02A0162 Rajab primates

Cynomolgus Used for Protocol 02A0162 - Islet Isolation and Allotransplantation in Non-human Primates

OSU lost funding from Novartis for xenotransplantation of kidneys using pigs and baboons. OSU is now bringing in NIH monies for same-species transplantation of islet cells (from the pancreas). The procedures for islet transplantation are documented in humans and are offered at 14 centers around the United States to patients selected under strict criteria.

This protocol is to "establish the use of this procedure (islet cell transplantation) in the clinical setting at OSU. We propose the use of non-human primates in studying our procedures prior to using humans."

Twenty cynomolgous macaque (macaca fascicularis) were initially approved for use in this protocol.

In the initial protocol primates would become diabetic via removal of their pancreas, which causes significant digestive problems, or injection of the compound streptozotocin, which is known to destroy the islet cells. With streptozotocin injections, transient vomiting will occur and since streptozotocin is injected systemically complications occur in the animal's liver and kidneys.

The animals arrive via Covance, a company providing purpose-bred research animals to the biomedical research community, (on their website animals are listed as research products), to Battelle, where the animals are used in drug evaluation studies, to The Ohio State University and Rajab's laboratory.

Initial Procotol
Five of the primates will be used for "practicing of our isolation technique."
The pancreas will be removed and the primate euthanized. For the allotransplanation, six primates will be donors and six primates will be the recipients.

The first primates arrive from Battelle on February 7, 2003.
Cynomolgous ID # 15057 (M) - Killed February 24, 2003 used as "practice" in isolating islet cells.
Cynomolgous ID # 14470 (M) - Killed March 4, 2003 used as "practice" in isolating islet cells.
Cynomolgous ID # 15179 (M) - Killed February 19, 2003 used as "practice" in isolating islet cells.
Cynomolgous ID # 14728 (F) - Killed March 13, 2003 used as "practice" in isolating islet cells.
Cynomolgous ID # 14487 (F) - Killed March 17, 2003 used as "practice" in isolating islet cells and cells used for transplant to primate #14470.
Cynomolgous ID # 14730 (F) - Killed March 17, 2003 used as "practice" in isolating islet cells and cells used for transplant to primate #14470.
Cynomolgous ID # 14470 (F) - March 11, 2003 begins injections of streptozotocin.
March 17, 2003 transplant of islet cells. On March 19 it is noted that islet transplant is not producing insulin. Killed March 20, 2003.

Amendments to Protocol
Approved by ILACUC on April 8, 2003

"In 4 of the 5 animals for which we planned to practice our isolation technique, we would like to attempt an autotransplantation. The pancreas will be removed however the animal will not be euthanized." The islet cells will be isolated. A second procedure will inject the isolated cells back into the animals.

Our reading of the amendment also indicates that the use of streptozotocin will cease. The researcher notes, "the results of the pancreatectomy give a uniform outcome (diabetic) compared with those of streptozotocin administration, which can range from no effect to death." If the investigator would have done any checking he would have already been aware of the complications in using streptozotocin.

The animals will be killed or as the researcher writes, "the study will end 10 days" after the pancreatectomy and islet injection.

Cynomolgous ID # 17243 (M) arrives at OSU on July 11, 2003.
July 16 pancreas removed and islet cells injected. Killed July 25, 2003

Cynomolgous ID # A7945 (M) arrives at OSU on October 24, 2003. This primate came from Battelle via another animal supplier, Primate Products, Miami, Florida.
November 5, 2003 pancreas removed. Primate #A7945 died during recovery.

November 6, 2003 and Battelle transfers to OSU six (6) primates.

Cynomolgous ID # 14747 (F) - November 10 pancreas removed and islet cells injected. Killed November 20, 2003.

Cynomolgous ID # 15020 (M) - November 10 pancreas removed and islet cells injected. Killed November 20, 2003.

Cynomolgous ID # 15011 (M) - November 12 pancreas removed however medical records seem to indicate islet cells were not injected as over the next week the primate receives insulin injections. This is a control animal. Killed November 20, 2003.

Cynomolgous ID # C02664 (F) - November 10 pancreas removed. This is a control animal. Killed November 20, 2003.

Cynomolgous ID # C00032 (F) - November 12 pancreas removed. This is a control animal so insulin is administrated over the next week. On November 17, glucose is given. Why? It is noted "monkey was unresponsive." At 1:00 "monkey found dead in cage."

