Pharmacological and Toxicological Studies of Palytoxin - ACS

Chapter 19

Pharmacological and Toxicological Studies of Palytoxin James A. Vick and Joseph Wiles

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U.S. Food and Drug Administration, 200 C Street, SW, Washington, DC 20204 Palytoxin is one o f the most potent coronary vasoconstrictors k n o w n , producing death by the iv routewithin minutes by diminishing the supply o f oxygen to the myocardium. Tests i n animals with a number o f vasodilators showed that papaverine and isosorbide dinitrate are effective antidotes, but must be injected directly into the ventricle o f the heart because o f the speed o f action o f the toxin. Sublethal doses o f this toxin given intragastrically and intravenously produce elevated plasma cortisol concentrations and protect against subsequent lethal intravenous challenge. This protection is lost with time; however, a second sublethal injection o f palytoxin, after circulating plasma cortisol have decreased and prior to lethal challenge, once again partially increases b l o o d steroid concentrations and reestablishes protection. Pretreatment with hydrocortisone also provided partial protect i o n against lethal doses o f the toxin. T h e one h o u r required for protection to develop is probably the time required for desensitization o f the endothelial wall to vasoconstrictors. Adrenalectomized animals do not develop any degree o f protection unless treated with exogenous hydrocortisone, substantiating the involvement o f steroids. T h e possibility o f an additional, additive i m m u n e mechanism i n the response o f the animals to palytoxin is also suggested. These studies have provided a foundation for the understanding o f how palytoxin works as well as for the development o f a therapeutic regime for treating palytoxin poisoning i n man. Palytoxin is a potent toxin extracted from a soft coral sea anemone, Palythoa vestitus, found i n certain S o u t h Pacific islands. Interesting legends concerning a "deadly seaweed" o r a "pool o f death," which the natives o f H a w a i i called L i m u make-o-Hana, led scientists to make inquiries about the material found i n these waters. They found that the toxic effects were not caused by a seaweed, but by the coral associated with it. Further investigation indicated that the toxin was actually o f marine origin and derived from a sea anemone. Initial isolation and testing ( i , 2), indicated that this substance was indeed highly toxic and that the empirical formula was C H N 0 . T h e stereochemistry o f palytoxin was studied by C h a et al. (3) and the actual configuration established by U e m u r a et al.(4). Earlier studies by Wiles et al. (5) in which palytoxin was administered by various routes showed that this material was extremely toxic to rabbits, dogs, and m o n keys. T h e effect o f route o f administration o n toxicity varies i n that intravenous (iv), intramuscular (im), and subcutaneous (sc) toxicity is high, yet intrarectal (ir) o r oral (po) palytoxin is relatively ineffective. It was also observed that palytoxin 3 Q

5 3

1 4

This chapter not subject to U.S. copyright Published 1990 American Chemical Society

Hall and Strichartz; Marine Toxins ACS Symposium Series; American Chemical Society: Washington, DC, 1990.

242

MARINE TOXINS: ORIGIN, STRUCTURE, AND MOLECULAR PHARMACOLOGY

caused marked irritation and tissue injury when applied topically to the skin or eyes o f animals. In additional studies, Wiles et al. (5) found that rats and rabbits given palytoxin by either the ir or po route appear to be protected against a subsequent iv o r i m injection. This tolerance, or immunity, appears to be related to the time between initial exposure and subsequent challenge. This chapter is concerned therefore with studies o f the mechanism o f action o f palytoxin, how it produces its lethal effects, as well as attempts to develop an antidote for this form o f poisoning.


