Antineoplastic agents (Linger) Flashcards
(131 cards)
1
Q
what are some of the cancers that are curable by chemotherapy
A
Acute lymphoblastic leukemia Acute myeloid leukemia Ewing sarcoma Gestational trophoblastic carcinoma Hodgkin disease Non-Hodgkin lymphoma Burkitt lymphoma Diffuse large cell lymphoma Follicular mixed lymphoma Lymphoblastic lymphoma Rhabdomyosarcoma Testicular carcinoma Wilms’ tumor
2
Q
what are some cancers where chemotherapy has significant activity ?
A
Acute lymphoblastic leukemia Acute myeloid leukemia Ewing sarcoma Gestational trophoblastic carcinoma Hodgkin disease Non-Hodgkin lymphoma Burkitt lymphoma Diffuse large cell lymphoma Follicular mixed lymphoma Lymphoblastic lymphoma Rhabdomyosarcoma Testicular carcinoma Wilms’ tumor
3
Q
what are some cancers where chemotherapy has minor activity
A
Brain tumors (astrocytoma) Cervical carcinoma Colorectal carcinoma Hepatocellular carcinoma Kaposi sarcoma Melanoma Pancreatic carcinoma Prostate carcinoma Soft tissue sarcoma
4
Q
what are some cancers where adjuvant chemotherapy is effective
A
Breast carcinoma Colorectal carcinoma (stage III) Osteogenic sarcoma Ovarian carcinoma (stage III) Testicular carcinoma
5
Q
what are some chemical carcinogens that cause cancer
A
tobacco smoke, azo dyes, aflatoxins, asbestos, benzene, and radon
6
Q
Hep B and Hep C
A
hepatocellular cancer
7
Q
HIV
A
hodgkins and NHL’s
8
Q
HPV
A
cervical cancer
head and neck cancer
9
Q
EBV
A
nasopharyngeal cancer
10
Q
what are the 3 main approaches to treating established cancer
A
surgical excision
irradiation
chemotherapy
11
Q
what is primary induction therapy
A
The first treatment given.
It is often part of a standard set of treatments, such as surgery followed by chemotherapy and radiation.
When used by itself, induction therapy is the one accepted as the best treatment.
i) Drug therapy administered as the primary treatment in patients who present with advanced cancer for which no alternative treatment exists
ii) Goals of therapy are to palliate tumor-related symptoms, improve overall quality of life, and prolong time to tumor progression
If it doesn’t cure the disease or it causes severe side effects, other treatment(s) may be added or used instead. It is also called first-line therapy, primary therapy, and primary treatment.
12
Q
what is neoadjuvant therapy
A
Treatment given as a first step to shrink a tumor before the primary treatment (usually surgery) is given. Can include chemotherapy, radiation therapy, and hormone therapy. It is a type of induction therapy.
13
Q
what is adjuvant therapy
A
Additional cancer treatment given after the primary treatment to lower the risk that the cancer will come back. Can include chemotherapy, radiation therapy, hormone therapy, targeted therapy (designed to identify and attack specific types of cancer cells with less harm to normal cells), or biologic therapy (treatment that uses substances made from living organisms).
