stenotic tissues
  is highly reduced leading to local tissue
  hypoxia i.e ischaemia and Release of free
  Radicals, platelets aggregation and
  accumulation of lactic and pyruvic acids in
  tissues Pain.
• 6) Chronic Disease leads to Gangrene resulting in
  the possibility of limb amputation.

49
48

• Classification of (I.C.)
• Fontaine Classification of Peripheral
• Arterial Obstructive Disease
• Stage Characteristics
• I Leg pain occurs during
  hard exercise
• II a Maximum walking distance
  before
  precipitation of pain is 200 meters.
• II b Pain occurs on walking less
  than 200 meters.
• III Pain occurs on walking a
  short distance and at
  rest.
• IV Pain at Rest with clear skin
  ulcers and gangrene.

50
49

• Risk Factors for (I.C.)
• 1) Smoking 2)
  Hypercholesterolemia
• 3) Hypertension 4) Diabetes
  mellitus
• 5) Angina 6) Old Age

51
50

• Strategy For Treatment
• 1) Proper treatment of the associated diseases.
• 2) With holding of smoking.
• 3) Drug treatment.
• Drugs Currently in use
• 1) Pentoxifylline Treatal 400mg 3x daily
• a) Methylxanthine Derivative that
  inhibits cyclic AMP
  phosphdiesterase leading to elevation
  of the level of cAMP.
• b) It Blocks Adenosine receptors.
• c) The net action is inhibition of
  platelets
  aggregation and dilatation of blood vessels.
  
• d) Effectiveness 39.

52
51

• Drugs for (I.C.) (Contin.)
• 2) Cilostazol 100
  mg 2x daily
• Actions As pentoxifylline plus
• a) Inhibition of Adenosine uptake
  ?elevation of its level more
  dialation.
• b) Decreases LDL Triglycerides.
• 3)Ticlopidine Tiklid 250mg 2x daily. It Blocks
  Fibrinogen receptors in platelets preventing
  their aggregation.
• 4) Naftidrofuryl 200mg
  2x daily
• a) Blocks 5 HT2 receptors in platelets
  and blood vessels leading to
  vasodilation.
• 5) Indobufen, Aspirin .etc., heparin.

53
52

• Ginexin F in (I.C.)
• 1) Intake of 120 240mg/day prolonged the
  distance walked by the patient without pain to an
  extent similar to pentoxifylline at a dose of
  1.2gm/day. (Tread Mill Exercise).
• 2) Duration of treatment 24 weeks.
• 3) Mechanisms
• 1- Induction of Vasodilation via direct
  and indirect mechanisms via
  release of NO.
• 2- Inhibition of platelets aggregation,
  induced by PAF by blocking its
  receptors and other aggregators via
  NO induced increase in cyclic GMP.
• 3- Antagonism to PAF induced ischemia
  resulting from accumulation of
  PMNL.
• 4- Scavenging of free O2 Radicals that
  constrict blood vessels.

54
53

• Stroke
• Definition Stroke is a cerebrovascular disease
  resulting from reduction in
  cerebral blood flow leading to
  ischaemia and death of brain cells.
• 1)The reduction in blood flow is due to
  atherothrombosis that occluded a cerebral
  artery 85 of cases).
• 2) It may also occur via occlusion of a cerebral
  artery by a clot that detached from another
  site in the body.
• 3) Non ischaemic strokes occur following
  rupture of a cerebral artery.

55
54

• Stroke Complication
• 1) Occlusion of a middle cerebral artery
  supplying part of the motor cortex leads
  to ischaemic stroke with
  Hemiplegia.
• 2) Other disabilities include Dementia, aphasia,
  and spasticity

56
55

• Consequencies of Ischaemic Stroke
• a) Stroke Decrease in Glucose O2 supply
  resulting in depletion of ATP
  in neurones with loss of membrane
  stability.
• b) Influx of ions and release of glutamic acid
  and free radicals that damage neurones
  and induce inflammation.
  
