Betterchem
Health     Drug Information     News     FindingHealthOnline     For Industry     Search     Site Map

 


Veterinary Drugs

 
Product and
NADA/ANADA Number
Trade Name
Ingredients
Ponazuril
141-188
MarquisTM
Ponazuril

                                                                   
Back to TOC


API Locator: A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U-Z

Home | Drug Thesaurus | Veterinary Master Files | Version with API Search | Services | Site Map

Summary of 
FDA Information:

FREEDOM OF INFORMATION SUMMARY Original New Animal Drug Application NADA 141-188 Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste "…for the treatment of
equine protozoal myeloencephalitis (EPM) caused by Sarcocystis neurona." For Oral Use in Horses Sponsored by: Bayer Corporation Agriculture Division Animal Health.Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste TABLE OF CONTENTS I. GENERAL INFORMATION 1 II. INDICATIONS FOR USE 1 III. DOSAGE FORM, ROUTE OF ADMINISTRATION, AND DOSAGE 1 IV. EFFECTIVENESS 1 A. Dosage Characterization 1 B. Clinical Field Study 1 5 C. Clinical Field Study 2 9 V. ANIMAL SAFETY 11 VI. HUMAN SAFETY 16 VII. AGENCY CONCLUSIONS 16 VIII. APPPROVED PRODUCT LABELING 16 NADA 141-188 Page ii.Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste I. GENERAL INFORMATION NADA Number: 141-188 Sponsor: Bayer Corporation Agriculture Division Animal Health P. O. Box 390 Shawnee Mission, Kansas 66201 Generic Name: ponazuril Trade Name: Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste Marketing Status: This is a prescription (Rx) product which
carries the following caution statement: "Federal (USA) law restricts this drug to use by or
on the order of
a licensed veterinarian." II. INDICATIONS FOR USE Marquis (ponazuril) is indicated for
the treatment of
equine protozoal myeloencephalitis (EPM) caused by Sarcocystis neurona. III. DOSAGE FORM, ROUTE OF ADMINISTRATION, AND DOSAGE Dosage Form: Marquis (ponazuril) is available in cartons containing four (4) syringe applicators and
one (1) syringe plunger. Each syringe barrel of
Marquis (ponazuril) will deliver 127 grams of
paste. Each gram of
paste contains 150 mg of
ponazuril (15% w/w). Route of
Administration: Marquis (ponazuril) is administered orally. Recommended Dosage: Each syringe barrel of
Marquis (ponazuril) contains enough paste to treat
one (1) 1,200 lb. (545 kg) horse for
seven (7) days, at a dose rate of
5 mg/kg (2.27 mg/lb.) body weight.
The plunger contains a dosage ring calibrated for
a dose rate of
5 mg/kg (2.27 mg/lb.) body weight and
marked for
horse weights from
600 to 1,200 lb. (273 to 545 kg).
The syringe barrels are packaged in units of
four with one reusable plunger.
This package provides sufficient paste to treat
one 1,200 lb. (545 kg) horse for
28 days at a dose rate of
5 mg/kg (2.27 mg/lb.) body weight. IV. EFFECTIVENESS A. Dosage Characterization To characterize the dose of
ponazuril necessary to treat
infections of
Sarcocystis neurona, several lines of
evidence were
considered. Studies have demonstrated that ponazuril is an effective anticoccidial drug for
the treatment of
gastrointestinal and
somatic coccidiosis in several species of
mammals and
birds, including cattle, sheep, swine, rabbits and
chickens at doses of
7-20 mg/kg.
Therefore, a series of
studies was
conducted to determine a dose of
ponazuril that would be effective in horses against Sarcocystis neurona. First, an in vitro test was
conducted to determine the dose of
drug necessary in the
cerebrospinal fluid of
the horse. Second, a pharmacokinetic study
defined the level of
drug that could be obtained in both serum and
CSF. Finally, two doses were
tested in naturally infected horses in a clinical field study
. NADA 141-188 Page 1.Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste 1. In vitro Susceptibility Study a. Type of
Study/Purpose: To evaluate the activity of
ponazuril against the intracellular stages of
Sarcocystis neurona in cell culture. b. Investigators: J. P. Dubey, Ph.D., USDA, Agricultural Research Service, Livestock and
Poultry Sciences Institute, Parasite Biology and
Epidemiology Laboratory, Beltsville, MD 20705 D. S. Lindsay, Ph.D., Virginia-Maryland Regional College of
Veterinary Medicine, Virginia Tech, 1410 Prices Fork Road, Blacksburg, VA 24061-0342 T. J. Kennedy, Ph.D., Bayer Corporation, Agriculture Division Animal Health, P.O. Box 390, Shawnee Mission, KS 66201 c. General Design: In vitro evaluation of
effectiveness to inhibit merozoite development in cell cultures. 1) Test Media: Bovine turbinate or
African green monkey kidney cells grown to confluence in supplemented RPMI media. 2) Treatments: 0.001, 0.01, 0.1, 1.0, 5.0 µg/mL of
ponazuril in the
culture media 3) Procedure: All cultures were
grown in 25 cm 2 plastic cell culture flasks, incubated at 37°C in a reduced atmosphere and
stored under
the same conditions.
The assay involved an assessment of
merozoite production. Cell monolayers were
infected with S. neurona merozoites, SN6 strain, isolated from
a horse with EPM. Two hours after inoculation of
the cells with merozoites, various concentrations of
ponazuril were
added to the media one time and
the cultures allowed to incubate for
10 days. After 10 days of
incubation, visual damage to the cell monolayer was
assessed, media removed and
quantified and
the number of
merozoites per mL determined by counting using a hemocytometer. d. Results: Using a time of
10 days post-treatment, ponazuril inhibited merozoite production by more than 94% in bovine turbinate cultures of
S. neurona treated with 0.1-1.0 µg/mL ponazuril and
greater than 97% inhibition of
merozoite production was
