This document discusses organ system maturation in different species. It begins with an overview of concepts like physiologic time and ontogeny recapitulating phylogeny. It then reviews challenges in selecting animal models for preclinical pediatric toxicity testing due to differences in developmental processes across species. The document also compares maturation of organ systems, reproductive development, and other milestones in rats and humans. It notes strengths and weaknesses of current safety assessment approaches and suggests modifications.
Heredity and evolution class 10th Questionssinghaniya12
Ncert chapter heredity and evolution class X you can find questions for exam preparation and there is lot of questions based on heredity and evolution chapter for it is doc file it contain short or long answer type question and it is like question paper of school
This Presentation is especially for the grade 10 as it is informaive and can be used for the CBSE syllabus of india ( of course ). hope this helps you alot and if any problems please let me know from the comments section below.................peace out......... and message me at bavitharavi@hotmail.com. this is also the chpter 9 of the cbse gr 10 science book biology.
Heredity and evolution class 10th Questionssinghaniya12
Ncert chapter heredity and evolution class X you can find questions for exam preparation and there is lot of questions based on heredity and evolution chapter for it is doc file it contain short or long answer type question and it is like question paper of school
This Presentation is especially for the grade 10 as it is informaive and can be used for the CBSE syllabus of india ( of course ). hope this helps you alot and if any problems please let me know from the comments section below.................peace out......... and message me at bavitharavi@hotmail.com. this is also the chpter 9 of the cbse gr 10 science book biology.
Discuss the methods Mendel utilized in his research that led to his success in understanding the process of inheritance
The science community ignored the paper, possibly because it was ahead of the ideas of heredity and variation accepted at the time. In the early 1900s, 3 plant biologists finally acknowledged Mendel’s work. Unfortunately, Mendel was not around to receive the recognition as he had died in 1884.
In the simplest of words, heredity refers to the passing of traits or characteristics through genes from one generation (parent) to the other generation (offspring). Heredity is very evidently seen in sexual reproduction. ... Variation is important because it contributes to the evolution and forms the basis of heredity.
Heridity and Evolution - Biology Class 10 CBSEAthira S
This Powerpoint Presentation is on the chapter Heredity and Evolution from class 10 Biology in CBSE Board. The contents of the presentation are from the NCERT science textbook for class 10 and Lakhmir Singh Biology Handbook Class 10.
Discuss the methods Mendel utilized in his research that led to his success in understanding the process of inheritance
The science community ignored the paper, possibly because it was ahead of the ideas of heredity and variation accepted at the time. In the early 1900s, 3 plant biologists finally acknowledged Mendel’s work. Unfortunately, Mendel was not around to receive the recognition as he had died in 1884.
In the simplest of words, heredity refers to the passing of traits or characteristics through genes from one generation (parent) to the other generation (offspring). Heredity is very evidently seen in sexual reproduction. ... Variation is important because it contributes to the evolution and forms the basis of heredity.
Heridity and Evolution - Biology Class 10 CBSEAthira S
This Powerpoint Presentation is on the chapter Heredity and Evolution from class 10 Biology in CBSE Board. The contents of the presentation are from the NCERT science textbook for class 10 and Lakhmir Singh Biology Handbook Class 10.
HISTORICAL ASPECTS OF IVF CULTURE MEDIA SINCE IVF IS A 44 YEAR OLD TECHNOLOGY AND CULTURE MEDIA BEING THE MOST OVERLOOKED AND CONCEPTUAL PORTION IN IN VITRO FERTILIZATION TECHNOLOGY. THIS PRESENTATION COVERS HOW IVF CULTURE MEDIA SEEN ORIGINATION FROM PAST TILL AT PRESENT ERA.
Relative Morphology of Extraembryonic Membranes in Mammals: Their Roles in Hi...Joseph Holson
Presented by John DeSesso and Joseph F. Holson in Symposium I ("A Detective Story: Is the Prenatal Toxicity of a Therapeutic in Rats Relevant to Human Risk?", J.F. Holson and L. B. Pearce, co-chairpersons) at the Forty-Third Annual Meeting of the Teratology Society, Philadelphia, PA, June 26, 2003.
