Detailed information on different system wise cytoprotective agents. Dr. Kiran Panchal B.J. Medical college, Ahmedabad

1. Cytoprotective Agents
Presented by : Dr. Kiran Panchal
Guided by : Dr. Manish Solanki
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 Definition
 Types of Cytoprotection
 Factors for cell Injury
 Cytoprotective drugs
 Recent advances
Outline of the seminar

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Cytoprotection: Defined as the ability of a pharmacological
agent to provide protection to cells against harmful agents.
Types of Cytoprotection:
1. Gastroprotection 4. Neuroprotection
2. Chemoprotection 5. Hepatoprotection
3. Cardioprotection
Definition & Types

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 Term Cytoprotection - First introduced  Andre Robert (1979)
 He used this term to refer to protection by PGs against
experimentally induced acute gastric lesions in rats.
 Szabo and Szelenyi suggest the term “Gastroprotection”.
History

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 Free radicals
 Physical agents
 Chemical agents
 Infectious agents
Factors for cell injury
 Hypoxia
 Immunologic reactions
 Genetic causes
 Nutritional

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Free radical
 Free Radical -- Highly reactive
Unstable species interact with
lipid, protein, carbohydrates
and causing cell injury.
 Free-radical generation -- leads
to further release of calcium &
excitatory neurotransmitters

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 Hypoxia
-A lack of oxygen in cells
and tissues that generally
result from ischemia
-It is reversible if oxygen
quickly restored.
-Irreversible than lead to death
Hypoxia

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1. Poisons such as arsenic, cyanide
2. Glucose or salts in hypertonic
3. Environmental or air pollutions
4. Alcohol & Narcotic drugs
5. Insecticides & herbicides
6. Drugs
Chemical agents
1.Mechanical trauma
2.Extremes of temperature
(i.e. Burns or deep cold)
3.Radiation & Electric shock
Physical agents
Physical & chemical agents

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Immunological reactions
- Such as in autoimmunity – Immune system may act against the
normal body cells
Infectious agents
1. Viruses 2. Bacteria 3. Fungi 4. Parasites
Genetic causes
1. Mutations 2. abnormalities in chromosome number
Other factors causing cell injury

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Gastroprotection: Defined as the ability of a pharmacological agent to reduce
or prevent gastric mucosal injury/necrosis produced by a variety of
ulcerogenic and necrotising agents.
Causative factors for mucosal injury
- Helicobacter pylori (H. pylori) infection
- Nonsteroidal anti-inflammatory drug (NSAID) ingestion
Others are (Bile reflux, Autoimmunity)
Gastroprotection
Major causative factor

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Gastric anatomy & physiology

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Histology

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1.  in mucus secretion
2.  in bicarbonate secretion
3. Strengthening of gastric mucosal barrier
4.  in mucosal blood flow
5.  in gastric motility
Mechanism of Gastroprotection

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6.  release of endogenous mediators/ of gastric Cytoprotection:
a) Prostaglandins, b) Sulfhydryls, c) Epidermal growth factor
7. Scavenging of free radicals
8.  release of endogenous mediators of gastric injury
9. Stimulation of cellular growth & repair
Mechanism of Gastroprotection

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1. Sucralfate
2. Colloidal bismuth
3. Stable PGE2 analogues
4. Newer Drug: Rebamipide
5. Carbenoxolone
Gastroprotective agents

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 Basic aluminum salt of sulfated sucrose.
 Polymerizes at pH < 4 by cross linking of molecules
 Strongly adheres to ulcer base to remain there for ~ 6 hours
Mechanism of action:
 Acts as a physical barrier preventing acid, pepsin and bile from
coming in contact with the ulcer base.
 Inhibiting hydrolysis of mucosal proteins by pepsin.
 Additional - Stimulation of local production of PGs and epidermal
growth factor.
Sucralfate

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ADR
- Constipation
- Hypophosphatemia (By binding to phosphate ions in intestine)
- Dry mouth
- Hypersensitivity reactions,
- Hyperglycemia
Sucralfate