observed when
infected cultures were
treated with 5 µg/mL. Results are shown in Table IV.1 NADA 141-188 Page 2.Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste Table IV.1 Percent reduction in merozoite production in cell cultures infected with S. neurona and
treated with various concentrations of
ponazuril African green monkey cells Ponazuril Concentration (µg/mL) Merozoite count ±1sd % Reduction None 1,406,438 ±276,817 NA 0.1 412,062 ±102,227 70.7 1.0 139,125 ±200,878 90.1 5.0 40,125 ±43,758 97.1 Bovine turbinate cells Ponazuril Concentration (µg/mL) Merozoite count ±1sd % Reduction None 4,175,125 ±464,794 NA 0.01 3,040,688 ±410,257 27.2 0.1 231,813 ±93,988 94.4 1.0 63,313 ±46,594 98.5 5.0 86,375 ±58,853 97.9 e. Conclusion: Ponazuril is effective against the merozoite stage of
Sarcocystis neurona in cell culture. 2. Pharmacokinetic Study a. Type of
Study/Purpose: Single phase multiple dose study
with blood and
cerebrospinal fluid samplings to determine the pharmacokinetics of
ponazuril when
given at 5 mg/kg as a 15% w/w oral paste formulation in normal horses. To determine the level of
ponazuril in the
serum and
cerebrospinal fluid of
horses prior to, during and
after the administration of
5 mg/kg daily for
28 days. b. Investigator: Dr. Martin Furr, Marion duPont Scott Equine Center, Virginia Tech University, Old Waterford Rd. at Morven Park, P.O. Box 1938, Leesburg, VA 20177 c. General Design: 1) Animals: Ten healthy horses, all male castrates, ranging in age from
3-15 years 2) Treatment: Daily dose of
5 mg/kg (2.27 mg/lb) for
28 days with a 15% oral paste formulation of
ponazuril 3) Treatment group assignment: Animals all received the same treatment. 4) Treatment Dose, Route, Frequency and
Duration: Animals received ponazuril at a rate of
5 mg/kg body weight daily for
28 days. NADA 141-188 Page 3.Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste 5) Clinical Examination/Clinical Scoring: Animals were
evaluated by physical examination, hematology and
serum chemistry and
cerebrospinal fluid indices. 6) Samples: Serum was
collected for
ponazuril assay at Days 0, 7, 14, 21, 28, 35, 36, 37, 38, 39, 40, 41, 42 and
49. Cerebrospinal fluid was
collected for
ponazuril assay at Days 0, 7, 14, 21, 28, 35, 42 and
49. d. Results: Maximum calculated serum and
CSF concentrations were
5.59 ug/mL and
0.21 ug/mL, respectively.
These occurred on days 18.2 and
15 for
serum and
CSF, respectively.
The terminal elimination half-life for
serum (calculated using Day 28 to 42 data) was
4.50 ± 0.57 days. Steady state was
achieved by approximately 20 days post dose, which
is consistent with the terminal elimination half-life of
approximately 4.5 days.
The ratio of
CSF to serum was
approximately 4%.
The mean concentration vs. time profiles in serum and
CSF are provided in Tables 1 and
2 below. Table 1. Serum Concentrations (ug/mL) of
Ponazuril, By Days 0 7 14 21 28 35 36 37 38 39 40 41 42 49 Mean 0 4.33 5.26 5.18 4.66 0.394 0.289 0.236 0.2 0.167 0.152 0.124 0.106 0.101 SD 0 1.098 0.877 1.187 0.6 0.186 0.131 0.103 0.105 0.085 0.102 0.088 0.073 0.086 Table 2. CSF Concentrations (ug/mL) of
Ponazuril, By Days 0 7 14 21 28 35 42 49 Mean 0 0.182 0.156 0.169 0.156 0.02 0.001 0.001 SD 0 0.076 0.033 0.055 0.048 0.011 0.003 0.003 e. Conclusions: Ponazuril, when
dosed at 5 mg/kg for
28 days, provides measurable drug concentrations in both serum and
cerebrospinal fluid. 3. Summary of
Dose Characterization: First, studies have demonstrated that ponazuril is an effective anticoccidial drug in several species of
mammals and
birds. Second, an in vitro evaluation has shown that ponazuril can significantly reduce Sarcocystis neurona merozoite production in cell cultures. Levels of
drug in the
range of
0.1-1.0 ug/mL were
94% effective when
tested in bovine turbinate cell cultures and
70.7% effective when
tested in African Green monkey cells.
Third, ponazuril, when
dosed to healthy horses at 5 mg/kg once daily for
28 days, provided mean daily steady state CSF concentrations ranging between 0.156 ug/mL to 0.182 ug/mL. In bovine cell culture this level was
adequate to effect a 94% parasite kill rate. NADA 141-188 Page 4.Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste B. Clinical Field Study 1 1. Type of
Study: The study
was conducted as a field evaluation of
two doses of
ponazuril (5 mg/kg and
10 mg/kg).
The study
was conducted by seven investigators involving a total of
102 acceptable cases. 2. Investigators: Dr. Frank Andrews, Large Animal Clinical Medicine, College of
Veterinary Medicine, University Of Tennessee, P.O. Box 1071, Knoxville, TN 37901-1701 Dr. Fairfield Bain, Hagyard-Davidson-Mcgee, 4250 Ironworks Road, Lexington, KY 40511-8412 Dr. Bill Bernard, Rood & Riddle Equine Hospital, 2150 Georgetown Road, Lexington, KY 40580 Dr. Doug Byars, Hagyard-Davidson-Mcgee, 4250 Ironworks Road, Lexington, KY 40511-8412 Dr. Martin Furr, Marion duPont Scott Equine Center, Virginia Tech University, Old Waterford Rd. at Morven Park, P.O. Box 1938, Leesburg, VA 20177 Dr. Robert Mackay, Dept. Large Animal Clinical Sciences, College of
Veterinary Medicine, Box 100-136, University of
Florida, Gainesville, FL 32610 Dr. Steven Reed, Dept. Large Animal Medicine, College of
Veterinary Medicine, The Ohio State University, 611 Vernon L.
Tharp Street, Columbus, OH 43210-6610 3. General Design: The use of
historical controls in the
evaluation of
compounds for
effectiveness is described in 21 CFR 514.117 (b)(4)(iv). Equine protozoal myeloencephalitis (EPM) caused by Sarcocystis neurona, is a neurologic disease of
horses that most often results in asymmetric incoordination (ataxia), weakness, and