In-vitro fertilization (IVF) is a process by which oocytes are fertilized by sperm outside the women’s womb, in vitro. It still represents one of the most exciting modern scientific developments and continues to have a tremendous impact on
people's lives.
Here, we will discuss all about the embryo development inside the dish.
Also we discuss which embryo to choose for transferring into female's uterus.
Dr. Heather Allen - The Swine Gut Microbiota: Status and OutlookJohn Blue
The Swine Gut Microbiota: Status and Outlook - Dr. Heather Allen, National Animal Disease Center, USDA, from the 2016 Allen D. Leman Swine Conference, September 17-20, 2016, St. Paul, Minnesota, USA.
More presentations at http://www.swinecast.com/2016-leman-swine-conference-material
dkNET Webinar: Population-Based Approaches to Investigate Endocrine Communica...dkNET
Abstract
Mechanisms of inter-organ signaling have been established as hallmarks of nearly every pathophysiologic condition, where many exist as related and complex diseases. While significant work has been focused on understanding how individual cell types contribute and respond to specific perturbations related to common, complex disease, an equally-important but relatively less-explored question involves how relationships between organs are altered in the context of an integrated living organism. Current technical advances, such as proteomic analysis of plasma or conditioned media, have allowed for a more unbiased visualization and discovery of additional inter-tissue signaling molecules. However, one important feature which is lacking from these approaches is the ability to gain insight as to the function, mechanisms of action and target tissue(s) of relevant molecules. To begin to address these constraints, we initially developed a correlation-based bioinformatics framework which uses multi-tissue gene expression and/or proteomic data, as well as publicly available resources to statistically rank and functionally annotate endocrine proteins involved in tissue cross-talk. Using this approach, we identified many known and experimentally validated several novel inter-tissue circuits. This was this first study to directly link an endocrine-focused bioinformatics pipeline from population data directly to experimentally-validated mechanisms of inter-tissue communication. While these validations provide strong support for exploiting natural variation to discover new modes of communication, these serve as simple proof-of-principle studies and, thus, have promising potential for expansion. Some of these will be discussed during the presentation.
Presenter: Marcus Seldin, Ph.D. Assistant Professor, Biological Chemistry, University of California Irvine
Upcoming webinars schedule: https://dknet.org/about/webinar
Transcript - Interpretation of Low-Incidence Findings in Reproductive and Dev...Joseph Holson
Transcript of Joe Holson's lecture on rare events in developmental and reproductive toxicity studies given at the 2002 Winter Meeting of the Toxicology Forum.
Findings of Developmental Toxicity Studies of HBOC-201 in Rodent and Canine M...Joseph Holson
Presented by Donald G. Stump and Joseph F. Holson in Symposium I ("A Detective Story: Is the Prenatal Toxicity of a Therapeutic in Rats Relevant to Human Risk?", Joseph F. Holson and L. B. Pearce, co-chairpersons) at the Forty-Third Annual Meeting of the Teratology Society, Philadelphia, PA, June 26, 2003.
Probable False Positive Finding of Rodent Prenatal Toxicity for a High Molecu...Joseph Holson
Introductory presentation ("Overview of Issues Concerning False Positive Findings in Reproductive Toxicology and Introduction of a Case Study of an Oxygen Therapeutic") in Symposium I ("A Detective Story: Is the Prenatal Toxicity of a Therapeutic in Rats Relevant to Human Risk?", Joseph F. Holson and L. B. Pearce, co-chairpersons) at the Forty-Third Annual Meeting of the Teratology Society, Philadelphia, PA, June 26, 2003.
Study Design Considerations Affecting Interpretation of Developmental Toxicit...Joseph Holson
Presented in continuing education course ("Developmental Toxicology Studies: Design, Interpretation, and Risk Assessment, J.F. Holson and R. D. Hood, co-chairpersons) at the Forty-Fourth Annual Meeting of the Society of Toxicology, New Orleans, LA, March 6-10, 2005.
