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SCREENING
ANTIEMETIC DRUGS
Dr. Prashant Shukla
Junior Resident
Dept. of Pharmacology
 INTRODUCTION
 PATHOGENESIS OF VOMITING
 CLASSIFICATION OF ANTI EMETIC
DRUGS
 CHOICE OF ANIMALS AND EMETOGENS
 PARAMETERS OBSERVED
 INVIVO MODELS
 INVITRO MODELS
 HUMAN MODELS
Contents
INTRODUCTION
 NAUSEA: Non observable subjective
feeling of having an urge to vomit.
 EMESIS
 ACUTE EMESIS (occurs within minutes and
resolves within 24 h)
 DELAYED EMESIS (occurs after 2-3 days)
 BREAKTHROUGH EMESIS (emesis occurring
after the prophylactic antiemetic treatment)
 RETCHING: Attempt to vomit w/o
expulsion of vomitus.
 EJECTION: Expulsion of vomitus
forcefully through mouth and nose.
DRUGS,RADIATION,METABOLIC PRODUCTS
MOTION
VESTIBULAR
LABYRINTH
SENSORY STIMULI
CORTEX
LIMBIC SYSTEM
SYMPATHETIC &
PARASYMPATHETIC
CEREBELLUM
VOMITING CENTRE
IN NTS
CTZ IN AREA
POSTREMA
BLOOD & CSF
VOMITING
PATHOGENESIS
CORTICAL
AFFERENTS
VISCERAL
AFFERENTS
Screening of anti-emetic drugs
Screening of anti-emetic drugs
CLASSIFICATION OF
ANTIEMETICS
1. 5HT3 antagonists: ondansetron, tropisetron,
palanosetron, granisetron
2. Centrally acting dopamine receptor
antagonists: prochlorperazine,
chlorpromazine
3. H1 receptor antagonists ex: Cyclizine,
hydroxyzine, promethazine, diphenhydramine
4. Muscarinic antagonists ex:Scopolamine
5. Proinetic agents: Metoclopramide,
Domperidone, Cisapride,Mosapride
6.Neurokinin receptor antagonists ex: Aprepitent
7. Cannabinoid receptor antagonists ex:
Dronabinol, Nabilone
8. Corticosteroids and NSAIDs
9. Benzodiazepines ex: Alprazolam, Diazepam
10. Phosphorated carbohydrate solutions
Ex: Aqueous solutions of glucose,
fructose and phosphoric acid
CHOICE OF ANIMALS
 Animals normally used-not useful
 Degenerate vomiting reflex – rodents
 Commonly used animals:
Dogs House musk shrew (Suncus
murinus)
Cats Least shrew (Cryptotis parva)
Ferrets Gerbils
Monkeys Pigeons
CHOICE OF EMETOGENS
 DRUG INDUCED
 RADIATION STIMULUS
 MOTION STIMULUS
PARAMETERS ASSESSED
 Behavioral changes
 Latency to first retching and vomiting
 Number of vomiting episodes
 Conditioned flavor avoidance (PICA) in
rats and mouse
DRUG INDUCED EMESIS
MODELS
1.
• Cisplatin- induced emesis model
2.
• Apomorphine- induced emesis model
3.
• CuSO4- induced emesis model
4.
• Methotrexate- induced emesis model
Cisplatin-induced emesis
model
Causes Both Acute And Delayed Emesis
Used as emetogen to evaluate acute emesis.
Solvent normal saline at 70oC followed by
slow cooling to 40oC
 Described by Gylys et al.
 Used to evaluate antiemetic properties of 5-HT3
receptor antagonists.
TEST GROUP:
Test drug is administered.
Ten mins later, cisplatin is
administered IV at a dose
of 3.2mg/kg/ml.
OBSERVATIONFOR
5HOURS
Dogs with no
obvious toxicity
are retested
after an interval
of 4 weeks.
CONTROL GROUP:
Vehicle is administered.
Ten mins later, cisplatin is
administered IV at a dose
of 3.2mg/kg/ml.
Cisplatin-induced dog model
Cisplatin-induced cat model
 Described by John et al.
 Cats of either sex, 2-6 kg.
TEST GROUP
Cisplatin is administered IV at
a dose of 3- 7.5 mg/kg/ml over
4 m.
