Flightmed archive for May-2002
Flightmed archive for May-2002
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Re: antiemetics
Our program utilizes Phenergan for N/V. We also use
the ReliefBand motion sickness watch-like product,
both for patients and crew. Zofran/Anzemet not
currently used, based on expense.
Steve Stroman, MD
Medical Director
EAGLE III
Green Bay
>On Sun, 26 May 2002, Frank G. Bartuska wrote:
>
>> Looking for some help. Now that Inapsine has the
pox upon it via the FDA
>> what is everyone using for control of N/V. We are
using Phenergan
>> currently. Researching Zofran and Reglan. Any
help would be greatly
>> appreciated.
>
>I've been doing a little research on this as well.
The literature I've
>come across seems to indicate that
Zofran/Anzemet/Kytril serotonin (5-HT3)
>antagonists, while very effective in chemotherapy,
radiation therapy, and
>post-surgery, are not effective against motion
sickness, which is probably
>the most common cause of nausea in our patient
population. In addition, it
>appears that there are QT-widening effects by these
medications as well,
>even in healthy volunteers.
>
>I know that a number of flight programs are using
Zofran and/or Anzemet
>and I'm curious what their experience/results have
been, besides the
>anecdotal report in the most recent Air Medical
Journal.
>
>Below are some results of a lit search on PubMed:
>
>
>
>1: Aviat Space Environ Med 2000 Nov;71(11 Pt 1):1111-
4
>
>The effects of serotonin (5-HT3) receptor antagonists
on gastric
>tachyarrhythmia and the symptoms of motion sickness.
>
>Levine ME, Chillas JC, Stern RM, Knox GW.
>
>Department of Psychology, The Pennsylvania State
University, University
>Park 16802, USA. mel157@psu.edu
>
>BACKGROUND: The purpose of this study was to
determine the effects of the
>serotonin (5-HT3) receptor-antagonist antiemetics
ondansetron and
>granisetron on the development of gastric
tachyarrhythmia, nausea, and
>other symptoms of motion sickness. METHODS: In a
double-blind,
>counterbalanced, repeated measures design, 12 motion
sickness susceptible
>college students participated in 3 sessions with an
intersession interval
>of 1 wk. Participants received either 8 mg of
ondansetron, 2 mg of
>granisetron, or placebo 1 h before exposure to a
rotating optokinetic
>drum. Electrogastrograms (EGGs) were recorded during
a 6-min baseline
>period and a subsequent 16-min drum rotation period.
Subjective symptoms
>of motion sickness (SSMS) were obtained every 3 min
during drum rotation.
>RESULTS: During drum rotation, gastric
tachyarrhythmia increased
>significantly more during the placebo condition than
during either of the
>serotonin (5-HT3) receptor antagonist conditions.
However, maximum SSMS
>scores were not different among conditions.
CONCLUSIONS: The serotonin
>(5-HT3) receptor antagonists inhibited the
development of
>tachyarrhythmia, but did not prevent the development
of nausea and other
>symptoms of motion sickness. The antiemetics
ondansetron and granisetron
>may act as gastric anti-dysrhythmics, but their
ability to arrest the
>development of gastric tachyarrhythmia was not
sufficient for the
>prevention of nausea.
>
>
>
>2: Br J Clin Pharmacol 1989 Feb;27(2):147-57
>
>The effect on motion sickness and oculomotor function
of GR 38032F, a
>5-HT3-receptor antagonist with anti-emetic properties.
>
>Stott JR, Barnes GR, Wright RJ, Ruddock CJ.
>
>R.A.F. Institute of Aviation Medicine, Farnborough,
Hampshire.
>
>The 5-hydroxytryptamine (5-HT3) receptor antagonist,
GR 38032F, which
>possesses potent anti-emetic properties in vomiting
induced by cancer
>chemotherapeutic drugs, has been tested to determine
its value in the
>prophylaxis of motion sickness induced by cross-
coupled stimulation. The
>double-blind trial compared GR 38032F with both a
placebo (lactose) and
>with hyoscine. In addition, studies of ocular pursuit
and saccadic eye
>movements were carried out following the
administration of each drug. 2.