Methods T h e palytoxin used was obtained from M o o r e and Scheuer, University o f H a w a i i . T h e crude toxin was purified and analyzed by Sephadex columns, reconstituted i n 5 0 % ethanol and water, stored i n a refrigerator, and bioassayed for potency at least once a week during use. A l l dilutions o f the palytoxin were made with glass distilled water. T h e toxicity o f palytoxin i n six unanesthetized animal species was established as well as the toxicity o f the toxin when administered by various routes. Tables I and II show the doses and numbers o f animals used i n this phase o f the study. A n t i d o t a l Therapy Studies. Thirty-seven dogs were anesthetized with sodium pentobarbital and were given 0.01 /ig/kg o f palytoxin iv into the right femoral vein and treated at onset o f cardiac symptoms with either papaverine (10—50 mg) o r isosorbide dinitrate (0.5-5.0 mg). (In initial studies, 70 dogs given 0.005-0.015 /ig/kg o f this particular batch o f palytoxin iv all died.) Criteria for administration o f therapy were a sharp drop i n arterial pressure, an increase i n the height o f the Q R S segment o f the E K G , a decrease i n heart rate, and the development o f difficult breathing. T h e therapeutic injections were made directly into the left ventricle o f the heart with a 4.5-in., 18-gauge needle due to the speed with which the palytoxin acts i n producing its lethal effects and thus the inadequacy o f iv or i m therapy which cannot reach the primary site o f palytoxin toxicity, the myocardial tissue. Protection Studies. A n i m a l s were given a sublethal dose o f palytoxin followed at various time intervals by a lethal dose. C o n t r o l and treatment data for each route o f administration and species studied are given i n the appropriate table (Tables III, I V , V , and V I ) . Rats (Table III) were given a dose o f 5 /ig/kg o f palytoxin either ir o r po followed at 1—72 hr by 0.25 /ig/kg i m . A second group o f rats were given palytoxin po, 10 /ig/kg, followed by an iv dose o f 0.20 /ig/kg. O n e group o f rabbits (Table I V ) was given 2.5 /ig/kg po, followed at 1-72 hr by 0.025 /ig/kg iv. A dose o f 0.5 /ig/kg was instilled into o n e eye intraocular (io) o f each rabbit i n another group, and this was followed at 2 - 4 8 hr by 0.032 /ig/kg palytoxin iv. T h e concentration o f the aqueous solution o f palytoxin administered to these animals was 5 - 1 0 /ig/mL. T h e challenge dose was administered through the marginal ear vein o f the rabbits, the femoral vein o f the rats, o r into the thigh muscle o f either species as indicated i n the appropriate tables. A d u l t mongrel dogs (Table V ) and rhesus monkeys (Table V I ) were anesthetized with sodium pentobarbital (30 mg/kg) and given sublethal dose o f palytoxin followed by challenge (lethal) doses. A r t e r i a l and venous b l o o d pressure was m o n i tored continuously using Statham strain gauges, recording o n an E & M physiograph. Respiratory rate, electrocardiogram ( E K G ) and heart rate were continuously m o n i tored using needle-tip electrodes placed i n either side o f the chest wall.


VICK & WILES

Pharmacological and Toxicological Studies ofPalytoxin


Table I. Intravenous Toxicity o f Palytoxin i n Several A n i m a l Species

Species

No. of Animals

Rabbit Dog Monkey Rat Guinea Pig Mouse

20 20 10 50 20 100

24-hr

LD

5Q

(Pglkg) 0.025 (0.024-0.026) 0.033 (0.026-0.041) 0.078 (0.60-0.090) 0.089 (0.080-0.098) 0.11 (0.070-0.170) 0.45 (0.33-0.62)

3

9 5 % confidence limits

Table II. Toxicity o f Palytoxin Administered by V a r i o u s Routes i n the R a t

Route

No. of Animals

Intravenous (iv) Intramuscular (im) Intratracheal Subcutaneous (sc) Intraperitoneal Intragastric (po) Intrarectal (ir)

20 20 20 20 20 20 20

24-hr LD (pg/kg)

50

»

0.089 (0.80-0.098) 0.24 (0.21-0.28) 0.36 (0.23-0.55) 0.40 (0.29-0.54) 0.71 (0.45-1.12) >40.0 >10.0

