A review of literature about Stiripentol and Rufinamide and their role in Dravets and Lennox Gastaut Syndrome respectively. It also looks at off label indications of these two orphan drugs.
Novel Drugs for Seizure disorder, Newer Drugs for seizure disorders, Recent Advances in treatment of seizure disorder, Recent Advances in Pharmacotherapy of sizure disorders, Recent Advances in Treatment of epilepsy, Newer Antiepileptics, Newer Anticonvulsants
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-Management of various of forms of epilepsies including treatment of status epilepticus
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This slides contains all you need to know about "Status Epilepticus" in a nutshell. It includes definition, investigation, emergency management of status epilepticus. This educational material is suitable for med students, paramedics, nurses & neurology residents.
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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
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Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
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Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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MIP 201T & MPH 202T
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This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
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Stiripentol and Rufinamide
1. Stiripentol & Rufinamide
Indications, Availability & Role in the Indian setting
Dr Pramod Krishnan, MD (Int Med), DM Neurology (NIMHANS)
Fellowship in Epilepsy (SCTIMST) (LMU, Munich)
World Sleep Federation Certified Sleep Medicine Specialist.
Consultant Neurologist and Epileptologist
Head of the Department of Neurology,
Manipal Hospital, Bengaluru.
3. Indication (FDA 2018, EMA 2007)
• Add-on therapy for seizures in
Dravet syndrome in patients 2
years of age or older, taking
Clobazam.
• No data to support the use as
monotherapy in Dravet syndrome.
• No data for age <2 yrs and >65 yrs.
4. • Enhanced GABAergic activity
through GABA-A receptor, by
increasing the opening
duration of GABA-A receptor
channels.
• Cytochrome P450 inhibition
causing increase in blood
levels of other AEDs, eg CLB
and its active metabolite.
• Neuronal LDH inhibitor, a
new target for epilepsy.
Mechanism of action
5. Pharmacokinetics
• Absorption: Median time to peak plasma concentration is 2 to 3 hours.
• Distribution: Protein binding is 99%.
• Elimination: The elimination half-life ranges from 4.5 to 13 hours,
increasing with doses of 500 mg, 1000 mg and 2000 mg.
• Metabolism: The main liver cytochrome P450 (CYP) isoenzymes
involved are CYP1A2, CYP2C19, and CYP3A4.
6. Dosage and Administration
Dosage forms:
• DIACOMIT Capsule: 250 mg (pink) or 500 mg (white)
• DIACOMIT Powder for Oral Suspension: 250 mg or 500 mg
Dosage:
• The dosage is 50 mg/kg/day, orally in 2 or 3 divided doses.
• Maximum recommended dose is 3000 mg/day.
• Powder for suspension should be mixed in 100 ml of water and should
be taken immediately after mixing, during a meal.
7. Warnings and Precautions Comments
Somnolence Stiripentol 67%, Placebo 23%
Anorexia Stiripentol 43%, Placebo 10%
Weight loss Stiripentol 27%, Placebo 6%
Nausea and vomiting Frequent.
Suicidal behaviour, ideation Increased.
Neutropenia Neutrophil count of <1500 cells/mm and
platelet count of <150,000/uL noted in 13% of
patients. Monitor CBC every 6 months.
Thrombocytopenia
Phenylketonuria Oral suspension contains phenylalanine.
Moderate/ severe renal impairment Avoid (renal excretion of metabolites)
Moderate/ severe hepatic impairment Avoid (metabolised in liver)
8. Teratogenicity, Fertility and Lactation
No human data.
Based on animal data:
• It caused embryofetal mortality, low pup weight, malformations.
• It was negative for genotoxicity in in-vitro and in vivo studies.
• No adverse effects on fertility.
• There is no data on lactation effects.
9. Effect of Stiripentol on other drugs
• Stiripentol is inhibitor and inducer of CYP1A2, CYP2B6, and CYP3A4.
• It is a potential inhibitor of enzyme/transporter activity.