>The prophylactic effect of GR 38032F on motion-
induced nausea was
>indistinguishable from that of placebo, whereas
following hyoscine
>subjects showed a highly significant (P less than
0.001) increase in
>tolerance to cross-coupled stimulation. Tests of
oculomotor function
>showed no effect on saccadic eye movement from either
drug. However, both
>drugs produced a significant (P less than 0.05)
though small reduction in
>eye velocity gain during pursuit eye movement. 3.
These findings suggest
>that the 5-HT3 receptor is not involved in the neural
pathways that bring
>about motion sickness, but that it may have a role in
the control of
>ocular pursuit. The absence of an anti-motion
sickness effect from a drug
>that is effective in the treatment of vomiting
induced by cancer
>chemotherapy serves to emphasize that different
neural mechanisms are
>involved in the generation of motion sickness.
>
>
>
>3: J Cardiovasc Pharmacol 1996 Jul;28(1):53-9
>
>Single-blind study of the effects of intravenous
dolasetron mesylate
>versus ondansetron on electrocardiographic parameters
in normal
>volunteers.
>
>Benedict CR, Arbogast R, Martin L, Patton L, Morrill
B, Hahne W.
>
>Division of Cardiology, University of Texas Health
Science Center,
>Houston, TX
>77030, USA.
>
>A single-blind, randomized, five-way cross-over,
safety and tolerability
>trial was conducted to determine whether intravenous
(i.v.) dolasetron
>mesylate at varying single doses induces changes in
ECG intervals in
>healthy volunteers and to compare these changes with
a single intravenous
>dose of ondansetron or placebo. Thirty healthy male
volunteers received
>1.2, 1.8, and 2.4 mg/kg i.v. dolasetron mesylate, 32
mg i.v. ondansetron,
>and placebo on 5 separate days. ECGs were recorded at
intervals during the
>24 h after study drug administration. The changes in
ECG intervals
>observed after dolasetron mesylate or ondansetron
were acute, transient,
>and asymptomatic. Dolasetron mesylate resulted in
slight but statistically
>significant dose-related increases in heart rate
(HR) and PR and QRS
>intervals (between h 0 and 4). A statistically
significant increase in QTc
>interval was detected with both dolasetron mesylate
(2.4 mg/kg) and
>ondansetron. Ondansetron also produced a slight but
statistically
>significant increase in JT interval and a decrease in
HR. These changes in
>ECG intervals were usually observed between h 0 and
4; all parameters
>returned to baseline within 8 h of treatment. The
results demonstrate that
>both dolasetron mesylate and ondansetron prolong the
QTc interval.
>However, dolasetron mesylate predominantly altered
ECG parameters
>indicative of ventricular depolarization (QRS
duration), whereas
>ondansetron predominantly affected ventricular
repolarization as measured
>by a prolongation in the JT interval. Both dolasetron
and ondansetron were
>well tolerated. The adverse event (AE) rate was 13.3%
(4 of 30); all AE
>were of mild or moderate severity and were
distributed across all dose
>arms.
>
>
>
>4: Pharmacol Biochem Behav 1989 Jan;32(1):207-10
>
>Blockade of 5-hydroxytryptamine3 receptors prevents
cisplatin-induced but
>not motion- or xylazine-induced emesis in the cat.
>
>Lucot JB.
>
>Wright State University, Department of Pharmacology,
Dayton, OH 45435.
