Purpose
To determine feasibility of drug registration for the selected drugs at USFDA based on the ICH E5 guideline.
Methods
Methodology involves two steps, they are 1. Determination of ethnic sensitivity of the selected drugs based on factors
such as pharmacokinetics (PK), pharmacodynamic (PD), therapeutic range, and metabolism etc., given in appendix D
of ICH E5 guidelines. 2. Determination of the need for the bridging studies after determining ethnic sensitivity of the
selected drugs based on the ICH E5 guidelines.
Results
After the extensive analysis of the selected drugs, drugs like nicorandil, may be ethnically insensitive based on ICH
E5 guideline.
Drugs like, nicorandil, may be approved by USFDA without need of bridging studies because they are ethnically
insensitive and medical practice across the ICH countries is mostly similar. The efficacy and safety of these drugs is
demonstrated by the fact that these drugs are on the market for at least 25 years and prescribed in the millions of the
patients.
Conclusion
Nicorandil may be ethnically insensitive among the selected drugs based on the ICH E5 guideline. Drugs like
nicorandil may be approved by USFDA (United States Food and Drug Administration) without need of bridging
studies
Clinical Pharmacology in Orphan Drug DevelopmentE. Dennis Bashaw
This is the fourth talk that I gave in Asia back in May. It was presented at the Konect (Korea National Enterprise for Clinical Trials) 3rd symposia that was held in Seoul at Seoul National University.
FACTORS ASSOCIATED WITH UNNECESSARY DRUG THERAPY AND INAPPROPRIATE DOSAGE IN ...Jing Zang
To assess factors associated with unnecessary drug therapy and inappropriate dosage in hospitalized patients. A hospital based cross-sectional study design was employed. The study was conducted in Jimma University Specialized Hospital, Jimma, which is 345 Km from South west of Addis Ababa. All patients who were admitted to medical ward from February 5 – March 21, 2011 were included in the study. Data on socio-demographic variables, past medical history, past medication history, current diagnosis, current medications, vital signs and relevant laboratory data were collected by using bed side patient interview guided semi-structured questionnaire and data abstraction formats for card review. The data were analysed by using SPSS version 16 for windows. Descriptive statistics, cross-tabs, chi-square and logistic regression were done. Out of 257 study participants 140(54.5%) had unnecessary drug therapy or inappropriate dosage. The only independent factors which predicted the unnecessary drug therapy in study population was polypharmacy while not considering organ function test, polypharmacy and clinically significant potential drug-drug interaction were independent factors associated with inappropriate dosage . The prevalence of unnecessary drug therapy or inappropriate dosage is significantly high.
Clinical Pharmacology in Orphan Drug DevelopmentE. Dennis Bashaw
This is the fourth talk that I gave in Asia back in May. It was presented at the Konect (Korea National Enterprise for Clinical Trials) 3rd symposia that was held in Seoul at Seoul National University.
FACTORS ASSOCIATED WITH UNNECESSARY DRUG THERAPY AND INAPPROPRIATE DOSAGE IN ...Jing Zang
To assess factors associated with unnecessary drug therapy and inappropriate dosage in hospitalized patients. A hospital based cross-sectional study design was employed. The study was conducted in Jimma University Specialized Hospital, Jimma, which is 345 Km from South west of Addis Ababa. All patients who were admitted to medical ward from February 5 – March 21, 2011 were included in the study. Data on socio-demographic variables, past medical history, past medication history, current diagnosis, current medications, vital signs and relevant laboratory data were collected by using bed side patient interview guided semi-structured questionnaire and data abstraction formats for card review. The data were analysed by using SPSS version 16 for windows. Descriptive statistics, cross-tabs, chi-square and logistic regression were done. Out of 257 study participants 140(54.5%) had unnecessary drug therapy or inappropriate dosage. The only independent factors which predicted the unnecessary drug therapy in study population was polypharmacy while not considering organ function test, polypharmacy and clinically significant potential drug-drug interaction were independent factors associated with inappropriate dosage . The prevalence of unnecessary drug therapy or inappropriate dosage is significantly high.
pharmacovigilance, adverse effects, causality assessment,methods, who-umc method with case study, FOR DOWNLOAD PPT MAIL ME ON iamgauravchhabra@gmail.com
DIA China 2017 Optimizing Clinical Trials with Advanced ToolsE. Dennis Bashaw
This is the companion talk to one I posted yesterday. This is the Third of the talks that I gave in Asia back in May. Both this talk and the "Making Every Patient Count" presentation were part of a larger program at the DIA China Annual meeting.
Essential medicines, as defined by the World Health Organization (WHO) are "those drugs that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in appropriate dosage forms, at a price the community can afford
A clinical trial is a culmination of the several stages of a drug or medical
device development program that begins with the discovery of a
candidate molecule followed by preclinical toxicology studies in ex vivo, in
vitro, and animal models. Once the candidate molecule shows promising
results in these stages, the next step involves clinical studies on human
subjects. Drug testing in humans is often the most lengthy and expensive
phase of the drug development timeline, and therefore requires extensive
effort and careful execution to maximize the candidate’s chances of
success. In addition to scientific evaluation, clinical studies require
approval by the United States Food and Drug Administration (US FDA),
the regulatory authority in the United States to administer the
experimental drug in humans as well as ship it across state lines. This
approval comes in the form of an Investigational New Drug (IND FDA)
application that is required to be submitted by sponsors, investigators, or
research institutes to the FDA to commence studies on human
participants. The following figure shows the various stages of the drug
development program (Figure 1) marking IND submission on the timeline.
The US Food and Drug Administration (FDA) has established a comprehensive drug
development strategy for US FDA. This strategy is designed to ensure that the drugs
being developed meet the highest standards of safety and efficacy.The IND is a comprehensive document that contains all the information
gained from preclinical and other studies in an organized format. The
FDA reviews and makes the decision to support further clinical studies
from information in the IND that ultimately forms the basis of marketing
approval. INDs can be submitted at any phase during clinical
development to protect the safety and rights of subjects (Phase I) and to
assure adequate scientific evaluation of the drug’s effectiveness and
safety (Phase II and III). The Code of Federal Regulations CFR Title 21.
Part 312 Investigational New Drug Application contains information on
INDs as well as their content and format and should be reviewed
thoroughly by sponsors or investigators prior to submission of an IND
application.
The IND data requirements are important for the development of new drugs and
medical devices. They provide detailed information about the safety and efficacy of a
drug or device before it can be approved for use by the public
IND Data Requirements and US FDA Submission Process.pdfProRelixInfo
A clinical trial is a culmination of the several stages of a drug or medical device development program that begins with the discovery of a candidate molecule followed by preclinical toxicology studies in ex vivo, in vitro, and animal models. Once the candidate molecule shows promising results in these stages, the next step involves clinical studies on human subjects. Drug testing in humans is often the most lengthy and expensive phase of the drug development timeline, and therefore requires extensive effort and careful execution to maximize the candidate’s chances of success. In addition to scientific evaluation, clinical studies require approval by the United States Food and Drug Administration (US FDA), the regulatory authority in the United States to administer the experimental drug in humans as well as ship it across state lines. This approval comes in the form of an Investigational New Drug (IND FDA) application that is required to be submitted by sponsors, investigators, or research institutes to the FDA to commence studies on human participants. The following figure shows the various stages of the drug development program (Figure 1) marking IND submission on the timeline.
pharmacovigilance, adverse effects, causality assessment,methods, who-umc method with case study, FOR DOWNLOAD PPT MAIL ME ON iamgauravchhabra@gmail.com
DIA China 2017 Optimizing Clinical Trials with Advanced ToolsE. Dennis Bashaw
This is the companion talk to one I posted yesterday. This is the Third of the talks that I gave in Asia back in May. Both this talk and the "Making Every Patient Count" presentation were part of a larger program at the DIA China Annual meeting.