• C) Ischaemia induced release of free O2
  radicals and Ca2 stimulate synthesis and
  release of Nuclear Factor kappa B
  (NF-KB) and Interferone regulating
  factor-1 which stimulate release of PAF,TNF and
  IL- Iß.
• d) The latter 3, stimulate adhesion of leukocytes
  to Endothelial cells.

57
56

• e) The leukocytes pass into the Brain parenchyma
  with release of inflammatory mediators and
  lysosomal enzymes and they stimulate release of
  the vasoconstrictor endothelin 1 resulting in
  further Ischaemia.
• Risk Factors
• 1) Smoking. 2)
  Hypertension.
• 3) Diabetes mellitus. 4)
  Hyperlipoproteinemia.

58
57

• Treatment Strategy
• A) For Non haemorrhagic ischaemic stroke
• 1) I.V. Administration of a thrombolytic
  drug within 3 hours of occurrence.
• 2) Then administration of drugs to
  prevent recurrencies
  i.e Anticoagulants.
• 3) Administer drugs to enhance stroke
  Recovery i.e Administration of
  Neuroprotective Agents.

59
58

• Treatment Thrombolytics
• 1)Recombinnant tissue Plasminogen Activator
• r t PA Alteplase
• It activates Plasminogen resulting in
  release of active Plasmin that degrades the
  clot.
• 2) Streptokinase Kabikinase 250000 i u i.v over
  30 minutes then 100000 i u every hour
  for 24 72 hours.
• It activates Plasminogen to release Plasmin.
• 3) Reteplase Retavase.
• 4) Others Monteplase Cleactor, Tenecteplase
  Metalyse

60
59

• Treatment Drugs for Prophylaxis
• This group comprises anti-coagulants,
  anti-platelets, hypolipidemics and anti-oxidants.
• 1) Warfarin Na Coumadin
• Dose 2 15mg/day. Maintenance dose 2
  6mg/day.
• 2) Phenindione Dindevan
• Dose100200mg/day. Maintenance dose
  100mg/day.
• These inhibit reduction of natural vitamin K
  via inhibition of vitamin K reductase required
  together with glutamic acid carboxylase for
  activation of some coagulation factors in the
  blood.

61
60

• 3) Aspirin Dose
  40 80mg/day
• It inhibits the enzyme prostaglandin
  cyclo-oxygenase-1 (COX-1) in platelets via
  acetylation of a serine amino acid at position
  516. Thus, no synthesis of TXA2 that aggregates
  platelets.
• 4) Ticlopidine Tiklid Dose. 250 mg 2x daily
• It blocks fibrinogen receptors in platelets.
  Thus, it inhibits fibrinogen induced
  aggregation.
• 5) Abiciximab Reopro.
• This is a monoclonal antibody that blocks the
  glycoprotein II b / III a receptors in platelets.

62
61

• 6)Edaravone Radicut
• This is free radical scavenger.
• 7) Atrovatatin. Lipitor 10 20 mg / day
• 8) Simvastatin.Zocor 10 20 mg / day.
• These two are hypolipidemic drugs. They
  inhibit cholesterol synthesis via inhibition of
  the enzyme.
• HMG CoA (HydroxymethylGlutaryl CoA)
• 9) Memantine.
• This is a neuroprotective agent that blocks
  NMDA receptor to prevent the damaging effects of
  Glutamic acid.
• 10) Ziconotide w-conotoxin
• This is N-calcium channel blocker. It acts
  presynaptically to inhibit glutamic acid release.

63
62

• Enhancement of post-stroke recovery via use of
• 1) Donepezil Aricept
• 2) Rivastigmine Exelon.
• 3) Galantamine Reminyl
• These inhibit the enzyme ACh esterase leading
  to elevation of the level of ACh.

