Topoisomerases are enzymes that regulate DNA topology during replication and transcription by introducing temporary breaks in DNA strands. Topoisomerase inhibitors can be classified as topoisomerase I or II inhibitors. Camptothecins like irinotecan and topotecan are topoisomerase I inhibitors that stabilize the covalent complex between topoisomerase I and DNA, preventing rejoining of DNA strands. They are used to treat colorectal cancer and other cancers. Anthracyclines like doxorubicin are topoisomerase II inhibitors that stabilize cleavable complexes and cause DNA damage. They are commonly used to treat breast cancer, lymphomas, sarcomas and other cancers. Both classes
the presentation include the different type of mechanism used by cancer cells to protect them from anticancer agents lead to produce resistance. the slide include definition of cancer as per WHO, type of tumors, treatment of cancer, goal of treatment, problem associated with chemotherapeutic agents, need of studing mechanisms of resistance for anticancer agents, resistance, different mechanism of drug resistance, epigenetics, drug efflux, drug inactivation, DNA damage repair, drug target alteration and cell death inhibitiond
the presentation include the different type of mechanism used by cancer cells to protect them from anticancer agents lead to produce resistance. the slide include definition of cancer as per WHO, type of tumors, treatment of cancer, goal of treatment, problem associated with chemotherapeutic agents, need of studing mechanisms of resistance for anticancer agents, resistance, different mechanism of drug resistance, epigenetics, drug efflux, drug inactivation, DNA damage repair, drug target alteration and cell death inhibitiond
An intensive material on the anticancer agents. Detailed idea of the various classes of anticancer and recent advances in each class. Newer anticancer drug delivery systems and the anticancer vaccines are also dealt in detail.
Introduction to Targeted Therapies in OncologyMohamed Abdulla
Describes the molecular background which represents the core for developing targeted therapies against specific biological events in malignant cellular clones.
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
An intensive material on the anticancer agents. Detailed idea of the various classes of anticancer and recent advances in each class. Newer anticancer drug delivery systems and the anticancer vaccines are also dealt in detail.
Introduction to Targeted Therapies in OncologyMohamed Abdulla
Describes the molecular background which represents the core for developing targeted therapies against specific biological events in malignant cellular clones.
The all the content in this profile is completed by the teachers, students as well as other health care peoples.
thank you, all the respected peoples, for giving the information to complete this presentation.
this information is free to use by anyone.
This presentation comprises of various chemotherapeutic agents used in ENT malignancies and other conditions. Its classifies the agents and briefly discusses the dosage and their common side effects.
Navigating Challenges: Mental Health, Legislation, and the Prison System in B...Guillermo Rivera
This conference will delve into the intricate intersections between mental health, legal frameworks, and the prison system in Bolivia. It aims to provide a comprehensive overview of the current challenges faced by mental health professionals working within the legislative and correctional landscapes. Topics of discussion will include the prevalence and impact of mental health issues among the incarcerated population, the effectiveness of existing mental health policies and legislation, and potential reforms to enhance the mental health support system within prisons.
We understand the unique challenges pickleball players face and are committed to helping you stay healthy and active. In this presentation, we’ll explore the three most common pickleball injuries and provide strategies for prevention and treatment.
Navigating the Health Insurance Market_ Understanding Trends and Options.pdfEnterprise Wired
From navigating policy options to staying informed about industry trends, this comprehensive guide explores everything you need to know about the health insurance market.
Global launch of the Healthy Ageing and Prevention Index 2nd wave – alongside...ILC- UK
The Healthy Ageing and Prevention Index is an online tool created by ILC that ranks countries on six metrics including, life span, health span, work span, income, environmental performance, and happiness. The Index helps us understand how well countries have adapted to longevity and inform decision makers on what must be done to maximise the economic benefits that comes with living well for longer.
Alongside the 77th World Health Assembly in Geneva on 28 May 2024, we launched the second version of our Index, allowing us to track progress and give new insights into what needs to be done to keep populations healthier for longer.