Essential medicines, as defined by the World Health Organization (WHO) are "those drugs that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in appropriate dosage forms, at a price the community can afford
A clinical trial is a culmination of the several stages of a drug or medical
device development program that begins with the discovery of a
candidate molecule followed by preclinical toxicology studies in ex vivo, in
vitro, and animal models. Once the candidate molecule shows promising
results in these stages, the next step involves clinical studies on human
subjects. Drug testing in humans is often the most lengthy and expensive
phase of the drug development timeline, and therefore requires extensive
effort and careful execution to maximize the candidate’s chances of
success. In addition to scientific evaluation, clinical studies require
approval by the United States Food and Drug Administration (US FDA),
the regulatory authority in the United States to administer the
experimental drug in humans as well as ship it across state lines. This
approval comes in the form of an Investigational New Drug (IND FDA)
application that is required to be submitted by sponsors, investigators, or
research institutes to the FDA to commence studies on human
participants. The following figure shows the various stages of the drug
development program (Figure 1) marking IND submission on the timeline.
The US Food and Drug Administration (FDA) has established a comprehensive drug
development strategy for US FDA. This strategy is designed to ensure that the drugs
being developed meet the highest standards of safety and efficacy.The IND is a comprehensive document that contains all the information
gained from preclinical and other studies in an organized format. The
FDA reviews and makes the decision to support further clinical studies
from information in the IND that ultimately forms the basis of marketing
approval. INDs can be submitted at any phase during clinical
development to protect the safety and rights of subjects (Phase I) and to
assure adequate scientific evaluation of the drug’s effectiveness and
safety (Phase II and III). The Code of Federal Regulations CFR Title 21.
Part 312 Investigational New Drug Application contains information on
INDs as well as their content and format and should be reviewed
thoroughly by sponsors or investigators prior to submission of an IND
application.
The IND data requirements are important for the development of new drugs and
medical devices. They provide detailed information about the safety and efficacy of a
drug or device before it can be approved for use by the public
IND Data Requirements and US FDA Submission Process.pdfProRelixInfo
A clinical trial is a culmination of the several stages of a drug or medical device development program that begins with the discovery of a candidate molecule followed by preclinical toxicology studies in ex vivo, in vitro, and animal models. Once the candidate molecule shows promising results in these stages, the next step involves clinical studies on human subjects. Drug testing in humans is often the most lengthy and expensive phase of the drug development timeline, and therefore requires extensive effort and careful execution to maximize the candidate’s chances of success. In addition to scientific evaluation, clinical studies require approval by the United States Food and Drug Administration (US FDA), the regulatory authority in the United States to administer the experimental drug in humans as well as ship it across state lines. This approval comes in the form of an Investigational New Drug (IND FDA) application that is required to be submitted by sponsors, investigators, or research institutes to the FDA to commence studies on human participants. The following figure shows the various stages of the drug development program (Figure 1) marking IND submission on the timeline.
Introduction
Brief description of the drug and the therapeutic class to which it belongs
Chemical and pharmaceutical information
Animal Pharmacolog
Animal Toxicology
Human/Clinical Pharmacology phase I
Therapeutic exploratory trials (Phase II)
Therapeutic confirmatory trials (Phase III)
Special Studies Geriatrics, pediatrics, pregnant or nursing women
Regulatory status in other countries
Prescribing information
Samples and Testing Protocol/s
With this new guidance, Dalton Pharma is committed to meeting the FDA's expectations in the development of botanical drugs, while also advancing the science of botanical medicine and improving patient outcomes. We believe that this guidance will set a new standard in the industry and help pave the way for safe and effective botanical medicines.
Stay tuned as we continue to lead the way in the botanical medicine space and provide the latest updates on our journey to better health for all.
Key areas in this whitepaper:
Botanical Drug Guidance, Purpose & Content; Regulations of Botanical Products as Drugs;
OTC monographing of Botanical drugs; Safety and efficacy required for OTC monograph inclusion; Approved Botanical Drugs; Phase 1, 2, 3 & IND Content Requirements; NDA data requirements for botanical drugs; Barriers to Botanical Drugs and NDA submissions & Approvals.
A Cross Sectional Study of Ethnic Differences in Occurrence and Severity of A...iosrphr_editor
Non-steroidal anti-inflammatory drugs are the most widely used "over the counter" medication all over the world despite their complications in different major organs. Present studies envisaged for knowing the occurrence and severity of adverse drug reactions from NSAIDs in different ethnic communities of Sikkim. A cross sectional study was undertaken in the medicine outpatients department of a secondary and tertiary care hospital. The patients belonging to Nepalese, Bhutias, Lepchas ethnic communities and others community (settlers from other parts of India) were included to analyzed the data based on the age and gender, ethnicity and ADRs, drugs and ADRs. Severity assessment was done using Hartwing and Siegel scale and causality assessment by Naranjo scale. Total 109 cases of ADRs, predominating in female were detected. Nepalese were the most affected and Gastrointestinal tract (GIT) being the most affected organ in them. Diclofenac showed maximum number of ADRs in all the communities. Maximum number of cases occurred on single day use (40.36%) of drugs. All the cases were belonging to the "possible category" and the maximum being the mild (72.48%) in nature. It is advisable to consider the ethnic/racial differences equally with other factors, to improve the safety and efficacy of a drug.
Regulatory requirements for drug approval - industrial pharmacy IIJafarali Masi
Regulatory requirements for drug approval - industrial pharmacy IIDrug Development Teams, Non-Clinical Drug Development, Pharmacology, Drug Metabolism and Toxicology, General considerations of Investigational New Drug (IND) Application, Investigator’s Brochure (IB) and New Drug Application (NDA), Clinical research / BE studies, Clinical Research Protocols, Biostatistics in Pharmaceutical Product Development, Data Presentation for FDA Submissions, Management of Clinical Studies.
A study to assess the self-esteem among adolescents of alcoholic dependent pa...SriramNagarajan16
Adolescence is a transitional stage of physical and psychological development that generally occurs during the
period from puberty to legal adulthood. Adolescence is usually associated with the teenage years, but its
physical, psychological or cultural expressions may begin earlier and end later. Self-esteem can be defined as an
individual’s judgment of his or her self-worth (Rosenberg 1965). Alcoholism also known as Alcohol use
disorder(AUD), is a broad term for any drinking of alcohol that results in ment al or physical health problems.
Methods
A descriptive research design was done in thrivallur district. 100 samples are included in our study. purposive
sampling techniques method was used in selecting the samples. Rosernberg self-esteem scale, were used to
collect data.
Results
The level of self-esteem among adolescents of alcohol dependent parent. (33%) are low self-esteem, (67%) are
moderate self-esteem, (0%) are high self-esteem.