64
63

• Ginexin F use in stroke
• Ginexin F can be used as a prophylactic agent
  following recovery from stroke to prevent
  recurrencies The patient will benefit from its
• a) Vasodilating action resulting from the
  direct effect and the indirect action of release
  of NO.
• b) Anti-oxidant effect that prevents
  availability of free oxygen radicals via
  scavengation due to its flavonoidal glycosides.
• c) Anti-aggregatory effect on platelets.
• d) Anti-inflammatory action.

65
64

• Tinnitus
• Definition Tinnitus is an otological complain
  taking the form of ringing in the ears. It
  affects about 10 12 of the population that are
  more than 65 years of age. In audiometric Normal
  subjects (normal hearers) the hearing level
  threshold is 20 25 dB (decibels) at frequencies
  ranging from 250 8000 Hz. The intensity of
  tinnitus is 10 44 dB at frequency of 3000
  8000 Hz. The sounds are due to spontaneous
  vibrations of the outer hair cells of the
  cochlea.

66
65

• Tinnitus (Contin.)
• The sounds heard may be unilateral (one
  ear is affected) or may be bilateral (both ears
  are affected). The sounds heard may be ringing in
  37 of patients, Buzzing in 11, hissing in 8,
  whistling in 7 and humming in 5 of the
  patients.
• Tinnitus may be objective meaning it is
  loud enough to be heard by the patient and his
  neighbors or it may be subjective heard by the
  patient only in most of the patients.
• Its effect is great in patients suffering
  from pain, depression or who are socially
  isolated and psychotic.

67
66

• Tinnitus (Contin.)
• The clicking buzzing may indicate Palatal
  myoclonus or contractions of the tensor tympani
  or stapelius muscle.
• The pulsatile sounds are also considered to
  be due to vibrations from turbulent blood flow
  that reaches the cochlea.

68
67

• Parts Affected in Tinnitus
• (Pathway)
• Damage or stimulation of the Kinocilia nerve
  attached to the Kinocilia cell in the inner ear
  sends impulses to the thalamus and then to the
  cerebral cortex. Tinnitus may result from an
  increase in the spontaneous firing rate of the
  auditory nerve as in the case of Salicylates. It
  may also occur following reduction in the
  activity of the auditory nerve inputs leading to
  disinhibition of the dorsal cochlear nucleus and
  an increase in spontaneous activity in the brain
  auditory system which is then expressed as
  tinnitus. e.g as in case of furosemide -induced
  tinnitus.

69
68

• Causes of Tinnitus
• 1) Poor blood perfusion of the inner ear due to
  vasoconstriction.
• 2) Rhythmic hyperactivity of the auditory reflex
  arc and impairment of the auditory neural
  pathway.
• 3) Dysfunction of the auditory nerve.
• 4) Stimulation of the tympanic nervous plexus
  following inflammation of the cavity of the
  middle ear (otitis media)
• 5) Hypersensitivity of Tympani nerve.
• 6) Oedema of cortis organ.

70
69

• Causes of Tinnitus (Contin.)
• 7) Stenosis of the carotid artery.
• 8) Atriovenous malformations.
• 9) Tumors in the Jugular vein.
• 10)Valvular heart disease. 11) High
  cardiac output
• .12)Impacted cerumen. 13) Head
  injury
• 14)Vestibular schwannoma (Acuostic Neurema)
• 15)Meningitis 16) Cerebllum Tumors
  17)Drugs.
• 18)Very loud noise. 19)Multiple sclerosis 20)
  Hypertension
• 21) Anxiety. 22) Soft plate disorders.

71
70

• Drugs that cause tinnitus
• 1) Salicylate and other non-selective COX enzyme
  inhibitors.
• 2) Aminoglycosides e.g Gentamycin Kanamycin
  Streptomycin.
• 3) Loop diuretics e.g Furosemide.
• 4) Vincristine.
• 5) Cisplatin.
• 6) Quinine and Quinidine.
• 7) Heavy metals poisoning.