Cynomolgous ID # C00102 (F) - November 12 pancreas removed and islet cells injected. During post-op the animal begins having problems. C00102 "became still in bottom of cage." Dextrose is given and responds by moving about the cage.
11/12/03 - 4pm C00102 is hypoglycemic again. Dextrose is again given.
11/12/03 - 6pm C00102 is "very lethargic and not very responsive." Dextrose is given and is now more responsive.
11/13/03 - 8am C00102 "continued lethargy episodes"
11/13/03 - 1:30pm prep for a glucose stimulation test "due to continued hypoglycemic episodes".
Cynomolgous C00102 died during test.

Amendments to Protocol
Approved by ILACUC on December 15, 2003

The amendment reads, "We required more animals for practicing our isolation technique than we originally anticipated. Additional, we would like to attempt an alternative location for transplantation of the islets." This means twenty (20) additional primates are approved for use and the researcher "would like to attempt the transplantation of islets under the kidney capsule."

March 11, 2004 and Battelle transfers seven (7) primates to OSU.

Cynomolgous ID # C02660 (M) - no experimental activity noted. See update below.

Cynomolgous ID # C02658 (M) - no experimental activity noted. See update below.

Cynomolgous ID # 15041 (M) - March 16 pancreas removed and islet cells injected. There is no indication as to whether or not the new procedure using the kidney capsule was in place. Over the next few days whenever blood glucose is noted as "Hi" insulin is given to the primate. March 26 the glucose tolerance test (GTT) is performed. While there is no record of the primate being killed, as in earlier records, the amended protocol indicates the "animal will be euthanized upon completion of this final test." The drug administrated also indicates the death of 15041.

Cynomolgous ID # 16447 (M) - March 25 pancreas removed and islet cells injected. There is no indication as to whether or not the new procedure using the kidney capsule was in place. Over the next few days whenever blood glucose is noted as "Hi" insulin is given to the primate. April 2 the glucose tolerance test is performed and we assume 16447 is killed via drug listed.

Cynomolgous ID # 17241 (M) - March 16 pancreas removed and islet cells injected. There is no indication as to whether or not the new procedure using the kidney capsule was in place. As of April 22, 2003 17241 remains alive and in the study.

Cynomolgous ID # 14781 (M) - March 25 pancreas removed and autotransplant of islet cells with the kidney capsule is used. 3/26 noted that animal is responsive. April 4, 2004 glucose test is performed and the animal killed.

Cynomolgous ID # 17738 (M) - records requested not received. UPDATE: Records received 11/18/05. Surgery 3/25/04 and keep on insulin until 4/5/05 at which time the primate was killed.

P.O.E.T. has many questions concerning protocol procedures for the entire protocol. OSU has been slow in releasing information concerning the health and status of the animals used in this protocol. That is why we are only now listing animal deaths that occurred in 2003. We will be meeting with OSU to discuss those concerns and will update this page in the near future. Please contact us if you have any questions concerning this protocol.

TWO MORE PRIMATES FOUND DEAD

April 8, 2004 nine (9) new primates were received from Battelle. They are identified below:

Cynomolgous ID # C07582 (M) - This macaque was transferred to John Bufords protocol 02A0167.

Cynomolgous ID # C01563 (M) - On May 5, the pancreas is removed and a vascular access port (VAP) is put in place. The primate recovered from surgery and does not appear to have any health issues. June 10, primate 1563 is killed.

Cynomolgous ID # C07841 (M) - May 5, the pancreas is removed, islet cells are injected, and a VAP is put in place.
The surgery ends at 1:05pm.
4:00pm, it is noted that primate 7841 is "not very responsive". Glucose is provided.
4:20pm, glucose is provided via VAP. "some improvement, still in crisis" . "weak pulse"
5:00pm "dead in cage attempts to resuscitate unsuccessful".
Necropsy gives indications that possibly there were problems with the surgery.

Cynomolgous ID # C07757 (M) - May 10, the pancreas is removed and primate 7757 is injected with islet cells. Over the next ten days the primate is given insulin and on May 18th killed.

Cynomolgous ID # C07889 (M) - May 10, the pancreas is removed and primate 7889 is injected with islet cells. Over the next ten days the primate is given insulin and on May 18th killed.