Conclusion
The overall study finding showed that 67% of the sample had moderate self-esteem among adolescents of
alcoholic dependent parent in Thiruvallur District.
Hazards of OTC medication - a community pharmacy practiceSriramNagarajan16
Over the counter (OTC) medication most common practice in India and concurrently patient complaint due to
OTC encounter by healthcare practitioner also uncountable. In OTC practice one can buy medicines without
prescriptions of register medical practitioner (RMP). In India, peoples are always practice OTC to relieve pain
and treat symptoms of the common cold, flu, and allergies. In present study, a survey was conducted in different
places of central India and collected data especially from Ratlam and Mandsaur District of Madhya Pradesh
state, India. During the survey, information was obtained from the individuals used OTC medication as per predesigned questioners. Subsequently, documented information was evaluated to find out risk of OTC medication,
if any. In evaluation, it was found that about 21% OTC drug may cause moderate to severe hazardous effect to
the patients used OTC medication. Patients with complaints of fever; body ache etc. used only NSAIDs from
OTC and later diagnosed as chikungunya, when complaints persisted and visit doctors’ clinic. OTC medication
has tremendous risk which may fatal for patients and chances of produce new complications due to misuse of
drugs. So, medication should be taken after diagnosis by register medical practitioner that will make a healthy
society.
A review article: antifungal activity of eucalyptus genusSriramNagarajan16
Plant essential oils are intricate blends of organic volatility that may have antifungal characteristics of interest in the
food, cosmetics and human health industries. As a result, in the quest for a natural and secure alternative, surveys of
the antimicrobial activity of essential oils in recent decades have become increasingly essential. This review describes
the anti-fungal therapeutic operations reported in the accessible research papers and scientific references of herbal
Eucalyptus oils from diverse verities. At the same time, a study of significant techniques used in the assessment of
antimicrobial activity and some of the processes involved in antimicrobial activities of essential oils was also carried
out. The focus of this review article is on the characteristics and antimicrobial procedures of Eucalyptus globulus
essential oils and the procedures involved in inhibiting these pathogenic micro-organisms.
The study on anatomy, risk factors, pathophysiology, treatment of osteoarthritisSriramNagarajan16
The review is to describe the osteoarthritis epidemiology, anatomy, pathophysiology, risk factors causing
osteoarthritis are also explained and treatment of osteoarthritis. Knee and hip are weight bearing joints are
mostly affected. Osteoarthritis of the knee is a condition characterized by the progressive destruction of the
cartilage and review tried to explain the stages of the knee and treatment for knee and describe the t otal knee
replacement. The goal of treatment for osteoarthritis of the knee include reduce pain and inflammation and
update treatment also explained.
A review article: antimicrobial and antidiarrheal activity of tinospora cordi...SriramNagarajan16
The objective to the paper emphasizes on the study of various models related to antimicrobial and antidiarrheal
activity of Tinospora cordifolia. The plant also possesses various pharmacological activities including its use as
antihyperglycemic, anti-inflammatory, antiarthritic, ant osteoporotic, enhance cognition (learning and memory),
antidiarrheal and immunomodulatory effects. The current works aims to justify the folklore use of the whole plant
of the Tinospora cordifolia for its antidiarrheal and antimicrobial potentiality. Tinospora cordifolia contains
phytochemical constituent such as alkaloids, diterpenoid lactones, glycosides, steroids, sesquiterpenoid, phenolics,
aliphatic compounds and polysaccharides. T. cordifolia is already an import- tent composition of many traditional
Indian medicine formulations, both its purified stem proteins and the derived peptides by enzyme hydrolysis could
be incorporated into food products or nutraceuticals or developed to be a safe and efficient drug for treating
oxidative stress and related disorders. Pretreatment with Tinospora cordifolia extracts provide significant protection
against castor oil and magnesium sulfate‑induced diarrhea, the extracts may presume to have antisecretory and
preventive action towards CCK release
A review article: a surpass effect of pterocarpus marsupium on peptic ulcer d...SriramNagarajan16
The Pterocarpus marsupium belong to family Fabaceae and is widely distributed in central, western and southern
regions of India. The role of Pterocarpus marsupium as anti-diabetic has been very well established. Its extract has
been prepared using many methods like infusion, maceration, decoction and percolation. Several chemical
constituents like pterostilbene, (-)-epicatechin, pteropines, marsupinol, etc., have been identified and isolated.
Pterocarpus marsupium extract also shows promising results in cataract and hypertriglyceridemia. This plant also
finds its use as cardiotonic and hepatoprotective agent. Studies have also been reported to demonstrate its ability as a
specific COX- 2 inhibitor. The present review explores its description, traditional uses, extraction methods, chemical
constituents, pharmacological activity and commercial significance so that its potential as a multipurpose medicinal
agent can be understood and appreciated.
Rheumatoid arthritis is a chronic inflammatory and systemic auto immune disease affecting people for the most part
between the ages of 20-25 yrs with accidental course. About 1% of the worlds population is afflicted by rheumatoid
arthritis and is 2-3 times more common in women than men. The rheumatoid arthritis due to the presence of pro
inflammatory markers, cytokines and leukotrines. The primary inflammatory markers are IL-1, TNF-α, IL-6, IL-15,
IL-16, IL-17, IL-18, IFN-γ, and the granulocyte macrophage colony stimulating factor, chemokines such as IL-8,
macrophage inflammatory protein-1 and monocyte chemo attractant protein-1. IL-1, TNF-α, IL-6, B cells therapy all
these blockade are therapeutic target for its treatment. estimate the anti arthritic activity of the plants are used in
different animal models to induced arthritis. Medicinal plants have been used as major sources of pure of human
diseases since time immemorial. Now a days most of the people depends on traditional medicines of the plants. The
medicinal plants derived medicines for the first time of primary health care because of least or no side effects.
Preliminary study of Prescription audit for evaluation of prescribing pattern...SriramNagarajan16
Prescription audit is necessary to know the art of prescription practices to improve rational pharmacotherapy.
Present study is an observational study and was undertaken from August 2018 to October 2018 for which data
was collected from Medical OPD. Prescribing is a technique with an expert academic pharmacological
knowledge.
Irrational prescribing leads to diminished therapeutic outcome. The present study is the first preliminary one at
Pandit Jawaharlal Lal Nehru Govt. Medical College and Hospital, Chamba- HP Before July 2016, it was a
district hospital College. It is a hilly district and caters the need of 5 Lakh people. A total of 420 prescriptions
were analyzed. These prescriptions comprised of 3000 drugs. Average drugs prescribed per patient were 7.3 .
male and female ratio was 40% and 60% respectively. More prescription were carried out in the age group of 51
- 60 yrs. Prescriptions in generic were only 3.65% fixed dose combination was used in 300 prescriptions and
comprised of 71.4% drugs. Oral prescriptions were used maximally and intravenous medication was minimally
used. Multivitamin prescriptions were observed in bulk.
A study on prescription pattern and rational use of statins in tertiary care ...SriramNagarajan16
Objectives
Our objectives are to evaluate prescription pattern and rational use of statins in a tertiary care corporate hospital.