14
Q
G1 phase
A
(1) Precedes DNA synthesis
(2) The cell synthesizes components necessary for DNA synthesis
15
Q
S phase
A
DNA synthesis
16
Q
G2 phase
A
synthesis of components for cell division (mitosis)
17
Q
M phase
A
(1) The cell divides into two daughter G1 cells
2) Each daughter cell may re-enter the cell cycle or pass into a nonproliferative stage (G0
18
Q
cyclophosphamide
A
nitrogen mustard
alkylating agent
19
Q
ifosfamide
A
nitrogen mustard
alkylating agent
20
Q
busulfan
A
alkyl sulfonate
alkylating agent
21
Q
cisplatin
A
platinum coordination complex
alkylating agent
22
Q
methotrexate
A
folic acid analog
antimetabolite
23
Q
fluorouracil (5-fluorouracil; 5-FU)
A
pyrimidine analog
antimetabolite
24
Q
mercaptopurine (6-mercaptopurine; 6-MP)
A
Purine analog
Antimetabolite
25
Vinblastine
Vinca alkaloid
Natural product
26
Vincristine
natural product
vinca alkaloid
27
Paclitaxel
Taxane
Natural product
28
Etoposide
Epipodophyllotoxin
Natural product
29
Doxorubicin
Antibiotic
Natural product
30
Bleomycin
anthracenedione
natural product
31
L-Asparaginase
Enzyme- Natural product
32
Imatinib
Protein tyrosine kinase inhibitor
33
trastuzumab
monoclonal antibody
34
leucovorin
antidote for methotrexate rescue
35
Mesna
Acrolein causes hemorrhagic cystitis (acrolein is a side product of cyclosphosphamide)
Mesna inactivates acrolein and is used for prophylaxis of chemotherapy-induced cystitis
36
Filgrastim
agent used to minimize adverse effects
G-CSF
stimulate production of white blood cells and shorten the length of the neutropenia
37
EPO
treatment of anemia - stimulate red cells production
38
Ondansetron
serotonin antagonist
minimize nausea and vomiting
39
what is the growth rate pattern of a typical tumor
initially rapid
decreases as the tumor size increases
-due to low nutrient and O2 availability
40
what is growth fraction
the ratio of proliferating cells to cells in the G0 stage
41
how does growth fraction compare in solid tumors versus disseminated tumors
iii) As a result of inadequate nutrient supply to the interior of solid tumors, solid tumors have a lower growth fraction than disseminated tumors
higher percentage of cells in solid tumors are found in G0 compared to disseminated tumors
v) As a general rule, antineoplastic drugs work best on tumors with a high growth fraction
42
how can growth fraction in slow growing solid tumors be changed with chemo?
vi) The growth fraction of slow-growing solid tumors can be increased by reducing the tumor burden through surgery or radiation, which promotes the recruitment of some of the remaining cells into active proliferation and increases their susceptibility to chemotherapeutic agents
vii) Examples of human tumors with growth fractions close to 100% are Burkitt lymphoma and trophoblastic choriocarcinoma, which are readily curable by single-agent chemotherapy
viii) Cancers of the lung or colon are slow-growing and have growth fractions less than 10%
43
what is the log cell kill hypothesis
i) Chemotherapy kills a fraction of cells rather than an absolute number per dose
44
what are pharmacologic sanctuaries
regions where tumor cells are less susceptible to antineoplastic agents
examplie--> interior of solid tumors or specific tissues (CNS, testes)
where transport constraints prevent certain chemotherapeutic drugs from entering and have been a major cause of treatment failure (e.g., acute lymphocytic leukemia in children)
45
this is the most common form of anticancer agent administration
Intermittent high dose therapy
(1) The most common form of anticancer agent administration
(2) Allows recovery of normal tissues (e.g., the patient’s immune system), also affected by antineoplastic agents, and reduces the risk of serious infection
(3) May be more effective with agents that are phase nonspecific (cell cycle nonspecific)
46
which drugs are more effective when administered by continuous infusion
drugs that are rapidly metabolized or excreted or both
cell cycle specific (act on only one portion of the cell cycle)
47
what are the advantages of drug combinations in chemotherapy
(1) Provides maximal cell killing within the range of tolerated toxicity
(2) Effective against a broader range of clones with different genetic abnormalities in a heterogeneous tumor population
(3) May delay or prevent the development of drug-resistant tumors
48
efficacy
Each drug used in combination therapy should have some individual therapeutic activity and, if possible, should be used at the maximally tolerated individual dose
49
principle of mechansim of interaction
Drugs that act by different mechanisms may have additive or synergistic therapeutic effects, thus increasing log cell kill and diminishing the probability of the emergence of drug resistant tumor cells
50
what is primary resistance of neoplastic cells
i) Some neoplastic cells exhibit primary resistance to currently available agents (an absence of response on the first exposure)
ii) Primary resistance is thought to be due to the genomic instability associated with the development of most cancers
51
what is acquired resistance of neoplastic cells
iii) Acquired resistance develops in response to exposure to a given antineoplastic agent
iv) Acquired resistance is often highly specific to a single drug, or class of drugs, and is usually based on a specific change in the genetic machinery of a given tumor cell with amplification or increase expression of one or more genes
52
what are the mechanisms of resistance to single antineoplastic agents
(1) Decreased drug transport into cells
(2) Reduced drug affinity due to mutations or alterations of the drug target
(3) Increased expression of an enzyme that causes drug inactivation
(4) Increased expression of DNA repair enzymes for drugs that damage DNA
53
what gene and gene product are associated with multidrug resistant phenotype in neoplastic cells
increased expression of the MDR1 gene, which encodes a cell surface transporter glycoprotein (P-glycoprotein)
54
what does P-glycoprotein pump do....