Cynomolgous ID # C07711 (M) - May 17, the pancreas is removed, a VAP is put in place and islet cells are injected. The primate recovers and does not appear to have any health issues. July 22, primate 7711 is killed.

Cynomolgous ID # C07268 (M) - May 17, the pancreas is removed, a VAP is put in place and islet cells are injected. There is a note in the medical record "VAP in jugular". We do not know if this is noted because it was a new placement location or as a clarification. The primate recovers and does not appear to have any health issues. July 22, primate 7268 is killed.

Cynomolgous ID # C07882 (M) - May 24, the pancreas is removed, a VAP is put in place and islet cells are injected. The primate recovers and does not appear to have any health issues. July 22, primate 7882 is killed.

Cynomolgous ID # C07716 (M) - May 24, the pancreas is removed, a VAP is put in place. At 8:00 am on May 25, 2004, primate 7716 is found dead. There appears to have been problems with the surgery.

POET had requested these records August 25, 2004 and they were received December 17, 2004. After our review we contacted OSU-ULAR about our concerns. On January 7, 2005 we sent a letter to Dr. Yonushonis, Director ULAR requesting an investigation about these deaths. Medical records indicate another surgeon, besides the principal investigator, was present for the surgeries in which the two primates died. As of February 9, 2005 we have yet to receive a response.

A new amendment was approved July 6, 2004 to use thirty-six (36) additional primates and to test an immunosuppressant drug.
January 21, 2005 - According to OSU-ULAR no animals have been received for this new amendment.

Cynomolgous ID # CO2658 (M) - Arrived at OSU on March 11, 2004 from Covance, animal supply company. June 1, 2004 the pancreas is removed and a VAP is put in place. Medical records stop on 7/27/04 with indications being that the primate is still alive. - Will make an updated request.

Cynomolgous ID # CO2660 (M) - Arrived at OSU on March 11, 2004 from Covance, animal supply company. June 1, 2004 the pancreas is removed, a VAP is put in place and islet cells are injected. . Medical records stop on 7/27/04 with indications being that the primate is still alive. - Will make an updated request.
On March 28, 2004 animal CO2660 was handcaught/masked for the GTT and killed.

Cynomolgous ID # M00744 (M) - Arrived at OSU on June 7, 2005 from Covance. This primate was born October 1, 2002 in Mauritius and shipped to the US (Covance - Denver) on April 7, 2005.

Medical records indicate healthy animals. No records after July 18, 2005 but at that time the primate is alive.
Sometime between July, 2005 and October, 2005 primate 744 is transferred to Dr. Buford's protocol, 04A0149. On 10/21/05 medical records note that the animal had a collar placement. No other records were provided.

Cynomolgous ID # M00755 (M) - Arrived at OSU on June 7, 2005 from Covance. This primate was born April 1, 2002 in Mauritius and shipped to the US (Covance - Denver) on April 7, 2005.

Medical records some abrasions on the primate. Surgery began on primate 0755, 8/17/05 at 7:30am. The animal died during the surgical prep. The medical records read that:

The 3rd year review for this protocol took place at the ILACUC meeting in December, 2005. There was also an amendment to add an additional ten (10) primates for use in the protocol. ILACUC approved with no discussion. When POET receives the updated protocol and amendment we will post any additional information.

Cynomolgous ID #CO6779 (F) - Arrived at OSU from Battelle on 8/30/05. Records to not indicate whether Rajab or Buford received this animal.

Update from records received 2/24/06 - On 12/30/05, five (5) rhesus monkeys arrived at OSU from Columbus Children's Research Institute.

Rhesus ID #01R0291 (M) - Transferred to John Buford, protocol 2004A0149, on 1/5/06.

Rhesus ID #00R0997 (M) - Went into surgery for allotransplant on 1/30/06 and recovered.

Rhesus ID #00R1081 (M) - 3/20/06 - No procedures performed at OSU to this date - Transferred to Dr. Buford protocol, 2004A0149 on 5/5/06.

Rhesus ID #R2287 - Originally assigned to Dr. Buford the monkey was transferred to Rajab on 1/5/06.

At the July 21st IACUC meeting an amendment to use 30 additional primates was approved. He is retesting a drug which from recent financial records is already approved and making millions of dollars for the company.

Note that Rajab had nothing to do with the initial testing of the drug for the market. Maybe he's testing for another company that has a similar product?