Methodology
It was a prospective observational study conducted for a period of 6 months and included various departments of 300
bedded multi specialty tertiary care corporate hospital. A total of 200 patients were included and the study criteria
was inpatients and induvial more than 18 years of either gender who are prescribed with HMG-CoA reductase
inhibitors.
Results
In the present study 200 patients belonged to the age group of above 18 years, out of which about 65% were male
and 35% were female. Atorvastatin (67%) was prescribed mostly and Rosuvastatin (29.5%) was also used.
Conclusion
It is finally concluded that Rational and prophylactic use of statins can reduce further complications of Diabetes
Mellitus (DM) and cardiac events.
Statins treatment is favourable in long term treatment of diseases, it is most effectively used in treatment of serious
disease conditions which has shown its immense therapeutic role in treatment
Antimicrobial activity and phytochemical analysis of whole plant Impatiens ba...SriramNagarajan16
Impatiens balsamina linn, belonging to the family of Balsaminaceae.It is distributed in tropical and sub tropical parts
of India. It issued in emetic, chathartic, diuretic and cancer. Present study is carried out to determine the anti
microbial properties of the ethanol extract of Impatiens balsamina.
A study on drug utilization evaluation of anticoagulant therapy INA tertiary ...SriramNagarajan16
Objectives
Evaluation of a prospective observational study of the Anticoagulants used in tertiary care hospital, to provide
information and correct rationale pertaining to Anticoagulants which also describes various distribution wise of
Anticoagulants by age groups, genders, pattern of prescription, drug wise, dose, route, class and department to assess
the statistical incidence regarding usage and its right provision.
Methodology
Study site was at SUNSHINE HOSPITALS, conducted for a period of 6 months. Both male and female individuals of
age group 16-75years were included.
Results
Study included assessment of utilization of Anticoagulants with total of 200 prescriptions; of which males (54.5%),
females (44.67%), age groups of 60-69 (34%) followed by age groups 70-80(27.5%), parenteral SC route (59%) and
followed by intravenous route. (38%) and oral route was rare (3%), orthopaedics (64, 32%), followed by cardiology
(43, 21.5%), neurology (29, 14.5%), pulmonology (22, 11%).
Conclusion
To conclude with, Anticoagulants are effective drugs in an array of treatment of diseases involving careful
consideration of factors such as potency, formulation, responsiveness and cost. Anticoagulanting agents were mostly
given in cases of post or pre operative care followed by prophylaxis for thrombosis for better patient outcome.
Zinper softgel caps: a natural nutrient helps to ease occasional nausea & pro...SriramNagarajan16
Chemotherapy –induced nausea and vomiting (CINV), also known by the term emesis, is one of the most
common and dreaded side effects following cancer treatment, and can strongly impact the quality of day –today living of cancer patients. Many Chemotherapeutic agents are associated with significant nausea and
vomiting which represent a challenge to effective therapy. The active ingredients present in Zinper softgels are
terpenes and oleoresin. The major identified components from terpenes are gingerol and shogaols. Zinper
softgels has staring potential as anti-tumor, anti-oxidant, anti inflammatory, anti-microbial, anti-emetic effect,
Anti-angiogenesis, anti-nausea and an effective adjuvant treatment for chemotherapy-induced nausea and
vomiting. The effectiveness of Zinper softgels in preventing or suppressing cancer growth has been examined in
a variety of cancer types, including lymphoma, hepatoma, colorectal cancer, breast cancer, skin cancer, liver
cancer, and bladder cancer. This article reviews the current available scientific literature regarding the effect of
Zinper softgels as A Natural Nutrient to Promote Healthy GI peristalsis in cancer patients.
A laboratory bioassay was conducted to investigate the antifeedant effect of Gomphrena serrata extracts on
sitophilus oryzae (rice weevil) belongs to the family Curculionidae. Antifeedants are natural or synthetic
compounds that stops or inhibits feeding by a pest and especially an insect. Gomphrena serrata- Amaranthacae
family comprises many species which are used in nutrition and traditional folk medicine. Study was done to
find the new active substance in the plant which could show antifeedant activity and compared with standard
Strychnos nuxvomica. The extracts of both sample and standard were obtained by cold maceration process. The
residue formed is collected and both the extracts were subjected to study the antifeedant activity. The activity is
performed by dilution method and found to be showing the antifeedant activity. The primary objective of our
work is simple and cost effective method to find out the active substance from natural resources.
Indiscriminate use of synthetic insecticides has led to problems such as the resurgence of primary pests,
secondary pest’s outbreak, resistance development, insecticide residue, health hazards, environmental
contamination and increased cost of insect control. So this study will be solution for these problems by utilizing
plant’s bioactive molecules. Plants are the most efficient producers of phytochemicals in the environment,
including secondary metabolites that are used by the plant in defence against insects. The secondary metabolites
produced from Gomphrena serrata could be utilized in the development of new biopesticides
Morphometric variations of right and left side mandibular foramen from corono...SriramNagarajan16
Background of the study
Variation of the mandibular foramen right and left side is very important ,because to know about the vital
structures passing through it and also the Variation is very important during the intra oral surgery like tooth
extraction, implantation ,mandibular fracture . The knowledge of variation in mandibular formen is very
important to avoid the anaesthestic error of inferior alvelor nerve blockage.
Objectives
The aim of this study is to determine the position of the Mandibular foramen conodylar process, coronoid
process, to the lingua in several dry adult mandibles.
Materials and methods
A total number of 200 human dry mandibles RIGHT AND LEFT SIDE MANDIBULAR FORAMEN were
examined of which 170 mandibles are normal and 30 mandible shows variations with the help of vernier caliber
.Measurement
The Measurement were taken as follows
i)Condylar Process to the Mandibular foramen
ii)Coronoid Process to the Mandibular foramen
iii)Mid portion of lingula to the Mandibular foramen
Result
According to our study, the following are the variations found,The length from the condylar process to the
mandibular foramen is more on right side compared to the left side.The length from the coronoid process to the
mandibular foramen is more on left side compared to the right side.The length from the midpoint lingua to the
mandibular canal is more on right side compared to left side
In vitro and in vivo evaluation on fishes of anti-inflammatory potential of A...SriramNagarajan16
Agaricus bisporus has been studied for many activities except for its anti-inflammatory potential completely both by
in vitro and in vivo experiments. In the present study it was evaluated for the same using egg albumin for in vitro
study and fish as the model for in vivo evaluation and found to have remarkable anti-inflammatory activity on both
experiments. As expected with any natural drug the activity was better at higher doses.
CALCI-Q tablets: The Calcium fortified with mineralsSriramNagarajan16
Calcium is very essential in muscle contraction, oocyte activation, building strong bones and teeth, blood clotting,
nerve impulse, transmission, regulating heart beat and fluid balance within cells. The requirements are greatest during
the period of growth such as childhood, during pregnancy, when breast feeding. Long term of calcium deficiency can
lead to oestoporosis in which the bone deteriorates and there is an increased rise of fractures. Eating a well-balanced
calcium supplment like Calci-q tablet can provide all the necessary nutrients and help prevent calcium deficiency.
The present paper Reviews the Role of Calci-Q tablets developed by R&D cell of Sain medicament Pvt Ltd.
Hyderabad in maintaining optimum health and wellbeing.