72
71

• Treatment Strategy
• 1)Assess tinnitus and identify its type using
• a) An audiometer.
• b) Determination of tone threshold.
• c) Speech Audiometry to determine
  hearing loss i.e (Number and word
  comprehension).
• d) Monitoring of oto-coustic emissions to
  assess the biomechanical performance
  of the outer hair cells.
• e) Examine the head, oral cavity, cranial
  nerves the 5th , 7th and 8th.

73
72

• Treatment Strategy (Contin.)
• 2) Treat any causative disorder if possible.
• 3) Withdraw any causative drug.
• 4) If the disease is due to exposure of loud
  sounds, protect the hearing process
  via use of ear-muff like devices or
  custom-molded devices that fit into external
  auditory meatus.
• 5) Administration of drugs noting that there is
  no 100 cure (up to 50 Reduction).

74
73

• Drugs Available for Treatment of Tinnitus
• A) Drugs that enhance blood flow to the cochlea
• 1- The calcium channel Blockers e.g
• a) Cinarizine Cerepar 25mg 3x daily
• b) Flunarizine Cibelium 5 -10mg/day.
• c) Nicergoline Semion 5 15 mg / day
  3x daily.
• Efficacy 20 30 .
• 2- Anti-aggregatory and vasodilators e.g
  pentoxifylline
• 3- Direct vasodilator PG releasers e.g
  Nicotinic acid.

75
74

• Treatment of Tinnitus (Contin.)
• B) Membrane Stabilizers
• Carbamazepine Tegretol
• Dose 50 100 mg / day
• It suppresses movement of Na and Ca2 into
  the cochlear nerve. Thus, it suppresses its
  activity to transmit impulses to the
  thalamus.
• Effectiveness 10 30 50 .
• C) Anxiolytics e.g
• Alprazolam xanax 0.5 mg 3x daily
• Lorazepam Ativan 1 2 mg / day.
• These releive anxiety and suppress stress
  leading to emotional balance.
• Effectiveness 50 .

76
75

• D) Amitriptyline Tryptisol
• 50 150 mg / day
• Effectiveness 10 30
• E) Non Drug Treatment
• a) A cupuncture which releases
  enkephalins and ß- endorphins.
• Effectiveness 5 30
• b) Electrical stimulation of cochlea
  via the external canal of the ear.
• Effectiveness 10 50

77
76

• Treatment of Tinnitus (Contin.)
• F) New Drugs
• 1) Memantine
• It blocks NMDA receptor of glutamic
  acid. It acts as a neuroprotector to
  the cochlear nerve.
• 2) POU4F3
• This is an inner ear cell
  transcriptor factor that encodes
  nucleic acids. It stimulates regeneration
  of damaged inner cells.

78
77

• Ginexin F and Tinnitus
• 1) Ginexin F when administered at a dose of
  40mg 3x daily for 12 weeks to patients with
  Tinnitus (subjective or idiopathic) resulted
  in a significant decrease in the severity
  of the disease in 57 of the patients.
• 2) The effectiveness of the drug is high in
  recently developing tinnitus.
• 3) Treatment of patients with 120mg/day for 2
  months suppressed tinnitus by 60 whereas
  Nicergoline (a Vasodilator) 15mg/day for 2
  months suppressed the symptoms by 40.
• 4) In another study, administration of the
  extract 200mg/day (I.V.) in form
  of infusion followed by oral doses of 80mg
  2x daily for 12 weeks decreased
  significantly the subjective Tinnitus volume
  by-3.5 dB.

79
78

• Mechanism of Action
• The beneficial action of Ginexin F in
  suppressing the severity of tinnitus may have
  been exerted via Ginexin-F- induced.
• 1) Vasodilation and enhancement of blood flow
  to the inner ears. The factors that are involved
  in this vasodilation include
• a) Direct effect on blood vessels
  resulting in inhibition of release of
  intracellular Ca2 with decrease in
  vasocontriction.
• b) Release of the vasodilators NO
  and PGI2 from the endothelium and smooth muscles
  of the blood vessels
• c) Antagonism of PAF- induced
  Platelets aggregation resulting in enhancement of
  the dilation.
• d) The antioxidant effect that
  prevents the availability of the vasoconstricting
  O2 free Radicals.