Human Clinical Relevance of Developmental and Reproductive Toxicology and Non...Joseph Holson
Presented at Forest Research Institute, May 13, 2004.
Abstract: Experimental animal models are essential to product development and toxicologic screening. The effective use of such models is dependent on the attributes of: validity, sensitivity, reproducibility, and practicability. For the two endpoints of toxicity of most societal concern, developmental effects, and cancer, experience has taught that differences between animals and humans in drug absorption, distribution, metabolism and elimination most often leads to differences in response both qualitatively, and quantitatively. In developmental toxicology, a high degree of concordance between experimental animal results and human outcomes has been demonstrated. Human reproductive outcomes are often concordant with experimental animal data, but this concordance seems to vary more among species as phenotypes diversify with approaching sexual maturity and subsequent reproductive senescence. This increase in phenotypic diversity also presents difficulties in a priori selection of animal models in non-clinical juvenile toxicity testing. Juvenile periods among species can be divided into pre-term neonatal, neonatal, infancy, childhood and adolescence, based on overall central nervous system and reproductive development. However, because physiologic time differs among species, temporality of target-organ maturation should be reconciled with the human pediatric therapeutic scenario prior to animal model selection. The heuristic impact and resultant guidance for proper selection and use of animal models for juvenile toxicity testing will be demonstrated through the use of case studies involving angiotensin-converting enzyme (ACE) inhibitors, quinilones, fluoxetine and isotretinoin.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
263778731218 Abortion Clinic /Pills In Harare ,sisternakatoto
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Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
3. Organization
• Prenatal Models and Ontogeny
• Concept of Physiologic Time
• Review of Adolph’s Seminal Work
• Difficulties in a priori Selection of Models
for Nonclinical Pediatric Toxicity
• Strengths and Weaknesses of Current
Safety Designs
4. Why are we interested
in organ system maturation?
It is essential for comparing
postnatal toxicity among species.
8. Animal: Human Concordance Studies
for Prenatal Toxicity
Authors
Attributes
Holson et al., 1981
(Tox Forum)
Kimmel et al., 1984
(NCTR Report)
Interdisciplinary team
Criteria for acceptance of data/conclusions
Concept of multiple developmental
toxicology endpoints
No measures of internal dose
Nisbet & Karch, 1983
Many chemicals
Relied on authors’ conclusions
Emphasis on fertility
No measures of internal dose
9. Animal: Human Concordance Studies
for Prenatal Toxicity
Authors
Attributes
Hemminki &
Vineis, 1985
Interspecies inhalatory doses adjusted
Relied on authors’ conclusions
23 occupational chemicals and mixtures
No measures of internal dose
Newman et al.,
1993
Provided detailed information
Only 4 drugs
Emphasis on morphology
Focus on NOAELs
No measures of internal dose
Schardein, 1995
Many chemicals
Relied on authors’ conclusions
No measures of internal dose
10. Ontogeny Recapitulates Phylogeny
(von Baer, 1828)
• General features appear earlier in
embryos than do specialized features
• Embryos of higher animals pass
through stages that are similar to
those of embryos of lower species
15. Ontogeny, Inc., based in Cambridge, MA, applies recent discoveries in
developmental biology to the treatment of human diseases. Ontogeny has
proprietary rights to a number of molecules known to induce cell
differentiation, including several members of the hedgehog gene family that
play a role in disorders involving the central nervous system, bone and
cartilage, fertility and cancer. Ontogeny has signed a collaborative
agreement with Biogen and with Genetics Institute to develop hedgehog
proteins for neurological disorders, and Boehringer Mannheim in bone
development and repair.