Submucosal plasmacytosis is a rare idiopathic condition consisting of a dense plasma cell infilterate of the mucous
membrane.It presents clinically as a diffuse, erythematous and less often ulcers are present .The etiology is still
unclear,but this condition is believed to be an immunological reaction to certain allergens .Here presenting a case
report of 86 year old male complained of multiple oral lesions and bleeding from lip region since one and half month
back,also complains of pain and burning sensation.
Huntington’s disease is an autosomal, dominant, slowly progressive, inherited, incurable, and a
neurodegenerative disease characterized by uncontrolled motor movements, cognitive impairment, behavior
abnormalities which may finally lead to dementia. The main cause of this disease is the mutation in the
huntingtin gene, which is an IT 15 gene. The Occurrence of this disease is more in western countries between
the age group of 35 to 45. Symptoms of this disease depend upon CAG triplet repeat. Main symptoms are
chorea, athetosis, jerks, weight loss, difficulty in speech are seen. Symptomatic treatment may improve the
quality of the life of the individual or may decrease complications.
Transverse Testicular Ectopia (TTE) is a rare congenital anomaly in which both testicles migrate towards the same
side of the scrotum. It is usually associated with other abnormalities such as Mullerian duct syndrome, inguinal
hernia, scrotal anomalies etc. We are presenting a case of Transverse Testicular Ectopia in a 30 year old male patient
having complaints of Left Inguinal Hernia previously operated for Left Orchidopexy with mesh placement.
Phytochemical screening and in vitro antioxidant activity of extracts of jasm...SriramNagarajan16
Objectives
The aims of this research were to carry out the preliminary phytochemical screening and antioxidant activity
of different extracts of J. sessiliflorum. The different anti-oxidant methods carried out were DPPH
scavenging method, NBT dye reduction method and nitric oxide scavenging method
Methods
Extracts were prepared by reflux method using different polarity solvents. The extracts were evap orated
using rotary evaporator. Antioxidant activities using DPPH, NBT dye reduction method and nitric oxide
scavenging methods and the correlation of their IC50 values with standards were carried out.
Results
The ethanolic herbs extract of J. sessiliflorum had the lowest IC50 values in all the anti-oxidant methods.
Moreover, the ethanolic extracts showed the presence greatest amount of phytochemical constituents. The
IC50 values were correlated with the IC50 values of standards in all the anti- oxidant activity determination
methods.
Conclusions
The results of the present study indicate that the extracts of J.sessiliflorum exhibited strong antioxidant
activity and thus it is a good source of antioxidant.
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.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
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
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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.
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.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
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.
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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
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Consideration of ethnic factors during drug approval process
1. Sudershan G G et al / Int. J. of Pharmacology and Clin. Res. Vol-2(1) 2018 [29-38]
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29
IJPCR |Volume 2 | Issue 1 | Jan – Jun- 2018
www.ijpcr.net
Research article Clinical research
Consideration of ethnic factors during drug approval process
Sudershan Goud Gokari1*
, Dr. Vijayanarayana2
, Sujitha Bajjuri2
, Ather Ali
Soharwardi2
1*
Associate Prof., Department of Pharmacy Practice, Anwarul-ul-loom College of Pharmacy, Hyderabad,
Telangana, India,
2
Associate Professor, Department of Pharmacy Practice, Manipal College of Pharmacy, Karnataka, India,
2
Asst.Prof., Department of Pharmacy, Anwarul-ul-loom College of Pharmacy, Hyderabad, Telangana,
India,
2
Assistant. Prof., Department of Pharmacy Practice, KCT College of Pharmacy, Gulbarga, Karnataka,
India.
*
Address for correspondence: SudershanGoudGokari, 13-3-087/62/1, Bharat nagar, jiyaguda, Hyderabad,
Telangana 500006.
ABSTRACT
Purpose
To determine feasibility of drug registration for the selected drugs at USFDA based on the ICH E5 guideline.
Methods
Methodology involves two steps, they are 1. Determination of ethnic sensitivity of the selected drugs based on factors
such as pharmacokinetics (PK), pharmacodynamic (PD), therapeutic range, and metabolism etc., given in appendix D
of ICH E5 guidelines. 2. Determination of the need for the bridging studies after determining ethnic sensitivity of the
selected drugs based on the ICH E5 guidelines.
Results
After the extensive analysis of the selected drugs, drugs like nicorandil, may be ethnically insensitive based on ICH
E5 guideline.
Drugs like, nicorandil, may be approved by USFDA without need of bridging studies because they are ethnically
insensitive and medical practice across the ICH countries is mostly similar. The efficacy and safety of these drugs is
demonstrated by the fact that these drugs are on the market for at least 25 years and prescribed in the millions of the
patients.
Conclusion
Nicorandil may be ethnically insensitive among the selected drugs based on the ICH E5 guideline. Drugs like
nicorandil may be approved by USFDA (United States Food and Drug Administration) without need of bridging
studies.
International Journal of Pharmacology and
Clinical Research (IJPCR)
ISSN: 2521-2206
2. Sudershan G G et al / Int. J. of Pharmacology and Clin. Res. Vol-2(1) 2018 [29-38]
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30
INTRODUCTION
There is need for study of ethnic factors when a
drug has to get approval in the foreign locations
where the clinical trials of drug have not been
conducted to avoid duplication of the clinical
studies, which are already done with lot of
expenses because, for the development of a single
drug it take years and 802 million dollars. [1] In
this context, The International Conference on
Harmonization of Technical Requirements for
Registration of Pharmaceuticals for Human Use
(ICH) issued ICH E5 guidance in February 1998
regarding the ethnic factors in the acceptability of
foreign clinical data. The ICH E5 guideline
provide a general frame work for evaluating the
potential impact of ethnic factors on the
acceptability of foreign clinical data, with the
underlying objective of minimizing duplication of
clinical data and it also describes the requirement
of bridging study for extrapolation of foreign
clinical data to a new region.
NEED FOR THE STUDY
All countries acknowledge the desirability of
utilizing foreign clinical data that meet the
regulatory standards and clinical trial practices
acceptable to the region considering the application
for registration.
However, concern that ethnic differences may
affect the medication’s safety, efficacy, dosage and
dose regimen in the new region has limited the
willingness to rely on foreign clinical data.
Historically, this has been one of the reasons,
therefore, the regulatory authority in the new
region has often requested that all, or much of, the
foreign clinical data in support of registration be
duplicated in the new region. Although ethnic
differences among populations may cause
differences in a medicine’s safety, efficacy, dosage
or dose regimen, many medicines have comparable
characteristics and effects across regions.
Requirements for extensive duplication of clinical
evaluation for every compound can delay the
availability of new therapies and unnecessarily
waste drug development resources.
The purpose of ICH E5 guidance is to facilitate
the registration of medicines among ICH regions by
recommending a framework for evaluating the
impact of ethnic factors upon a medicine’s effect,
i.e., its efficacy and safety at a particular dosage
and dose regimen. It provides guidance with
respect to regulatory and development strategies
that will permit adequate evaluation of the
influence of ethnic factors while minimizing
duplication of clinical studies, cost, time and
supplying medicines expeditiously to needy
patients for their benefit. [2]
To realise full potential of ICH E5 guideline
goals, there is need to identify and register more
drugs which are approved for their efficacy and
safety in one country and prescribed in the millions
of the patients for the decades and not approved in
the another country based on the ICH E5 guideline
by appropriate institutions like World Health
Organization (WHO), Non-Governmental
Organizations (NGOs’), pharma companies etc., to
realize the goals of ICH E5 guideline.