The speakers included:
Professor Orazio Schillaci, Minister of Health, Italy
Dr Hans Groth, Chairman of the Board, World Demographic & Ageing Forum
Professor Ilona Kickbusch, Founder and Chair, Global Health Centre, Geneva Graduate Institute and co-chair, World Health Summit Council
Dr Natasha Azzopardi Muscat, Director, Country Health Policies and Systems Division, World Health Organisation EURO
Dr Marta Lomazzi, Executive Manager, World Federation of Public Health Associations
Dr Shyam Bishen, Head, Centre for Health and Healthcare and Member of the Executive Committee, World Economic Forum
Dr Karin Tegmark Wisell, Director General, Public Health Agency of Sweden
Struggling with intense fears that disrupt your life? At Renew Life Hypnosis, we offer specialized hypnosis to overcome fear. Phobias are exaggerated fears, often stemming from past traumas or learned behaviors. Hypnotherapy addresses these deep-seated fears by accessing the subconscious mind, helping you change your reactions to phobic triggers. Our expert therapists guide you into a state of deep relaxation, allowing you to transform your responses and reduce anxiety. Experience increased confidence and freedom from phobias with our personalized approach. Ready to live a fear-free life? Visit us at Renew Life Hypnosis..
Antibiotic Stewardship by Anushri Srivastava.pptxAnushriSrivastav
Stewardship is the act of taking good care of something.
Antimicrobial stewardship is a coordinated program that promotes the appropriate use of antimicrobials (including antibiotics), improves patient outcomes, reduces microbial resistance, and decreases the spread of infections caused by multidrug-resistant organisms.
WHO launched the Global Antimicrobial Resistance and Use Surveillance System (GLASS) in 2015 to fill knowledge gaps and inform strategies at all levels.
ACCORDING TO apic.org,
Antimicrobial stewardship is a coordinated program that promotes the appropriate use of antimicrobials (including antibiotics), improves patient outcomes, reduces microbial resistance, and decreases the spread of infections caused by multidrug-resistant organisms.
ACCORDING TO pewtrusts.org,
Antibiotic stewardship refers to efforts in doctors’ offices, hospitals, long term care facilities, and other health care settings to ensure that antibiotics are used only when necessary and appropriate
According to WHO,
Antimicrobial stewardship is a systematic approach to educate and support health care professionals to follow evidence-based guidelines for prescribing and administering antimicrobials
In 1996, John McGowan and Dale Gerding first applied the term antimicrobial stewardship, where they suggested a causal association between antimicrobial agent use and resistance. They also focused on the urgency of large-scale controlled trials of antimicrobial-use regulation employing sophisticated epidemiologic methods, molecular typing, and precise resistance mechanism analysis.
Antimicrobial Stewardship(AMS) refers to the optimal selection, dosing, and duration of antimicrobial treatment resulting in the best clinical outcome with minimal side effects to the patients and minimal impact on subsequent resistance.
According to the 2019 report, in the US, more than 2.8 million antibiotic-resistant infections occur each year, and more than 35000 people die. In addition to this, it also mentioned that 223,900 cases of Clostridoides difficile occurred in 2017, of which 12800 people died. The report did not include viruses or parasites
VISION
Being proactive
Supporting optimal animal and human health
Exploring ways to reduce overall use of antimicrobials
Using the drugs that prevent and treat disease by killing microscopic organisms in a responsible way
GOAL
to prevent the generation and spread of antimicrobial resistance (AMR). Doing so will preserve the effectiveness of these drugs in animals and humans for years to come.
being to preserve human and animal health and the effectiveness of antimicrobial medications.
to implement a multidisciplinary approach in assembling a stewardship team to include an infectious disease physician, a clinical pharmacist with infectious diseases training, infection preventionist, and a close collaboration with the staff in the clinical microbiology laboratory
to prevent antimicrobial overuse, misuse and abuse.
to minimize the developme
CHAPTER 1 SEMESTER V - ROLE OF PEADIATRIC NURSE.pdfSachin Sharma
Pediatric nurses play a vital role in the health and well-being of children. Their responsibilities are wide-ranging, and their objectives can be categorized into several key areas:
1. Direct Patient Care:
Objective: Provide comprehensive and compassionate care to infants, children, and adolescents in various healthcare settings (hospitals, clinics, etc.).
This includes tasks like:
Monitoring vital signs and physical condition.
Administering medications and treatments.
Performing procedures as directed by doctors.
Assisting with daily living activities (bathing, feeding).
Providing emotional support and pain management.
2. Health Promotion and Education:
Objective: Promote healthy behaviors and educate children, families, and communities about preventive healthcare.
This includes tasks like:
Administering vaccinations.