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 Water soluble but precipitates at pH < 5
Mechanism of action:
- May  gastric mucosal PGE2, mucus and HCO3 production.
- May precipitate mucus glycoproteins and coat the ulcer base.
- May detach and inhibit H.pylori directly
-  luminal availability of epidermal growth factor and stimulation
phospholipid rich mucus.
ADR
- Nausea, Diarrhoea, Abdominal pain, Headache, Discolored tongue
Colloidal bismuth Subcitrate

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 Misoprostol (Synthetic PGE1 analogue) Dose: 200 μg qid
Mechanism of action:
- Decreasing intracellular cyclic AMP and gastric acid secretion
- Stimulation of mucin and bicarbonate secretion
-  mucosal blood flow
- Also reducing NSAID-induced mucosal damage
ADR:
- Diarrhea, with or without abdominal pain and cramps
- Clinical exacerbations of inflammatory bowel disease
Prostaglandin analogue

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Rebamipide
 Amino acid analog of 2 (1H) quinolinone
Mechanism of action
-  in the gastric concentrations of PGE
-  in the mucosal blood flow through enhanced nitric oxide synthase
activity
- Free radical scavenging effect on reactive oxygen species
- Replacement of lost tissue through by  the expression of epidermal
growth factor (EGF) and EGF receptors

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 Use - Gastric ulcers and patients with acute gastritis
 Dose: 100 mg TDS
Pharmacokinetics
- Good oral absorption
- 98 % plasma protein bound
- Metabolized in the liver ( cytochrome P450 )
- Drug interactions  Very low
ADR
- Gastrointestinal like constipation, bloating, diarrhea, nausea and vomiting
- Hypersensitivity and rash was seen in less than 1% of patients
Rebamipide

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Carbenoxolone
An anti-ulcer drug obtained from glycyrrhiza (obtained from licorice)
Rapid absorption from stomach & intestine
Structure similar to Steroid
Mechanism of action:
-  release of endogenous prostaglandins
-  gastric mucous secretion
-  the exfoliation and increasing the half life of gastric mucosal cells
ADR
- Mineralocorticoid like action (Fluid retention, Hypokalemia)

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Chemoprotection
Chemoprotection: Defined as the drugs that are used with
certain types of chemotherapy to protect the body from or
minimize the side effects of the chemotherapy.
 Common chemoprotective agents
- Amifostine
- Dexrazoxane
- Mesna

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Amifostine
Amifostine also called Ethyol (phosphorylated aminothiol)
Mechanism of action
Producing the free thiol WR-1065 (Intracelullarly)
WR-1065 - free radical scavenger
act as cytoprotector against side effects of both
chemotherapeutic agents and ionizing radiations

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Amifostine
Dose: 910 mg/m2 (15-minute infusion) iv 30 minute before chemotherapy
200 mg iv before radiotherapy
Indication:
1. Prophylaxis of cisplatin induced neuropathy/nephrotoxicity.
2. Radiotherapy related xerostomia
ADRs:
- Short term side effects - nausea, vomiting, hypotension
- Infusion related reaction – Flushing, chills, coldness
- Delayed adverse effect - Hypocalcaemia
- Rare – Stevens johnson syndrome

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Dexrazoxane
 Iron chelating agent (EDTA derivative)
Mechanism of action:
Penetrates cell membranes
Converted intracelullarly to a ring-opened chelating agent
Interferes with iron-mediated free radical generation thought to be
responsible
Indication:
- Reducing the incidence and severity of cardiomyopathy associated with
doxorubicin administration in women with metastatic breast cancer

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Dexrazoxane
 Dose:
- 500 mg/m2 dexrazoxane for injection to 50 mg/m2 doxorubicin (Slow IV
infusion)
 ADRs:
- Most ADRs due to concurrent antineoplastic agent
- Alopecia, sepsis, neurotoxicity
- Injection site pain, phlebitis,
- Myelosuppression

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Mesna
 Synthetic sulfhydryl compound
Mechanism of action:
- Reacts chemically with the urotoxic ifosfamide metabolites resulting in
their detoxification
- Also binds to the double bonds of acrolein & to other urotoxic metabolites
& inhibits their effects on the bladder
Indication:
- Prophylactic agent in reducing the incidence of ifosfamide-induced
hemorrhagic cystitis
- Prevention of cyclophosphamide induced hemorrhagic cystitis