In this context drugs approved in the Japan for
the decades and whose efficacy and safety is
proved by the fact that they are prescribed in the
millions of the patients are identified and there
feasibility of registrations at United States Food
and Drug Administration (USFDA) is studied to
realise the goals of ICH E5 guideline.
RATIONALE FOR THE SELECTED
DRUGS
After the extensive analysis of literature, drugs
like Nicorandil, because this drug were not
available for the patients in USA even though the
efficacy and safety of the this drug is well proved
and demonstrated by the fact that this drug is on the
market in the ICH group of countries like European
union and Japan for at least 15 years and prescribed
for the millions of the patients. [3]
USA being an important player in ICH group of
countries may take full advantage of this fact by
providing these drugs to its needy patient
population at earliest by evaluating these drugs
based on the ICH E5.
Approval of These drugs with or without
bridging studies based on the ICH E5 guideline
helps in the realization of the goals of ICH E5
guideline i.e., minimizing duplication of clinical
studies, cost, time and supplying medicines
expeditiously to needy patients for their benefit at
the right time.
In this context, drugs whose efficacy and safety
is well established and approved in the Japan for
3. Sudershan G G et al / Int. J. of Pharmacology and Clin. Res. Vol-2(1) 2018 [29-38]
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31
the decades are identified and there feasibility for
registrations at USFDA is studied to realise the
goals of ICH E5 guideline.
AIM OF THE STUDY
To determine feasibility of drug registration for
the selected drugs at USFDA based on the ICH E5
guideline.
Objectives of the study
1. To determine ethnic sensitivity of the selected
drugs based on factors given in appendix D of
ICH E5 guidelines.
2. To determine the need for the bridging studies
after determining ethnic sensitivity of the
selected drugs.
METHODOLOGY
Methology involves following parameters. They
are as follows
Regulatory consideration
As per ICH E5, the pharmaceutical industry
should first submit the clinical data package. The
clinical data package would be assessed by the
regional regulatory authority regarding the nature
and quality of the data, irrespective of its
geographic origin. A clinical data package would
be defined as a “complete” clinical data package
for submission and potential approval if it meets all
of the regional regulatory requirements. Foreign
clinical data component of the complete data
package can be acceptable depending upon whether
it can be extrapolated to the population of the new
region. ICH states that clinical trials should be
designed and conducted according to regulatory
standards in the new region, be adequate and well-
controlled, utilize endpoints that are considered
appropriate for assessment of treatment and clinical
disorders should be evaluated using medical and
diagnostic definitions that are acceptable to the new
region. If clinical data does not fit into the above
criteria, it might not be accepted.
Regional regulatory authority might ask for
additional clinical trials if the foreign clinical data
do not meet the regional regulatory requirements.
Ethnic consideration
A medicine's sensitivity to ethnic factors can be
judged by pharmacokinetic, pharmacodynamic, or
other characteristics which suggest the potential for
clinically significant or minimal impact by intrinsic
and/or extrinsic ethnic factors on safety, efficacy
and dose response.
The critical properties of a medicine for
assessment of sensitivity to ethnic factors have
been enumerated in appendix D of the ICH E5
guideline. The critical properties of a medicine that
make it less likely to be sensitive to ethnic factors
include linear pharmacokinetics (PK), flat
pharmacodynamic (PD) curve, wide therapeutic
range, minimal metabolism, high bioavailability,
low potential for protein binding, little potential for
interactions, nonsystemic mode of action, and little
potential for inappropriate use.
The critical properties of a medicine that make
it more likely to be sensitive to ethnic factors
include nonlinear pharmacokinetics (PK), steep
pharmacodynamic (PD) curve, narrow therapeutic
range, high metabolism, genetic polymorphism,
administration as a prodrug with the potential for
ethnically variable enzymatic conversion, high
inter-subject variability, low bioavailability, high
likelihood of use in a setting of multiple co-
-medications and high potential for inappropriate
use. [2]
Analysis of the selected drugs for the
requirement of bridging studies
ICH E5 define bridging study as a study
performed in the new region to provide
pharmacodynamic or clinical data on efficacy,
safety, dosage and dose regimen in the new region
that will allow extrapolation of the foreign clinical
data to the population in the new region.
Generally, for medicines characterized as
insensitive to ethnic factors, the type of bridging
study needed (if needed) will depend upon
experience with the drug class and upon the
likelihood that extrinsic ethnic factors (including
design and conduct of clinical trials) could affect
the medicine’s safety, efficacy, and dose-response.
A bridging study may not be needed in
following two conditions if (a) Medicine is
ethnically insensitive and extrinsic factors such as
medical practice and conduct of trials are similar in
each region and (b) Medicine is ethnically sensitive
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32
but the two regions are ethnically similar and there
is sufficient experience with pharmacologically
related compounds in the two regions.
Bridging study with pharmacologic endpoints
may be needed if region is ethnically dissimilar,
drug is ethnically sensitive, but extrinsic factors are
similar, a controlled PD study in new region using
a pharmacologic endpoint or established surrogate
endpoint could bridge foreign data.
A controlled clinical trial in the new region may
be necessary when there are doubts about choice of
dose, there is little or no experience with
acceptance of controlled clinical trials conducted in
the foreign region, medical practice is different
between regions (e.g., concomitant medication,
control arm), drug class is not familiar to new
region or pharmacodynamic data suggest
interregional differences in response.
Even if foreign clinical data demonstrate safety
and efficacy, there may still be a safety concern in
the new region regarding need to accurately
determine rates of common adverse events in new
region and need to detect serious adverse events in
the new region. [2]
All the above factors are summarized in the following
table. [2, 15]
Table 1: Requirement for the Bridging Studies
Medicine Ethnicity of region Medical
Practice
Drug
Class
Clinical
Experience
Bridging
Studies
Ethnically Insensitive - Similar - - No
Ethnically Sensitive Similar - - Sufficient No
Ethnically Sensitive Dissimilar Similar Familiar - PD
Doubts about choice of dose - Different Unfamiliar Insufficient CCT
Safety concern in the new
region
Need to accurately determine rates of common adverse events in new
region
Need to detect serious adverse events in the new region
safety
study
PD: Pharmacodynamics; CCT: Controlled clinical
trials
The selected drugs will be determined whether
there are ethnically sensitive or not based on
parameters discussed above, then the requirement
of the bridging study will be determined based on
the following table.
SUMMARY OF THE METHODOLOGY
Selection of the drug
Analysis of the drug based on factors given in appendix D of ICH E5 guidelines to determine ethnic sensitivity
After analysis, drugs are compared with the table for the requirement of the bridging studies.
RESULTS
After the extensive literature search, few drugs
were selected. Analysis of one drug, Nicorandil, is
presented here. Each of these drugs were evaluated
on the criteria laid down in ICH E5 guideline for its
sensitivity to ethnic factors and requirement of
bridging study for extrapolation of foreign clinical
trial data. Nicorandil is analysed and results are
presented as below.