it is a cell surface transporter
(2) The P-glycoprotein pump is an ATP-dependent transporter that confers resistance to anthracyclines, vinca alkaloids, etoposide, paclitaxel, dactinomycin, and others
(3) The P-glycoprotein transporter may be inhibited by calcium channel blockers such as verapamil
55
what normal tissues in the body are major sites of toxicity of chemotherapy agents...
ii) Since antineoplastic agents target cells that are highly proliferative (high growth fraction), rapidly proliferating normal tissues are the major sites of toxicity of these agents (high growth fraction tissues include bone marrow, gastrointestinal tract, hair follicles, buccal mucosa, and sperm forming cells)
56
which group of antineoplastic agents can cause treatment-induced tumors
alkylating agents
57
which adverse effects occur with nearly all antineoplastic agents
vomiting, nausea, stomatitis (inflammation of mouth and lips) and alopecia
some others include:
-lower sperm count or even azoospermia
-developmental growth of children exposed to chemo may be depressed
58
what are the outcomes of myelosuppression that is induced by chemotherapy
leukopenia
thrombocytopenia
anemia
predisposition to infection and impaired wound healing
59
blood counts in chemo reach their low point around what days? when do they recover ? return to normal?
(a) Blood counts normally reach their nadir (low point) 10-14 days after treatment with recovery by day 21 and a return to normal by day 28
(b) Most regimens are given in cycles of 21-28 days
60
how can the amount of adverse effects on pt's be reduced?
route of administration--> reduce systemic exposure
local perfusion of drugs
removal of bone marrow prior to treatment and reimplanting it after
use GM-CSF agents (sargramostim) and G-CSF (filgrastim, pegfilgrastin) to stimulate production of white blood cells
use prelvekin to counteract thrombocytopenia
use erythropoietin or darbepoetin to stimulate red blood cell production
61
which agents cause severe nausea and vomiting
cisplatin
dacarbazine
doxorubicin
mechlorethamine
62
which other agents cause minimal emesis
methotrexate and fluorouracil
63
what is an importnat anti-emetic agent that can reduce nausea and vomiting
(ii) Serotonin antagonists: ondansetron***
64
what is stomatitis
how can it be prevented
inflammation of the oral mucosa
(a) Typically begins as erythema and edema and may progress to painful ulcerations that persist from several days to a week or more
(b) There is currently no means to prevent stomatitis except to modify the chemotherapeutic agent causing these symptoms
(c) Meticulous oral hygiene helps to diminish pathogenic oral flora and decreases the risk of secondary infections and treatment with topical oral anesthetics (lidocaine solution) can relieve pain and help maintain adequate oral intake
65
when does alopecia occur?
1-2 weeks after initiating treatment
(b) Cessation of therapy typically causes hair to return to pretreatment levels, although the hair may be different in texture and/or color
66
which agents cause the most profound alopecia
cyclophosphamide, dactinomycin, doxorubicin, paclitaxel, and vincristine
67
what are bisphosphonates used for
(a) Metastatic disease that localizes in the bone can cause fractures and bone pain
(b) A number of agents, such as bisphosphonates, are available to inhibit osteoclast action and bone resorption and may be used to delay the time to the first skeletal complication.