80
79

• Retinopathy
• Definition Retinopathy is a common ocular
  microvascular
  Disease resulting from unwell
  controlled Diabetes mellitus and hypertension.
  Its ultimate Destination is
  Blindness.
• Signs a) Generalized and focal retinal
  arteriolar narrowing.
• b) Atriovenous nicking.
• c) Retinal haemorrhages.
• d) Swelling of the optic disk.
• Other Causes Inflammation and Endothelial
  dysfunction.

81
80

• Pathophysiology of Hypertension-induced Disease
• 1)The high untreated blood pressure induces
  vasoconstriction and spasms resulting in
  narrowing of retinal arterioles.
• 2) This is followed by intimal thickness,
  hyperplasia of medial wall, hyaline degeneration
  and necrosis of retinal vessels and their
  endothelial cells.
• 3) Thus, Retinal Ischaemia results together with
  haemorrhages, hard exudates, occlusion of vein
  branches and swelling of optic disc.

82
81

• Pathophysiology of Diabetes - induced Retinopathy
• This is multifactorial since it involves
  polyol accumulation, glycation, Oxidative stress
  and activation of protein kinases.
• a) Polyol Accumulation
• 1) The increased glucose in the blood is
  converted intra cellularly into sorbitol
  via the enzyme Aldose
  reductase.
• 2) Sorbitol then exerts osmotic toxicity leading
  to damage of vascular cells,
  retina and the optic nerve.

83
82

• b) Protein Glycation
• With the high level of glucose available some
  of it interacts with proteins to form glycated
  proteins which stimulate free O2 radical
  production. These damage the neural cells.
• c) Oxidative Damage
• Some of the high glucose undergo auto
  oxidation to release free O2 Radicals.
• d) Activation of Protein kinases
• An increase in the activity of the protein
  kinase-B2 is believed to stimulate production of
  matrix proteins such as collagen and fibronectin
  and enhances synthesis of endothelin resulting in
  thickening of the basement membrane and an
  increase in retinal vascular permeability leading
  to macular oedemas and decreases in the retinal
  blood flow.

84
83

• Growth Factors (GF)
• In the process of Retinopathy some GF are
  believed to be involved in the disease. These
  include
• a) vascular Endothelial GF which
  increases with hypoxia, PAF release and retinal
  Ischaemia resulting in an increase in capillary
  permeability and formation of oedemas.
• b) The Transforming GF-ß which is
  normally released by pericytes to inhibit
  endothelial proliferation and angiogenesis is
  found to be elevated during Retinopathy resulting
  in enhanced endothelial proliferation and
  angiogenesis.

85
84

• Diagnosis
• Via a) Ophthalmoscopy
• And b) Fluorescein Angiography
• Treatment Strategy
• 1) Control well the Diabetes mellitus via
  effective drugs to ensure that the pre-prandial
  glucose level is 90 130 mg/100ml plasma and the
  glycosylated Haemoglobin Hb AIC is less than 7
  in plasma.
• 2) Control the hypertension so that the diastolic
  blood pressure is in the range of 82 87 mm Hg
  and the systolic blood pressure in the range of
  144 154 mm Hg.

86
85

• Treatment of Retinopathy (Contin.)
• 3) Administration of Anti-oxidants e,g Vit E.
• 4) Application of Laser Photocoagulation or
• 5) Application of Vitrectomy but this does not
  affect macular oedema.
• Expected Future treatments
• 1) New Aldose reductase inhibitors since the
  available sorbinil is ineffective.
• 2) Inhibitors of PKC-B e.g Ruboxistaurin.
• Dose 32mg / day (not available now)
• 3) Suppression of expression of vascular
  Endothelial GF (Corticoids are effective but are
  hyperglycemic.)