Nicorandil
Nicorandil belongs to the class of compounds
known as potassium channel activators which are
5. Sudershan G G et al / Int. J. of Pharmacology and Clin. Res. Vol-2(1) 2018 [29-38]
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33
characterized by their arterial vasodilator
properties. In addition, nicorandil has venodilating
properties which are attributable to a nitrate group
in its chemical structure. Therefore, by combining
these two vasodilator mechanisms, nicorandil
represents a novel type of compound for use in the
treatment of angina pectoris. Furthermore,
increasing experimental evidence suggests that
potassium channel activation may also exert a
direct cytoprotective effect by augmenting normal
physiological processes which protect the heart
against ischaemic events. [16]
Linearity of Pharmacokinetics
The plasma concentrations (the area under the
curve) show linear proportionality to the dose (5
mg to 40 mg). The drug disposition parameters
(distribution volume, mean residence time, total
body clearance and apparent elimination half-life)
remain unchanged within the therapeutic dose
range. [16, 17, 18]
Bioavailability
After oral administration, nicorandil is absorbed
rapidly and maximum plasma concentrations are
reached after about 30-60 minutes. [17, 21] The
absolute bioavailability of nicorandil is 75±23%,
indicating that no significant first pass effect exists.
[37, 38] Although food has been shown to delay the
absorption of nicorandil (16%), it does not affect
the extent of absorption. Thus nicorandil tablets
can be taken with meals. [17, 21]
Protein Binding
Nicorandil is not extensively bound to human
plasma proteins (free fraction estimated to be about
75%). [17, 21]
Metabolism and Prodrug Character
Nicorandil is metabolized extensively and the
major route of elimination is through kidney [32,
36], Less than 2% of the dose is excreted through
the biliary route. As a consequence the parent drug
is excreted poorly in urine (very low renal
clearance), whereas 2‐nicotinamidoethanol, a
pharmacologically inactive denitrated metabolite, is
the major nicorandil related compound excreted in
urine. [17, 21, 23]
Fig 2: Concentration-time curves of nicorandil [19, 20]
Interactions & Use in a Setting of Multiple
Co-medications
No pharmacological or pharmacokinetic
interactions have been observed in humans or
animals with beta-blockers, digoxin, rifampicin,
cimetidine, acenocoumarol, a calcium channel
blocker or a combination of digoxin and
furosemide. Nevertheless, there is the possibility
that nicorandil may potentiate the hypotensive
effects of other vasodilators, tricyclic
antidepressants or alcohol.
As the hypotensive effects of nitrates or nitric
oxide donors are potentiated by phosphodiesterase
6. Sudershan G G et al / Int. J. of Pharmacology and Clin. Res. Vol-2(1) 2018 [29-38]
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34
5 inhibitors, the concomitant use of nicorandil and
phosphodiesterase 5 inhibitors is contraindicated.
Gastrointestinal perforations in concomitant use
of nicorandil and corticosteroids have been
reported. Caution is advised when concomitant use
is considered. [17, 20, 21, 24]. There are
interactions with nicorandil which can be taken
care by proper presentation in prescribing
information.
Pharmacodynamics
In reported clinical study, 12 mild to moderate
hypertensive patients were taken to investigate
acute antihypertensive efficacy of three different
doses of nicorandil. All doses of nicorandil
similarly and significantly (P < 0.01) reduced
supine blood pressure, with a peak after 4-6 hour
(10 mg: -21/-8 mm of Hg; 20 mg: -20/-9 mm of Hg;
30 mg: -29/-17 mm of Hg), The three different
doses of nicorandil caused similar acute blood
pressure reductions without change in the heart
rate, or in the urine volume and urinary sodium [25]
indicating that pharmacodynamic curve is flat.
Efficacy studies
The efficacy of nicorandil is well established.
Clinical usefulness of this product was shown in
two separate series of double-blind controlled
clinical studies conducted in patients with various
types of angina pectoris. The response rates of the
product in various types of angina pectoris in open
clinical studies (21 reports of Phase II & III
studies) are summarized below.
Table 9: Response rates of the Nicorandil in various types of angina pectoris in open clinical studies
Diagnosis Efficacy rate (Good response or better)
Total 72.2% (369/511)
Effort angina 69.8% (185/265)
Effort and rest angina 69.1% (96/139)
Rest angina 94.3% (50/53)
Variant angina 73.0% (27/37)
Post-infarction angina 64.7% (11/17)
(including) Unstable angina 82.4% (14/17)
Nicorandil is an effective and potent antianginal
agent at a dose of 10-40 mg, which in monotherapy
controls 69-80% of patients with stable chronic
angina. [20]
Relative efficacy
Clinical studies employing exercise tolerance
test as major end point show that nicorandil at
doses 10 to 20 mg twice daily is as efficacious as
other anti-anginal agents (including diltiazem,
nifedipine, isosorbide mononitrate, isosorbide
dinitrate, propranolol, metoprolol and atenolol) in
treating patients with chronic stable angina. Long-
term uncontrolled studies show that nicorandil
maintains its efficacy with no evidence of tolerance
developing up to 2 years after commencement of
therapy. [17, 21, 26]
Nicorandil medication affords similar improvement as
propranolol in patients with angina pectoris. [42]
Comparative trials have shown that the efficacy
of nicorandil compares with that of drugs from the
main classes of antianginal drugs- beta-blockers
(atenolol, propranolol) and a calcium channel
blocker (diltiazem). Patients treated for as long as 3
months or 1 year have shown sustained efficacy to
the drug. The long duration of action allows
effective treatment with a well-tolerated twice a
day regimen. [28]
The efficacy of nicorandil in preventing
coronary artery spasm in patients with vasospastic
angina was compared to nifedipine in provocation
test using methylergometrine. Nicorandil was
shown to be at least as effective as nifedipine. [17,
28]
A systematic review study suggests therapy
with nicorandil is as effective as standard therapy
and that nicorandil can also be used as a first-line
agent in patients with stable angina. [29]
Nicorandil exerts its pharmacodynamic actions
even in the state of nitrate tolerance induced by
Isosorbide Mono-Nitrate (ISMN). The antianginal
and anti-ischemic effects of nicorandil are long
lasting, allowing a twice a day dose regimen for the
treatment of Coronary Artery Disease (CAD).
Nicorandil is effective in the long-term treatment of
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35
angina pectoris in the dose range of 10-40 mg twice
a day. It is well tolerated, and only a few dose
adjustments were necessary during long-term
therapy. [30]
Safety
In the European clinical development
programme, the total incidence of adverse events
among nicorandil recipients was reported to be
similar to that in patients who received comparator
drugs. Mild to moderate headache was the most
frequently reported adverse event, occurring in
36% of patients with angina pectoris treated with
oral nicorandil. The incidence of headache was
highest during initial treatment with the drug but
generally resolved within a few days. Headache
was the most frequent reason for treatment
withdrawal in the European clinical development
programme, accounting for 5% of all withdrawals
in nicorandil recipients, and was less frequent with
a lower dosage (5 mg twice daily) than a higher
dosage (10 mg twice daily).
A later prescription-event monitoring study
involving 13, 260 patients also reported that
headache was the most frequent adverse event
reported during nicorandil treatment (9.4 events per
1000 patient-months during the treatment period).