3

9 5 % confidence limits



Table III. Toxicity o f Palytoxin i n Rats W h e n a n I n i t i a l Sublethal Dose is Followed by a L e t h a l Dose


Initial Injection

Challenge Injection

Dose

Time After Initial Injection

Route

(ug/kg)

(hr)

im (control) ir

0.25 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 0.20 10.0 10.0 10.0 10.0

po

iv (control) po

—

Route

Dose (ug/kg)

—

N o challenge (control) 4 im 24 im 48 im N o challenge (control) 1 im 4 im 24 im 48 im 72 im

-

-

N o challenge (control) iv 1 4 iv iv 24

—

0.25 0.25 0.25

0.25 0.25 0.25 0.25 0.25

0.20 0.20 0.20

Mortality Fraction (within 48 hr after challenge) 6/12 0/8 0/8 0/8 3/8 0/8 7/8 7/8 5/8 3/8 8/8 6/6 0/6 5/5 5/5 1/5

Table I V . Toxicity o f Palytoxin i n Rabbits W h e n a n Initial Sublethal Dose is Followed by a L e t h a l Dose Initial Injection

Route iv (control) po

iv (control) Intraocular

Dose (ug/kg) 0.025 2.5 2.5 2.5 2.5 2.5 2.5 0.032 0.5 0.5 0.5 0.5 0.5

Challenge Injection Time After Initial Injection (hr)

Route

—

—

N o challenge (control) iv 1 iv 4 iv 24 iv 48 iv 72

-

-

N o challenge (control) iv 2 4 iv iv 24 iv 48

Dose (ug/kg)

0.025 0.025 0.025 0.025 0.025

0.032 0.032 0.032 0.032

Mortality Fraction (within 48 hr after challenge) 6/12 0/6 3/6 4/6 2/6 0/6 6/6 6/6 0/6 6/6 6/6 3/6 4/6


19. VICK & WILES

Pharmacological and Toxkological Studies of Palytoxin

Table V. Toxicity of Palytoxin in Dogs (Normal) When an Initial Sublethal Dose is Followed by a Lethal Dose Initial Injection

Dose (ug/kg)


Route iv (control) po

iv

0.05 2.5 2.5 2.5 2.5 2.5 2.5 0.1 0.01 0.01 0.01 0.01 0.01 0.01 0.01


Route

Dose (ug/kg)

-

-

—

N o challenge (control) iv 4 iv 24 iv 48 iv 72 iv 7 days N o challenge (control) iv Immediately iv 2 iv 4 iv 24 iv 48 iv 72 iv 7 days

0.05 0.05 0.05 0.05 0.05

0.05 0.05 0.05 0.05 0.05 0.05 0.05

Mortality Fraction (within 48 hr after challenge) 6/6 0/2 3/4 2/3 0/2 2/2 1/1 0/2 4/4 4/5 2/2 4/4 1/4 0/8 4/8

Table VI. Toxicity of Palytoxin in Monkeys (Normal) When an Initial Sublethal Dose is Followed by a Lethal Dose Initial Injection

Route iv

Dose (ug/kg) 0.01 0.005 0.01 0.005


Dose Route

N o challenge (control) N o challenge (control) 72 iv 72 iv

(Ug/kg)

