Na ion channel blocker protein toxin from pufferfish,... early studies from patent application documented below. At low doses only pain nerves affected,...higher doses leads to "zombie effect", and still higher doses, death by Fugu.
Drug is currently going through phase 2 in Canada and should enter phase 2 in China shortly. European testing proceeding by pharma partner.
Interesting parts below are bolded for quick reading.
http://www.wextech.ca/page/investorinfo/mediacoverage.htm
United States Patent 6,407,088
Dong , et al. June 18, 2002
http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=/netahtml/search-adv.htm&r=1&p=1&f=G&l=50&d=ptxt&S1=tetrodin&OS=tetrodin&RS=tetrodin
A clinical study was carried out from Sep. 21 to Oct. 10, 1999 to examine the analgesic effect of tetrodotoxin injection (TTX purity 89%, brand name TETRODIN, batch no. 990122, Nanning Maple Leaf Pharmaceutical Co., Ltd., Guangxi, China) on 11 people who had chronic pain from advanced cancer.
1.1 Objects of Study
Eleven late term cancer patients volunteered to participate in this study. Computerized tomography (CT)-scans and pathological examination confirmed that all the patients had cancer. They all had moderate or severe pain according to the WHO endorsed criteria on "pain grading".
Among the 11 patients 6 were male, 5 were female. The oldest was 76, and the youngest 26. Five had liver cancer in late stage. One patient had leiomyosarcoma (smooth muscle sarcoma) accompanied by postoperative liver cancer. Two were postoperative relapse of stomach cancer. One was postoperative relapse of carcinoma of the esophagus. One was postoperative relapse of rectal cancer. One was colon carcinoma accompanied by liver cancer. All the patients joined this clinical trial voluntarily.
1.2 Drug and Dosage
Tetrodotoxin injection i.m., 30 .mu.g/2 ml. All the patients were intramuscularly injected with 30 .mu.g tetrodotoxin each time, twice a day (once every 12 hours). This was applied for 3 days (a total of 180 .mu.g of tetrodotoxin).
1.3 Criteria of Evaluation
Following the clinical evaluation method as described below, the analgesic effect of tetrodotoxin on 11 people was determined. This study did not have a design control group; it was an open trial where both patients and doctors know what drug was being used.
Classification of Pain Intensity and Recording Method
The protocol required that no other analgesic drugs be taken for 24 hours before participating in the study. Nor were any other analgesic drugs taken during the 3-day period of the use of tetrodotoxin. Pain was evaluated using the Numeric Pain Intensity Scale, which is described below. Pain was initially evaluated prior to the initial tetrodotoxin injection. After each administration of tetrodotoxin (at 8:00 AM and 8:00 PM each day), a research staff member observed and recorded the pain intensity of every patient at the following 14 time intervals: 5 min, 10 min, 15 min, 20 min, 30 min, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h 7 h, 8 h, and 12 h.
2.1 Recording the Method of Pain Intensity
For this test the WHO recommended method of 0.about.10 Numeric Pain Intensity Scale was used to calculate and record the pain intensity of the people in this test. Briefly, patients would self-evaluate their pain based upon a 0 to 10 numeric scale as shown below and then report it to a research assistant. ##STR2##
0=no pain; 1-4=mild pain; 5-6=moderate pain; 7-10=severe pain
Determination of Analgesic Effect
3.1 Pain Intensity Difference (PID)
PID is calculated by taking the pain intensity number before administration, and subtracting the pain intensity number at every time point after administration.
3.2 Pain Relief
After calculating the patient's pain intensity at each time interval, the researcher assesses the pain relief and assigns a value from one of the following five choices.