Metabolic/transport pathway Drugs for dose reduction
CYP1A2 Theophylline, Caffeine
CYP2B6 Sertraline, Thiotepa
CYP3A4 Midazolam, Triazolam, Quinidine, Clobazam
CYP2C8, CYP2C19 Diazepam, Clopidogrel, Norclobazam
P-gp Carbamazepine
BCRP Methotrexate, Glyburide, Prazosin
10. Effect of other drugs on Stiripentol
• Potent CYP1A2, CYP3A4, or CYP2C19 inducers (rifampin, PHT, PB,
CBZ) can lead to decrease in Stiripentol concentration.
• Concomitant use of such inducers with Stiripentol should be avoided,
or dosage adjustments should be made.
• Concomitant use of Stiripentol with CNS depressants, including
alcohol, may increase the risk of sedation.
12. 2013; 11: CD010483
Guerrini R, Tonnelier S, d’Athis P, Rey E, Vincent
J, Pons G. Stiripentol in severe myoclonic
epilepsy in infancy (SMEI): a placebo-controlled
Italian trial. Epilepsia 2002; 43: 155.
Chiron C, Marchand MC, Tran A, et al.
Stiripentol in severe myoclonic epilepsy in
infancy: a randomised placebo-controlled
syndrome-dedicated trial, STICLO study group.
Lancet 2000; 356: 1638–42.
13. • Multicenter placebo-controlled double-blind randomized studies.
• Dravets syndrome with age between 3 to 18 years.
• Inadequately control with CLB and VPA.
• At least 4 generalized clonic or tonic-clonic seizures/month.
• Stiripentol 50 mg/kg/d Vs Placebo.
• Duration of double blind treatment was 2 months.
• Only generalised clonic and tonic-clonic seizures were recorded.
Lancet 2000; 356: 1638–42
14. a= Responder is defined as a patient with a greater than 50% decrease in frequency of seizures.
b Fisher Exact Test.
c Frequency of generalized tonic-clonic or clonic seizures during month 2.
d Wilcoxon Test with two-sided t-approximation.
e=Nominal p value, as Study 2 was stopped early.
Chiron et al Guerrini et al
15. In Study 1 and Study 2, respectively, 43% and 25% of patients reported no generalized
clonic or tonic-clonic seizure for the duration of the study
Proportion of Patients by Category of Seizure Response for Stiripentol and Placebo in Study 1
and Study 2 Pooled, Baseline to 2nd Month of Treatment.
16. Developmental Medicine & Child Neurology 2018, 60: 574–578
• 41 patients started stiripentol, with median age at enrolment 5 years 7 months
(11mo–22y) and median duration of treatment 37 months (2–141mo).
• 20/41 patients had ≥ 50% long-term reduction in frequency of GTCS.
• Frequency of focal seizures decreased by ≥ 50% in 11/20 patients.
• Frequency of status epilepticus was decreased by ≥ 50% or more in 11/27
patients. Of these, 9/11 had 90% reduction in status, and 7/11 had no further
status epilepticus.
17. • Dosage was titrated up to 67mg/kg/day or a maximum of 4g per day.
• If patients were concurrently taking CLB or VPA, the doses of these
medications were kept below 0.5mg/kg/day and 30mg/kg/day
respectively, whenever possible.
• 30/41 patients reported adverse events.
• Most common: anorexia (50%), weight loss (50%), sedation (34%),
behavioural changes.
• 1 patient- worsening of absence and myoclonic seizures.
• 1 patient- recurrent pancreatitis on concurrent valproate.
• 1 patient- protein losing enteropathy.
Dosage
Adverse effects
18. • Female baby, seizures since 2 months of age, with initial normal development.
• Thereafter, polymorphic seizures, migratory seizures, psychomotor retardation.
• MRI unremarkable. EEG showed multifocal IEDs and slowing.
• Genetic work up: negative.
• Failed VPA, PHT, VGB, OXC, TPM, Ketogenic diet.
• Seizure reduction with LEV and CLN.