16. Concept of Physiologic Time
Comparisons among Species
Comparisons among Developmental Stages
17. Maturational Data for Various
Species
Human
Gestation
(days)
Minimal
Breeding
Age
(weeks)
Human to
Animal
Life Span
Syrian
Hamster
Mouse
Rat
Rabbit
Guinea
Pig
Rhesus
Monkey
267
16
20
22
32
63
167
7
10.5
44
33
728
1.0
5
6.5
66
28
32
12
4
10
17
218
4.4
18. Background
• Adolph (1949) showed that metabolic rates scale
across species according to (body weight)0.73.
• Boxenbaum (1982) demonstrated that the
disposition kinetics of xenobiotics in species is
scaled by the same relationship.
• These concepts led to the mathematical
relationships that are used to standardize
experimental dose regimens and to scale across
species in PBPK models.
19. Physiologic Time
A method for scaling the lifespan of different
species so that comparable stages of maturation
are congruent, regardless of chronological age
An example of the concept of physiologic time that
is intrinsic to PBPK models:
0.25
T1/2 =
Body Weight rat
Body Weight human
20. Time to Develop Adult
Characteristics
100
Rat
Human
%
Adult
Status
0
0
5
10
Age (years)
15
20
21. Relationship Between Extent of Maturation
and Birth in Rats and Humans
100%
Adult
Status
= Birth
Maturation
Human
Rat
Conception
Physiologic Time
23. Ontogeny of Physiologic Regulation
in Selected Mammals
Hamster Rat Rabbit Cat Pig Human
Stagemarks
Implantation
First Heart Beat
Exterioception
Hemoglobin 8% in Blood
Body Weight 1gm
Thyroid Iodine
Lung Surfactant
Liver Glycogen 0.05%
Birth
Water 85% of Fat-free
Na/K one gm/gm
Anoxia Tolerance 10 min.
Body Fat 5%
Arterial Pr. 50 mm/Hg
Lethal Temp Shift
Resistance to Cooling
4
After Adolph 1970
8 10
20
40
80 100
Days After Conception
200
400
24. Perinatal Changes in Fetal Water
and Fat Content
Fat-Free Water Fraction
Gestation
Duration,
Days
Hamster
Rat
Rabbit
Cat
Guinea
Pig
Human
Age at
90% H2O
Days for
Transit to
80% H2O
15*
17*
23*
23
19
20
38*
56*
96*
27
72
170
16
21
32
65
67
114
266
* Prenatal
Body Fat Fraction
Age at
2% Fat
Days for
Transit to
6% Fat
20
22
32
65
39*
116
210*
17
6
8
10
21
3
27
After Adolph and Heggeness, 1971
25. Comparative Perinatal Water
Content
95
Pig
Rabbit
90
% Water
In a
Fat-Free
Body
85
*
GP
Rat
= Birth
Human
*
*
Water fraction
decreases with
age in all
species
*
Hamster
*
*
80
*
75
10
30
100
Days After Conception
300
After Adolph and Heggeness, 1971
26. Comparative Water Content at Birth
95
90
% Water
In a
Fat-Free
Body
Hamster
Rabbit
Rat
Do
g
85
Mouse
Pig
Human
Cat
80
Longer gestation
develops drier
(“denser”)
animals
Guinea
Pig
75
10
30
100
Days After Conception
300
After Adolph and Heggeness, 1971
27. Comparative Ontogeny of Fat Content
30
Hamster
Rat
Rabbit
25
Guinea Pig
Cat
% Fat
In
Body
20
Fetal Guinea Pig
and human deposit
fat prior to birth
Pig
Human
*
15
*
= Birth
*
10
5
0
10
* * *
30
*
*
100
Days After Conception
300
After Adolph and Heggeness, 1971
28. Comparative Perinatal Fat Content
15
10
Hamster
% Fat
In
Body
Guinea Pig
Birth
Birth
5
0
10
20
30
40
50
60
Days After Conception
After Adolph and Heggeness, 1971
70
80
29. Difficulties in a priori Selection