Immediately after this, Test
drug is administered.
OBSERVATIONFOR
4HOURSFOREMETICEPISODES
Cisplatin is administered IV at
a dose of 3- 7.5 mg/kg/ml over
4 m.
Immediately after this, Vehicle
is administered.
 Animals are subjected to overnight fasting.
Cisplatin-induced ferret model
TEST GROUP
Test drug and Cisplatin (IV at a
dose of 10 mg/kg/ml) are
administered.
If Test drug is given orally, give
cisplatin 30 mins later.
OBSERVATIONFOR
4HOURSFOREMETIC
EPISODES
CONTROL GROUP
Vehicle and Cisplatin (IV at a
dose of 10 mg/kg/ml) are
administered.
Pigeon model S. murinus
model
Rat model
4 mg/kg IV 20 mg/kg IP 3-10 mg/kg IP
Duration
between
administration of
drug/ vehicle
and cisplatin
depends upon
expected time of
drug action
Duration between
administration of
drug/ vehicle and
cisplatin is 30
mins.
Cisplatin is
administered 30
mins after rats
have been pre-
treated with
drug/ vehicle.
Observed for
emetic episodes
Observed for 2h
for behavioral
changes as well
as emetic
Observe for pica
(ingestion of
non-food
substances)
Apomorphine- induced
emesis model
Apomorphine is an opiate that acts as a
potent central dopamine agonist
directly at the area prostrema via
dopamine receptors.
As the vestibular pathways are also
involved in apomorphine-induced
emesis, the active animals develop
emesis readily than sedated and
immobile animals.
Dogs most sensitive followed by ferret.
Use of apomorphine in cats is
controversial as administration of
apomorphine can cause excitation in
cats.
Suncus murinus is unresponsive to
apomorphine.
Dog model Ferret model Rat model
0.3 mg/kg SC 0.25 mg/kg SC 10 mg/kg IP
Duration between
administration of
drug and
apomorphine
depends upon
expected time of
drug action
Duration between
administration of
drug and
apomorphine is
30 mins.
Apomorphine is
administered to
rats pre-treated
with drug/
vehicle.
Observed for
emetic episodes
Observed for 60
mins for
behavioral
changes as well
as emetic
Observe for pica
(ingestion of non-
food substances)
Copper sulfate-induced emesis
model
COPPER SULFATE (CuSO4)
Powerful oxidizing agent and an irritant to mucosa
membranes. If administered orally, it causes irritation
of gastric mucosa and leads to nausea and vomiting.
Solvent: Distilled water
Dog model Cat model
100 mg/kg via an
orogastric tube
40 mg/kg orally
Observed for 1 hour for
emetic episodes
Cats are administered test
drug/ vehicle followed by
oral administration of
threshold dose of CuSO4.
Dogs with no obvious
toxicity are retested after
an interval of 2 weeks.
Observed for emetic
episodes
Ferret model Sun murinus
model
Chick model
40 mg/kg orally 40 mg/kg
intragastric
50 mg/kg orally
Drug/ vehicle
pretreated ferrets
are administered
CuSO4.
Duration between
administration of
drug and CuSO4
is 30 mins.
Duration between
administration of
drug and CuSO4
is 10 mins.
Observed for
latency and
frequency of
emetic episodes
Observed for 60
mins for emetic
episodes
Observed for
latency and
frequency of
emetic episodes
MTX- induced Delayed emesis
model
Animals: Dogs, cats, ferrets & shrews.
MTX is prepared by dissolving in 5% Dextrose.
Test drug/vehicle is administered at 24, 36, 48
&60 h after MTX.
Observed under video camera for 72h.
Animals can be retested with MTX at least 6
weeks later
Motion-induced emesis model
o Dogs are probably as sensitive to motion-
induced emesis as man.