Providing education on nutrition, hygiene, and development.
Offering breastfeeding and childbirth support.
Counseling families on safety and injury prevention.
3. Collaboration and Advocacy:
Objective: Collaborate effectively with doctors, social workers, therapists, and other healthcare professionals to ensure coordinated care for children.
Objective: Advocate for the rights and best interests of their patients, especially when children cannot speak for themselves.
This includes tasks like:
Communicating effectively with healthcare teams.
Identifying and addressing potential risks to child welfare.
Educating families about their child's condition and treatment options.
4. Professional Development and Research:
Objective: Stay up-to-date on the latest advancements in pediatric healthcare through continuing education and research.
Objective: Contribute to improving the quality of care for children by participating in research initiatives.
This includes tasks like:
Attending workshops and conferences on pediatric nursing.
Participating in clinical trials related to child health.
Implementing evidence-based practices into their daily routines.
By fulfilling these objectives, pediatric nurses play a crucial role in ensuring the optimal health and well-being of children throughout all stages of their development.
India Clinical Trials Market: Industry Size and Growth Trends [2030] Analyzed...Kumar Satyam
According to TechSci Research report, "India Clinical Trials Market- By Region, Competition, Forecast & Opportunities, 2030F," the India Clinical Trials Market was valued at USD 2.05 billion in 2024 and is projected to grow at a compound annual growth rate (CAGR) of 8.64% through 2030. The market is driven by a variety of factors, making India an attractive destination for pharmaceutical companies and researchers. India's vast and diverse patient population, cost-effective operational environment, and a large pool of skilled medical professionals contribute significantly to the market's growth. Additionally, increasing government support in streamlining regulations and the growing prevalence of lifestyle diseases further propel the clinical trials market.
Growing Prevalence of Lifestyle Diseases
The rising incidence of lifestyle diseases such as diabetes, cardiovascular diseases, and cancer is a major trend driving the clinical trials market in India. These conditions necessitate the development and testing of new treatment methods, creating a robust demand for clinical trials. The increasing burden of these diseases highlights the need for innovative therapies and underscores the importance of India as a key player in global clinical research.
2. • Topoisomerases are ubiquitous and essential for all organisms
as they prevent and resolve DNA and RNA entanglements and
resolve DNA supercoiling during transcription and replication.
Topoisomerase I Topoisomerase II
3. • Type I Topoisomerase enzymes binds to a DNA molecule, it cuts one
strand, simultaneously generating a covalent phosphoester bond
between the released 5′ phosphate on the DNA & a tyrosine residue in
the enzyme.
• Formation of phosphotyrosine bond does not require ATP or another
source of energy.
• The free 3′-hydroxyl end of the DNA is held noncovalently by the
enzyme.
• The DNA strand that has not been cleaved is then passed through the
single-stranded break. The cleaved strand is then resealed & thus
removes negative supercoils.
5. CAMPTOTHECINS
Mechanism of Action:
• Camptothecins are called topoisomerase "poisons “
• Kill cells not by inhibiting topoisomerase catalysis, but by
stabilizing the normally transient reaction intermediate in
which the enzyme (Top1) is covalently linked to DNA.
6. • Addition of camptothecin
results in the formation of the
ternary complex (Drug-Top1-
DNA) & prevents relegation of
DNA
• These lesions are reversible and
disappear with removal of the
drug
• Collision between advancing
replication fork with the ternary
complex leads to DNA damage
and cell death.
• This may also account for S
phase specificity of cell cycle of
camptothecin cell toxicity.
7. Mechanism Of Resistance:
• Decreases Expression of top I
• Mutation in top I enzyme with decreased affinity for the drug.
• Increased expression of multidrug resistance phenotype with
over expression of P glycoprotein. Results in enhanced efflux
of drug and decreased intracellular accumulation of drug
• Decreased formation of the cytoxic metabolite SN 38 through
decreased activity and /or expression of carboxylesterase
enzyme.