87
86

• Ginexin F and Retinopathy
• 1) Intake at a dose of 80mg/day for 6 months
  produced significant improvements in
  patients with Diabetes- induced
  retinopathy.
• 2) Administration of a dose of 320mg /day for 3
  months to diabetics with Retinopathy
  together with their normal diabetes
  treatment increased significantly some
  parameters that are decreased in the diabetics
  e.g it increased retinal blood flow rate.
  Furthermore it decreased some of those
  parameters that are increased such as
  peroxidation of membranes, fibrinogen, blood
  viscosity, blood viscoelasticity and erythrocytes
  rigidity.

88
87

• Ginexin and Retinopathy (Contin.)
• 3)Exposure of cultured retinal pigment epithelia
  to Ginexin F at a concentration of
  50 100 µg/ml protected the cell
  against UVB light-induced death and protected
  the cells when used in a dose of 0.5 1 mg
  /ml against H2O2 induced oxidative damage and
  against hypoxia induced damage.
  
• Thus, it has the potential to prevent Macular
  degeneration that are produced
  via exposure to sunlight cellular
  oxidation resulting from hypoxia. In this
  regard it was more effective than vitamin E.

89
88

• Mechanisms through which Ginexin F induces its
  beneficial actions in Retinopathy
• 1) Enhancement of retinal blood flow via direct
  vasodilation and in an indirect
  way via release of the vasodilators NO
  and prostacyclin.
• 2) Antagonism of PAF receptors leading to
  inhibition of PAF induced platelets
  aggregation and PAF induced
  expression of vascular endothelial growth
  factor (VEGF).
• 3) Anti-oxidant activity that prevents formation
  of the highly damaging and inflammatory
  O2 free radicals.

90
89

• Glaucoma
• Definition Glaucoma is an ocular disease caused
  by sustained increase in intraocular pressure
  (I.O.P.). This increase damages the optic nerve
  leading to loss of vision. The normal I.O.P. is
  10 21 mm Hg but in glaucoma it increases above
  30 mm Hg.
• Other factors that predispose to the disease
  include reduction in blood supply to the optic
  nerve, ocular trauma and migraine.
• Symptoms In the first stage there are no clear
  symptoms except the high I.O.P. later symptoms
  include Blurred vision ocular pain, redness,
  headache, nausea vomiting and seeing halos around
  light.

91
90

• Types of Glaucoma
• a) Open-angle Glaucoma this is the most common
  in 90 of the patients. Beside the high
  I.O.P. and using scanning laser imaging one
  can see optic-disk damage,
  enlargement of the optic-disk cup and
  haemorrhages.
• b) Closed angle Glaucoma In this type there is
  an increase in the I.O.P. resulting
  from failure of the aqueous humor to
  flow through the pupil into the
  anterior chamber and hence No outflow through the
  trabercular system.

92
91

• Drugs Available for treatment of Glaucoma
• 1)Timolol 0.25 0.5 Eye Drops Timpotic 4x.
  It is non selective ß- blocker.
• 2) Betaxolol hydrochloride 0.25 0.5 Eye drops
  Betopic 4x daily.
• It is a selective ß1- blocker.
• These Drugs decrease aqueous humor Synthesis.
  
• 3) Pilocarpine hydrochloride 0.5 4 Eye drops
  Isoptocarpine 4x daily.
• It increases aqueous humor out flow from the
  anterior chamber of the eye into the
  trabercular mesh work.