spasticity. EPM can occur as a peracute, acute, or
chronic condition.
The clinical signs are caused by direct neuronal damage by the parasite, as well as damage secondary to inflammation and
the pressure exerted by inflammation within neural spaces.
The evaluation of
ponazuril as a potential anti-protozoal agent for
the treatment of
EPM was
conducted using historical controls. Historical controls were
used for
this study
due to the progressive nature of
the disease if left untreated and
the lack of
approved therapeutics for
the treatment of
this disease. Effectiveness was
based on a standardized neurologic grade scoring method with neurological examination corroborated with videotape reviews by an expert panel. a. Purpose: This study
was designed to evaluate the safety and
effectiveness of
15% w/w ponazuril oral paste formulation when
used according to label directions under
field conditions in adult horses infected with Sarcocystis neurona and
exhibiting neurological signs of
equine protozoal myeloencephalitis (EPM). b. Animals: There were
one hundred two adult horses, 32 females, 9 males and
61 geldings, ranging in age from
2-30 years. Approximately 70% were
Thoroughbreds NADA 141-188 Page 5.Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste and
Quarter Horses, with the remainder represented by Saddlebreds, Tennessee Walkers, Hanoverians, Appaloosas, Arabians and
mixed breeds. c. Enrollment Criteria: 2 years of
age or
older, weight appropriate for
age and
breed, acceptable overall physical condition score on physical examination, hematology, and