68
what are the 5 major types of alkylating agents
nitrogen mustards
methylhydrazines
alkyl sulfonates,
nitrosoureas,
triazenes
b) Although they do not alkylate DNA platinum compounds are included under alkylating agents
69
MOA of alkylating agents
i) Alkylating agents are strong electrophiles and exert their cytotoxic effects by forming covalent linkages with DNA
ii) Alkylation of DNA leads to intra- and inter-strand cross-linking, which prevents the tumor from unwinding DNA for mRNA production or DNA replication
iii) Alkylation of DNA (particularly guanine bases) can also lead to miscoding through abnormal base pairing with thymine or in depurination by excision of guanine residues, which leads to DNA strand breakage
iv) Cross-linking of DNA is a major cause of the cytotoxic action of alkylating agents and replicating cells are most susceptible to these agents
70
mechlorethamine
nitrogen mustard
alkylating agent
71
are alkylating agents cell cycle specific or non specific
non specific
although cells in the G1 and S phase are most susceptible
72
what occurs with IV administration of alkylating agents
iii) Acute toxicity (nausea and vomiting) occurs within 30-60 min of IV administration (pretreatment with a serotonin (5-HT3) receptor antagonist (e.g, ondansetron) can mediate emetogenic effects)
73
what occurs with delayed toxicity of alkylating agents
bone marrow depression with leukopenia, thrombocytopenia, nephrotoxicity, alopecia, mucosal ulceration, and intestinal denudation
74
what is essential during administration of alkylating agetns
v) Frequent monitoring of blood counts is essential during administration of these agents due to the possible development of severe leukopenia or thrombocytopenia (may necessitate discontinuation of therapy)
75
what are the key adverse effects of alkylating agents
what are they at risk for
nausea,
vomiting
myelosuppression
tissue damage at site of administration
increased risk for secondary malignancies--> especially AML
76
adverse effects of cyclophosphamide (alkylating agent- nitrogen mustard)
antidote?
hemorrhagic cystitis due to the accumulation of the metabolite acrolein
use Mesna parenterally!
mesna neutralizes the effects of acrloein in the acid environment of the urinary tract
77
what are the adverse effects of cisplatin?
what are the antidotes
renal tubular damage
-overcome with hydration, diuresis
ototoxicity -tinnitus and hearing loss
- unaffected by diuresis
- worse in children
marked nausea and vomiting may occur (use ondansetron and high dose corticosteroids)
78
what are the adverse effects of Busulfan (alkyl sulfonate- alkylating agent)
hyperpigmentation, pulmonary fibrosis, and adrenal insufficiency
79
are antimetabolites cell cycle specific or non specific ?
cell cycle specific
| S phase
80
what are the main categories of antimetabolites
folic acid analogs
pyrimidine analogs
purine analogs
81
what are the acute toxic effects of antimetabolites
cause little acute toxicity after an initial dose; they must be absorbed into each cell and enter into the pathway that the drug disrupts before many effects can be quantified
82
MOA of methotrexate (folic acid analog- antimetabolite)
(1) Inhibits dihydrofolate reductase and blocks the conversion of folic acid to tetrahydrofolic acid, which serves as the key one-carbon carrier for enzymatic processes involved in the de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine
83
methotrexate at low doses- uses?
methotrexate at high doses-uses?
(2) At low doses, methotrexate is actively transported into the cell by membrane proteins and is less harmful on healthy tissues (common in the treatment of rheumatoid arthritis, colitis, psoriasis, and some cancers)
(3) High-dose methotrexate therapy, where methotrexate enters healthy cells by diffusion across the concentration gradient, causes injury to healthy tissues
84
what antidote is used to rescue "healthy cells" from the toxic effects of methotrexate
leucovorin (folinic acid) is administered
(5) Leucovorin enters the thymidylate synthesis pathway in the healthy cells and allows thymidine synthesis to proceed, thus sparing the patient severe gastrointestinal and bone marrow toxicity
85
what are the adverse effects of methotrexate
mucositis
diarrhea
myelosuppression- neutropenia, thrombocytopenia
nausea/vomiting
immunosuppression
hepatotoxicity
fatigue
86
MOA of Fluorouracil (5-FU)
5-FU is a prodrug whereby the active compound FdUMP covalently binds thymidylate synthetase and blocks de novo synthesis of thymidylate;
active compounds (FdUTP and FUTP) are incorporated into both DNA and RNA, respectively, interfering with DNA synthesis, DNA function, RNA processing, and mRNA translation
87
5-FU is the most widely used agent in what ?
colorectal cancer
88
what re the adverse effects of 5-FU
anorexia
nausea
stomatitis
diarrhea
89
what is cytarabine (Ara-C) and what are its uses>
pyrimidine analog
antimetabolite
used exclusively for hematologic malignancies NOT solid tumors
90
Mercaptopurine MOA (6-MP)
inhibits de novo purine nucleotide synthesis and DNA and RNA synthesis due to triphosphate incorporation
91
Mercaptopurine must be used with caution with what other drug?