of Models for Preclinical Pediatric Toxicity
30. Relationship Between Development
and Phenotypic Diversity
Extent of Differentiation
Embryonic
Period
Fetal
Period
Postnatal
Period
Degree of
Phenotypic
Variability
Birth
Time in Development (Age)
31. Presence of Enzymes During Embryonic (E),
Fetal (F), and Neonatal (N) Periods
CYP1A1
CYP1A2
CYP1B1
CYP2E1
CYP3A4
CYP3A5
CYP3A7
CYP2C8
CYP2C9
CYP2D6
Flavin-containing monooxygenase
Prostaglandin synthetase
Lipoxygenase
Perosidase
Epoxide hydrase
GSH-S-transferase
UDP-glucuronyltranferase
Sulfotransferases
E
+
–
+
–
–
–
Rat
F N
+ +
– +
+
+
–
–
–
Mouse
E F N
+ + +
–
+
+ +
+
– –
– –
– –
+
+
Hamster
E F N
Rabbit
E F N
G. Pig
E F N
+
+
+
–
+
+
–
+
+
Data extracted from Juchau et al., Kulkarni, 1997; Miller et al., 1996;
Oesterheld, 1998; Raucy and Carpenter, 1993. CYP=cytochrome P450
+
+
Human
E F N
+ + –
– – +
+ +
+ + +
– – +
+ + +
+ + –
+ +
– – +
+ +
+
+
+
+
+
+
+
32. Selected Milestones of Reproductive
Development in Rats and Humans
Event
Rat
Human
gd 13
gd 35-37
gd 13-14
gd 40-42
gd 17
gd 60-70
gd 15 - pnd 16
fetal - to puberty?
Oocytes initiate meiosis
gd 17
gd 84
Arrest of meiosis in females
pnd 5
by pnd 56
Testes descend into scrotum
pnd 21
gd 220-225
Pubertal period: females
pnd 30-38
12-13 years
Pubertal period: males
pnd 35-60
13-15 years
Germ cells in genital ridges
Gonads begin sexual differentiation
Leydig cells differentiate
Sertoli cells proliferate
33. Comparison of Times
in Male Sexual Development
Birth
Conception
Genital Tubercle
Genital Development Static
Formation
Rat
Human
Adult Status
Secondary Sexual
Characteristics
3 Days
19 Days
50 Days
14 Days
8 Months
14 Years
34. Challenges of “Mining” the Literature
• Limited attention given to the issue of postnatal
models for safety assessment
• There is a paucity of reviews / data compilations
• Isolated key information is embedded in papers
addressing other concerns
• Analysis requires interdisciplinary expertise and
commitment of resources
• Many and substantial data gaps (species and
organ systems) exist
36. Effects on Prenatal and Postnatal
Development Including Maternal Function
ICH 4.1.2 (Segment
III)
GD 6
Female
(Rat)
PND 20
Gestation
Lactation
(Macroscopic Pathology)
F1
Denotes Treatment Period
Denotes Possible Transfer Via Milk
Weaning Growth
PN day 21 9 wks
PN day 17
Mating
2 wks
Gestation
3 wks
PN day 80
Behavioral/Anatomic Measures
Motor Activity
Auditory Startle
Water Maze
Developmental Landmark
Vaginal Patency
Preputial Separation
F2
37. Comparison of Prenatal
and Postnatal Toxicity Profiles
Maternal
Toxicity
Developmental
Log of Dose
Prenatal – valid and insightful
– Embryonic exposure
– Mode of action
Postnatal – valid only
– when xenobiotic level is
measured in both mother and
offspring
38. Comparison of Prenatal and Postnatal
Modes of Exposure
Prenatal
Embryo/Fetus
Placenta
Treatment
Mother
Prenatal
Postnatal
Mammae
Neonate
Postnatal
Drug Transfer to
Offspring
Nearly all transferred
Apparent selectivity (“barrier”)
Drug Levels in Offspring
Cmax and AUC measured
Not routinely measured
Maternal Blood vs.