serum chemistry values clinically acceptable, and

a diagnosis of
EPM supported by clinical examination and
a positive Western Blot for
S. neurona on CSF. Primary Diagnostic Criterion - Standardized clinical examination consistent with EPM (presence of
an asymmetric neurological deficit) Neurologic Grading Scale: 0 – Normal, no deficit detected 1 – Deficit just detected at normal gait 2 – Deficit easily detected and
is exaggerated by backing, turning, swaying, loin pressure or
neck extension 3 – Deficit very prominent on walking, turning, loin pressure or
neck extension 4 – Stumbling, tripping and
falling down spontaneously 5 - Recumbent, unable to rise Other enrollment criteria: cervical radiographs with no suggestion of
spinal cord compression or
vertebral canal stenosis (determined by calculation of
adjusted minimal sagittal vertebral canal diameters and
subjective assessment of
radiographs), cerebrospinal fluid (CSF) positive Western blots for
Sarcocystis neurona IgG, CSF cytology (less than 500 red blood cells/mL), CSF indices-(Total Protein <90, IgG index >0.3, albumin quotient <2.2), negative CSF for
equine herpes virus-1 (EHV-1 titer below 1:4), and

normal serum values for
Vitamin E (>2.0 µg/mL). d. Exclusion Criteria: Animals that received therapy for
EPM within the last 3 months, animals outside of
the specifications above, animals with a questionable diagnosis (seizure disorders, behavioral disorders), any other clinical signs that may indicate diseases other than EPM. e. Treatment Groups and
Controls: Animals were
randomly assigned to one of
two treatment groups and
dosed orally with either 5 mg/kg or
10 mg/kg of
ponazuril in a 15% paste body weight daily for
28 days.
The client did not know the dose. By study
conclusion, 47 had been assigned to the 5 mg/kg dose and
55 to the 10 mg/kg dose. f. Challenge: Natural infection. g. Dosage form: The formulation used during this study
was identical to the product intended for
market, a 15% w/w ponazuril paste. h. Route of
Administration: Oral i. Dose, Frequency and
Duration: Animals were
dosed at either 5 or
10 mg/kg body weight once per day for
28 days. j. Treatment Success or
Failure: Success was
based on the clinical response and
a masked scoring of
videotapes made during the neurological examinations. Animals had to improve at least one grade on the neurological examination at 90 days after the NADA 141-188 Page 6.Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste end of
treatment, and