[26]
Safety has been assessed in a total of 1680
subjects who were treated with nicorandil, with 458
patient years of exposure to treatment. Adverse
events usually occurred early in the course of
treatment. After 30 days of treatment, fewer than
10% of patients reported adverse events. [31]
A Prescription Event Monitoring (PEM) study
of nicorandil was undertaken to assess the drug's
overall safety in everyday clinical practice. The
study was based on a cohort of 13,260 patients and
86,760 patient-months of nicorandil treatment. This
PEM study reported information on the 'real-world'
use of nicorandil and shows generally that the drug
is safe when used in the recommended dosage. [32]
No clinically relevant modifications in the
pharmacokinetics have been seen in the elderly,
liver disease and chronic renal failure. [33, 34]
In comparative trials with anti-anginal agents,
such as propranolol, diltiazem, nifedipine,
Isosorbide Di-Nitrate (ISDN) and isosorbide 5
mononitrate, the overall incidence of adverse
events was not significantly different between
nicorandil and the reference drug. Side-effect
distribution was comparable between nicorandil
(32%) and diltiazem (30%).
Nicorandil can be safely combined with other
anti-anginal drugs. Furthermore, due to its
favourable pharmacokinetics, nicorandil is less
likely to have interactions when combined with
another therapeutic agent. Nearly one-third of the
patients enrolled in the nicorandil clinical
programme were 65 years old or older. Overall, the
incidence of the most frequent adverse events in the
elderly was reported to be similar.
There is no evidence that nicorandil induces
proarrhythmia, exacerbation of myocardial
ischaemia or abrupt withdrawal syndrome. With the
progressive titration scheme, no symptomatic
decrease in blood pressure was reported when
nicorandil was administered in the range of 10–80
mg/day. Heart rate was not significantly affected in
the same dose range. Long term treatment with
nicorandil did not induce oedema or weight gain.
Nicorandil did not adversely affect the lipid profile
or the glucose level. [31] Other than headache, the
most frequently reported adverse events were
dizziness, nausea and malaise.
There have been case reports of mouth ulcers
developing during nicorandil treatment, but there is
at present no clear evidence of a causal relationship.
[26] It is in the market for over 26 years. [20]
Extensive clinical experience with nicorandil is
considered to have demonstrated the therapeutic value
of the compound and no new or unexpected safety
concerns arose from the Nicorandil and it was
therefore judged that the benefits of taking Nicorandil
outweigh the risks.34
Therapeutic Dose Range (An Indicator of
Safety & Tolerability)
Nicorandil has wide therapeutic range from 2.5
mg to 80 mg. [17, 19, 20, 21] There is no tolerance
and cross tolerance to dosage as observed with
nitrates. [17, 18, 19, 21] There is no experience of
massive over dosage in humans and the LD50 in
dogs is in the range 62.5 to 125 mg/kg and in
rodents it is in the order of 1200 mg/kg. [24, 34]
Inappropriate Use
Nicorandil is not listed in the abused drug list of
National institute on Drug Abuse therefore there is
less scope for inappropriate use. [15]
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36
SUMMARY OF THE NICORANDIL
Nicorandil belongs to the class of compounds
known as potassium channel activators which are
characterized by their arterial vasodilator
properties. In addition, nicorandil has venodilating
properties which are attributable to a nitrate group
in its chemical structure. Therefore, by combining
these two vasodilator mechanisms, nicorandil
represents a novel type of compound for use in the
treatment of angina pectoris.
The plasma concentrations show linear
proportionality to the dose (5 mg to 40 mg) and it
shows absolute bioavailability of nicorandil is
75±23% with no significant first pass effect.
Nicorandil is not extensively bound to human
plasma proteins (free fraction estimated to be about
75%) and it is metabolized extensively in liver and
converted into pharmacologically inactive
denitrated metabolites.
When patients were treated with nicorandil, the
three different doses of nicorandil caused similar
acute blood pressure reductions indicating that
pharmacodynamic curve is flat. Clinical studies
shows that nicorandil twice daily is as efficacious
as other anti-anginal agents (including diltiazem,
nifedipine, isosorbide mononitrate, isosorbide
dinitrate, propranolol, metoprolol and atenolol) in
treating patients with chronic stable angina. Long-
term studies show that nicorandil maintains its
efficacy with no evidence of tolerance.
Genetic polymorphism and inter subject
variability with nicorandil is not reported and it has
low potential for interactions. Moreover nicorandil
is not listed in the abused drug list of National
institute on Drug Abuse therefore there is less
scope for inappropriate use.
Nicorandil has wide therapeutic range.
Extensive clinical experience with nicorandil is
considered to have demonstrated good safety
profile value of the compound and no new or
unexpected safety concerns arose from the
Nicorandil .Therefore it can be concluded
nicorandil is safe and well tolerated. Nicorandil may
be ethnically insensitive as it satisfies most of the
factors mentioned in appendix D of the ICH E5 for
the ethnical insensitivity.
Table 10: Properties that make Nicorandil less sensitive to ethnic factors
S.NO PARAMETERS YES/NO
1 Linear pharmacokinetics Yes
2 A flat pharmacodynamic Yes
3 A wide therapeutic dose range Yes
4 Minimal metabolism or metabolism distributed among multiple pathways Yes
5 High bioavailability Yes
6 Low potential for protein binding Yes
7 Little potential for interactions Yes
8 Non-systemic mode of action NO
9 Little potential for inappropriate use Yes
Table 11: Properties that make Nicorandil more sensitive to ethnic factors
S.NO PARAMETERS YES/NO
1 Non-linear PK NO
2 A steep PD curve NO
3 A narrow therapeutic dose range NO
4 Highly metabolized Yes
5 Genetic polymorphism NO
6 Administration as a prodrug, with the potential for ethnically variable enzymatic conversion NO
7 High inter-subject variability NO
8 Low bioavailability NO
9 High likelihood of use in a setting of multiple co-medications Yes
10 High likelihood for inappropriate use NO
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37
DISCUSSION
After the extensive analysis of the selected
drug, Nicorandil may be ethnically insensitive
based on ICH E5 guideline. Drugs like Nicorandil
may be approved by USFDA without need of
bridging studies because they are ethnically
insensitive and medical practice across the ICH
countries is mostly similar. The efficacy and safety of
these drugs is demonstrated by the fact that these
drugs are on the market for at least 25 years and
prescribed in the millions of the patients.
Approval of These drugs with or without
bridging studies helps in the realization of the goals
of ICH E5 guideline i.e., minimizing duplication of
clinical studies, cost and supplying medicines
expeditiously to patients for their benefit.
CONCLUSION
Nicorandil may be ethnically insensitive based
on the ICH E5 guideline. Drugs like Nicorandil
may be approved by USFDA (United States Food
and Drug Administration) without need of bridging
studies because they are ethnically insensitive and
medical practice across the ICH countries is mostly
similar.
FUTURE DIRECTIONS
Approval of nicorandil with or without bridging
studies at various regulatory authorities in the
world should be tried by appropriate institutions
like WHO, NGOs’, pharma companies etc., to
realize the goals of ICH E5 guideline i.e.,
minimizing duplication of clinical studies, cost and
supplying medicines expeditiously to needy
patients for their benefit.
To realise full potential of ICH E5 guideline
goals, there is need to identify and register more
drugs which are approved in one country and not
approved in the another country.
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