8. IRINOTECAN
• It is a prodrug
• Active metabolite : SN-38
Pharmacokinetic:
• 50 % protein bound, SN-38 shows extensive protein binding : 95
%
• Half life (t1/2) irinotecan : 6-12 hrs, SN-38: 10-20 hrs
• Renal excretion accounts for 25 % of administered dose
• Remaining is eliminated by hepatic metabolism and biliary
excretion
DOSE :
• Administered intravenously as a weekly infusion of 125 mg/m2
for 4 weeks with a 2 -week rest period or, alternatively, 240 to 350
mg/m2 every 3 weeks
10. 2. Small Cell Lung Cancer
- Cisplatin/ Carboplatin + Irinotecane combination in extensive
stage
3. Non small cell lung cancer
4. Locally Advanced or Metastatic Gastric cancer
- FOLFIRI regimen as first line therapy
- Irinotecane as single agent (preffered) or in combination with
other cytotoxic drugs (cisplatin or docetaxel or Capcetabine)
are used in second line or third line settings.
5. Recurrent or Metastatic Cervical cancer : Second line therapy
11. Side effects :
Myelosupression
Diarrhea : two mechanism :
1. Acute Cholinergic Effects (< 24 hrs)
----- treatment : ATROPIN (0.25- 1mg I/V)
2. Mucosal Cytoxicity : ( > 24 hrs)
----- treatment : LOPERAMIDE (4mg P/O as loading dose 2
mg every 2 hrs can be stopped if pt. is diarrhoea free for 12 hrs)
• SN- 38 is glucuronidated in the liver by UGT 1 A 1 , and
deficiencies in this pathway may increase the risk of diarrhea and
myelosuppression
Nausea, vomiting, Mild Alopecia
Dose adjustment is recommended for:
Patients who are homozygous for UGT1A1 * 28 allele
Hepatic dysfunction
12. TOPOTECAN
Pharmacokinetics:
• 30 % protein bound
• 40% oral bioavailability;
• Topotecan penetration into the CNS is greater than that of
other camptothecins, CSF drug levels reach 30 % of plasma
levels
• T1/2 : 2-3 h (IV) or 3-6 h (oral)
• Renal excretion is the major route of elimination of the drug
and its metabolites
Dose Adjustment:
• 50 % dose reduction is recommended for patients with mild
renal impairment (creatinine clearance 40 to 60 mL/min).
• Renal Dysfunction
13. Uses
• Metastatic ovarian cancer
• Cervical cancer (Stage IV B, recurrent disease)
• Small cell lung cancer
• Non-small cell lung cancer
• AML, MDS
Dose :
• Administered intravenously at a dose of 1.5 mg/m2 as a 30-
minute infusion daily for 5 days, followed by a 2-week period
of rest
14. Side effects:
• Myelosuppression M/C (especially neutropenia)
• Thrombocytopenia and moderate to sever anaemia are less
common
• Nausea , vomiting, Diarrhoea , Low grade fever, fatigue,
alopecia, skin rash---- Milder toxicities
• Microscopic Hematuria (< 10 %)
15. New formulations of Camptothecin
• New formulations of camptothecin conjugates and analogs are
currently in clinical development in an effort to improve the
therapeutic index
17. • Type II topoisomerase enzymes function as homo- or
heterodimers and require ATP for catalysis.
• Topoisomerase dimer binds to DNA, forming a double-strand
DNA break in which the proteins are covalently bound to the 5 '
end of broken DNA strands to form the Top2 cleavable
complex.
• In this state the protein dimer is stabilized, forming a gate in the
DNA through which a second DNA double-helix strand can
pass in an energy-dependent fashion and finally broken DNA is
• relegated
DNA is unable to
relegate,leading to
double-strand DNA
breaks & cell death
18. ANTHRACYCLINS
• Anthracyclines are natural products derived from Streptomyces
peucetius variation caesius
MOA :
• Intercalation in the DNA: The drugs insert nonspecifically
between adjacent base pairs and bind to the sugar-phosphate
backbone of DNA. This causes local uncoiling and, thus, blocks
DNA and RNA synthesis
• Inhibits transcription: Inhibits topo II by forming a cleavable
complex with DNA and topII. Creates uncompensated DNA helix
torsional tension, leading to eventual DNA breaks.
• The quinone structure of anthracyclines enhances the catalysis of
oxidation-reduction reactions, thereby promoting the generation of
oxygen free radicals, which may be involved in antitumor effects
as well as toxicity associated with these drugs.
19. Mechanism of Resistance
• Increased expression of the multidrug resistance gene with
elevated P glycoprotein levels, which leads to incresed drug
efflux and decreased intracellular drug accumulation
• Decrease expression of top II
• Mutation in top II with decrease binding affinity for
doxorubicin
• Increase expression of sulfhydryl proteins, including
glutathione and glutathione dependent protein
20. Doxorubicin & liposomal Doxorubicin
• Doxorubicin differs from daunorubicin
by a single hydroxyl group at C 14
• Doxorubicin is also available in a polyethylene glycol
(PEG)ylated liposomal form--Liposomal Doxorubicin
• Protected from chemical and enzymatic degradation, reduced
plasma protein binding, and decreased uptake in normal
tissues.
• Penetrates tumour tissue in to which doxorubicin is released.
21. Pharmacokinetic :
• 75 % of doxorubicin and its metabolites are bound to plasma
protien. Half life T1/2: 20 to 48 hrs
• Metabolized in the liver to active hydroxylated metabolite
doxorubicinol and 40-50 % of drug eliminated via bile excretion
in feces.
• Urinary excretion of doxorubicin and other anthracyclines is low,
comprising less than 10 % of the administered dose.
Dose Adjustment :
• Doxorubicin dose may be reduced by 50 % for plasma bilirubin
concentrations ranging from 1.2 to 3.0 mg/dL, by 75 % for values
of 3.1 to 5.0 mg/dL, and withheld for values greater than 5
mg/dL.
22. USES : Breast Cancer
Adjuvant CT Regimen in Her2 Negative Disease
All regimens are Cat 1
24. USES REGIMENS
Hodgkins Lymphoma ABVD (M/C)
BEACOPP, Escalated BEACOPP
Standford V
Non Hodgkins Lymphoma (DLBCL) R- CHOP (Rituximab,
Cyclophosphamide,
Hydroxyldaunrubicin i.e doxorubicin,
Vincristin , Prednisone)
Ewings Sarcoma Localized disease : VAC/ IE (Vincrist,
Doxo, Cyclo alternating with ifosfamide,
Etoposide)
Metastatic : VAdriaC
Osteosarcoma (first line therapy for
primary / Neoadjuvant/ Adjuvant /
Metastatic)
Cisplatin and Doxorubicin
MAP (high dose Mtx, doxorubicin,
cisplatin)
MAP + ifosfamide
Muscle invasive bladder cancer
(neoadjuvant/ adjuvant)
Metastatic bladder cancer
ddMVAC (Mtx, Vinblastin, Doxorubicin,
Cisplatin) with Growth factor support
25. Other uses : ALL, AML, CLL,
Non small cell lung cancer
NHL, Mantle Cell Lymphoma, Mycosis
fungoides ,
Gastric Ca., Thyroid Ca.
Nephroblastoma, Neuroblastoma, Wilms
Tumour
Recurrent ovarian cancer (After Failure
of platinum based chemotherapy)
Carboplatin + Liposomal Doxorubicin
(CAT 1)
Advance Kaposis Sarcoma Liposomal Doxorubicin (Response rate
51-76 %)
Multiple Myeloma Liposomal Doxorubicin in combination
with Bortezomib
26. • DOSE:
- Doxorubicin : 30 to 75 mg/m2 every 3 weeks intravenously
- Liposomal Doxorubicin : 20 to 60 mg/m2 every 3 weeks
intravenously
27. SIDE EFFECTS:
• Myeosuppresion
• Mucositis
• Alopecia (usually reversible in 3mths after termination of treatment)
• Nausea & vomiting
• Diarrhea
• Potent vesicant : Extravasation can lead to sever necrosis of skin
and local tissues
(Longer infusions are recommended by Central Venous Catheter)
Acute Treatment : Ice & dimethyl sulfoxide
Extensive treatment : Surgical debridemnt and skin grafts (sever
cases)
• Flare reaction ( erythema) at infusion site
• Red orange discolouration of urine, Hyperpigmentation of nails
• Radiation Recall (inflammatory reaction at sites of previous
radiation and can lead to pericarditis, Pleural effusion, skin rash)
• Secondary Leukemia
• Cardiac toxicity
28. Liposomal Doxorubicin:
Side effects
• Associated with less nausea / vomiting and mild
myelosuppression.
• Hand-foot syndrome
• Acute infusion reaction manifested by flushing, dyspnea,
edema, fever, chills, rash, bronchospasm and hypertension
29. DAUNARUBICIN
• Daunorubicin is similar in structure doxorubicin
• More lipid soluble then doxorubicin
Pharmacokinetic:
• Extensively binds to plasma protein (60 -70 %)
• Metabolized in liver and also undergoes substantial
elimination by the kidneys .
• Half life (t1/2) : 18.5 hrs
• Dose reduction for hepatic and renal dysfunction is
recommended
30. Uses
• FDA approved : ALL and AML.
Also used in Ewing's sarcoma,
nephroblastoma,
CML, NHL.
• Dose : administered intravenously 30 to 45 mg/m2 on 3
consecutive days in combination chemotherapy .
Side effects:
• Myelosuppression,
• Nausea, vomiting, diarrohea
• Mucositis, Alopecia (usually reversible within 5-7 weeks after
termination of treatment)
• Cardiac toxicity (Cummulative dose of > 550 mg/ m2)
• Strong Vesicant
31. EPIRUBICIN
DOSE : 60 to 120 mg/m2 every 3 to 4 weeks given intravenously
(Incidence of N/V ,
alopecia, cardiac toxicity
is less with epirubicin
compared to doxorubicin)
32. Idarubicin
• Idarubicin is a synthetic derivative of daunorubicin, lacking
the 4-methoxy group .
• Uses : AML , ALL
• DOSE : 12 mg/m2 given I/V for 3 consecutive days .
• Idarubicin has similar toxicities as daunorubicin, including
myelosuppression, nausea, vomiting, alopecia, cardiac toxicity,
and tissue necrosis in cases of extravasation
• 50 % dose reductions are recommended for Sr bilirubin of 2.6
to 5 mg/dL and it should not be given if the bilirubin is greater
than 5 mg/dL.
33. CARDIAC TOXICITY
Acute cardiotoxicity:
• Reversible
• Develops during or within days of anthracycline infusion
• Clinical signs include tachycardia, hypotension,
electrocardiogram changes, and arrhythmias- may result in
transient congestive heart failure ( CHF)
• Incidence of which has been significantly reduced by slowing
doxorubicin infusion rates.
• It is rarely a fatal
34. Chronic cardiotoxicity :
• It is the most common type of anthracycline damage and is
irreversible.
• Dose dependent
• Peaks at 1 to 3 months but can occur even years after therapy.
• Clinical signs include fatigue, dyspnea on exertion, orthopnea,
sinus tachycardia, S3 gallop rhythm, pedal edema/pleural
effusions, and elevated jugular venous distention …. dilated
cardiomyopathy with CHF
• Fatal
35. Mechanism of Anthracycline Cardiotoxicity
• The production of free radicals generated during
cardiomyocyte anthracycline metabolism results in membrane
lipid peroxidation, with the consequent activation of the
extrinsic and intrinsic apoptotic pathways.
• Free radicals are generated by enzymatic reduction of the
anthracycline quinone ring and by formation of iron
anthracycline complexes .
• The intrinsic antioxidant defense of the cardiomyocyte is more
limited than other organs, leading to its apparent selective
toxicity profile.
37. Predisposition to cardiac damage includes
• Previous H/O coronary artery disease, other valvular or
myocardial conditions, and hypertension
• Mediastinal irradiation
• Older ( > 70 years) or younger ( < 4years ) age,
• Prior use of anthracyclins or other cardiac toxins
• Co administration of other chemotherapy agent (eg Paclitaxel ,
cyclophosphamide)
• Concurrent trastuzumab appears to potentiate anthracycline
cardiotoxicity
38. • Sequential administration of paclitaxel doxorubicin in
breast cancer patients is associated with cardiomyopathy at
total doxorubicin doses above 340 to 380 mg/m2, whereas the
reverse sequence of drug administration did not yield the same
systemic toxicities
• Doses of epirubicin below 1,000 mg/m2 and daunorubicin
below 550 mg/m2 are considered safe.
• Liposomal doxorubicin is associated with less cardiac toxicity.
• In pediatrics, it is important to be aware that conduction
disturbances ( second-degree atrioventricular block) and
arrhythmias ( both supraventricular and ventricular) may be
detected during therapy, but have no known acute/chronic
consequence.
39. Monitoring of Cardiac function during treatment:
Electrocardiography
(Include sinus tachycardia, low voltage, poor R wave progression,
and nonspecific T wave changes )
Serial non invasive monitoring of LVEF:
A. Echocardiography :
Left ventricular diastolic dysfunction left ventricular systolic
dysfunction, particularly affecting the septal motion. With full
development of cardiomyopathy, there is global hypokinesis and
muscle wall thinning.
B. Radionuclide scans. (MUGA Scan)
Biomarkers:
• Sr cardiac troponin T levels : measure of active myocardial
myocyte necrosis
• Brain natriuretic peptide levels : peptide synthesized in the
ventricles correlate with degree of heart failure
40. Percutaneous Endomyocardial biopsy (Rare):
• Multifocal areas of patchy and interstitial fibrosis ( stellate
scars) and occasional vacuolated myocardial cells (Adria cells)
• Myocyte hypertrophy and degeneration, loss of cross-
striations, and absence of myocarditis are also characteristic of
this diagnosis
41. • Numerous studies demonstrate the danger of embarking on
anthracycline therapy in patients with underlying cardiac
disease (e.g., a baseline LVEF of less than 50 % ) and of
continuing therapy after a documented decrease in ejection
fraction by more than 10 % ( if this decrease falls below the
lower limit of normal ) .
• A low LVEF is a contraindication for anthracycline therapy
42. • Schwartz et al. have developed a monitoring algorithm with
scheduled frequent ejection fraction measurements, that, when
used, has demonstrated a four-fold reduction in the risk of
congestive heart failure
Schwartz et al Am J Med 1987; 82:1109.
High Risk : known heart disease, ECG
Abnormalities, RT, Cyclophosmaide therapy
or EF < 40 %
43. • In a small prospective study, Nousiainen et al. reported that it
was possible to distinguish patients likely to develop
cardiactoxicity from others by LVEF measures at baseline and
at 200 mg/m2 doxorubicin.
• A fall of 10 % or more at this low cumulative dose had 72 %
specificity and 90% sensitivity in detecting later cardiotoxicity
44. Prevention of Cardiotoxicity
Altering Infusional Protocol
• When doxorubicin is given by a low-dose weekly regimen ( 10
to 20 mg/m2/wk) or by slow continuous infusion over 96
hours, cumulative doses of more than 500 mg/m2 can be given
Alternate anthracycline derivatives
Liposomal analogoues ( liposomal Doxorubicin)
Angiotensin-converting enzyme inhibitors, β -blockers, statins
and diuretics are used
45. Dexrazoxane
• Dexrazoxane is FDA approved to prevent anthracycline
induced cardiotoxicity in women with metastatic breast cancer
who have received a total cumulative dose of doxorubicin of
300 mg/m2 & would benefit from continued treatment.
• MOA : Dexrazoxane chelates iron and copper, thereby
interfering with the redox reactions that generate free radicals
and damage myocardial lipids
• Recommended dose is to give dexrazoxane I.V. 30 minutes
before doxorubicin at a ratio of dex:dox of 10:1
46.
47. MITOXANTRONE
• Mitoxantrone is the only clinically approved anthracenedione.
MOA :
• DNA intercalator and stabilizes the Top2- DNA complex, leading
to double-strand DNA breaks
• Relative to anthracyclines, mitoxantrone is less likely to undergo
oxidation-reduction reactions and form free radicals, thereby
decreasing its cardiac toxicity.
Pharmacokinetic:
• Extensively bound to plasma protein (78 %)
• Metabolized in liver by microsomal P450 system
• Elimination is mainly by H-B route , 25 % is excreted in feces
• Renal clearance 10 %
• Half life (t1/2 ) : 75 hrs (median)
48. USES :
• Advanced, Hormone refractory prostate cancer (used in
combination with pednisone as initial therapy)
• AML
• ALL
• Metastatic breast cancer
• Liver cancer
• NHL
49. Toxicities:
• Myelosuppression
• Nausea,vomiting, alopecia, and mucositis are less common
compared to doxorubicin.
• Cardiac toxicity is generally seen at cumulative doses greater
than 160 mg/m2
• Vesicant
• Blue discolouration of fingernails ,sclera and urine (for 1-2 days
after treatment)
• Use with caution in pts with abnormal LFT (dose modification
should be considered)
50. Dactinomycin
• Actinomycins were the first anticancer antibiotics isolated
from Streptomyces
• The derivative presently in use is dactinomycin.
• Structurally, dactinomycin is a "chromopeptide," consisting of
a planar phenoxazone ring (which produces the yellow-red
color of the drug), attached to two peptide side chains .
• MOA : Dactinomycin can intercalate into DNA between
adjacent guanine-cytosine bases, thereby poisoning Top2 and
leading to lethal double-strand DNA breaks.
51. Mechanism of resistance :
• Increased expression of the multidrug resistant gene with
elevated P-glycoprotein levels leads to increase drug efflux
and decrease intracellular accumulation
Pharmacokinetic
• Clinical pharmacology not well characterized
• Metabolized only to some extent
• Most of the drug is eliminated in unchanged form by biliary
(50 %) and renal (20 %) excretion
• Half life (T1/2) : 36 hrs
53. Side Effetcs :
• Myelosuppression,
• Nausea, vomiting,
• Alopecia,
• Erythema, and acne.
• Radiation recall
• Veno-occlusive disease of the liver
• Severe tissue necrosis in cases of extravasation.
54. EPIPODOPHYLLOTOXIN: ETOPOSIDE
• Glycoside derivatives of podophyllotoxin, an antimicrotubule
agent extracted from the mandrake plant
• Primarily function as Top2 poisons rather than through
antimicrotubule mechanisms
MOA :
• Inhibits Top II by stabilizing the Top II DNA complex and
preventing unwinding of DNA
• Cell cycle specific agent with activity in late S and G2 phase
55. Mechanism of resistance :
• Increased expression of the multidrug resistance gene with
elevated P glycoprotein levels, which leads to increased drug
efflux and decreased intracellular drug accumulation
• Decrease expression of top II
• Mutation in top II with decrease binding affinity to drug
• Enhanced activity of DNA repair enzyme
56. Pharmacokinetic:
• 90 – 95% is protein bound mainly to albumin
• 25-75 % Bioavailability (I/V)
• Half life t1/2 : 3-12 hrs
• Majority of etoposide is cleared unchanged by the kidneys
(40-60 %)
• 25 % dose reduction is recommended in patients with a
creatinine clearance of 15 to 50 mL/min. And 50 % in
patients with a creatinine clearance less than 15 mL/min.
57. Etoposide
• USES
• Small cell carcinoma
• Testicular carcinoma
USES Regimens
Small Cell Lung Carcinoma
Testicular Cancer (First line
therapy)
Metastatic testicular ca Oral Etoposide
58. USES Regimens
Hodgkins Lymphoma BEACOPP
Escalated BEACOPP
Stanford V
Ewings Sarcoma (Local / metastatic) VAC/IE (Vincristine, Doxorubicin,
Cyclophosphamide alternating with
ifosfamide, Etoposide)
VIDE
Osteosarcoma : Second line (relapsed/
refractory/ metastatic )
Etoposide in combination with
cyclophosphamide/ Ifosfamide and
other cytotoxic drugs
Other uses includes :
ALL, AML
NHL, Primary cutaneous T cell
Lymphoma
Myelodysplastic syndrome
Multiple Myeloma
Endometrial, Ovarian germ cell tumour,
Gestational Trophoblastic Neoplasm,
NSCLC, Retinoblastoma
59. SIDE EFFECTS
• Myelosuppression (Thrombocytopenia is less common than
leukopenia)
• Mild to moderate nausea, vomiting, diarrhea, mucositis, and
alopecia , metallic taste during infusion of drug
• Among the Top2 poisons, epipodophyllotoxins are associated
with the greatest risk for development of secondary malignancies
4% 6-year cumulative risk.
• Myelomonocytic (FAB M4 ) and monoblastic (FAB M5 )
variants of AML are the most common presentations of
epipodophyllotoxin-related leukemia resulting from balanced
translocations affecting the breakpoint cluster region of the MLL
gene at chromosome 11 q23
60. Teniposide
• Teniposide contains a thiophene group in place of the methyl
group on the glucose moiety of etoposide
USES :
• FDA approved for refractory pediatric acute lymphoid leukemia
(165 – 250 mg/ m2 weekly or twice weekly)
• Also used in adult neuroblastoma and NHL
Dose:
• Adults: ranges from 30 to 100 mg/m2 intravenously, used either
alone or in combination chemotherapy
Side Effects :
• Same as Etoposide
• Associated with greater hypersensitivty reaction
Dose adjustment for hepatic and renal dysfunction