Offspring Levels
Maternal often a surrogate
Maternal levels probably NOT
a good predictor
Exposure Route to
Offspring
Modulated IV exposure,
via placenta
Oral, via immature GI tract
Commentary
Timing of exposure is
critical
Extent of transfer to milk and
neonatal bioavailability is key to
differentiating indirect (maternal)
effects
from neonatal sensitivity
39. Critical Periods for Structural
and Functional Effects
Structural
Development
Sensitivity
Functional
Development
Organogenesis
Time
41. ACE Inhibition in Developing Rats
• RAS (renin-angiotensin system) matures around
GD17
• No ‘apparent’ effect in initial reproductive
studies
• Subsequent postnatal studies with direct
administration to pups
– Growth retardation
– Renal alterations (anatomic and functional)
– Death
42. Examples of Perinatal/Juvenile
Toxicants
• The following examples are not the result of an exhaustive
literature search.
• In most instances, the cause of postnatal morbidity/
mortality has not been investigated or is not known.
• The absence of standard blood biochemistry/hematology
assays and target organ pathology hinders the identification
of sites and modes of action.
43. Examples of Perinatal/Juvenile (?)
Developmental Toxicants
Toxicant
Exposure
Period
Species
Endpoint
Estrogen
PND1-5
mouse
cervical/vaginal
cancer
adult
Dunn & Green, 1963;
Takasagi & Bern, 1964
DES
prenatal
human
vaginal cancer/
reprod. tract effects
pubescence
Herbst & Skully, 1970
DES
Sex hormone
PND1-5
PND1-5
mouse
mouse
vaginal adenosis
vaginal adenosis/
cancer
adult
adult
Forsberg, 1976
GD15, 16, 17
mouse
vaginal adenosis,
transverse ridges
adult
Walker, 1980
(DES)
DES
Time of
Manifestation
(14 mo.)
Reference
Bern et al., 1976
44. Selective Juvenile Toxicity of Quinilones
Drug
Ofloxacin
(and other
quinilones)
Species &
Treatment
Effects
Remarks
Multiple Species,
postnatal exposure.
20mg/kg (dog, 3 mo.)
600mg/kg (rat, 5 wk)
Chondrotoxic
effects. Cartilage
erosion in weightbearing joints.
Human relevance
unknown; drugs
contraindicated in juvenile
patients.
Gait alterations in
juvenile dogs only.
Mechanism: Probable
deficiency of bioavailable
Mg2+ in cartilage
(quinilones chelate
divalent cations).
No effect in routine
segment III studies.
Modified from Stahlmann et al., 1997.
45. Reasons for Increased Attention to
Juvenile Toxicity
• New Trends in Drug Discovery
– Chiral molecules
– Rational, structure-based molecular design
– Targeted pharmacology
• Attention to Sensitive Subpopulations in Human Risk
Assessment
– Food Quality Protection Act
– FDA Modernization Act
46. Challenges
• Identifying and managing risks
– Modulation of growth
– Alteration of functional maturation
• Examples:
– EGF, TGF, Leptin, KGF, CRF
47. Pediatric Classifications
• Neonates
Birth to 1 month
• Infants
1 month to 2 years
• Children
2 to 12 years
• Adolescents
12 to <16 Years
• Comparable categories for animal species dependent on
individual organ or system
49. Primary Reasons that Experimental
Models
Appear to be Invalid
• Findings at, or extrapolated to, exaggerated doses
• Exposure to and internal dose of noxious agent not
measured
• Timing of exposure does not coincide with the
appearance of the developmental target
• Duration of exposure not scaled to physiologic time
• Incorrect / unvalidated endpoints assessed
• Too little knowledge / data concerning mode of action
50. Conclusions
• Parallelism exists among species regardless of
lifespan.
• Additional measurements and changes to current
guidelines could increase our ability to predict
postnatal toxicity.
• Molecular biology and genomics have influenced
pharmaceutical development toward agents with
increasing specificity.
• For novel, selective pharmaceutical agents,
nonclinical testing must be preceded by literature
mining and analysis.