COMMONLY USED MODELS
o CAT MODEL
o SUNCUS MURINUS MODEL
o RAT MODEL
Cat model Suncus murinus
model
Rat model
Vertical
oscillations at 0.3
Hz through a
distance of 75 cm
Horizontal
oscillations of 4
cm at 1 Hz for 10
min
60 min double
rotations
Repetitive licking,
salivation often
dripping out of
mouth, or
vomiting
Emetic episodes
are noted during
motion as well as
after motion
cease
↑ kaolin intake
indicates motion
sickness
↑ latency/
↓frequency of
emesis in cats
pretreated with
drug indicates
* Animal can be
exposed only
twice in 1 week
d/t adaption to
motion stimuli
↓ kaolin intake in
rats pretreated
with drug
indicates
antiemetic action
Radiation- induced emesis
model
RADIATION INDUCED EMESIS
MODEL
oDOG MODEL
oFERRET MODEL
oRAT MODEL
 Ferrets are most sensitive to
radiations followed by dogs. Cats are
resistant to radiations.
Dog model Ferret model Rat model
60Co; 8 Gy
administered to
total body
surface
60Co; 201 cGy 4Gy of total body
irradiation
(abdominal >
head irradiation)
One group gets
drug & other
group gets no
medications
Emesis incidence
of 100% is
reported at 201
cGy in ferret
Exposure to
radiation induces
pica in rats
↑ latency/
↓frequency of
emesis in cats
pretreated with
drug indicates
antiemetic action
↑ latency/
↓frequency of
emesis in cats
pretreated with
drug indicates
antiemetic action
↓ kaolin intake in
rats pretreated
with drug
indicates
antiemetic action
Model for anticipatory nausea &
vomiting
 Anticipatory nausea and vomiting is
described as conditioned response to
cues present at the time of exposure to
toxins as a result of pairing.
 Often ass. with cancer chemotherapy.
S. murinus
model
•Either sex, 20-50 g
•Weaned at 20 days
•Housed in transparent cages
•Obs. Chamber well illuminated
LiCl 100 mg/kg IPVehicle
Observed (45 min); 2nd /3rd conditioning trial after 72 h,
144h
Test group Control group
6 days later
LiCl 100 mg/kg IPVehicle
Test drug or vehicle is administered
Physiological saline is given
Observe for emetic episodes
Rat
model
4 conditioning trials (using LiCl) 72 hours apart
Drug/ vehicle is given to the rats
72 hours after 4th conditioning trial
0.1% saccharin sol. is delivered via surgically implanted
cannulae every 5 min for 1 min (6inj in 30m)
Rats are observed for gaping (equivalent to emesis)
GAPING
In vitro models
 Used to demonstrate the
pharmacological activity of newer anti-
emetic agents.
 5-HT3 # are the most potent of all anti-
emetics.
 The experimental drugs can be
evaluated for 5-HT3 receptor
antagonist activity using in vitro
5-HT3 Receptor antagonists
1. Distal colon (20mm) of
GP
2. Krebs-Henseleit solution
3. 2-methyl-5-HT (Agonist)
4. Tropisetron (Antagonist)
5. Temp: 37˚C
6. Vol. (Inner bath) 10 mL
7. pH: 7.3- 7.5
↑
TROPISETRON
↑ ↑
↑ conc./doses of 2-methyl-5-HT
No effect of 2-
methyl-5-HT
PictorialRepresentationOnly
Human Models
Apomorphine induced:
Apomorphine, 0.05 mg/kg, SC is an appropriate
challenge dose for testing compounds for
antiemetic activity in normal human
volunteers.
Ipecac induced
Healthy men are given single 5-minute
infusions of ondansetron 30 minutes before
oral administration of 30 ml syrup of
ipecacuanha. Emetic episodes and nausea
are assessed over an 8-hour period.
Screening of anti-emetic drugs
RECENT ADVANCES
IN ANTI-EMETIC DRUGS
Drug name Class Indication Approval year
Granisetron 5-HT3 # CINV Aug 2016
Dronabinol oral
sol.
CB-1 #,
CB-2 #
CINV Jul 2016
Rolapitant NK-1# CINV Sep 2015
Netupitant +
Palonosetron
NK-1# +
5-HT3 #
CINV Oct 2014
Doxylamine
succinate +
Pyridoxine HCl
DR
H1# Nausea
and
vomiting of
pregnancy
Apr 2013
REFERENCES
 Drug screening methods by SK Gupta
 The Pharmacological Basis of Therapeutics
Goodman & Gilman- 12th edition.
 Basic and clinical Pharmacology Betram G
Katzung- 12 th Edition
 J Clin Pharmacol. 1978 Feb-Mar;18(2-3):95-9.An
apomorphine-induced vomiting model for
antiemetic studies in man Proctor JD, Chremos
AN, Evans EF, Wasserman AJ.
