Asthma:-

It is a syndrome characterized by airflow obstruction that varies markedly, both spontaneously and with treatment.
Symptoms-wheezing, breathlessness, cough, chest tightness
Prevalence-10-12% adults, 15% children Developed country>Developing countries

Risk Factors
Endogenous Factors
Genetic predisposition Atopy
Airway
hyperresponsiveness
Gender
Ethnicity? Obesity?
Viral infections
Environmental Factors
Indoor allergens Outdoor allergens occupational sensitizers Passive smoking Respiratory infections
Triggers:-
Allergens-Dermatophagoides species(dust mite), environmental exposure, grass pollen, ragweed, tree pollen, fungal spores, pets furs, cockroaches etc
Virus infection-upper respiratory tract virus such as rhinovirus, respiratory syncytial virus, coronavirus etc
Pharmacological agents-beta blockers, ACE inhibitors, aspirin
Exercise(may exacerbate )
Physical factors-cold air, hyperventilation
Food
Air pollutants-sulfur dioxide, irritant gases
Irritants-household sprays paint fumes
Occupational factors
Hormonal factors-fall in progesterone thyrotoxicosis
Gastrointestinal reflex
stress
Types of asthma-
Atopic asthma-classical type I IgE mediated hypersensitivity, allergen sensitization, seen from childhood, +ve history of asthma in family, skin test +ve
Non-atopic asthma-no allergen sensitization, no
such history, skin test –ve, virus infection?
Drug induced asthma-sensitive to certain drugs like aspirin, NSAIDS etc
Occupational asthma-stimulants such as fumes, organic and chemical dusts(wood, cotton), gas(toluene), penicillin products etc
Exercise induced asthma-begins after exercise and stops after 30 minutes, worsen in cold and dry climate
pathogenesis
pathology
Inflammation
Inflammatory mediators
Effects of inflammation
Airway remodeling
Chronic inflammation of lower airways
Mucosal infiltration of activated eosinophils and T lymphocytes
Thickening of basement membrane
Goblet cell metaplasia
Smooth muscle hypertrophy and thickening
Shedding of epithelium
Occlusion of airway by mucosal plug
Inflammation
Allergic type of inflammation occurs
From trachea to terminal bronchiole
Predominantly in bronchi
Airway hyperresponsiveness
Cells involved in inflammation-mast cell macrophages dendritic cell eosinophils neutrophils T lymphocytes and structural cells
Early phase reaction-mediated by granules release from mast cell, bronchoconstriction, vasodilation and increase permeability
Late phase reaction-inflammation with recruitment of eosinophils, T lymphocytes, neutrophils, macrophages etc and subsequent release of mediators.
Mast cell-activated by IgE dependant mechanism, initiate acute bronchoconstriction action by releasing histamine, prostaglandinD2,leukotrienes etc
Macrophage-activated by low affinity IgE receptor, produce various inflammatory mediators
Dendritic cell-macrophage like major APC in airways, TSLP(Thymic stromal lymphopoietin) by epithelial cell induced chemokine release for TH2 cells
Eosinophils-infiltration is characteristic feature of asthma, activated by IL-5, causes exacerbation of asthma by producing mediators
Neutrophil-activated and infiltration
T cell-release cytokines, causes recruitment of eosinophils, also causes maintenance of mast cells, in asthma TH2 cell produce IL- 5(eosinophil recruitment) IL-4, IL-13(increase IgE production and mucus secretion).CD4+ cell also involved
Structural cells-epithelial cells(TSLP),
fibroblasts etc
Inflammatory mediators-
Histamine, prostaglandin D2, cysteinly leukotrienes-cause smooth muscle contraction, increased microvascular leakage, increased mucus secretion, act as chemoattractant for inflammatory cells
Cytokines- IL-4, IL-5, IL-13-causes allergic inflammation, IL-1beta, TNF-alpha-amplification of inflammation, TSLP(Tymic stromal lmphopoietin)- from epithelial cells act as chemoattractant for TH2 cells, IL-10, IL-12-anti inflammatory
Chemokines-attract inflammatory cells, Eotaxin(CCL11) attract eosinophil via CCR3 receptor, TARC(CCL17) and MDC (CCL 22) from epithelial cell attract TH2 cell via CCR4.
Oxidative stress-increase in ROS production
NO-act as relaxant but mainly causes
vasodilatation leading to leakage
Transcription factor-NF-kB, activator protein-

Effects of inflammation-
Epithelium-dysfunction, damage, loss of enzyme, loss of relaxant factors, loss of barrier functio
Fibrosis- subepithelial fibrosis, basement membrane thickening, deposition of III and V collagen(by factors release from eosinophil)
Smooth muscle- increased responsiveness to constrictor mediators, in chronic cases hypertrophy/hyperplasia by growth factors released by inflammatory mediators
Vascular response-vasodilation, angiogenesis, microvascular leakage
Mucus hypersecrection- by goblet cell hyperplasia, increase in mucus plug, leading to blocking of airway
Neural effect-reflex cholinergic bronchoconstriction by increased muscarinic action