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Mesna
Dose:
- Total daily dose - 60% of the ifosfamide dose & 20 % of cyclophosphamide
ADRs:
- Nausea, vomiting, Somnolence, anorexia
- Abdominal pain, arthralgia, myalgia, Paresthesia, photophobia, fatigue
- Leucopenia, thrombocytopenia, alopecia

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Cardioprotection
Cardioprotection:: Defined as “all mechanism that contribute to
the preservations of the heart by reducing or even preventing
myocardial damage”.
- Cardioprotective drugs are important in the treatment of patients
at risk for cardiovascular disease.
 Common Cardioprotective agents
- Trimetazidine
- Ivabradine
- Ranolazine

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Trimetazidine
Cellular anti-ischemic drug
 Cytoprotective effect on myocardial energy metabolism
Mechanism of action:
- Inhibit the b-oxidation of free fatty acid and reduces the myocardial o2
demand.
- Inhibit the superoxide cytotoxicity to protect the myocardium from the
ischemia
- Direct inhibition of cardiac fibrosis

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Trimetazidine
Indications:
- long-term treatment of angina pectoris
Dose:
- 40 to 60 mg OD
ADRs:
Common: dizziness, headache, abdominal pain, dyspepsia, urticaria
Rare: Extrapyramidal symptoms such as tremor, rigidity, akinesia,
hypertonia, Gait disorder, Restless leg syndrome

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Ivabradine
Bradycardic drug
Mechanism of action:
- Relatively selective If sodium channel blockers
- Controls the spontaneous diastolic depolarization in the sinus node and
regulates heart rate.
Indications:
1. Chronic stable angina pectoris in coronary artery disease patients with normal
sinus rhythm
2. Chronic heart failure with tachycardia
Dose: 5 mg BD initially & then increase upto 7.5 mg BD
ADRs : Bradycardia, Hypertension, Atrial fibrillation, Luminous Phenomena

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Ranolazine
 Anti-angina
Mechanism of action:
- Direct effects on cardiac myocyte Na+ channels (inhibit late Na current)
Indication:
- Chronic angina
Drug:
- 500 mg BD initially then increase upto 1000 mg
ADRs:
- Dizziness, constipation, headache, syncope, palpitations

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Neuroprotection
Neuroprotection: Defined as an effect that may result in salvage,
recovery or regeneration of the nervous system, its cell, structure and
function.
 Concept  Providing a treatment that prolongs the brain’s tolerance
to ischemia
- Drugs that block the excitatory amino acid pathways -- protect neurons
and glia -- animals
- Not yet been proven to be beneficial in human trial
- Only one drug cerebroprotein approved as a Neuroprotective agents.

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Mechanism of neuronal cell injury
 In ischemic stroke  Reduced blood flow  Acute cell injury
Return of blood flow (reperfusion) leucocytes present  may
occlude small vessels and release toxic products
 Excessive glutamate mediated neurotransmission
 Impaired voltage sensitive Na+ and Ca+ channel functioning
 Impaired GABA mediated inhibition and alterations in acid base
balance
 Free-radical generation also leads to further release of calcium and
excitatory neurotransmitters

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Cerebroprotein hydrolysate
 Short biological peptide
Mechanism of action:
- Protection against ischemic and neurotoxic lesions
- Reduces excitotoxic damage
- Scavenges free oxygen radicals
Indications:
- Acute ischemic stroke - Traumatic brain injury
- Vascular dementia - Alzheimer’s disease

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Cerebroprotein hydrolysate
Dose: 60 to 180 mg daily dose
Slowly perfused in 250 ml saline in 1- 2 hour (Intravenously)
Maintenance dose (30 mg - IM route)
ADRs:
- Headache, nausea, vertigo, increased sweating, agitation, fever,
hallucination, flu-like syndrome
C/I:
- Hypersensitivity, epilepsy, severe renal impairment
Safety has not been established in pregnancy and children

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Neuroprotective agents?
No of drugs have been tried as a Neuroprotective agents but they
failed to prove any beneficial effects.
1. NMDA antagonist
Dextrorphan: Not in used (due to hallucinations, agitation
hypotension)
Selfotel: Showed higher mortality in patients than in placebo-
treated; thus, trials were stopped prematurely
Aptiganel HCL: trial was terminated due to lower benefit-to-risk
ratio

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Neuroprotective agents?
Gavestinel: Although reported to be safe & tolerated, no
improvement was observed in 3-month outcome.
Others
Nalmefene: No clinical benefit was found by giving IV within 6 hr. of
symptom onset of stroke (Phase III CT)
Lubeluzole: Exact mechanism unclear but it may block Na channel,
reduce NO
After trail it was not confirm that lubeluzole was effective in acute
stroke patients or not?? So clinical research with this drug has been
abandoned.