• Complete seizure freedom (for 1 year, ie last follow up) after adding Stiripentol.
• Development improved. EEG did not improve.
19. • Girl child, aged 12 years, FTNVD.
• Cluster of seizures at 13 months of age, with fever.
• Thereafter, frequent, refractory cluster of focal and generalised seizures with
psychomotor retardation.
• MRI unremarkable. Inter-ictal EEG showed slowing.
• Genetic test confirmed the diagnosis.
• Failed VPA, PB, CLB, TPM, CBZ
• Seizure free with Stiripentol 1000 mg/d, VPA 600 mg/d, and CLB 20 mg/d.
• Seizure free during a follow up of 2 years, 10 months.
20. Chiron C, Tonnelier S, Rey E, Brunet ML, Tran
A, d'Athis P, et al. Stiripentol in childhood partial
epilepsy: randomized placebo controlled trial with
enrichment and withdrawal design. Journal
of Child Neurology 2006;21(6):496-502.
21. • 32 Stiripentol responders were randomized for 2 months to continue Stiripentol (n =
17) or withdraw to placebo (n = 15).
• Primary endpoint: Seizure increase by at least 50% after randomization. There were
6 patients on Stiripentol and 8 patients on placebo (not significant).
• Secondary end point: Decrease in seizure frequency compared with baseline. This
was greater on Stiripentol (—75%) than on placebo (—22%) (P< .025).
• Adverse effects: Stiripentol (71%) vs Placebo (27%); none were severe.
• Stiripentol and CBZ combination reduced seizure frequency in children with
refractory partial epilepsy, but failed to meet primary end point.
J Child Neurol 2006;21:496–502
22. Acta Neurol Scand. 2017;1–6.
• Results: 5 adults with SRSE and cross-sensitivity to AEDs.
• Stiripentol (STP) was added when previously used AEDs had demonstrated cross-
sensitivity and failed to control seizures.
• With STP, the dose of GAs was reduced, and SRSE eventually ceased without
additional adverse effects or rash.
• The mean time to SRSE cessation after initiation of STP was 30.8 days (range, 18-46
days), mean duration of GA was 101.2 days (range, 74-128 days), and mean number of
AEDs was 9.0 (range, 6-11).
23. Stiripentol is an inhibitor of lactate dehydrogenase in astrocytes.
Results: Stiripentol alleviated mechanical hyperalgesia induced by L5 spinal nerve
transection in a dose-dependent manner, when intrathecally administered to mice 7, 14,
and 28 days after L5 spinal nerve transection.
Administration of L-lactate negated the analgesic effect elicited by stiripentol.
Conclusions: This study demonstrated that stiripentol was effective against neuropathic
pain and suggested that the astrocyte–neuron lactate shuttle was involved in such pain.
24. • Stiripentol inhibits neuronal LDH 5 enzyme.
• As this isoenzyme is the last step of hepatic oxalate production, stiripentol can
reduce hepatic oxalate production and urine oxalate excretion.
• Stiripentol protected the kidneys against calcium oxalate crystal deposits in acute
ethylene glycol intoxication and chronic calcium oxalate nephropathy models.
• A young girl affected by severe type I hyperoxaluria received stiripentol for several
weeks, and urine oxalate excretion decreased by two-thirds.
• Stiripentol may be useful in genetic hyperoxaluria and ethylene glycol poisoning.
J Clin Invest. 2019;129(6):2571–2577
25. Summary
• Mechanism: It is an orphan AED that potentiates GABAergic
transmission through GABA-A receptor, and inhibits neuronal LDH.
• It is a potent inducer of CYP450 system.
• Indication: add on therapy in Dravet syndrome refractory to VPA and
CLB.
• Off label use: as add-on therapy in MMPSI, PCDH19 related epilepsy
and Status epilepticus.
• Adverse effects: Sedation, weight loss, cytopenia, and behavioural issues
27. Preparation
• 1-[(2,6-difluorophenyl)methyl]-1H-1,2,3-triazole-4 carboxamide
• BANZEL® (rufinamide) pink film-coated tablet, 200 mg, 400 mg.