had to be corroborated by video review to be considered a success. 4. Results: Of 113 horses evaluated, 11 were
eliminated for
non-compliance with the protocol, six at 5 mg/kg and
five at 10 mg/kg. At a dose rate of
5 mg/kg (2.27 mg/lb.) for
28 days, 28 of
47 horses (60%) improved at least one grade by Day 118 based upon investigator’s evaluation. At 10 mg/kg (4.54 mg/lb.) for
28 days, 32 of
55 animals (58%) improved at least one grade by Day 118 based upon investigator’s evaluation. In order to corroborate the cases deemed successes by the clinical investigators, independent experts reviewed the videotapes of
the success cases in a masked fashion. Of the 28 success cases at the
5 mg/kg dose, four horses did not have sufficient videotapes for
review.
Thus, of
the remaining 24 success cases with videotapes, 18 were
corroborated as successes (75% corroboration). Likewise, in the
10 mg/kg group, there were
32 success cases, 7 of
which
lacked videotapes.
Thus of
the remaining 25 cases with videotapes, 14 were
corroborated as successes (56% corroboration). Because there was
no difference between the 5 and
10 mg/kg doses with respect to the clinical investigators' assessments of
success, the
5 mg/kg dose was
selected. NADA 141-188 Page 7.Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste EPM EFFECTIVENESS – USING CLINICAL INVESTIGATOR’S NEUROLOGICAL SCORES ONLY DAY 0 EPM SCORES FROM CLINICAL INVESTIGATOR’S ASSESSMENT Treatment EPM SCORE D0 = 2 IMPROVED D118* EPM SCORE D0 = 3 IMPROVED D118* EPM SCORE D0 = 4 IMPROVED D118* 5 mg/kg ** 28 15 15 10 4 3 % Improved 54% 67% 75% 10 mg/kg ** 26 15 25 16 4 1 % Improved 58% 64% 25% * based on clinical investigator’s neurological assessment ** included all horses, whether videotaped or
not EPM EFFECTIVENESS – USING CORROBORATED VIDEOTAPE OUTCOMES DAY 0 EPM SCORES FROM CLINICAL INVESTIGATOR’S ASSESSMENT Treatment EPM SCORE D0 = 2 IMPROVED D118* EPM SCORE D0 = 3 IMPROVED D118* EPM SCORE D0 = 4 IMPROVED D118* 5 mg/kg ** 13 10 9 7 2 1 % Improved 77% 78% 50% 10 mg/kg ** 12 5 12 8 1 1 % Improved 42% 67% 100% * based on corroborated video outcomes ** did not include horses that were
classified as successes by the clinical investigator but were
missing a videotaped examination (N = 4 for
5 mg/kg group and
N = 7 for
10 mg/kg group) 5. Statistical Analysis: Twenty-eight out of
47 (60%) and
32 out of
55 (58%) animals received a lower maximum score by the clinical investigator at three month’s post-treatment when
compared with pretreatment in the
5 and
10 mg/kg dose groups, respectively.
There was
no significant difference in the
proportion of
animals that showed improvement when
comparing the two dose groups (Pearson’s Chi-square, p=0.8867). No statistical analyses were
performed on the CSF Western Blot data. All animals were
found Western Blot CSF positive by at least one of
two laboratories at the
beginning of
the study
.
The Western Blot of
the CSF did not appear to be a major factor in determining treatment success nor a reliable measure of
treatment success.
The neurological examination (corroborated with masked videotape reviews) appeared to be the most reliable source for
determining treatment success. Descriptive statistics were
calculated for
serum and
cerebrospinal fluid variables. For serum IgG, 27.5% and
31.9% of
the animals experienced an increase in the
serum IgG Index in the
5 mg/kg and
10 mg/kg dose groups, respectively.
The CSF IgG levels NADA 141-188 Page 8.Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste were
decreased in the
two treatment groups by 77.5% and
61.7%, respectively. Changes in Relative Quantity (RQ), an experimental test purported to measure the relative quantity of
protein produced in response to parasite infection, showed no correlation with the corroborated EPM success/failure outcomes. No statistical differences were
found between successes and
failures with respect to RQ differences (Chi-square, p > 0.05). Descriptive statistics were
generated for
hematology, serum chemistry and
CSF indices.
The primary purpose of
these evaluations was
to determine if significant changes were
seen in these variables and
to determine the medical significance of
such changes.
The masked videotape reviews were
also assessed using descriptive statistics.
The corroboration of
each clinical investigator’s neurological examinations (improved horses) with those of
independent videotape reviews indicated over 65% corroboration for
both treatment groups combined. 6. Conclusions: At 5 mg/kg for
28 days, 28 of
47 horses (60%) improved at least one grade by Day 118. Seventy-five percent (75%) of
those improved, that had also been videotaped, were
corroborated by videotape assessment. At 10 mg/kg, 32 of
55 animals (58%) improved at least one grade by Day 118 and
56% of
those improved, that had also been videotaped, were
corroborated using videotape assessment. 7. Adverse Reactions: Eight animals were
noted to have unusual daily observations. Two horses exhibited blisters on the nose and
mouth at some point in the
study
, three animals showed a skin rash or
hives for
up to 18 days, one animal had loose stools throughout the treatment period, one had a mild colic on one day and
one animal had a seizure while on medication. C. Clinical Field Study 2 1. Type of
Study: The study
was conducted as an additional field evaluation using historical controls. 2. Investigators Dr. Frank Andrews, Large Animal Clinical Medicine, College of
Veterinary Medicine, University of
Tennessee P.O. Box 1071, Knoxville, TN 37901-1701 Dr. Bill Bernard, Rood & Riddle Equine Hospital, 2150 Georgetown Road Lexington, KY 40580 Dr. Martin Furr, Marion duPont Scott Equine Center, Virginia Tech University, Old Waterford Rd. at Morven Park, P.O. Box 1938, Leesburg, VA 20177. Dr. Robert MacKay, Dept. Large Animal Clinical Sciences, College of
Veterinary Medicine, Box 100-136, University of
Florida, Gainesville, FL 32610 Dr. Steven Reed, Dept. Large Animal Medicine, College of
Veterinary Medicine, The Ohio State University, 611 Vernon L.
Tharp Street, Columbus, OH 43210-6610 3. General Design: The use of
historical controls in the
evaluation of
compounds for
effectiveness is described in 21 CFR 514.117 (b)(4)(iv). Equine protozoal myeloencephalitis (EPM) caused by Sarcocystis neurona, is a neurologic disease of
NADA 141-188 Page 9.Marquis™ (15% w/w ponazuril) Antiprotozoal Oral Paste horses that most often results in asymmetric incoordination (ataxia), weakness, and