0: no relief
I: mild relief (the pain abates about 25%)
II: moderate relief (the pain abates about 50%)
III: significant relief (the pain abates about 75%)
IV: complete relief (the pain disappears completely)
3.3 Evaluating "Quality of Life"
Pain affects every patient's normal life and ability to continue with their everyday routine. This is generally referred to as their quality of life. Depending on the severity of the pain that is being experienced by each individual it can cause patients to experience irritability, depression and poor appetite. The researcher must consider any changes in the patient's quality of life, in the evaluation of the analgesic effect of any new drug. The numeric scale in the line below expresses the high and low reference numbers. It should be noted that this "quality of life" evaluation is a subjective issue and that the research doctor relies on the patient's descriptions of any changes (before and after administration of tetrodotoxin) in their quality of life as the primary means of input for making this evaluation. Issues that are questioned in regard to the quality of life include, routine daily activity, emotions, mobility (walking ability), normal work (includes both work outside the home and housework), sleeping state or pattern, relations with other persons, enjoyment of life.
Quality of life was evaluated by subjects themselves before and every 8 hours after administration.
The quality of life includes mood, walking ability, normal work (includes both work outside the home and housework), and relations with other people, sleep, and enjoyment of life. The numeric scale in the line below expressed the interfere extent of quality of life.
0: Does not interfere
1.about.3: Mildly interferes
4.about.7: Moderately interferes
8.about.9: Severely interfere
10: Completely interfere ##STR3##
4. Results
4.1 Analgesic Effect
All subjects experienced various degrees of pain relief within 30 min. after the first administration of tetrodotoxin. Some of them reported noticeable pain relief in 5 min. After 3 days of the twice daily administration of tetrodotoxin, the pain intensity of all subjects was reduced to 0 in all but one patient who recorded a 1.
The results demonstrate that all of the patients, were totally relieved of their pain for between 20-30 days after the final administration of tetrodotoxin on the 3rd day. None of the patient's showed the slightest signs of having any symptoms of addiction following the three days of tetrodotoxin administration.
4.2 Effect on Daily Quality of Life
The patients reported that their "quality of life" was affected negatively, either moderately or severely by the pain caused by their cancer and/or their cancer treatment and medication. During the three day tetrodotoxin treatment and for the following 20.about.30 days, their quality of life showed distinct and dramatic improvements that were described, for example as severe interference that was reduced to moderate or mild interference. After 3 days of administration of tetrodotoxin, most of the patients could return to a normal life. Some of them returned to playing the popular game mahjong (a type of Chinese playing cards) with healthy people. They were able to go to the public bathhouse to bathe, an activity that had become to difficult to do due to the pain and anguish caused by the cancer. One of them took a long journey from Harbin to Beijing by train.
4.3 Side Effects
10-20 min after administration, all the patients felt numbness or tingling in their lips, tip of the tongue, ends of fingers and toes. These symptoms lasted at most about 30 min., then disappeared without any treatment. Two patients who had a long history of using dolantin experienced mild to moderate nausea accompanied by mild vomiting after only the first injection of tetrodotoxin. On the second injection, these symptoms did not appear. Some of the patients' blood pressure decreased 10-15 mm Hg, which recovered to normal 40-50 min later without any treatment. One of patients (after the first injection only) showed tachycardia with vomiting, this also disappeared 10-15 minutes later, without needing any treatment.
5. Conclusions
The following is observed when comparing tetrodotoxin to other analgesic drugs.
5.1 Less frequent administration of tetrodotoxin is required. The patient only needs one injection of 30 .mu.g every 12 hours for up to 3 days. With these patients, the three-day administration of tetrodotoxin was immediately effective in reducing or eliminating their pain.
5.2 The short course of treatment of tetrodotoxin of only 3 days, as compared to any other strong analgesic that must be administered consistently and continuously to be effective, demonstrates that tetrodotoxin has considerable advantages over any other of the currently used analgesics.
5.3 Rapid effect. Tetrodotoxin takes effect at 5-30 min after administration.
5.4 Analgesic effect lasts longer. After 3 days of the twice daily administration of tetrodotoxin, the analgesic effect lasted 20-30 days. No patient reported the reappearance of pain in the period from the fourth to the twentieth day. In most instances the pain relief was effective for the entire 30 day monitoring period.
5.5 No signs of addiction or withdrawal occurred during or after treatment with tetrodotoxin. All of the other currently used narcotic analgesics are highly addictive and have untoward side effects.
5.6 Slight side effects. The subjects had only slight side effects, such as low blood pressure, nausea and vomiting. All of the side effects disappeared without any treatment within 15 to 60 minutes.