• BANZEL® (rufinamide) oral suspension, 40 mg/ml.
• Measure oral suspension using provided adapter and dosing syringe.
• In Europe, Australia: INOVELON 100 mg film coated tablets.
• Initial U.S. Approval: 2008
• Manufacturer: Esai.
28. Indication (FDA 2008, EMA 2007)
• Adjunctive treatment of seizures
associated with LGS in children
aged 1 year or more, and adults.
• In Europe and Australia: patients
aged 4 years or more.
• No data in children below 1 year
of age and adults >65 years.
29. Pharmacology
Mechanism of action:
• Prolongs the inactivation phase
of Na channel activity, thus
reducing neuronal
hyperexcitability.
• Limits sustained repetitive firing
of Na-dependent action
potentials.
• Can inhibit glutamate receptor
subtype 5 (mGluR5).
30. Pharmacokinetics
• Non-linear pharmacokinetics.
• Absorption: Oral bioavailability is 85%, and improved by food. The rate
of absorption reduces with increase in dose.
• Peak plasma concentrations occur between 4 and 6 hours.
• Distribution: Protein binding is 27%.
• Metabolism: In liver. Not cytochrome P450 dependent. Inactive
metabolites are excreted in urine.
• Elimination: elimination half-life is approximately 6-10 hours.
• Weak inhibitor of CYP 2E1 and a weak inducer of CYP 3A4 enzymes.
31. Dosage
Age < 4 years:
• Start at 10 mg/kg/d administered in two equally divided doses.
• Increase by 10 mg/kg every other day to 45 mg/kg/d, or 30 mg/kg/d if
combined with VPA. (not to exceed 3200 mg/d).
Children >4 years of age:
• Start at 200 mg/d and increase based on weight and VPA use.
Adult:
• Start at 400 to 800 mg/d.
• Increase by 400-800 mg every other day until a maximum daily dose of
3200 mg/d is reached.
32. Warnings and Precautions Comments
Somnolence Rufinamide 24%, Placebo 13%.
Fatigue Rufinamide 10%, Placebo 8%.
Dizziness Rufinamide 2.7%, Placebo 0%
Ataxia and gait disturbance Rufinamide 5.4%, Placebo 0%
Headache Frequent.
Suicidal behaviour, ideation Rare. Increased.
QT interval shortening Contraindicated in familial short QT syndrome
Multi-organ hypersensitivity reactions Reported. Occurs within 4 weeks.
Status epilepticus 0.9 to 4.1% of patients in studies.
Leucopenia Can occur.
Renal impairment No dose adjustment required. Hemodialysis
can reduce levels by 30%.
Mild to moderate hepatic impairment Cautious dose titration.
Severe hepatic impairment Avoid.
33. Pregnancy and Lactation
• Pregnancy category C. No human data.
Based on animal data:
• Teratogenicity: At clinically relevant doses, it resulted in low fetal
weight, fetal skeletal abnormalities, embryo-fetal death, bone and liver
tumors, fetal visceral and skeletal abnormalities.
• Lactation: either lactation or medication should be discontinued.
• Fertility: may be impaired.
35. Rufinamide and Valproate
• Patients stabilized on Rufinamide should begin VPA at a low dose, and
titrate to a clinically effective dose.
• Similarly, patients on VPA should begin Rufinamide lower than 10
mg/kg/d (pediatric patients) or 400 mg/day (adults).
Rufinamide and Hormonal Contraceptives
• Concurrent use of Rufinamide with hormonal contraceptives may
render this method of contraception less effective.
• Additional non-hormonal forms of contraception are recommended.
37. Neurology® 2008;70:1950–1958
• Multi-center, double-blind, placebo-controlled,
randomized, parallel-group study.
• 138 patients received either Rufinamide (n=74) or placebo
(n=64) in addition to their other AEDs.
• The maximum target dose of Rufinamide was 45
mg/kg/day in two divided doses or matched placebo.