0.05 0.05

Mortality Fraction (within 48 hr after challenge) 1/2 0/4 1/4 0/4


245

246


T h e dogs were given 2.5 ug/kg o f palytoxin (po) o r 0.001 /ig/kg (iv) followed i n hr to 7 days by an L D . Q Q dose o f 0.05 ug/kg (iv). Certain dogs were given two doses o f 0.001 /ig/kg (iv) 7 days apart and challenged w i t h 0.05 /ig/kg (iv) 2 4 hr o r 15 days after the second sublethal dose. In a series o f range-finding studies i n monkeys, the lethal dose o f palytoxin was established at 0.05 ug/kg (iv). O n e o f two monkeys survived a dose o f 0.01 ug/kg and four o f four survived a dose o f 0.005 ug/kg. Therefore, and as i n the dog (challenge) study, the monkeys were given either 0.01 o r 0.005 /ig/kg, followed i n 7 2 hr by a dose o f 0.05 /ig/kg (iv). B l o o d samples for determination o f hydrocortisone concentrations were taken from a group o f 10 dogs p r i o r to and at 2, 24, 48, and 7 2 hr and 15 days after receiving a sublethal dose o f 0.001 /ig/kg o f palytoxin iv. Concentrations were measured using standard techniques as described by Sweat (6) and Peterson et al. 2


(7).

Adrenalectomized mongrel dogs and rhesus monkeys were studied 2 weeks foll o w i n g surgery. (Steroids were given to the animals only i n the immediate postoperative period.) They were anesthetized and prepared for recording o f physiological data as previously described. T h e dogs were given an initial dose o f 0.001 /ig/kg o f palytoxin iv followed i n 7 2 hr by a dose o f 0.05 /ig/kg iv. T h e monkeys were given palytoxin 0.005 /ig/kg iv followed i n 7 2 hr by an iv dose o f 0.05 ug/kg. A n additional 6 dogs and 4 monkeys (adrenalectomized) were given 5 0 mg/kg o f hydrocortisone sodium succinate iv into the femoral vein 1 hr p r i o r to challenge w i t h the lethal dose (0.05 ug/kg) o f palytoxin. Six n o r m a l dogs and 4 n o r m a l monkeys were given one dose o f 5 0 mg/kg hydrocortisone 1 hr prior to receiving 0.05 ug/kg palytoxin to further assess the role o f steroids i n palytoxin poisoning. T h e concentration o f the aqueous solution o f palytoxin given to the dogs and monkeys was 5.6 / i g / m L , and was injected directly into the exposed femoral vein o f each a n i m a l . T h e animals given intragastric palytoxin were fasted for 2 4 hr p r i o r to testing. A l l animals were observed for 7 2 hr o r u n t i l death.

Results T h e iv toxicity o f palytoxin is shown i n Table I. Rabbits and dogs appear to be the sensitive to palytoxin; rats and guinea pigs appear less sensitive. Table II shows the comparative toxicity o f palytoxin administered by several routes - again iv palytoxin is extremely toxic w h i l e ir and p o are relatively without toxic effects.

Antidotal Therapy Studies.

O n e o f the most challenging considerations i n treating p o i s o n i n g by palytoxin was that the average time to death i n the dogs was 3.5 m i n . A t t e m p t s at iv therapy were ineffective i n that stagnation o f venous b l o o d flow occurred so rapidly that antidotes were p o o l e d i n the venous circulation. D i r e c t injections o f either papaverine o r isosorbide dinitrate into the left ventricular o f the heart were made i n attempts to reverse the cardiotoxic effects o f the toxin. A d d i tional doses o f either agent were required at 1 - 2 - h r intervals over a 12-hr period to m a i n t a i n n o r m a l cardiovascular function. In general, dogs responded more favorably to the administration o f isosorbide dinitrate than to papaverine. O f the dogs treated i n this fashion, 4 9 % survived (18/37). T h e effects o f a lethal dose o f palytoxin o n E K G , heart rate, respiration, and b l o o d pressure o f dogs are shown i n F i g u r e 1. F i g u r e 2 shows the ability o f a vasodilator to alter the otherwise lethal course o f events o f this c o m p o u n d . In those animals w h i c h expired, death appeared due to profound coronary vasoconstriction and subsequent cardiac failure.

Protection Studies.

T h e responses o f rats and rabbits given a sublethal dose o f palytoxin followed by lethal challenges are shown i n Tables III and I V .