93
92

• 4) Acetazolamide Tablets (500mg) Diamox 500mg
  2x daily. It decreases Aqueous humor
  synthesis.
• 5) Brinzolamide Azopt 1 Eye drops 3x. Both are
  carbonic anhydrase inhibitors.
• 6) Argon laser trabeculoplasty. Used to reduce
  the resistance of the trabercular
  mesh work to outflow of the aqueous humor.
• 7) Surgical trabeculectory.
• An opening is created in the anterior
  chamber angle to allow aqueous
  humer to flow from the anterior
  chamber below the conjunctiva.

94
93

• Ginexin F use in Glaucoma
• 1) Intake of 40 mg 3x daily for 4 weeks by
  Glaucoma patients produced significant
  improvement in the visual field
  indices but did not decrease the I.O.P.
• 2 Treatment of Glaucoma patients with 40 mg 3x
  for 2 days significantly increased the
  velocity of blood flow in artery by 23 but did
  not affect the I.O.P.
• 3) Treatment of rats before performing partial
  retinal degeneration using cautery
  decreased the loss of Retinal ganglion
  cells from 30 in control to 5 in
  treated animals

95
94

• Mechanisms of Action of Ginexin-F
• The beneficial actions of Ginexin-F in Glaucoma
  may be due to
• 1- Its Vasodilatory action in retinal
  blood flow.
• 2- Its platelets antiaggregatory effect
  that decreases blood viscosity and
  enhances its flow to the
  Retinal cells.
• 3- Scavenging of free O2 Radicals that act
  to damage the retinal
  cells.
• Thus, in Glaucoma Ginexin-F can be used with
  other drugs to induce neuroprotective action.

96
95

• Shock
• Shock occurs when the circulation of the
  arterial blood is not adequate to perfuse various
  organs.
• Types
• 1) Hypovolemic results from loss of blood via
  haemorrhages or loss of
  electrolytes and water as in case of severe
  burns, vomiting or diarrhoea.
• 2) Cardiogenic shock results from inadequate
  cardiac function.
• 3) Obstructive shock due to obstruction of the
  systemic or pulmonary circulation as in
  cases of massive pulmonary
  embolism.
• 4) Septic Shock caused by severe infection with
  gram negative rods e.g E. coli and gram
  positive cocci e.g Staphylococcus.

97
96

• 5) Neurogenic shock results from spinal cord
  injury or fear mediated via reflex vagal
  stimulation.
• 6) Anaphylactic shock due to antigen antibody
  reactions.
• Major Symptoms
• 1- Hypotension 2-
  Confusion
• 2- Arrhythmias 4-
  Decrease in urine flow
• Treatment
• 1) In case of haemorrhage infuse packed red cells
  with saline or physiological saline or lactated
  Ringer solution 0.5 2 liters .
• 2) Following correction of volume deficits
  administer Dopamine hydrochloride 200mg in 500ml
  NaCl injection at a rate of 1 -2 µg/kg/min. It
  elevates the blood flow.
• 3) Other symptomatic treatment as required.

98
97

• Ginexin F and Shock
• In patients with hypovolemic shock
  administration of 400mg I.V. infusion over 4
  hours followed by 400mg orally/day for several
  days hastened recovery.
• Mechanism of Action
• The beneficial actions may be due to
  blockade of PAF Receptors that mediate PAF
  actions when it is released in high quantities
  during shock.

99
98

• Other Potential Uses of Ginexin F
• 1) Treatment of spontaneous abortions.
• 2) Treatment of premenstrual Syndrome.
• 3) Stimulation of Hair Growth.
• 4) Treatment of Raynauds Disease

100
99

• Side Effects of Ginexin F
• Nausea, vomiting, diarrhoea, headache, dizziness,
  palpitations, flatulence, allergy.
• Precautions
• 1) It enhances the actions of anticoagulants and
  anti- Platelets.
• 2) It inhibits Mono amine Oxidase enzyme.
• 3) No reports about its effects on pregnancy
  outcome.

101
100

• Finally, it should be recognized that any
  treatment that does not harm the patient it is
  worthwhile to consider it. A drug success rate
  may be 30 40 but may cure a specific patient.