38. • LGS pts aged 4-30 years.
• Refractory seizures
(including atypical absence
seizures and drop attacks).
• On treatment with 1 to 3
concomitant stable dose
AEDs.
• Atleast 90 seizures in the
month prior to study entry.
• Weight of atleast 18 kg.
• Absence of progressive
lesions on CT/MRI.
• 1-2 weeks.
• Dose increased to a target
dosage of 45 mg/kg/d (3200
mg in adults of > 70 kg), in
two divided doses.
• 4 weeks.
• Stable therapy.
• 10 weeks.
• Final dose at titration kept
stable.
Inclusion Criteria
Baseline phase
Titration phase
Maintenance phase
39. Before
treatment
After
treatment
Median
reduction in
seizures
Before
treatment
After
treatment
Median
reduction in
seizures
P value
Total seizures over 4
weeks (median)
290
(n=74)
204 33% 205
(n=64)
205 12% 0.0015
Tonic and atonic
seizures over 4
weeks (median)
92
(n=73)
61 43% 93
(n=60)
76 -1.4% <0.0001
Efficacy of Rufinamide in patients with seizures associated with LGS syndrome
N= number of patients.
Status epilepticus was seen in 3 patients taking rufinamide but not in patients taking placebo.
• Rufinamide group showed reduced frequency of absence and atypical absence seizures (p
0.03) and atonic seizures (p 0.02) compared with placebo.
• No benefit in myoclonic seizures, tonic-clonic seizures.
40. Rufinamide in LGS
• Drop-attacks, spasms, and tonic seizures show the highest response
rates reaching 73%, 99% and 50% reduction, compared to focal seizures.
• Mean number of seizure-free days was 42.2% greater than placebo.
• Etiology of LGS did not affect seizure response.
• No specific combination of AEDs that seem to be more effective in
children with LGS when Rufinamide is co-administered.
• Therapeutic drug monitoring is recommended.
Yıldız EP, et al. Turk J Pediatr. 2018;60(3):238–243.
Olson HE, et al. Epilepsy Behav. 2011;20(2):344–348.
41. • Percentage of reduction in total seizures and >50% reduction in drop attacks in patients with
LGS.
• Noted from class I or class II studies of approved antiseizure medications.
• Dark bars represent study drug results, with placebo response in light bars.
• Modified from Pediatr Neurol, 47(3), VanStraten AF, Ng YT. Update on the management of
Lennox-Gastaut syndrome. 153–161.
43. Cochrane Database of Systematic Reviews 2018, Issue 4. Art. No.: CD011772
• 4 trials (1563 subjects) included refractory focal epilepsy.
• 2 trials (196 subjects) included confirmed LGS patients.
• The trials were of short duration and funded by Esai.
• RR for ≥50% reduction in seizure frequency: 1.79 (95% CI 1.44 to 2.22).
• Adverse events, treatment withdrawal were more with Rufinamide.
44.
45. Summary
• Mechanism: It is an orphan AED that prolongs the inactivation of the
sodium channel and limits sustained firing of Na-dependent potentials.
• Weak inducer of CYP450 system and is affected by inducers.
• Indication: add on therapy in LGS.
• Best response is for seizures causing falls (tonic and atonic seizures).
• Off label use: MMPSI, focal epilepsy.
• Adverse effects: Headache, Sedation, dizziness, shortening of QT
interval and behavioural issues.
46. Stiripentol and Rufinamide availability
Stiripentol:
• Not approved for use in India.
• Available in the grey market.
• Manufacturer: Biocodex.
• Distributor: Novartis.
• Some issues with US availability
• Alan Pharmaceuticals, UK
• Price: 60 tabs = 524$
Rufinamide:
• Not approved for use in India.
• Available in the grey market.
• Manufacturer: Esai.
• Distributor: Esai, Glenmark.
47. • Any drug imported as a use for a
strictly academic trial need not
require commercial license, provided
it is NOT being used for a trial of
approval.
• However appropriate clearance needs
to be taken prior from CDSCO