Allopurinol
(3) Biotransformation includes metabolism to the inactive metabolite 6-thiouric acid by xanthine oxidase (first pass metabolism).
Allopurinol, a xanthine oxidase inhibitor, is often used as supportive care in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis.
Simultaneous administration of allopurinol and oral 6-MP results in increased levels of 6-MP and increased toxicity. In this setting, the oral dose of mercaptopurine must be reduced by 50-75% (IV dose unaffected).
92
what are the adverse effects of mercaptopurine
myelosuppression, immunosuppression, and hepatotoxicity
93
what antimetabolite purine analog drug may be used in full doses with allopurinol?
Thioguanine
94
what are the antimitotic drugs
Vinca alkaloids
| Taxanes
95
Vinblastine and Vincristine
MOA?
Vinca alkaloids- Natural products
bind to B-tubulin and inhibit microtuble ASSEMBLY
cell cycle specific M-phase
96
drug resistance to vinblastine and vincristine ?
membrane efflux pump P-glycoprotein
97
what are the adverse effects of the vinca alkaloids
hair loss
local cellulitis if extravasated
myelosuppression --> more so with vinblastine
Vincristine causes more predictable cumulative neurological toxicities (numbness and tingling of the extremities with loss of deep tendon reflexes, followed by motor weakness)
98
Paclitaxel
drug type and MOA
Taxane
bind to β-tubulin and promote microtubule formation and stabilization***
99
what are the adverse effects of Paclitaxel
bone marrow suppression
peripheral and sensory neuropathy
100
Etoposide
drug type and MOA
Epipodophyllotoxins
iii) Cell cycle specific agents that block cell division in the late S-G2 phase
inhibits topoisomerase II --> leads to DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA and enzyme
101
camptothecin analogs MOA
adverse effects
natural products
iii) MOA: inhibit the activity of topoisomerase I; results in DNA damage and blockade of DNA replication and transcription
adverse effects--> diarrhea !
102
what are the classes of antitumor antibiotics
anthracyclines -doxorubicin, daunorubicin
anthracenediones - bleomycin
103
MOA of doxorubicin and dactinomycin
where is doxorubicin metabolized
(a) Inhibits topoisomerase II
(b) Intercalates DNA and blocks synthesis of DNA and RNA and blocks DNA strand scission
(c) Generates semiquinone and oxygen free radicals
(d) Binds to cellular membranes to alter fluidity and ion transport
extensive liver metabolism
104
are the anthracyclines cell cycle specific or non specific
non specific b/c they intercalate DNA
105
what are the adverse effects of doxorubicin
nausea
red urine
alopecia
myelosuppression
stomatitis
cardiotoxicity - long term effect (due to free radicals)
106
MOA of bleomycin
small peptide that binds to DNA resulting in single- and double-strand breaks and also inhibits DNA biosynthesis
cell cycle specific G2
107
how is bleomycin eliminated from the body
mainly through renal excretion
108
what are the adverse effects of bleomycin
(4) Pulmonary toxicity is dose-limiting; typically presents as pneumonitis with cough, dyspnea, dry inspiratory crackles, and infiltrates on chest x-ray;
also causes allergic reactions, fever, hypotension, skin toxicity, mucositis, and alopecia
109
MOA of L-Asparaginase
how does it work against acute lymphoblastic leukemia
Hydrolyzes circulating L-aspargine into aspartic acid and ammonia --> inhibiting protein synthesis
iv) Acute lymphoblastic leukemia tumor cells lack the enzyme asparagine synthetase and require an exogenous source of L-asparagine, rendering them selective to and vulnerable to asparaginase and pegaspargase
110
what are the main adverse effects of L-asparaginase
acute
chronic
v) Main adverse effect is an acute hypersensitivity reaction (fever, chills, nausea, vomiting, skin rash, urticaria);
delayed toxicities include an increased risk of clotting and bleeding
pancreatitis
CNS toxicity including lethargy, confusion, hallucinations, and coma
111
how are steroid hormones used in cancer treatment
i) Useful as antineoplastic agents because of their antilymphocytic effects
ii) Commonly used as one component of combination chemotherapy
iii) Antitumor effects may be related to inhibition of glucose transport, phosphorylation, or induction of cell death in immature lymphocytes
112
"nib" ending
protein tyrosine kinase inhibitors
113
MOA of imatinib
(1) MOA: inhibits the tyrosine kinase domain of the Bcr-Abl oncoprotein and prevents phosphorylation of the kinase substrate by ATP;
also inhibits the kinases platelet-derived growth factor receptor (PDGFR), stem cell factor, and c-kit
114
what is imatinib used clinically for
CML- characterized by the t(9;22) philidelphia chromosomal translocation resulting in Bcr -Abl fusion protein
GI stromal tumors
hypereosinophilia syndrome
115
with what other drugs must you use Imatinib with caution
in drugs that might interact with CYP3A4 b/c imatinib is metabolized in the liver by CYP450's
116
what are the adverse effects of Imatinib
myelosuppression,
fluid retention with ankle and periorbital edema,
diarrhea,
myalgias
117
what is Lapatinib MOA and what is it used for
inhibits internal kinase domain of HER2/neu epidermal growth factor receptor
breast cancer
118
ending with "mab"
monoclonal antibodies
119
Trastuzumab MOA
and clinical use
binds to the HER2/neu receptor (also known as ErbB-2, a member of the family of epidermal growth factor receptors) that is expressed on the surface of cells (about 25-30% of breast cancers) and inhibits intracellular signaling events and neoplastic cell proliferation
The HER2 receptor participates in receptor-receptor interactions that regulate cell differentiation, growth, and proliferation and overexpression of the HER2 receptor contributes to the process of neoplastic transformation
used in breast cancer
120
what are the adverse effects of trastuzumab
cardiotoxicity (ventricular dysfunction and heart failure)
***evaluate ventricular function before and after therapy
iv) Discontinuance of trastuzumab should be strongly considered in patients who develop a clinically important decrease in left ventricular function.
121
Rituximab
CD20 antigen
NHL
122
alemtuzumbab
CD52
| chronic lymphocytic leukemia
123
Gemtuzumab
CD33
AML
124
deferoxamine
iron toxicity
125
N-acetylcystein use
Tylenol toxicity antidote
126
What is the main reason for giving allopurinol prophylactically prior to starting a course of chemotherapy?
reduce the risk of hyperuricemia
127
Blocks central serotonergic (5-HT₃) receptors
ondansetron
128
A 43 y/o HIV-positive male with a 6 month history of CD20+ diffuse large B-cell lymphoma, a subtype of non-Hodgkin lymphoma, presents to the oncology clinic for infusion of a combination of chemotherapeutic agents (this is his third of six scheduled infusions). His current CD4 count is 150 cells/mm3. Which agent is contraindicated?
```
bleomycin
prednisone
rituximab
vinblastine
vincristine
```
vinblastine
adverse effects include myelosuppression
129
A 63 y/o female is diagnosed with metastatic colon carcinoma. Biopsy is positive for overexpression of the epidermal growth factor receptor (EGFR). Which agent is most appropriate?
```
Alemtuzumab
Bevacizumab
Cetuximab
Gemtuzumab
Rituximab
Trastuzumab
```
cetuximab
130
A 63 y/o female is diagnosed with metastatic colon carcinoma. An agent is used that blocks the interaction of vascular endothelial growth factor (VEGF) with the VEGF receptor. Which agent is described?
```
Alemtuzumab
Bevacizumab
Cetuximab
Gemtuzumab
Rituximab
Trastuzumab
```
bevacizumab
131
A 39 y/o female with acute lymphoblastic leukemia has been admitted to the hospital for induction chemotherapy, which includes the following.
Cytarabine – 5 g IV Q 12 hr for 8 doses
Vincristine – 2 mg IV push weekly
Prednisone – 100 mg/day
Asparaginase – 15,000 U/day for 14 days
Allopurinol – 300 mg/day
On day 3, she is confused and has difficulty performing a finger-to-nose neurologic examination. After 3 weeks, she complains of numbness in her hands and feet. An eyelid lag and ataxia are noted. What is the most likely cause of her mental status?
```
Allopurinol
Asparaginase
Cytarabine
Prednisone
Vincristine
```
- CNS toxicity - asparaginase***- confusion
| - parasthesias - vincristine