5.7 Tetrodotoxin also produced evident detoxification in the patients who were dependent on dolantin.
5.8 Tetrodotoxin improves the condition of cancer patients during their treatment. Tetrodotoxin does not have any direct effect on any of the cancers themselves. However, it was observed that the overall health and mental attitude of the patients improved substantially as they were relieved of the pain from their cancer.
Individual Case Results
Case 1
Mr. Gao, is a 44 year old male. He developed abdominal pain and was diagnosed with smooth muscle pain in the back wall of his celiac for which he underwent a surgical procedure. One year later, his abdomen pain relapsed and he was operated on again. The pathological examination from the second operation revealed that he had developed a smooth muscle sarcoma (leiomyosarcoma), later finding that his sarcoma had spread to his liver and that he now required and received anti-cancer treatment (chemotherapy). He began to inject Dolantin, because he could not bear the severe pain in his abdomen. He needed to inject Dolantin at least 3 times per day. Initially he was taking the Dolantin by intramuscular injection, and finally he needed to use intravenous injection in order to have the Dolantin take effect faster. Just prior to when he received the tetrodotoxin treatment, he had taken over 100 injections of Dolantin in the previous month. At the beginning, when he stopped using Dolantin, he experienced morphine-like withdrawal symptoms, such as whole body weakness and pain, trembling when standing up and difficulty walking. He voluntarily received tetrodotoxin treatment. His pain intensity scale was 8 before using tetrodotoxin. 5 minutes after the first injection of tetrodotoxin, his pain intensity on the 0 to 10 scale decreased to 0. After 3 days of treatment, he was able to go to the public bathhouse to bathe by himself. He went to a friend's home to play mahjong. To the date of this report, he is living normally and continues to feel comfortable without any pain.
Case 2
Mr. Zhang, is a 26 year old male. He felt pain in his liver area and was diagnosed with advanced liver cancer. His illness progressed to where he could not bear the severe abdominal pain and abdominal distention. He began to use Dolantin and other painkillers to relieve his pain. He volunteered to receive tetrodotoxin treatment. Before the first administration of tetrodotoxin, his pain intensity on the 0 to 10 scale was 8. On the second day of injecting tetrodotoxin, his pain intensity was reduced to 0. His life quality was also improved significantly. After completing 3-day's treatment, he traveled by train from Harbin to Beijing for further treatment of his cancer.
Case 3
Ms. Xie is a 76 year old female. She was diagnosed with rectal cancer and underwent surgery in 1996. In 1998, her rectal cancer spread to her liver. Her pain increased to where she was having difficulty dealing with the pain. She voluntarily received tetrodotoxin treatment. Her pain, intensity scale was reduced to 0 from 6, within 20 minutes after the first injection of tetrodotoxin. Her quality of life score also decreased to 6 from 10 after the first injection of tetrodotoxin. At the end of the 3 days of treatment with tetrodotoxin, she recovered to what she considered to be her normal life-style.
Case 4
Mr. Jin is a 63 year old male. He suffered from liver cancer for 8 years. In the last 6 months, his pain had escalated to where he could not be relieved of his pain by the use of other painkillers. He volunteered to receive the tetrodotoxin treatment. His pain intensity scale decreased to 0 from 7 on the second day of the tetrodotoxin treatment. His quality of life was also improved significantly.
Case 5
Ms. Duang, a 46 years old female, was diagnosed with lumbago, after which the symptoms associated with the lumbago gradually worsened. Painkillers were effective for managing the pain from her lumbago. Six months prior to this test, she started to experience pain in her left leg that became more and more severe. She was prescribed the progressively stronger painkillers, Tramadol, Pentazocine and Dolantin during this six months. During this same six months she was diagnosed with cancer that was initially of the liver, and had metastasized to bone cancer. The bone cancer was located in the L.sub.3, L.sub.4 and T.sub.11 vertebrae and was evidenced by the presence of osteolytic lesions. Ms Duang volunteered to receive tetrodotoxin treatment. Immediately prior to starting the tetrodotoxin treatment, her pain intensity on the 0 to 10 scale was 9. Ten minutes after her first injection of tetrodotoxin, her pain intensity decreased to 7, and 20 minutes after her first injection, her pain intensity decreased to 2. At the conclusion of the 3 days treatment with tetrodotoxin her pain was entirely eliminated.