>
>5-Hydroxytryptamine3 antagonists have been reported
to prevent emesis
>elicited by cisplatin and radiation. This study
investigated the
>possibility that drugs with this mechanism of action
may be useful in
>preventing emesis elicited by other stimuli. The
drugs ICS 205-930 (0.1
>and 1.0 mg/kg) and MDL 72222 (0.1 and 1.0 mg/kg) were
administered SC to
>cats before challenging them with either provocative
motion or an emetic
>dose of xylazine. In no instance was a significant
reduction in emesis
>evident. Zacopride was also administered before
motion testing (0.01 to
>10.0 mg/kg) and found to not have efficacy. To test
the possibility that
>species or route of administration were factors in
the negative results,
>1.0 mg/kg of ICS 205-930 was administered SC before
IV infusion of 7.5
>mg/kg of cisplatin. There was a total suppression of
emesis for the
>duration of the six-hour observation periods. This
result verifies other
>work which found 5-hydroxytryptamine3 antagonists to
be effective in
>preventing emesis elicited by cancer chemotherapeutic
treatments. However,
>there is no evidence that they are effective in other
syndromes, such as
>motion sickness and xylazine-induced emesis.
>
>
>
>5: Eur J Cancer Clin Oncol 1989;25 Suppl 1:S21-4;
discussion S25-7
>
>The clinical pharmacology of ondansetron.
>
>Blackwell CP, Harding SM.
>
>Department of Human Pharmacology, Glaxo Group
Research Limited, Greenford,
>Middlesex, U.K.
>
>Ondansetron, a 5-HT3 antagonist proposed for use in
the treatment of
>chemotherapy-induced emesis, was first given to man
in 1984 and in the 4
>years subsequent to this, the drug was given to more
than 220 different
>healthy volunteers. In pharmacodynamic studies, there
was evidence to
>suggest that ondansetron was gastroprokinetic but
reduced transit time
>through the small bowel. Ondansetron was of no
benefit in a model of
>motion sickness. The pharmacokinetics of ondansetron
have been defined in
>volunteers using intravenous and oral dosage regimens
proposed for the
>clinic. Ondansetron had a terminal plasma half-life
of 3.0-3.5 h and
>plasma clearance (principally metabolic) of the order
of 600 ml/min, and
>there was no evidence of accumulation at steady
state. The absolute oral
>bioavailability of ondansetron was 59%. Metabolic
studies showed the drug
>to be excreted predominantly in urine and faeces,
with a metabolite
>profile in urine similar to that seen in the animal
species used for
>toxicological testing. Ondansetron is both safe and
well tolerated at
>daily doses of up to 64 mg given to volunteers.
>
>
> --
>-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-
=-=-=-=-=-=-=-=-=-=-
>Rollie Parrish
>FlightWeb: For Air Medical Professionals
>http://www.flightweb.com
>
>
>
>
>
>_______________________________________________
>Flightmed mailing list
>To unsubscribe or change your email address, go to
http://www.pairlist.net/mailman/listinfo/flightmed
>
On Sun, 26 May 2002, Frank G. Bartuska wrote:
> Looking for some help. Now that Inapsine has the pox upon it via the FDA
> what is everyone using for control of N/V. We are using Phenergan
> currently. Researching Zofran and Reglan. Any help would be greatly
> appreciated.
I've been doing a little research on this as well. The literature I've
come across seems to indicate that Zofran/Anzemet/Kytril serotonin (5-HT3)
antagonists, while very effective in chemotherapy, radiation therapy, and
post-surgery, are not effective against motion sickness, which is probably
the most common cause of nausea in our patient population. In addition, it
appears that there are QT-widening effects by these medications as well,
even in healthy volunteers.
I know that a number of flight programs are using Zofran and/or Anzemet
and I'm curious what their experience/results have been, besides the
anecdotal report in the most recent Air Medical Journal.
Below are some results of a lit search on PubMed:
1: Aviat Space Environ Med 2000 Nov;71(11 Pt 1):1111-4
The effects of serotonin (5-HT3) receptor antagonists on gastric
tachyarrhythmia and the symptoms of motion sickness.
Levine ME, Chillas JC, Stern RM, Knox GW.