 Clin Pharmacol Ther. 1993 Jul;54(1):53-
7.Ipecacuanha-induced emesis: a human model
for testing antiemetic drug activity.Minton N1,
Swift R, Lawlor C, Mant T, Henry J.
Screening of anti-emetic drugs

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Screening of anti-emetic drugs

  • 1. SCREENING ANTIEMETIC DRUGS Dr. Prashant Shukla Junior Resident Dept. of Pharmacology
  • 2.  INTRODUCTION  PATHOGENESIS OF VOMITING  CLASSIFICATION OF ANTI EMETIC DRUGS  CHOICE OF ANIMALS AND EMETOGENS  PARAMETERS OBSERVED  INVIVO MODELS  INVITRO MODELS  HUMAN MODELS Contents
  • 3. INTRODUCTION  NAUSEA: Non observable subjective feeling of having an urge to vomit.  EMESIS  ACUTE EMESIS (occurs within minutes and resolves within 24 h)  DELAYED EMESIS (occurs after 2-3 days)  BREAKTHROUGH EMESIS (emesis occurring after the prophylactic antiemetic treatment)
  • 4.  RETCHING: Attempt to vomit w/o expulsion of vomitus.  EJECTION: Expulsion of vomitus forcefully through mouth and nose.
  • 5. DRUGS,RADIATION,METABOLIC PRODUCTS MOTION VESTIBULAR LABYRINTH SENSORY STIMULI CORTEX LIMBIC SYSTEM SYMPATHETIC & PARASYMPATHETIC CEREBELLUM VOMITING CENTRE IN NTS CTZ IN AREA POSTREMA BLOOD & CSF VOMITING PATHOGENESIS CORTICAL AFFERENTS VISCERAL AFFERENTS
  • 8. CLASSIFICATION OF ANTIEMETICS 1. 5HT3 antagonists: ondansetron, tropisetron, palanosetron, granisetron 2. Centrally acting dopamine receptor antagonists: prochlorperazine, chlorpromazine 3. H1 receptor antagonists ex: Cyclizine, hydroxyzine, promethazine, diphenhydramine 4. Muscarinic antagonists ex:Scopolamine
  • 9. 5. Proinetic agents: Metoclopramide, Domperidone, Cisapride,Mosapride 6.Neurokinin receptor antagonists ex: Aprepitent 7. Cannabinoid receptor antagonists ex: Dronabinol, Nabilone 8. Corticosteroids and NSAIDs 9. Benzodiazepines ex: Alprazolam, Diazepam 10. Phosphorated carbohydrate solutions Ex: Aqueous solutions of glucose, fructose and phosphoric acid
  • 10. CHOICE OF ANIMALS  Animals normally used-not useful  Degenerate vomiting reflex – rodents  Commonly used animals: Dogs House musk shrew (Suncus murinus) Cats Least shrew (Cryptotis parva) Ferrets Gerbils Monkeys Pigeons
  • 11. CHOICE OF EMETOGENS  DRUG INDUCED  RADIATION STIMULUS  MOTION STIMULUS
  • 12. PARAMETERS ASSESSED  Behavioral changes  Latency to first retching and vomiting  Number of vomiting episodes  Conditioned flavor avoidance (PICA) in rats and mouse
  • 13. DRUG INDUCED EMESIS MODELS 1. • Cisplatin- induced emesis model 2. • Apomorphine- induced emesis model 3. • CuSO4- induced emesis model 4. • Methotrexate- induced emesis model
  • 14. Cisplatin-induced emesis model Causes Both Acute And Delayed Emesis Used as emetogen to evaluate acute emesis. Solvent normal saline at 70oC followed by slow cooling to 40oC
  • 15.  Described by Gylys et al.  Used to evaluate antiemetic properties of 5-HT3 receptor antagonists. TEST GROUP: Test drug is administered. Ten mins later, cisplatin is administered IV at a dose of 3.2mg/kg/ml. OBSERVATIONFOR 5HOURS Dogs with no obvious toxicity are retested after an interval of 4 weeks. CONTROL GROUP: Vehicle is administered. Ten mins later, cisplatin is administered IV at a dose of 3.2mg/kg/ml. Cisplatin-induced dog model
  • 16. Cisplatin-induced cat model  Described by John et al.  Cats of either sex, 2-6 kg. TEST GROUP Cisplatin is administered IV at a dose of 3- 7.5 mg/kg/ml over 4 m. Immediately after this, Test drug is administered. OBSERVATIONFOR 4HOURSFOREMETICEPISODES Cisplatin is administered IV at a dose of 3- 7.5 mg/kg/ml over 4 m. Immediately after this, Vehicle is administered.