Case 6
Ms. Li is a 72 year old female who was experiencing abdominal distension and poor appetite. When an initial treatment did not take effect, an ultrasonic examination of her abdomen was done and she was diagnosed to have cancer of the liver. Her cancer appeared to be relieved after treatment by chemotherapy, but her abdominal distension and abdominal pain became worse. By the start of the test use of tetrodotoxin the painkillers that she was using could not relieve her pain. She volunteered to receive tetrodotoxin treatment in an attempt to reduce her pain. Before the administration of tetrodotoxin, her pain intensity on the 0 to 10 scale was 7. Ten minutes after she received her first of tetrodotoxin, her pain intensity scale was reduced to 0. After 3 days of treatment with tetrodotoxin, she was able to carry on with her life as if she had recovered back to normal.
Case 7
Mr. Li is a 36 year old male, who was diagnosed with advanced liver cancer. The pain in the region of his liver had increased to where he was not relieved of his pain by intramuscular injections of Dolantin. He volunteered to receive tetrodotoxin treatment. Previous to the administration of tetrodotoxin, his pain intensity on the 0 to 10 scale was 7. Twenty minutes after the first injection of tetrodotoxin, his pain intensity was reduced to 3. After the third injection of tetrodotoxin his pain intensity stabilized at 0. After 3 days of treatment his quality of life had improved significantly, achieving 0 interference.
Case 8
Mr. Cheng is a 60 year old male. He was diagnosed with mucinous adreno-carcinoma of the stomach and received surgery to remove the cancer. Three months after the operation, his abdomen became distended and he started to experience severe abdominal pain. A CTscan showed that the cancer had further extensively spread to his lungs, liver, abdominal cavity and lymph nodes. He volunteered to receive tetrodotoxin treatment. Prior to the first administration of tetrodotoxin, his pain intensity on the 0 to 10 scale was 8. Twenty min after injecting tetrodotoxin his pain intensity scale reduced to 0. After 3 days treatment he recovered to what he considered a normal life.
Case 9
Mr. Shi is a 59 year old male. He was diagnosed with carcinoma of the esophagus after one year of consistent retro-sterna pain that eventually became dysphagia. This was so severe in the last month that it was causing him to vomit after eating. After having surgery to remove the cancer, his pain was severe and was not relieved from the regular injections of Dolantin that he was prescribed. He volunteered to receive tetrodotoxin treatment. Prior to his first administration of tetrodotoxin, his pain intensity on the 0 to 10 scale was 8. After the second injection of tetrodotoxin, his pain intensity was reduced to 0. Following the 3 days of tetrodotoxin treatment he had recovered to what he considered a normal life.
Case 10
Ms. Liu is a 69 year old female who, three years after her operation to remove stomach cancer, found that the lymph node of her left cervical was swelling. A pathological examination showed that her stomach cancer had spread to the lymph node. For some time before she volunteered to receive tetrodotoxin treatment, her pain had increased to where she had difficulty dealing with it. Before the first administration of tetrodotoxin, her pain intensity on the 0 to 10 scale was 9. Three hours after the first injection of tetrodotoxin, her pain intensity scale reduced to 2, and after 3 days of treatment with tetrodotoxin, her pain intensity scale stabilized at 0.
Case 11
Ms. Tan is a 52 year old female whose rectal cancer relapsed one year after she had undergone surgery. The lump in her perineum was abscessed. The regional pain was extreme and was accompanied by headaches and dizziness at times so severe that she could not speak. She volunteered to receive tetrodotoxin treatment. Before the first administration of tetrodotoxin her pain intensity on the 0 to 10 scale was 7. One hour after the first injection of tetrodotoxin, her pain intensity was reduced to 0. At the completion of 3 days of treatment with tetrodotoxin she recovered to what she considered a normal life. |