Update from data received in 2007 - September 24, 2006 and the primates continue to arrive at OSU. This time, 3 males and 3 females, arrived from Covance Research Products, located in Alice Texas. "Research Products" a telling name for a company that sells animals for research.

The female cynomolgous macaques are identified as MO2009, MO2003 and MO2043. The males are MO2073, MO2081 and MO2100. The primates will have their pancreas removed and placed on a drug regimen.

The primates are in a 90 day study and as we suspected the primates have been killed. During our previous request we received another amendment filed by Rajab in March 2006 which requested another 10 macaques. IACUC approved this amendment which will continue the immunosuppression therapy experiments using primates.

Now here is the interesting piece - while the animals are living and dying in Rajab experiments - he and others at OSU publish papers addressing results from human studies which are using the same drugs.

Update from Nov. 07 request - In March 2007, six primates are received and in July another six primates arrive, all from Charles River Laboratories
Update from March 08 request - In December 2007, four primates arrive from Charles River Laboratories, Houston, TX - protocol 2002A0162

Primate ID	D.O.B.	Sex	Arrival at OSU	Death	Comments
26-32	2/2003	M	3/12/07	7/18/07 30mg ketamine	5/22 - GTT 11:00 siting in cage eatling apple slice
26-38	8/2003	M	3/12/07	7/18/07 30mg ketamine	note surgeries
36-12	9/2003	M	3/12/07	4/17/07 - cause of death undetermined
36-19	3/2003	M	3/12/07	7/19/07 50 mg ketamine for GTT - killed	record history - vomitting - surgery-dehydrated
36-29	3/2003	M	3/12/07	4/16/07 - killed during pancrectomy	no additional comments or records
36-184	3/2003	M	3/12/07	4/16/07 - killed during pancrectomy	no additional comments or records
105-84	4/2002	M	7/26/07		10/25 remains in experiment
105-128	4/2004	M	7/26/07		10/25 remains in experiment
105-137	4/2004	M	7/26/07		10/25 remains in experiment
105-150	4/2004	M	7/26/07		10/25 remains in experiment
26-106	2/2004	M	7/26/07		10/25 remains in experiment
36-6	3/2004	M	7/26/07		10/25 remains in experiment
26-49	2/2004	M	12/18/07		Quarantine from 12/26/07 to 2/3/08 No additioanl procedures last update 3/6/08
125-28	12/2002	M	12/18/07		Quarantine from 12/26/07 to 2/3/08 Two blood draws with last update 3/6/08
36-38	9/2002	M	12/18/07		Quarantine from 12/26/07 to 2/3/08 Two blood draws with last update 3/6/08 Noted 2/22/08 not eating all biscuits
105-120	4/2002	m	12/18/07		Quarantine from 12/26/07 to 2/3/08 Two blood draws with last update 3/6/08 Noted 2/22/08 appears to be taking biscuits in cage but not eating some or any 3/1/08 ate all biscuits 3/3/08 ate almost all biscuits

Feb. 2008, an amendment, to use additional 6 primates, for protocol 2002A0162 is submitted and approved by IACUC. Apparently results from his current tinking are not producing the results he expected or wants from treatments of Exenatide. His words:

So what is it that Rajab is investigating as he continues killing primates? Can we hear an answer?

In January 2008, an amendment was approved to 10 mice. Mice will receive non-human primate islets incorporated with paramagnetic particles to evaluate labeling of the islets. The mice are lacking in a functional immune system, thereby preventing the islets from rejecting after transplantation.

Mice will be made diabetic by injection of streptozotocin 3 days prior to transplant. At 3 days post-transplant the mice will be killed.

A new protocol is submitted by Amar Rajab and approved - 2008A0021, Islet Xenotransplantation of Tilapia Islets in the Non-Human Primate.

Ten (10) primates were approved for these new experiments which will "attempt the transplantation of tilapia islets in the non-human primate as a pre-clinical analysis of their ability to regulate blood glucose levels in primates."

Diabetes will be induced via two methods, total pancreatecmony and streptozotocin, chemical. In 2003, Rajab states, "the results of the pancreatectomy give a uniform outcome (diabetic) compared with those of streptozotocin administration, which can range from no effect to death." So why use streptozotocin?

So what happens to those primates who are given streptozotocin and fail to develop diabetes? IACUC failed to ask that question. After 28 days all 10 animals will be killed.

We requested an update on primate numbers and status from OSU on March 3, 2008.- Received May 12, 2008.