Almughtaribeen university

Faculty of medicine
Pharmacology

Principles of dose ..
The identification of novel, clinically active agents has been central
to progress in cancer chemotherapy. Examples of new agents, and of
areas and targets being mined for new agents are presented in Table
44-1. The optimal use of such agents, of which more than 40 have
been identified over the past 50 years, has been crucial.

Table 44-1

Molecular Targets for Cancer Treatment. 

Dose is a significant determinant of the antitumor activity and
toxicology for the “classical” established cytotoxic
chemotherapeutic agents.1 Higher doses (1.2- to twofold) made
possible by growth factors (G-CSF, GM-CSF) are variably more
effective. High-dose stem cell protection (four- to tenfold) therapy,
made possible by hematopoietic stem cell support, has proven that
cure can be achieved for selected hematological neoplasms. The
effect of dose for biotherapeutic agents and hormones is complex
and is currently under study.
The schedule of drug administration may be important to the
therapeutic index independent of dose. For example, cytokinetic
studies relating to drug schedule have led to the improved use of
agents such as cytosine arabinoside (cytarabine, ara-C) in both
experimental and clinical leukemia (see below). 2, 3 Combination
chemotherapy has been crucial in the development of curative
regimens for hematologic malignancies, pediatric solid tumors, testis
cancer, and ovarian cancer, and to the adjuvant regimens for breast,
lung, bowel cancer, and osteosarcomas.4, 5 The rationale for
combination chemotherapy is complex and is dealt with under the
various topical headlines. The principal rationale(s) include (1) the
pragmatic-almost all therapy that has proven curative in the clinic
involves the use of agents in combination (Table 44-2), and (2) the
fact that genetic instability results in tumor cell heterogeneity. 6–8

Table 44-2

Number of Agents and Curative Treatment for Childhood Acute

Lymphoblastic Leukemia (ALL). 
Although dose and combination chemotherapy are generally
considered separately, they have an important and complex
relationship.9, 10 There is currently an impressive increase in the
number of putative molecular targets for cancer treatment
development (see Table 44-1). A major clinical research challenge
will be not only to maximize the effectiveness of individual agents
but, particularly, to integrate these drugs into optimal combination
strategies.

Contents
 Dose
 Schedule of Drug Administration
 Combination Chemotherapy
  References
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Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK12635
 Drugs in
extremities of
age

Infant and children: they

differ in: 
More extracellular body
water. 
Surface area and body
weight is less in
neonates. 
Lower fat content. 
More gastric emptying. 
B.B.B is more
permeable. 
Renal clearance is less
sufficient…………etc 
2.    Elderly : 
Reduce total body
water. 
Reduced gastric acid
secretion and gastric
emptying 
Decreased albumin ,
hepatic blood
flow………etc 
Renal clearance is less
sufficient

Age-Appropriate
Dosing
When starting a new
drug, start with a low
dose and titrate slowly
to the desired clinical
effect. While the
manufacturers of many
commonly used
medications do not
delineate the lower-
dosage
recommendations
necessary for elderly
patients, you can bypass
this problem by starting
with one-third to half
the recommended
dosage.
After observing that the
patient tolerates the new
drug, slowly increase
the dose until the
desired result is
obtained. This approach
is particularly important
in minimizing potential
harmful drug effects in
patients with severely
reduced renal
function.14

The elderly portion of

the population is
expanding more rapidly
than the population as a
whole, and the
recognition and
prevention of
medication side effects
in this group is one of
the most critical safety
and economic issues
facing the healthcare
system today. While the
magnitude of this
problem demands
multidisciplinary
involvement,
hospitalists can be key
players in making a
difference. TH
Dr. Landis is a
rheumatologist and a
freelance writer
References
1. Bates DW, Spell N,
Cullen DJ, et al. The
costs of adverse drug
events in hospitalized
patients. Adverse
Drug Events
Prevention Study
 Group. JAMA. 1997
Jan 22-29;277(4):307-
311. Comment
in: JAMA. 1997 Jan
22-29;277(4):341-
3422: JAMA. 1997
May 7;277(17):1351-
1352; author reply
1353-1354.
2. Zarowitz BJ,
Stebelsky LA, Muma
BK, et al. Reduction
of high-risk
polypharmacy drug
 combinations in
patients in a managed
care
setting. Pharmacothe
rapy.
2005;25(11):1636-
1645. Comment
in: Pharmacotherapy.
2006 Jun;26(6):886-
887; discussion 887.
3. Byron C, Hochberg
MC. Changing the
patterns of
Coxibs/NSAIDs
 prescribing: balancing
CV and GI risks.
Medscape. Available
at www.medscape.co
m/viewprogram/5060.
Last accessed May 2,
2007.
4. Shapiro K. The
Complexities of
Geriatric Pain
Management. 20th
Annual Meeting of
the American Pain
Society. Medscape 
 CME. Available
at www.medscape.co
m/viewarticle/416593.
Last accessed May 2,
2007.
5. Lau DT, Kasper JD,
Potter DE, et al.
Potentially
inappropriate
medication
prescriptions among
elderly nursing home
residents: their scope
and associated
resident and facility
characteristics. Healt
h Serv Res. 2004 Oct;
39(5):1257-1276.