4/14/08
Darryl See, MD CLINICAL REPORT:
· SPECIFIC PHARMACOLOGICAL EFFECT DATA
· GENERAL PHARMACOLOGICAL DATA
Dear Sirs:
I have studied and observed the potential toxicity and pharmacodynamics of Enercel® in vitro, in animals and in humans. Furthermore, I have reviewed all the studies by other investigators. A summation of these findings is as follows:
A. In vitro: Enercel® at a dose of 100 ul/mg was applied to confluent monolayers of both MOLT-5 and K562 cells. 5% ethanol was applied to control plates. Tissue culture media with fresh Enercel® at 100 ul/mg was added daily. The cells were observed for necrosis for 3 days. There was no toxicity (0 on a scale of 5).
B. Mice: Either placebo (5% ethanol) or Enercel® at a dose of 0.35 cc SQ was administered to 10 mice per group for 28 consecutive days. The animals were observed clinically each day for toxicity. There was no ataxia, lethargy or respiratory distress. After 28 days, sections of harvested brains, kidneys, livers, pancreases and hearts were examined for inflammation and/or necrosis. None was found. A repeat study using the same parameters was performed. Again, there was no clinical or microscopic toxicity.
Rats with experimentally-induced mammary gland tumors were treated with Enercel®, 0.05 ml IM/day. Control animals were given 1 ml IM. No necrosis was noted in biopsies from either group.
Mice were treated with 0.5 ml Enercel® Plus IM daily for 30 days and evaluated for clinical and microscopic toxicity. There were no changes in color of the mucous membranes, hair, tail scaling, diarrhea, oral intake, movement, or posture. After sacrifice, internal organs were normal as to gross appearance, size, consistency, weight and blood vessels. Microscopic evaluation did not show any toxicity.
C. Humans: Eighty-two patients were treated with Enercel® nasal spray 2 puffs three times/day for 1 month. No clinical toxicity was noted.
Once-hundred twenty-three children less than 5 years of age were enrolled in a placebo-controlled study of acute diarrheal disease. The test group received 3 ml IM of Enercel® twice daily for up to 5 days. No clinical signs of toxicity were noted.
A single-dose study of Enercel®--100 ml intravenously—was performed. No clinical or laboratory evidence of toxicity was noted.
Investigator Class Dose Toxicity
See in vitro 100 ul/mg None
See animal 0.35 cc SQ None
See animal 0.35 cc SQ None
Bergoc animal up to 1 ml IM None
Botelli animal 0.5 ml IM None
Keresti human nasal spray 2 tid None
Izaguirre human 3 ml IM bid None
Bertacchini human single dose 100 ml IV None
REPRODUCTIVE FUNCTION: While no formal reproductive studies have been performed, many couples with one or both using Enercel® have successfully initiated and maintained a viable pregnancy. A number of tests of reproductive function have been anecdotally performed in persons of childbearing years that were using Enercel® chronically. Gamete viability and numbers are not decreased in either males or females. There is no evidence that the product has a negative effect on uterine or ovarian structure or function. Similarly, hormonal levels are not influenced to the degree that reproductive capacity would be affected. Using historical and age and sex matched controls, the reproductive capacity of Enercel® users appears to match the general population.
EMBRYO-FETAL TOXICITY: Hundreds of women chronically taking Enercel® have become pregnant. Neither the direct post-delivery period nor childhood years evidenced developmental or in utero disorders. Since the components of Enercel® are present in micromolar amounts, none is expected to pass into breast milk. Therefore, Enercel® is safe in lactating females. There is no documented negative effect of Enercel® in pregnant women. Furthermore, Enercel® has proven to be safe to all tissues and organs including fetuses. However, World Health Advanced Technologies, Ltd., advises that women, who are pregnant, should not take Enercel® without clearance from their Medical Health Professional due to the lack of controlled studies in pregnancy.
MUTAGENIC POTENTIAL: A formal in vitro study has been performed to evaluate several parameters of Enercel use, including mutagenicity. Enercel® at a dose of 100 ul/mg tissue was not mutagenic to mammalian cells (mouse lymphoma cells).
CARCINOGENIC DATA: Long-term studies in animals to assess the carcinogenic potential of Enercel® have not been conducted. However, several cell lines have been observed for cancer formation in vitro. Even doses as high as 100 ul/mg have not induced carcinogenesis. In fact, in K562 cancer lysis assays, cancer kill was increased with the addition of Enercel®.
SPECIFIC PHARMACOLOGICAL EFFECT DATA: Given that Enercel® is a homeopathic preparation and the constituents are therefore in micromolar amounts, it is not possible to determine specific pharmacology. However, indirect effects can readily be measured.
A. In vitro: 100 ul/mg of Enercel® in a variety of in vitro systems produced the following: Significant increases in: IGF-1; HGH; lysis of K562 cancerous target cells; cytochrome p450 isozyme levels and glutathione peroxidase.
Natural killer cell function against target cells from patients with Chronic Fatigue
Syndrome and AIDS was significantly enhanced.
B. Animals: Splenic Natural Killer Cell function again YAC-1 targets and indirect antiviral effect again coxsackievirus B4 were increased in mice. General well-being, slowed tumor growth and improved survival were observed in rats with experimentally-induced mammary tumors.
C. Humans: Children with acute diarrhea treated with 3 ml IM q 12 hr. showed improvement after 18 hrs for the following parameters: improved hydration and peristasis; diminished diarrhea and body temperature.
Persons with a variety of late-stage cancers improved as follows: anti-tumor immune function; tolerance of radiation and chemotherapy; reduction in tumor burden and extension of life expectancy.
Eight-seven patients with pancreatic cancer showed a positive response to Enercel® for the following parameters: pain control; appetite; nausea and vomiting; physical activity and depression.
Patients with atrophied muscle showed skeletal muscle improvement after direct injections as follows: hydration, cytoplasm sodium concentration and cellular resting potential.
Persons with post-polio syndrome (PPS) that were given Enercel® had improvements in immune function and muscle strength.
Patients with a variety of respiratory illnesses showed decreased cough, improved sense of well-being and decreased need for other medications after treatment with Enercel® by nasal spray.
Human subjects with nasal rhinitis were treated for 1 month with Enercel® by nasal spray. Symptoms that improved significantly included: nasal congestion, sneezing, dripping, and itching tearing and irritated eyes.
GENERAL PHARMACOLOGICAL DATA: As discussed above, Enercel® has a positive function in many different systems. A study by Izaguirre has uncovered a general effect of Enercel® with may explain its utility in a variety of conditions.
Alternate cellular energy (ACE) activity in most cells of the body is vital for their optimal
function. Many illnesses result in severely depressed ACE levels and resulting cellular dysfunction. Using titrating doses, ACE levels were substantially increased in a dose-related fashion in monitored cells. Clinical correlation (improvement in diarrhea) was also shown.
DRUG INTERACTIONS DATA: Clinical studies in humans have not evidenced any direct drug-drug interactions. Drug levels of concomitant medications were in the expected range when evaluated. An exception can occur with drugs that are metabolized by the cytochrome p450 system in the liver. See showed that 7 of the 9 most common isozymes had significantly increased activity with Enercel® addition. Therefore, levels of cytochrome p450-metabolized drugs may be lower than expected and doses may need to be increased. Fortunately, it is implicit that drugs at usual doses will not reach toxic levels when administered with Enercel®. Drugs that may have their levels diminished due to enhanced cytochrome p450 levels from Enercel® include (but not limited to): caffeine; clozapine; haloperidol; theophylline; antihistamines (astemizole, loratadine and terfenadine); benzodiazepines (except lorazepam and oxazepam); tricyclic antidepressants (TCA); beta-blockers; risperdal; codeine; tramadol; protease inhibitors; ketoconazole, lovastatin; glyburide; erythromycin; tegretol; calcium channel blockers; dilantin; warfarin and non-steroidal anti-inflammatory drugs. Although these are theoretical considerations, in practice usual doses of these drugs appear to remain in the therapeutic range when co-administered with Enercel®. A tremendous advantage of widespread p 450 activation is the capacity to prepare drugs and toxins such as aflatoxins for excretion by the kidneys and liver—therefore, toxic and side effects may be limited.
PHARMACOKINETICS: It is not possible to measure the components of Enercel® in the bloodstream. However, it is useful to observe the physiologic effect after different dosing schedules. Such endpoints as diarrhea, nausea and vomiting, cough, rhinitis and muscle hydration have been evaluated daily in patients treated with various schedules of Enercel®. The dose response curve is strictly linear when Enercel® is given either parenterally or by nasal spray. The clinical half-life of the IM dose is about 6 hours—therefore qd or bid doses are sufficient. The half-life of the nasal spray is about 4 hours—schedules of tid or qid are required.
LOCAL TOLERANCE DATA: The local response to Enercel® injections and nasal spray has been extensively evaluated. Some local pain and minor infections have been noted after Enercel® injections, but these have all been explainable by the use of the needles themselves and not the Enercel® content. Of interest, the incidence of local infections after Enercel® inoculations appears to be less than historical controls. The vigorous immune stimulation of Enercel® may account for this. Botelli has examined the local effects of Enercel® injections in mice. The animals were given daily intramuscular inoculations of Enercel® and examined daily for necrosis, erythema and tenderness of both the superficial and deeper skin layers. There were no visual or microscopic changes at any of the sites.
Hazelwood and colleagues evaluated patients with atrophied muscles that were injected with Enercel®. No local effects were observed. Keresti observed the nasal mucosa of patients that were treated with up to 2 puffs of Enercel® nasal spray daily for 1 month. No erythema, venous congestion or dripping of the nasal mucosa was noted.
OTHER DATA/PEDIATRIC USE: The World Health Advanced Technologies, Ltd. database contains hundreds of anecdotal reports of children receiving Enercel® without toxicity or side-effects. These include children with severe illnesses such as pneumonia and copious diarrhea. A formal study of Enercel® at a dose of 3 ml IM in a Pediatric population failed to show any local or systemic toxicity. A study of Enercel® nasal spray included a large number of children. Again, no toxicity was noted.
The database of Enercel®-treated individuals has failed to demonstrate a single case of anaphylaxis. This is not surprising given the low allergenicity of the Enercel® components in conjunction with their extremely low concentrations.
OVERVIEW: The toxicity of Enercel® has been assessed by multiple controlled studies. In vitro concentrations of up to 100 ul/mg, animal trials of 1 ml IM and clinical studies of 100 ml IV have all confirmed the safety of Enercel®. The pharmacology has been evaluated by endpoint analysis—titrating doses allow for positive laboratory and clinical efficacy. There are no drug-drug interactions other than a beneficial effect on concomitant drug concentrations due to a predictable and consistent upregulation of hepatic p450 isozymes. In addition, the safety of Enercel® has been established in pregnant and lactating women, fetuses and children. No episodes of anaphylaxis have been reported.
REFERENCES:
1. Alternative Cellular Energy-Based Therapy of Childhood Diarrhea. Presentation 54 annual meeting Am Soc Trop Med Hygiene. Izaguirre RR, Reyes-Guzman M, Fuentes RC, Mena CE, