Hematology & Oncology-Pharmacology (USMLE)

Enzyme inhibited by methotrexate
dihydrofolate reductase

↓ dTMP → ↓ DNA and ↓ protein synthesis

List 3/4 cancers treated using methotrexate.
leukemias

lymphomas

choriocarcinoma

sarcoma

List 3/4 non-neoplastic uses of methotrexate.
abortion

ectopic pregnancy

rheumatoid arthritis

psoriasis

Methotrexate toxicity (3/4)
myelosuppression (reversible with lecovorin rescue)

macrovesciular fatty change in liver

mucositis

teratogenic

Which SERM increases the risk of endometrial carcinoma?
tamoxifen

*raloxifine does not because it is an endometrial antagonist

Breast cancer Rx (2)
tamoxifen

raloxifene

*also used to prevent osteoporosis

Which S-phase antimetabolite causes myelosuppression that is not reversible with leucovorin?

What drug is used instead to treat overdose?

Name one other side effect of this drug.

5-fluorouracil (5-FU)

thymidine

photosensitivity

Enzyme inhibited by 5-fluorouracil (5-FU)
thymidylate synthase → ↓ dTMP → ↓ DNA and ↓ protein synthesis

*pyrimidine analog bioactivated to 5F-dUMP, which covalently complexes folic acid

Which antimetabolite is synergistic with methotrexate?
5-FU

5-FU use (2)
colon cancer and other solid tumors

basal cell carcinoma (topical)

Cisplatin, carboplatin MOA
cross-link DNA

Cancers treated by cisplatin, carboplatin (3/4)
testicular

bladder

ovary

lung

Anticancer drugs (2) that cause nephrotoxicity and acoustic nerve damage
cisplatin

carboplatin

How is nephrotoxicity due to cisplatin and carboplatin prevented?
amifostine (free radical scavenger)

chloride diuresis

Antitumor antibiotic that can cause pulmonary fibrosis and skin changes
bleomycin

*minimal myelosuppression

Alkylating agent that can cause pulmonary fibrosis and hyperpigmentation
busulfan

Bleomycin MOA
induces free radical formation, which causes breaks in DNA strands

List 2 cancers treated using bleomycin.
testicular cancer

Hodgkin’s lymphoma

What cancer is treated using busulfan?
CML

What alkylating agent is used to ablate patient’s bone marrow before bone marrow transplantation?
busulfan

*alkylates DNA

Name 2 antitumor antibiotics that inhibit topoisomerase 2.
etoposide (VP-16)

teniposide

List 3 cancers treated using etoposide and teniposide.
small cell carcinoma of the lung

prostate cancer

testicular carcinoma

Antitumor antibiotic that can cause myelosuppression, GI irritation, alopecia (2)
etoposide

teniposide

In fibrinolysis, what is the precursor molecule for plasmin?
plasminogen

– plasmin digests fibrin

List 3 drug types used to reduce clotting.
platelet aggregation inhibitors

anticoagulants

thrombolytics

List 4 drug types used in bleeding disorders.
plasminogen activation inhibitors

protamine sulfate

vitamin K

plasma fractions

List 4 types of platelet aggregation inhibitors.
cyclooxgenase inhibitors

ADP receptor blockers

phosphodiesterase inhibitors

blockers of platelet GP 2b/3a receptors

How does thromboxane A2 affect platelet degranulation and aggregation?
causes platelet degranulation and aggregation

– drugs that antagonize TXA2 synthesis inhibit platelet aggregation and prolong bleeding time

What eicosanoid and enzyme is inhibited by aspirin? Is this process irreversible or reversible?
thromboxane A2

irreversible acetylation of the enzyme COX

– anuclear platelet cannot synthesize new proteins
– cannot synthesize new enzyme during its 10-day lifetime

Describe the uses of aspirin for the brain and heart (2).
prophylactic treatment of transient cerebral ischemia

reduce incidence of recurrent MI

decrease mortality in post-MI patients

How does thromboxane A2 affect the affinity of platelet receptor GP 2b/3a for fibrinogen?
How does thromboxane A2 affect the affinity of platelet receptor GP 2b/3a for fibrinogen?
increases affinity

List 2 irreversible inhibitors of ADP receptor P2Y12 (expression of Gp2b/3a).
clopidogrel (preferred because of fewer adverse effects)

ticlopidine

What CYP450 enzyme converts the prodrug of clopidogrel into an active metabolite?
CYP2C19

– patients who are CYP2C19 poor metabolizers have lower plasma levels of the active metabolite

List an inhibitor of CYP2C19.
omeprazole (proton pump inhibitor)

– reduces plasma levels of clopidogrel (irreversible inhibitor of ADP receptor P2Y12)

Clopidogrel use
acute coronary syndrome

coronary stenting

decreases incidence or recurrence of thrombotic stroke

What enzyme is inhibited by cilostazol and dipyridamole?

How does this drug affect coronary blood vessels?
What enzyme is inhibited by cilostazol and dipyridamole?

How does this drug affect coronary blood vessels?

phosphodiesterase 3

↑ cAMP in platelets, thus inhibiting platelet aggregation; vasodilators

What protein is responsible for allowing platelets to aggregate using the platelet receptor Gp2b/3a?
fibrinogen

Monoclonal antibody against the Gp2b/3a receptor
abciximab

*prevents platelet AGGREGATION

Cyclic peptide reversible antagonist of the Gp2b/3a receptor
eptifibatide

Nonpeptide reversible antagonist of the Gp2b/3a receptor
tirofiban

How does binding of heparin to antithrombin 3 affect the inhibition of thrombin?
accelerates inhibition of thrombin

Compare the following characteristics of low molecular weight heparin and unfractionated heparin:

bioavailability

half-life

dosing frequency

higher F

longer t1/2

less frequent dosing requirements

*replacing UFH in many clinical situations
*can be administered subcutaneously and without laboratory monitoring
*not easily reversible

What clotting factor is inhibited by low molecular weight heparin?
10a

*less effect on thrombin than unfractionated heparin
*more effect on 10a

What complex found in unfractionated heparin accelerates inactivation of 2a by antithrombin 3?
What complex found in unfractionated heparin accelerates inactivation of 2a by antithrombin 3?
ternary complex

– ternary complex not necessary to accelerate inactivation of 10a by antithrombin 3

What assay is used to monitor heparin levels?
partial thromboplastin time (aPTT) assay

*tests integrity of intrinsic and common pathways of coagulation
*not usually necessary to monitor LMWH blood levels

List the uses of heparin in the following systems:

PVS

respiratory

CVS (2)

CNS

obstetrics

DVT

pulmonary embolism (immediate anticoagulation)

MI, acute coronary syndrome

stroke

anticoagulation during pregnancy (drug of choice because, like fondaparinux and unlike, it does not cross placenta)

List 4 adverse effects of heparin.
bleeding

hypersensitivity rxn

heparin-induced thrombocytopenia (HIT)

osteoporosis

In heparin-induced thrombocytopenia type 2, antibodies recognize complexes of heparin and a platelet protein _____.
In heparin-induced thrombocytopenia type 2, antibodies recognize complexes of heparin and a platelet protein _____.
platelet factor 4

*leads to platelet aggregation and release of platelet contents
*thrombocytopenia + thrombosis
*therapy: discontinuance of heparin and administration of a DTI or fondaparinux

What drug can be given to reverse heparin action if bleeding occurs?
protamine sulfate

*positively charged molecule that binds negatively charged heparin

How does fondaparinux action on antithrombin 3 counteract the effects of heparin?
How does fondaparinux action on antithrombin 3 counteract the effects of heparin?
– specific inhibitor of 10a
– negligible antithrombin activity
– approved for prevention and treatment of DVT

List 3 direct thrombin inhibitors (directly bind to the active site of thrombin).
lepirudin

bivalirudin

argatroban

What assay is used to monitor lepirudin?
What assay is used to monitor lepirudin?
aPTT

What enzyme is inhibited by warfarin?
vitamin K epoxide reductase

*results in production of inactive clotting factors because they lack the gamma-carboxylglutamyl side chains

What chemical group is required by clotting factor precursors to become active?

What enzyme carries out this process?
What chemical group is required by clotting factor precursors to become active?

What enzyme carries out this process?

carboxyl group

gamma-glutamyl carboxylase

What assay is used to monitor warfarin levels?
prothrombin time (PT) / INR

*extrinsic and common pathways
*prolongs PT because it decreases amount of functional factor 7

Which clotting factors are decreased with warfarin use?
Which clotting factors are decreased with warfarin use?
2

7

9

10

protein C and S

After how many hours does warfarin reach its peak anticoagulant effect?
72-96 hours (3-4 days)

The duration of action of a single dose of warfarin is _____ to _____ days.
2

5

Administration of what vitamin can overcome the anticoagulant effects of warfarin?
vitamin K

– 24 hours

What is the major adverse effect of warfarin usage?
hemorrhage

Reduced activity of what protein leads to cutaneous necrosis with warfarin usage?
Reduced activity of what protein leads to cutaneous necrosis with warfarin usage?
protein C

Warfarin pregnancy category
category X

Are anticoagulants or thrombolytics (fibrinolytics) effective against pre-existing clots?
thrombolytics

What type of agents convert plasminogen to plasmin?
What type of agents convert plasminogen to plasmin?
thrombolytic agents

What thrombolytic is produced by beta-hemolytic streptococci?
streptokinase

* rarely used since the advent of newer agents

What 2 clotting factors are degraded by streptokinase?
factor 5

factor 7

Urokinase drug type and use
thrombolytic (fibrinolytic)

lysis of pulmonary emboli

List 3 tissue plasminogen activators. Why are these preferred over streptokinase and urokinase?
List 3 tissue plasminogen activators. Why are these preferred over streptokinase and urokinase?
alteplase

reteplase

tenecteplase

What 4 thrombolytic agents are used in the management of acute MI and early ischemic stroke?
What 4 thrombolytic agents are used in the management of acute MI and early ischemic stroke?
alteplase

reteplase

tenecteplase

APSAC (antistreplase)

Identify the 1 plasminogen activation inhibitor.
Identify the 1 plasminogen activation inhibitor.
aminocaproic acid

Identify a chemical antagonist of heparin. What amino acid is in high concentration in this chemical?
protamine sulfate

arginine

– cationic protein interacts with anionic heparin to form complex with no anticoagulant activity

*NOTE: does not affect fondaparinux

List 4 causes of vitamin K deficiency.
List 4 causes of vitamin K deficiency.

Administration of what vitamin intramuscularly is required by law in the U.S.?
vitamin K

What vitamin is administered prior to delivery to mothers who are taking anticonvulsants?
vitamin K

– induce vitamin K metabolism

DOC for anticoagulation during pregnancy (2)
heparin (and LWMH)

fondaparinux

*contrast to warfarin, which crosses placenta

Alternative to heparin for anticoagulating patients with HIT
direct thrombin inhibitor

Warfarin toxicity (3/4)
bleeding

teratogenic

skin/tissue necrosis

drug-drug interaction

Warfarin overdose treatment (2)
vitamin K

fresh frozen plasma (rapid reversal)

Is heparin or warfarin larger?
heparin (large anionic, acidic polymer)

warfarin (small lipid-soluble molecule)

Heparain and warfarin route of administration
heparin: parenteral (IV, SC)

warfarin: oral

Does heparin or warfarin inhibit coagulation in vitro?
no

Describe the following with use of thrombolytics:

PT

PTT

platelet count

↑ PT

↑ PTT

↔ platelet count

Thrombolytics toxicity
bleeding (contraindicated in patients with active bleeding, history intranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension)

Which COX enzyme is the dominant isoform in gastric epithelial cells?
COX-1

What enzyme acts as the major source of cytoprotective prostaglandin formation?
COX-1

Which COX enzyme is induced by growth factors, tumor promotors, and cytokines?
COX-2

Which COX enzyme is the major source of prostanoids in inflammation and cancer?
COX-2

In which 2 organs is COX-2 a constitutive enzyme?
kidney

brain

What endothelial enzyme is the primary source of vascular prostacyclin?
COX-2

The anti-inflammatory action of NSAIDs is mainly related to their inhibition of _____ enzyme.
COX-2

* gastric damage is due to inhibition of COX-1

List 5/9 nonselective COX inhibitors.
diclofenac

etodolac

ibuprofen

indomethacin

ketoprofen

ketorolac

naproxen

piroxicam

tolmetin

List 3 COX-2 selective inhibitors.
celecoxib

etoricoxib

meloxicam

List 3 “anti” actions of NSAIDs.
anti-inflammatory

antiplatelet

analgesic

antipyretic

Which prostaglandin sensitizes nerve endings to the action of chemical mediators released by inflammatory processes?
PGE2

* by decreasing PGE2 synthesis, NSAIDs repress pain sensation

Are NSAIDs or opioids more effective in managing pain due to inflammation?
NSAIDs

Describe the proposed MOA of NSAIDs in relieving headaches.
inhibition of vasodilatory effect of prostaglandins in cerebral vasculature

Which prostaglandin is responsible for inducing fever?
PGE2

* inhibited by NSAIDs

What enzyme is the dominant source of prostaglandins that mediate the rise in temperature?
COX-2

NSAID of choice used to treat acute gout
indomethacin

List 3 NSAIDs that have not been successful in the treatment of acute gout.
aspirin
* inhibit urate excretion at low doses
* may increase risk of renal calculi at high doses

salicylates

tolmetin
* ineffective in gouty arthritis

Which prostaglandin mediates the flushing seen with use of niacin?
PGD2

* inhibited by aspirin

Drug of choice for closure of ductus arteriosus in premature infants
indomethacin

List 2 mechanisms by which NSAIDs cause gastric damage.
inhibition of COX-1 in gastric epithelial cells

ulceration by local irritation of the gastric mucosa

Which NSAID has the lowest risk of GI adverse effects?
celecoxib

* low risk
– ibuprofen
– aspirin
– diclofenac

Which 2 NSAIDs have the highest risk of GI adverse effects?
piroxicam

ketoprofen

* medium risk
– naproxen
– indomethacin
– olmetin

How do NSAIDs affect renal blood flow?
decrease in renal blood flow

List 2 renal disorders associated with NSAIDs use.
acute interstitial nephritis

analgesic nephropathy

List 2 prostglandins synthesized by the kidney in response to decreased renal blood flow.
PGE2

PGI2

* offsets effects of vasoconstricting mediators and maintain renal perfusion

In regards to decreased renal blood flow, what adverse effects are associated with decreased PGE2 and PGI2?
PGE2: increase sodium and water retention

PGI2: hyperkalemia and acute renal failure

What type of hypersensitivity is associated with acute interstitial nephritis?
type 1

* most common drugs include antibiotics and NSAIDs

Chronic interstitial nephritis caused by prolonged and excessive consumption of analgesics, particularly combinations of different agents
analgesic nephropathy

* can lead to renal papillary necrosis
* chronic interstitial nephritis can develop in response to papillary necrosis and lead to progressive chronic renal failure

Which sulfonamide NSAID is associated with rashes (hypersensitivity reactions)?
celecoxib

What GI problems can result from concomitant use of NSAIDs and corticosteroids?
GI ulceration

What problem can result form concomitant use of NSAIDs and warfarin?
bleeding

Why are aspirin and other salicylates contraindicated in children and young adults (<20 years) with viral illness?
Reye’s syndrome

* drug of choice: acetaminophen

NSAIDs contraindication
pregnancy

* especially close to term

Which NSAID is unique in its ability to IRREVERSIBLY acetylate cyclooxgenase?
aspirin

* others are all reversible inhibitors

How do salicylates affect the following:

CO2

ventilation

elevated CO2 (uncouples oxidative phosphorylation)

hyperventilation (stimulate respiratory center)

* toxic levels: central respiratory paralysis

Why are the effects of NSAIDs irreversible on platelets, but reversible on endothelial cells?
platelets lack nuclei

Which eicosanoid is inhibited by aspirin?
thromboxane A2

Name an autoimmune inflammatory disorder treated using NSAIDs.
rheumatoid arthritis

What is the association between frequent use of aspirin and risk of colon cancer?
50% decrease in risk

What doses (in general) are associated with the following properties of salicylates:

analgesic

antipyretic

anti-inflammatory
What doses (in general) are associated with the following properties of salicylates:

analgesic

antipyretic

anti-inflammatory

analgesic and antipyretic at low doses

anti-inflammatory at higher doses

* low doses (<100 mg daily) used for cardioprotective effects

List 2 byproducts of aspirin metabolism by esterases in tissues and blood.
List 2 byproducts of aspirin metabolism by esterases in tissues and blood.
salicylate

acetic acid

What “order” of kinetics is followed by aspirin?
first-order

Aspirin adverse effects

GI

bleeding time

hypersensitivity

GI: gastric ulceration

prolonged bleeding time (no effect on PT, PTT)

hypersensitivity: diversion to leukotrienes leads to asthma-like symptoms

How do low doses of aspirin affect uric acid secretion?
reduces uric acid secretion

* low doses compete with uric acid for secretion into tubular fluid
* uric acid uses same transport system as anionic drugs such as aspirin, sulfinpyrazone, and probenecid

At what dosage of aspirin does elimination follow first-order kinetics?
At what dosage of aspirin does elimination follow first-order kinetics?
≥500 mg

How do large doses of aspirin affect uric acid secretion?
increase uric acid excretion

* compete with uric acid for reabsorption

Aspirin contraindication
chronic liver disease

Aspirin pregnancy category
trimesters 1 and 2: category C

trimester 3: category D

Mild chronic salicylate intoxication
salicylism

Patient with joint pain presents with headache, dizziness, tinnitus, mental confusion, and hyperventilation.
salicylism

Describe the acid-base imbalances that occur in acute salicylate overdose.
respiratory alkalosis

metabolic acidosis

* prolonged exposure depresses medulla

What is the benefit of COX-2 selective inhibitors over nonselective ones?
fewer GI side effects

* constitutively active in kidney; thus cause renal toxicities similar to those caused by nonselective types

Are nonselective or selective COX-2 inhibitors cardioprotective??
Are nonselective or selective COX-2 inhibitors cardioprotective??
nonselective COX inhibitors

* coxibs associated with cardiovascular thrombotic events

What is the only selective COX-2 inhibitor available in the USA?
celecoxib

Why were the COX-2 selective inhibitors rofecoxib and valdecoxib withdrawn?
association with thrombotic events

Meloxicam MOA
COX-2 selective inhibitor

* not as selective for COX-2 as coxibs

How does acetaminophen differ from NSAIDs in action?
analgesic and antipyretic

NO ANTI-INFLAMMATORY OR ANTIPLATELET EFFECTS

Drug of choice for pain relief in osteoarthritis
acetaminophen

* inadequate for inflammatory conditions such as rheumatoid arthritis, but may be used as adjunct

Drug of choice for children with fever and flulike symptoms
acetaminophen

Drug of choice for short-term treatment of fever and minor pain during pregnancy
acetaminophen

Acetaminophen overdose antidote
acetylcysteine

Ticlopidine toxicity
neutropenia

Cilostazol, dipyridamole use (3/4)
inermittent claudication

coronary vasodilation

prevention of stroke or TIAs (combined with aspirin)

angina prophylaxis

Abciximab use (2)
acute coronary syndromes

percutaneous transluminal coronary angioplasty

Abciximab toxicity (2)
bleeding

thrombocytopenia

6-mercaptopurine, 6-thioguanine MOA
purine (thiol) analog → ↓ de novo purine synthesis

What enzyme activates 6-MP and 6-TG?
HGPRTase

Cancers treated using 6-MP (2)
leukemias (not CLL)

lymphomas (not Hodgkin’s)

6-MP toxicity (3)
bone marrow

GI

liver

What enzyme metabolizes 6-MP?
xanthine oxidase

*increased toxicity with allopurinol

Cancer treated using 6-TG
acute lymphoid leukemia

*can be given with allopurinol

Cytarabine

MOA

use (3)

toxicity (3)

pyrimidine analog; inhibition of DNA polymerase

AML, ALL, high-grade non-Hodgkin’s lymphoma

leukopenia, thrombocytopenia, megaloblastic anemia

Dactinomycin (ACTinomycin D)

MOA

use

toxicity

intercalates in DNA

Wilms’ tumor, Ewing’s sarcoma, rhabdomyosarcoma

myelosuppression

Children ACT out.

Doxorubicin (adriamycin), danorubicin

MOA

use

toxicity

generates free radicals; noncovalently intercalate in DNA; breaks in DNA leads to decreased replication

Hodgkin’s lymphomas; also for myelomas, sarcomas, and solid tumors (breast, ovary, lung)

cardiotoxic (dilated cardiomyopathy), myelosuppression, alopecia

What drug is used to prevent cardiotoxicity with doxorubicin (adriamycin), danorubicin use?
dexrazoxane (iron-chelating agent)

Cyclophosphamide, ifofsfamide

MOA

use (3)

toxicity

covalently X-link (interstrand) DNA at guanine N-7; require bioactivation by liver

non-Hodgkin’s lymphoma, breast and ovarian carcinomas, immunosuppression

myelosuppression, hemorrhagic cystitis

Alkylating agents that cross the BBB
nitrosureas (carmustine, lomustine, semustine, streptozocin)

*brain tumors (including glioblastoma multiforme)
*CNA toxicity (dizziness, ataxia)

Alkaloids that bind to tubulin in M-phase and block polymerization of microtubules so that mitotic spindle cannot form (2)
vincristine

vinblastine

Cancers treated using vincristine, vinblastine (3/4)
Hodgkin’s lymphoma

WIlms’ tumor

choriocarcinoma

ALL

Microtubule inhibitor that can cause neurotoxicity (areflexia, peripheral neuritis) and paralytic ileus
vincristine

Vin- drug that causes bone marrow suppression
vinblastine

Microtubule inhibitors that hyperstabilize polymerized microtubules in M-phase so that mitotic spindle cannot break down (anaphase cannot occur)
taxols (e.g. paclitaxel)

Taxols use (2) and toxicity (2)
ovarian and breast carcinomas

myelosuppression and hypersensitivity

What cell phase cycle is associated with hydroxyurea?
(inhibits) S-phase

Cancers treated using hydroxyurea (2)
melanoma

CML

Most commonly used glucocorticoid in cancer chemotherapy
prednisone

List 2 cancers treated using prednisone.
CLL

Hodgkin’s lymphoma (part of the MOPP regimen)

Prednisone toxicity (5/9)
Cushing-like symptoms

immunosuppression

cataracts

acne

osteoporosis

hypertension

peptic ulcers

hyperglycemia

psychosis

Monoclonal antibody against HER-2 (erb-B2), a tyrosine kinase
trastuzumab (herceptin)

*helps kill breast cancer cells that overexpress HER-2, possibly through antibody-dependent cytotoxicity

Trastuzumab (herceptin) use and toxicity
metastatic breast cancer

cardiotoxicity

List 2 cancers treated using imatinib (gleevec).
CML

GI stromal tumors

Imatinib toxicity
fluid retention

Monoclonal antibody against CD20, which is found on most B cell neoplasms
rituximab

Rituximab use (2)
non-Hodgkin’s lymphoma

rheumatoid arthritis (with methotrexate)

Heparin MOA Cofactor for activation of antithrombin. Decreases thrombin and factor Xa. Clinical use, heparin Immediate anticoagulation for PE, acute coronary syndrome, MI, DVT. Used during pregnancy (doesn’t cross placenta). Follow PTT. WE WILL WRITE A CUSTOM ESSAY SAMPLE ON …

Heparin Class: Anticoagulant, Antithrombotic Uses: Prevention of DVT, Pulmonary embolism, myocardial infarction, DIC, Afib with embolization, anticoagulant in transfusion and dialysis procedures, maintain patency of indwelling ivs Action: Prevents conversion of fibrinogen to fibrin and prothrombin to thrombin by enhancing …

List 2 disorders associated with gastroparesis. diabetes Parkinson’s disease * post-surgical, idiopathic List 3/6 symptoms of gastroparesis abdominal distension hypoglycemia (diabetes) nausea premature fullness while eating a meal weight loss without trying vomiting WE WILL WRITE A CUSTOM ESSAY SAMPLE …

Coagulation factors affected by warfarin (Coumadin) drugs are… :VIII, IX and X :I, II, V and VII :II, VII, IX and X :II, V and VII II, VII, IX and X Which one of the following statements concerning Vitamin K …

Indications of Warfarin Prophylaxis and treatment of: -Venous thrombosis -Pulmonary Embolism -Thromboembolism disorders -Atrial Fibrillation with risk of embolism -Prophylaxis of systemic embolism post MI (LV thrombus) Which form of Warfarin is more important to us S-Warfarin is more important …

Competitive inhibitors change Km or Vmax “Kompetitives change Km. Also K for POTency (POTassium)” Parameters of pharmacokinetics “ADME” Absorption, Distribution, Metabolism, Excretion WE WILL WRITE A CUSTOM ESSAY SAMPLE ON ANY TOPIC SPECIFICALLY FOR YOU FOR ONLY $13.90/PAGE Write my …

David from Healtheappointments:

Hi there, would you like to get such a paper? How about receiving a customized one? Check it out https://goo.gl/chNgQy