spasticity. EPM can occur as a peracute, acute, or
chronic condition.
The clinical signs are caused by direct neuronal damage by the parasite as well as damage secondary to inflammation and
the pressure exerted by inflammation within neural spaces.
The evaluation of
ponazuril as a potential anti-protozoal agent for
the treatment of
EPM was
conducted using historical controls. Historical controls were
used for
this study
due to the progressive nature of
the disease if left untreated and
the lack of
approved therapeutics for
the treatment of
this disease. Effectiveness was
based on improvement in the
neurologic grade from
day 0 to day 28. a. Purpose: This study
was designed to evaluate the safety and
effectiveness of
15% w/w ponazuril oral paste formulation when
used according to label directions under
field conditions in adult horses infected with Sarcocystis neurona and
exhibiting neurological signs of
equine protozoal myeloencephalitis (EPM). b. Animals: There were
twelve adult horses, 6 females, 2 males and
4 geldings, ranging in age from
2-19 years. Seventy-five percent were
Thoroughbreds and
Quarter Horses, with the remainder represented by 1 Saddlebred, 1 Tennessee Walker and
1 Hanoverian. c. Enrollment Criteria: 2 years of
age or
older, weight - appropriate for
age and
breed, acceptable overall physical condition score on physical examination, hematology and
serum chemistry values clinically acceptable and
a diagnosis of
EPM supported by clinical examination. Primary Diagnostic Criterion-standardized clinical examination consistent with EPM, (presence of
an asymmetric neurological deficit) 0 – Normal, no deficit detected 1 – Deficit just detected at normal gait 2 – Deficit easily detected and
is exaggerated by backing, turning, swaying, loin pressure or
neck extension 3 – Deficit very prominent on walking, turning, loin pressure or
neck extension 4 – Stumbling, tripping and
falling down spontaneously

© 2011 Betterchem.com