Airway remodeling
Several changes can be seen
Irreversible narrowing of lumen
Decline in lung function
Smooth muscle hyperplasia
Fibrosis

Summary-
Asthma is chronic inflammatory disorder with airway hyperresponsiveness and airway obstruction.
various risk factors and triggers
Types-atopic and non-atopic
Eosinophilic infiltration and thickening of B.M.
Hyperplasia of gland and vasodilatation
IgE dependant mast cell activation and release of
various mediators
Early and late phase reactions with dendritic cell and TH2 cell
Various mediators-cytokine, chemokines, PGs etc
Epithelium shedding, fibrosis, hypertrophy of muscle
and increased permeability
Airway remodeling

 Phases of Clinical Trials

preclinical Drug Development

Before clinical drug development can begin, many years of preclinical development occur.

Basic research teams consisting of chemists. pharmacologists, biologists, and biochemists.

This team identify promising therapeutic categories and classes of compounds.

Animal Testing

Compounds are selected for secondary pharmacology evaluations and toxicology testing in animal models.

Compound that is pharmacologically active and safe in at least two nonhuman species may then be selected for study in humans.

Investigational New Drug (IND):

Before the drug can be tested in humans, an Investigational New Drug (IND) application must be filed with an appropriate regulatory agency.

IND  contains supporting preclinical information and the

proposed clinical study designs.

Phases of clinical trials

Development of a new drug in humans is divided into four phases.

Different phases refer to different types of studies rather than a specific time course of studies.

The generalized sequence of studies may be tailored to each new drug during development.

Pre-approval segments (Phases 1 through 3).

Post-approval segment (Phase 4).

Phase 1

Studies that involve normal subjects, are included in Phase 1.

Phase 1 of the clinical program begins After the regulatory agency has approved the drug for testing in humans.

Goal:

To demonstrate safety in humans.

To collect sufficient pharmacokinetic/pharmacological information for determination of the dose strength and regimen for Phase 2 studies.

Study Subjects:

Typically conducted in healthy adult subjects.

Other Evidences obtained:

Metabolic profile.

Adverse events associated with increasing dosages.

Evidence of efficacy.

Pharmacokinetic profile…includes information

about absorption (initial studies has an oral formulation).

Drug-drug interactions.

Assessment of bioequivalence of various formulations.

Dose range and route of administration.

Dosing/Sampling (Phase 1)

The initial dose may be based on animal pharmacology or toxicology data.

Doses are increased gradually until an adverse event is observed.

Sampling is done by collecting Blood and urine.

First Study (single dosing)

Second Study (Multiple dosing).

Study Design (Phase 1)

Placebo controlled, double-blind(so that the drug effects, such as drug induced can be distinguished from the nondrug effects)

Escalating single-dose study is initiated.

Healthy  volunteers are recruited.

Sometimes  patients are used (e.g testing anticancer drug that may be too toxic to administer to healthy volunteers).

Include two or three cohorts, with six or eight subjects receiving the active drug and two subjects receiving placebo.

The groups may receive alternating dose levels which allow assessment of dose response (i.e., adverse events) relationship.

Study Setting (Phase 1)

Participants in the first study are usually hospitalized or enrolled in a clinic.

Why???

Clinical measurements can be performed under controlled conditions.

Any medical emergency can be handled in the most expeditious manner.

Maximum Tolerated Dose(MTD)

The first study in humans is usually not considered successfully completed until an MTD has been reached.

Relationship between a clinical event (e.g., emesis) and a particular dose level observed under controlled conditions can provide information that will be extremely useful when designing future trials.

Multiple-dose safety

A multiple-dose safety study typically is initiated once the first study in humans is completed.

Goal:

To define an MTD with multiple dosing before to initiating well-controlled efficacy testing.

Study Design:

Should simulate actual clinical conditions in as many ways as possible.

The inclusion of a placebo group is essential to allow the determination of drug-related versus nondrug-related events.

Dosages, frequency, dose escalations, and dose tapering, should simulate the regimen to be followed in efficacy testing.

Study Duration:

dosing in the second study lasts for 2 weeks.

length of the study may be increased depending on the pharmacokinetics of the drug.

if the drug is to be used to treat a chronic condition, a 4-week study duration may be appropriate.

Study Subjects:

minimum enrollment of 24 subjects should be anticipated.

subjects would be hospitalized for the duration of the study.

Samples:

Blood and urine.

Pharmacokinetic data

To determine:

whether the pk parameters obtained in the 1st study accurately predicted the multiple dose pharmacokinetic behavior of the drug.

verification of pharmacokinetic linearity (i.e., dose proportionality of C,,, and AUC)observed in the  1st study.

whether the drug is subject to autoinduction of clearance upon multidosing.

Existence and accumulation of metabolites that could not be detected in the previous single-dose study

Demerits of ADR clinical Trials

Pre-marketing trials cannot detect important reactions that occur at rates of 1 in 10,000.

Only pharmacologically predictable ADRs may be identified in clinical trials.

ADRs are only assessed by the clinicians who run them so rare/potentially serious ADRs often remain undetected.

ADR’s and Clinical Trials

Evidence of safety must be demonstrated for regulatory authorities to permit marketing.

The degree of exposure of the drug is an important factor in understanding the toxicologic results of the study.

However, it is not possible to discover the complete safety profile of a new drug prior to its launch.

These involves on average 2500 patients.

Patient selected for ADR detection should be without the multiple disease states or complex drug histories.

Phase 2

Focus on efficacy.

Pharmacokinetic information obtained in Phase 1 studies is used to optimize the dosage regimen.

Not as closely monitored as Phase 1 studies.

Conducted in patients.

Information Obtained:

These studies are designed to obtain information

On:

Efficacy.

Pharmacologic effects.

Pharmacokinetics.

Efficacy trials (Phase 2)

Efficacy trials should not to be initiated until the MTD has been defined.

Therapeutic window:

On completion of the efficacy trial, a therapeutic

window for plasma drug concentrations can be defined by reviewing the correlation between plasma drug concentrations and key safety and efficacy parameters.

Goal:

To improve efficacy and safety of the drug. 

By individualizing the dosage based upon previous plasma drug concentration profiles in the same patient.

Study Design (Phase 2)

Pharmacokinetic information obtained in healthy volunteers (during phase 1) is key to the design of successful efficacy trials.

During the planning stage of an efficacy trial, the focus is on the dosage regimen and its relationship to efficacy measurements.

Dosage regimen:

Following information obtained earlier must be considered when choosing an optimal dosage regimen for the study.

Disease or physiological states of the test patients 

(e.g., organ dysfunction as a function of age).

concurrent medications (e.g., enzyme inducers or inhibitors).

Safety data

Phase 3

Phase 3 clinical trials will be initiated if:

earlier clinical studies establishes: 

Drug’s therapeutic properties.

Cinical pharmacologic properties.

Toxicologic properties.

and if it is still considered to be a promising drug.

Study Subjects:

Phase 3 studies enroll many more patients.

Study Site:

conducted both in a hospital or controlled setting and in general practice settings.

Goals:

to confirm the therapeutic effects.

to establish dosage range and interval.

to assess long-term safety and toxicity.

to identify less common side effects and AEs that develop latently.

to evaluate/quantify specific effects of the drug, such as drowsiness.

to establish a place for the drug in its therapeutic class.

to identify the most appropriate population or subpopulation for the study drug.

Relative safety profiles:

to establish better safety profile of the investigative

compound as compared to its already available/existing alternative.

Drug Interactions (Phase 3)

Polytherapy ….high risk of drug-drug interactions,both from pK and pD perspectives.

Closer inspection of drug interactions is warranted in Phase 3 clinical trials.

The likelihood of drug interactions and may be predicted from in vitro data.

Evaluation of Drug Interactions :

The potential for interactions needs to be evaluated from two perspectives:

potential that the new drug may affect the pharmacokinetics of other drugs

(depends on the ability of the new drug to affect various enzyme and carrier-mediated clearance processes).

the potential that other drugs may affect the pharmacokinetics of the new drug.

(requires knowledge of the components of clearance 

General practitioners (phase 3)

Early clinical trials are conducted at university medical centers with specialized physicians.

General physicians are exposed to study drugs during this phase because they will be the one writing most of the prescriptions post marketing.

Phase 4

Phase 1, 2, and 3 studies depends on strict inclusion and exclusion criteria.

Phase 4 emphasizes on collection of safety information.

Phase 4 studies employ mainly observational study designs.

Post marketing surveillance and any additional studies requested by the regulatory agency are conducted during Phase 4.

Data collection (Phase 4)

Is an extensive, scientific exercise.

Involves:

Detailed blood work.

Special laboratory tests.

Careful physiologic monitoring.

Patient Population:

Post marketing studies, however, are often targeted for much larger patient populations (5000- 10,000 or more).

Groups in Clinical Trials

Comparative groups to assess the efficacy and safety of the investigational drug relative to other drugs currently marketed. 

Control group

The control groups take either placebo or active medication.
Sometimes more than one control group is used in a study.

Cohort group
group taking the investigational drug.

Placebo & Active Medication
Placebo Should be as similar as possible to the drug being investigated.(e.g., same color. taste. and shape).

Active medication taken by the control group also should be as similar as possible to the drug being investigated (e.g.. same color, taste, and shape).
To  maintain the blind:
If the formulations cannot be made with similar appearances a placebo of each formulation could be made.
So subjects would take one active formulation and the placebo of the other formulation.