Hall and Strichartz; Marine Toxins ACS Symposium Series; American Chemical Society: Washington, DC, 1990. 2

3

7

FIBRILLATION

6

t VENTRICULAR

\

5

t

^

4

PALYTOXIN .01 ug/kg

100

200

1 lliillliiilliliililllliiiiiiiiiillllllhiiiliiilW

8

9

10

11

12

iliiSi minutes

(Reproduced from R e f . 10.)

Figure 1. Effect o f a lethal dose o f palytoxin o n E K G , heart rate, respiration, and b l o o d pressure.

mm Hg

PRESSURE

BLOOD

RESPIRATION

HEART RATE

EKG


4t


0 0

»***

PALYTOXIN •01 ug/kg

,

200

*

> " < < • > • '

VASODILATOR

/8|i

• "

'

'» M N»

' \

\

\

\-

J

SURVIVOR

Figure 2. Effect o f treatment with isosorbide dinitrate i n reversing the otherwise lethal effect o f palytoxin. (Reproduced from Ref. 10.)

PRESSURE mm Hg

BLOOD

RESPIRATION

TIME

EKG

HEART RATE


s

o

o

i

a

o S

s

is

2 2

z o

M H


19. VICK & WILES


Rats showed an increase tolerance to i m palytoxin at 4 and at 24 hr when the initial dose had been given ir (0/8 vs. 6/12 mortalities). A n initial oral po dose also provided some protection against lethal iv challenge, 1/5 vs 6/6 mortalities at 24 hr, however, after these times protection was lost. Rabbits showed a similar trend to that seen i n the rats when the initial dose was administered by either the po (0/6 vs. 6/12 at 48 hr) o r the io (3/6 vs. 6/6 at 24 hr). Anesthetized dogs and monkeys responded similarly to palytoxin (Tables V and VI). In the dog, maximum protection was seen against lethal challenge at 48 (1/4 vs. 6/6) and at 74 (0/8 vs. 6/6) hr after the initial sublethal iv doses. A t 7 days after initial dosing only 4 o f 8 dogs survived lethal challenge, however, a second sublethal injection administered 7 days after the initial sublethal dose but prior to the lethal challenge reestablished the ability o f the animals to withstand a lethal dose o f palytoxin (6/6 survived) at 24 hr and (4/5 survived) at 15 days (Figure 3). M o n k e y s given sublethal iv doses o f palytoxin also showed some protection at 48 hr, 0/4 vs. 3/3 mortality. T h e protection afforded intact dogs by a sublethal injection o f palytoxin appeared to be i n part associated with an increased b l o o d steroid concentration i n that the postinjection period during which there was the greatest protection was also the period when the highest b l o o d steroid concentrations were recorded (Figure 3). B l o o d steroids increased from a control o f 4.2 /tg/100 m L to 18.7 /zg/100 m L at 72 hr, decreasing to 7.0 /ig/100 m L at 7 days. A second sublethal injection at 7 days increased steroid levels to 23.0 /ig/100 m L and provided maximum protection against a lethal dose o f palytoxin. O f note is the observation that steroid concentrations decreased to 9.8 /zg/100 m L 15 days after the second sublethal dose o f palytoxin yet 8 0 % o f the animals still survived lethal challenge. Adrenalectomized dogs and monkeys given sublethal doses o f palytoxin iv did not develop any protection against lethal challenge (Table V I I ) , nor did the b l o o d steroid levels increase at any time during the study. However, the administration o f hydrocortisone 1 hr prior to challenge did protect both adrenalectomized dogs and monkeys against the otherwise lethal dose o f palytoxin. In addition, 3 o f 6 normal dogs and 2 o f 4 normal monkeys given hydrocortisone 1 hr prior to lethal challenge with palytoxin survived (Figure 4). Discussion Palytoxin is probably one o f the most potent toxins k n o w n to humans. Intravenous L D ^ values i n the six species that have been studied are consistently less than 0.5 /xg/kg. In addition, palytoxin possesses a speed o f action and other pharmacologic properties that are markedly different from those exhibited by other toxic materials. F o r example, when injected iv o r sc, palytoxin is extremely toxic; yet when given po or ir, it is relatively non-toxic. It is also very interesting that the doses o f palytoxin required to k i l l are somewhat different i n anesthetized vs. unanesthetized animals. T h e signs noted i n intact, unanesthetized animals following iv administration o f palytoxin vary somewhat i n the different species. Rats, guinea pigs, rabbits, and mice become drowsy and inactive. Prostration, dyspnea, and convulsions often occur just prior to death. N o other signs were observed, probably due to the speed with which palytoxin acts. M o n k e y s become drowsy, weak, and ataxic; then collapse and die. V o m i t i n g occurs. T h e drowsiness seen i n monkeys is not seen i n dogs. Instead, dogs normally defecate, vomit, become weak, ataxic, collapse, and die within 5 to 10 m i n . If death is delayed, a shocklike state is seen. Body temperature falls and extensive hemorrhage into the gastrointestinal tract occurs. B l o o d y vomitus 0