Department of Psychology, The Pennsylvania State University, University
Park 16802, USA. mel157@psu.edu
BACKGROUND: The purpose of this study was to determine the effects of the
serotonin (5-HT3) receptor-antagonist antiemetics ondansetron and
granisetron on the development of gastric tachyarrhythmia, nausea, and
other symptoms of motion sickness. METHODS: In a double-blind,
counterbalanced, repeated measures design, 12 motion sickness susceptible
college students participated in 3 sessions with an intersession interval
of 1 wk. Participants received either 8 mg of ondansetron, 2 mg of
granisetron, or placebo 1 h before exposure to a rotating optokinetic
drum. Electrogastrograms (EGGs) were recorded during a 6-min baseline
period and a subsequent 16-min drum rotation period. Subjective symptoms
of motion sickness (SSMS) were obtained every 3 min during drum rotation.
RESULTS: During drum rotation, gastric tachyarrhythmia increased
significantly more during the placebo condition than during either of the
serotonin (5-HT3) receptor antagonist conditions. However, maximum SSMS
scores were not different among conditions. CONCLUSIONS: The serotonin
(5-HT3) receptor antagonists inhibited the development of
tachyarrhythmia, but did not prevent the development of nausea and other
symptoms of motion sickness. The antiemetics ondansetron and granisetron
may act as gastric anti-dysrhythmics, but their ability to arrest the
development of gastric tachyarrhythmia was not sufficient for the
prevention of nausea.
2: Br J Clin Pharmacol 1989 Feb;27(2):147-57
The effect on motion sickness and oculomotor function of GR 38032F, a
5-HT3-receptor antagonist with anti-emetic properties.
Stott JR, Barnes GR, Wright RJ, Ruddock CJ.
R.A.F. Institute of Aviation Medicine, Farnborough, Hampshire.
The 5-hydroxytryptamine (5-HT3) receptor antagonist, GR 38032F, which
possesses potent anti-emetic properties in vomiting induced by cancer
chemotherapeutic drugs, has been tested to determine its value in the
prophylaxis of motion sickness induced by cross-coupled stimulation. The
double-blind trial compared GR 38032F with both a placebo (lactose) and
with hyoscine. In addition, studies of ocular pursuit and saccadic eye
movements were carried out following the administration of each drug. 2.
The prophylactic effect of GR 38032F on motion-induced nausea was
indistinguishable from that of placebo, whereas following hyoscine
subjects showed a highly significant (P less than 0.001) increase in
tolerance to cross-coupled stimulation. Tests of oculomotor function
showed no effect on saccadic eye movement from either drug. However, both
drugs produced a significant (P less than 0.05) though small reduction in
eye velocity gain during pursuit eye movement. 3. These findings suggest
that the 5-HT3 receptor is not involved in the neural pathways that bring
about motion sickness, but that it may have a role in the control of
ocular pursuit. The absence of an anti-motion sickness effect from a drug
that is effective in the treatment of vomiting induced by cancer
chemotherapy serves to emphasize that different neural mechanisms are
involved in the generation of motion sickness.
3: J Cardiovasc Pharmacol 1996 Jul;28(1):53-9
Single-blind study of the effects of intravenous dolasetron mesylate
versus ondansetron on electrocardiographic parameters in normal
volunteers.
Benedict CR, Arbogast R, Martin L, Patton L, Morrill B, Hahne W.
Division of Cardiology, University of Texas Health Science Center,
Houston, TX
77030, USA.
A single-blind, randomized, five-way cross-over, safety and tolerability
trial was conducted to determine whether intravenous (i.v.) dolasetron
mesylate at varying single doses induces changes in ECG intervals in
healthy volunteers and to compare these changes with a single intravenous
dose of ondansetron or placebo. Thirty healthy male volunteers received
1.2, 1.8, and 2.4 mg/kg i.v. dolasetron mesylate, 32 mg i.v. ondansetron,
and placebo on 5 separate days. ECGs were recorded at intervals during the
24 h after study drug administration. The changes in ECG intervals
observed after dolasetron mesylate or ondansetron were acute, transient,
and asymptomatic. Dolasetron mesylate resulted in slight but statistically
significant dose-related increases in heart rate (HR) and PR and QRS
intervals (between h 0 and 4). A statistically significant increase in QTc
interval was detected with both dolasetron mesylate (2.4 mg/kg) and
ondansetron. Ondansetron also produced a slight but statistically
significant increase in JT interval and a decrease in HR. These changes in
ECG intervals were usually observed between h 0 and 4; all parameters
returned to baseline within 8 h of treatment. The results demonstrate that
both dolasetron mesylate and ondansetron prolong the QTc interval.
However, dolasetron mesylate predominantly altered ECG parameters
indicative of ventricular depolarization (QRS duration), whereas
ondansetron predominantly affected ventricular repolarization as measured
by a prolongation in the JT interval. Both dolasetron and ondansetron were
well tolerated. The adverse event (AE) rate was 13.3% (4 of 30); all AE
were of mild or moderate severity and were distributed across all dose
arms.
4: Pharmacol Biochem Behav 1989 Jan;32(1):207-10
Blockade of 5-hydroxytryptamine3 receptors prevents cisplatin-induced but
not motion- or xylazine-induced emesis in the cat.
Lucot JB.
Wright State University, Department of Pharmacology, Dayton, OH 45435.
5-Hydroxytryptamine3 antagonists have been reported to prevent emesis
elicited by cisplatin and radiation. This study investigated the
possibility that drugs with this mechanism of action may be useful in
preventing emesis elicited by other stimuli. The drugs ICS 205-930 (0.1
and 1.0 mg/kg) and MDL 72222 (0.1 and 1.0 mg/kg) were administered SC to
cats before challenging them with either provocative motion or an emetic
dose of xylazine. In no instance was a significant reduction in emesis
evident. Zacopride was also administered before motion testing (0.01 to
10.0 mg/kg) and found to not have efficacy. To test the possibility that
species or route of administration were factors in the negative results,
1.0 mg/kg of ICS 205-930 was administered SC before IV infusion of 7.5
mg/kg of cisplatin. There was a total suppression of emesis for the
duration of the six-hour observation periods. This result verifies other
work which found 5-hydroxytryptamine3 antagonists to be effective in
preventing emesis elicited by cancer chemotherapeutic treatments. However,
there is no evidence that they are effective in other syndromes, such as
motion sickness and xylazine-induced emesis.
5: Eur J Cancer Clin Oncol 1989;25 Suppl 1:S21-4; discussion S25-7
The clinical pharmacology of ondansetron.
Blackwell CP, Harding SM.
Department of Human Pharmacology, Glaxo Group Research Limited, Greenford,
Middlesex, U.K.
Ondansetron, a 5-HT3 antagonist proposed for use in the treatment of
chemotherapy-induced emesis, was first given to man in 1984 and in the 4
years subsequent to this, the drug was given to more than 220 different
healthy volunteers. In pharmacodynamic studies, there was evidence to
suggest that ondansetron was gastroprokinetic but reduced transit time
through the small bowel. Ondansetron was of no benefit in a model of
motion sickness. The pharmacokinetics of ondansetron have been defined in
volunteers using intravenous and oral dosage regimens proposed for the
clinic. Ondansetron had a terminal plasma half-life of 3.0-3.5 h and
plasma clearance (principally metabolic) of the order of 600 ml/min, and
there was no evidence of accumulation at steady state. The absolute oral
bioavailability of ondansetron was 59%. Metabolic studies showed the drug
to be excreted predominantly in urine and faeces, with a metabolite
profile in urine similar to that seen in the animal species used for
toxicological testing. Ondansetron is both safe and well tolerated at
daily doses of up to 64 mg given to volunteers.
--
-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-
Rollie Parrish
FlightWeb: For Air Medical Professionals
http://www.flightweb.com
_______________________________________________
Flightmed mailing list
To unsubscribe or change your email address, go to http://www.pairlist.net/mailman/listinfo/flightmed
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