  • 17.  Animals are subjected to overnight fasting. Cisplatin-induced ferret model TEST GROUP Test drug and Cisplatin (IV at a dose of 10 mg/kg/ml) are administered. If Test drug is given orally, give cisplatin 30 mins later. OBSERVATIONFOR 4HOURSFOREMETIC EPISODES CONTROL GROUP Vehicle and Cisplatin (IV at a dose of 10 mg/kg/ml) are administered.
  • 18. Pigeon model S. murinus model Rat model 4 mg/kg IV 20 mg/kg IP 3-10 mg/kg IP Duration between administration of drug/ vehicle and cisplatin depends upon expected time of drug action Duration between administration of drug/ vehicle and cisplatin is 30 mins. Cisplatin is administered 30 mins after rats have been pre- treated with drug/ vehicle. Observed for emetic episodes Observed for 2h for behavioral changes as well as emetic Observe for pica (ingestion of non-food substances)
  • 19. Apomorphine- induced emesis model Apomorphine is an opiate that acts as a potent central dopamine agonist directly at the area prostrema via dopamine receptors. As the vestibular pathways are also involved in apomorphine-induced emesis, the active animals develop emesis readily than sedated and immobile animals.
  • 20. Dogs most sensitive followed by ferret. Use of apomorphine in cats is controversial as administration of apomorphine can cause excitation in cats. Suncus murinus is unresponsive to apomorphine.
  • 21. Dog model Ferret model Rat model 0.3 mg/kg SC 0.25 mg/kg SC 10 mg/kg IP Duration between administration of drug and apomorphine depends upon expected time of drug action Duration between administration of drug and apomorphine is 30 mins. Apomorphine is administered to rats pre-treated with drug/ vehicle. Observed for emetic episodes Observed for 60 mins for behavioral changes as well as emetic Observe for pica (ingestion of non- food substances)
  • 22. Copper sulfate-induced emesis model COPPER SULFATE (CuSO4) Powerful oxidizing agent and an irritant to mucosa membranes. If administered orally, it causes irritation of gastric mucosa and leads to nausea and vomiting. Solvent: Distilled water
  • 23. Dog model Cat model 100 mg/kg via an orogastric tube 40 mg/kg orally Observed for 1 hour for emetic episodes Cats are administered test drug/ vehicle followed by oral administration of threshold dose of CuSO4. Dogs with no obvious toxicity are retested after an interval of 2 weeks. Observed for emetic episodes
  • 24. Ferret model Sun murinus model Chick model 40 mg/kg orally 40 mg/kg intragastric 50 mg/kg orally Drug/ vehicle pretreated ferrets are administered CuSO4. Duration between administration of drug and CuSO4 is 30 mins. Duration between administration of drug and CuSO4 is 10 mins. Observed for latency and frequency of emetic episodes Observed for 60 mins for emetic episodes Observed for latency and frequency of emetic episodes
  • 25. MTX- induced Delayed emesis model Animals: Dogs, cats, ferrets & shrews. MTX is prepared by dissolving in 5% Dextrose. Test drug/vehicle is administered at 24, 36, 48 &60 h after MTX. Observed under video camera for 72h. Animals can be retested with MTX at least 6 weeks later
  • 26. Motion-induced emesis model o Dogs are probably as sensitive to motion- induced emesis as man. COMMONLY USED MODELS o CAT MODEL o SUNCUS MURINUS MODEL o RAT MODEL
  • 27. Cat model Suncus murinus model Rat model Vertical oscillations at 0.3 Hz through a distance of 75 cm Horizontal oscillations of 4 cm at 1 Hz for 10 min 60 min double rotations Repetitive licking, salivation often dripping out of mouth, or vomiting Emetic episodes are noted during motion as well as after motion cease ↑ kaolin intake indicates motion sickness ↑ latency/ ↓frequency of emesis in cats pretreated with drug indicates * Animal can be exposed only twice in 1 week d/t adaption to motion stimuli ↓ kaolin intake in rats pretreated with drug indicates antiemetic action
  • 28. Radiation- induced emesis model RADIATION INDUCED EMESIS MODEL oDOG MODEL oFERRET MODEL oRAT MODEL  Ferrets are most sensitive to radiations followed by dogs. Cats are resistant to radiations.