249


Figure 3. Effect of repeated injections of palytoxin on blood steroids and survival. (Reproduced from Ref. 10.)


2

s

ο

Π

i

η

M

1

ο g ο

M

S

©

in


-

iv iv iv

0.005 0.005 0.005 No

0.001 0.001 0.001 No

iv iv iv

-

(Ug/kg)

Route

Route

0.05 0.05 0.05

-

0.05 0.05 0.05

-

(Pglkg)

Dose

Adrenalectomized animals. A n i m a l s not adrenalectomized.

N o challenge (control) 72 iv 72 iv — iv

N o challenge (control) 72 iv 72 iv — iv

Time After Initial (hr)

Challenge Injection

50 mg/kg iv hydrocortisone 1 hr prior to challenge. 60 mg/kg iv hydrocortisone 1 hr prior to challenge.

Monkey

Dog

Species

Dose

Initial Injection

b

a

0/2 2/2 0/4 2/4

b

a

4/10 6/6 0/6 3/6

Mortality (within 48 hr after challenge)

Table VII. Toxicity of Palytoxin in Adrenalectomized Dogs and Monkeys When an Initial Sublethal Dose is Followed by a Lethal Dose



Figure 4. Effect o f pretreatment w i t h hydrocortisone (50 mg/kg) o n response o f animal to a lethal injection o f palytoxin (0.01 /xg/kg).