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Neuroprotective agents?
2. GABA agonist
Clomethiazole
- Decreases excitatory neurotransmission by increasing activity of
inhibitory pathways.
- In Europe, clomethiazole approved as an anticonvulsant and
sedative.
- Efficacy of clomethiazole as a Neuroprotective agent in ischemia was
investigated in Europe.
- But overall study result was negative. The primary endpoint, was not
significantly better with clomethiazole than with placebo.

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Neuroprotective agents?
Other drugs
 Calcium channel blockers (nimodipine)
 Serotonin agonist (repinotan)
 Free radical scavenger (tirilazad, NXY-059)
 Monoclonal antibodies (Enlimomab)
 Fibroblast growth factor (fiblast)
Unfortunately, none of the clinical trials showed efficacy
for the above investigational treatment

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Hepatoprotection
 Hepatoprotection is the ability of drugs to prevent the liver from injury.
Hepatoprotective drug
Metadoxine
 It is pyridoxine- pyrrolidone carboxylate compound.
Mechanism of action
-  the activity of aldehyde dehydrogenase enzyme
-  glutathione levels in the hepatocytes
- Prevent the lipid peroxidation induced damage
- Stimulates the liver regeneration

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Metadoxine
 Indications:
1. Acute alcoholic intoxication
2. Alcoholic fatty liver
 Dose:
- Oral – 1000 mg daily
- Parenteral – 300 to 600 mg daily IM/IV
 ADRs:
- Diarrhoea
- Skin rash

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Recent or current clinical trial on cytoprotection
 CAPRI (RCT), assessing the effect of cyclosporine in patients with STEMI
undergoing PCI will be reported in 2018.
 A Phase II study of exenatide in patients with STEMI, the EMPRES trial
(NCT01938235), is ongoing.
The SOLSTICE study investigated losmapimod (novel inhibitor of the stress-
activated kinase p38 MAPK)
There was an  in left ventricular ejection fraction and  in end systolic
and diastolic pressures both at 3–5 days and 12 weeks post infarct.

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Recent or current clinical trial on cytoprotection
International Citicoline Trial on Acute Stroke (ICTUS)
Citicoline – Nutrional supplement commonly used for memory retention
Shown to prevent neuronal degeneration in animal studies
Hence - ICTUS trial was conducted to evaluate to efficacy of citicoline
Total 2298 patients with moderate-to-severe acute ischemic strokes (AIS)
Unfortunately, this trial did not show better efficacy for citicoline compared
with placebo.

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Recent or current clinical trial on cytoprotection
 Minocycline – Oral antibiotic (tetracycline group)
 In addition to antibiotic properties  anti-inflammatory & antiapoptotic
effects
 Shown to be Neuroprotective in animal models of stroke
- Efficacy of Oral Minocycline (Single-blinded open-label study)
- 50 patients with AIS (minocycline (200mg/day) OR (placebo) 5 days
& assessed at 1, 7, 30, and 90 days
- Showed significant improvement after 30 days & 90 days
However larger Phase II & III trials are awaited

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Recent or Current Clinical trial on cytoprotection
 ALISAH trial  Albumin in Subarachnoid Hemorrhage
 Shown to have -- Multiple Neuroprotective effects (Antioxidant activity,
inhibition of apoptosis, improved cellular metabolism & reduced edema)
Hence a multicenter pilot trial ALISAH was conducted (SAH)
47 pts. (3 different dosage levels of human albumin - daily for 7 days)
Higher dose showed better outcome than the lower dose
Phase III trial to determine the efficacy of albumin in subarachnoid
hemorrhage is currently in progress

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Thank You