  • 29. Dog model Ferret model Rat model 60Co; 8 Gy administered to total body surface 60Co; 201 cGy 4Gy of total body irradiation (abdominal > head irradiation) One group gets drug & other group gets no medications Emesis incidence of 100% is reported at 201 cGy in ferret Exposure to radiation induces pica in rats ↑ latency/ ↓frequency of emesis in cats pretreated with drug indicates antiemetic action ↑ latency/ ↓frequency of emesis in cats pretreated with drug indicates antiemetic action ↓ kaolin intake in rats pretreated with drug indicates antiemetic action
  • 30. Model for anticipatory nausea & vomiting  Anticipatory nausea and vomiting is described as conditioned response to cues present at the time of exposure to toxins as a result of pairing.  Often ass. with cancer chemotherapy.
  • 31. S. murinus model •Either sex, 20-50 g •Weaned at 20 days •Housed in transparent cages •Obs. Chamber well illuminated LiCl 100 mg/kg IPVehicle Observed (45 min); 2nd /3rd conditioning trial after 72 h, 144h Test group Control group 6 days later LiCl 100 mg/kg IPVehicle Test drug or vehicle is administered Physiological saline is given Observe for emetic episodes
  • 32. Rat model 4 conditioning trials (using LiCl) 72 hours apart Drug/ vehicle is given to the rats 72 hours after 4th conditioning trial 0.1% saccharin sol. is delivered via surgically implanted cannulae every 5 min for 1 min (6inj in 30m) Rats are observed for gaping (equivalent to emesis) GAPING
  • 33. In vitro models  Used to demonstrate the pharmacological activity of newer anti- emetic agents.  5-HT3 # are the most potent of all anti- emetics.  The experimental drugs can be evaluated for 5-HT3 receptor antagonist activity using in vitro
  • 34. 5-HT3 Receptor antagonists 1. Distal colon (20mm) of GP 2. Krebs-Henseleit solution 3. 2-methyl-5-HT (Agonist) 4. Tropisetron (Antagonist) 5. Temp: 37˚C 6. Vol. (Inner bath) 10 mL 7. pH: 7.3- 7.5 ↑ TROPISETRON ↑ ↑ ↑ conc./doses of 2-methyl-5-HT No effect of 2- methyl-5-HT PictorialRepresentationOnly
  • 35. Human Models Apomorphine induced: Apomorphine, 0.05 mg/kg, SC is an appropriate challenge dose for testing compounds for antiemetic activity in normal human volunteers. Ipecac induced Healthy men are given single 5-minute infusions of ondansetron 30 minutes before oral administration of 30 ml syrup of ipecacuanha. Emetic episodes and nausea are assessed over an 8-hour period.
  • 38. Drug name Class Indication Approval year Granisetron 5-HT3 # CINV Aug 2016 Dronabinol oral sol. CB-1 #, CB-2 # CINV Jul 2016 Rolapitant NK-1# CINV Sep 2015 Netupitant + Palonosetron NK-1# + 5-HT3 # CINV Oct 2014 Doxylamine succinate + Pyridoxine HCl DR H1# Nausea and vomiting of pregnancy Apr 2013
  • 39. REFERENCES  Drug screening methods by SK Gupta  The Pharmacological Basis of Therapeutics Goodman & Gilman- 12th edition.  Basic and clinical Pharmacology Betram G Katzung- 12 th Edition  J Clin Pharmacol. 1978 Feb-Mar;18(2-3):95-9.An apomorphine-induced vomiting model for antiemetic studies in man Proctor JD, Chremos AN, Evans EF, Wasserman AJ.  Clin Pharmacol Ther. 1993 Jul;54(1):53- 7.Ipecacuanha-induced emesis: a human model for testing antiemetic drug activity.Minton N1, Swift R, Lawlor C, Mant T, Henry J.