19. VICK & WILES


and diarrhea are often noted. T h e massive hemorrhage observed i n the gut o f the dog is not prominent i n other species. P o o l i n g o f b l o o d i n the hepatosplanchnic bed has been previously reported i n dogs given a variety o f toxins and may be a species-specific effect (8). E a r l y death i n dogs and monkeys given palytoxin appears to be due to profound coronary vasoconstriction and rapid cardiac failure. Careful analysis o f E K G recordings indicates that this toxin produces intense myocardial ischemia which results i n either ventricular fibrillation or cardiac arrest. Palytoxin appears to act directly o n the smooth muscle o f the vessel walls to produce this marked coronary vasoconstriction. This constriction is undoubtedly widespread throughout the body, yet it is primarily the reduction i n flow to the heart that produces the irreversible damage and subsequent death. It is also important to note that palytoxin produces vasoconstriction i n a dose considerably less than the doses reported for other potent vasoconstrictors. G o o d m a n and G i l m a n (9) report that angiotensin II produces noticeable changes i n vessel tension at 1-10 /ig/kg; this is at least 100 times the dose o f palytoxin that not only produced changes i n vessel tension but resulted i n death o f the animal. T h e direct injection o f potent vasodilatory agents such as papaverine o r isosorbide dinitrate, into the ventricles o f the heart reverses the action o f palytoxin i n approximately one-half o f the animals. These extreme measures are required because palytoxin kills quickly. Antidotes injected into the venous circulation were not able to reach the heart because the stagnation o f venous b l o o d occurs so rapidly that antidotes are simply pooled o n the venous side o f the circulation and never reach the heart. In these studies isosorbide dinitrate appeared to be approximately twice as effective as papaverine i n reversing the toxic effects o f palytoxin. Pretreatment with hydrocortisone protected 50% o f the animals against a lethal challenge with palytoxin. This is undoubtedly related to the reported action o f this steroid i n protecting the vascular tree. T h e observation that a m i n i m u m o f 1 hr is required between injection o f hydrocortisone and the development o f protection indicates that this may be the time required for desensitization o f the endothelial wall to vasoconstrictors or, to some other u n k n o w n action o f steroids i n the body. A d d i t i o n a l data shows that increased protection against lethal challenge is associated with an increase i n steroid concentration which is the result o f prior sublethal palytoxin administration. In addition, protection is partially lost as the concentrat i o n o f the steroid decreases, yet a second sublethal dose o f palytoxin given when protection has decreased w i l l once again increase b l o o d steroid concentration and reestablish protection against a lethal dose o f toxin. It follows, therefore, that adrenalectomized animals which cannot develop increased plasma steroid levels are not protected against palytoxin. T h e possibility exists that the i m m u n e mechanism may also be involved i n this phenomenon i n that repeated sublethal doses o f palytoxin do not maintain the same high concentrations o f b l o o d steroids, yet protection against lethal challenge remains almost maximal. T h e cause o f death from palytoxin can be attributed to several factors. Early death is probably due to intense spasm o f coronary vascular smooth muscle, resulting i n marked reduction i n cardiac output. This may be an early manifestation o f what later becomes a general necrotizing effect o f palytoxin o n b l o o d vessels, which ultimately causes cell destruction throughout the body. T h e delayed deaths may be due to a less profound yet widespread decrease i n b l o o d flow and oxygen supply, causing ischemia and, ultimately, anoxia to major organ systems. This w o u l d account for the gradual reduction i n cardiac function and respiration seen i n the later animal deaths. Kidney damage due to accumulation o f metabolites could also be a factor which contributes to death from palytoxin.


253

254


These studies have provided a foundation for the understanding o f the possible mechanism by w h i c h palytoxin kills and for the development o f a therapeutic regim e n w h i c h might have application to humans.


Literature Cited 1. Scheuer, P.J. Program Chem. Org. Nat. Prod. 1964, 22, 265-283. 2. Mosher, H.S.; Fuhrman, F.A; Buckwald, H.D.; Fisher, H.G. Science 1964, 144, 1100-1110. 3. Cha, J.K.; Christ, W.J.; Finan, J.; Fujioka, H.; Kishi, Y.; Klein, L.; Ko, S.; Leder, J.; McWhorter, W.; Pfaff, K.; Yonaga, M. J. Am Chem. Soc. 1982, 104, 7369-7371. 4. Uemura, D.; Hirata, Y.; Iwahita, T.; Naoki, H. Tetrahydron 1985, 41, 1007-1017. 5. Wiles, J.S.; Vick, J.A.; Christenson, M.K. Toxicon 1974, 12, 427-433. 6. Sweat, M.L. Anal. Chem. 1954, 26, 773. 7. Peterson, R.E.; Karrer, A.; Guerra, S.L. Anal. Chem 1957, 29, 144-149. 8. Vick, J.A. Mil. Med. 1973, 138, 279-285. 9. Douglass, W. W. In The Pharmacological Basis of Therapeutics, 3rd ed., Goodman, L.; Gilman, A., Eds.; The MacMillian Company: New York, 1965; p. 653. 10. Vick, J.; Wiles, J. Toxicol. Appl. Pharmacol. 1975, 34, 214. RECEIVED June 30, 1989


Pharmacological and Toxicological Studies of Palytoxin - ACS

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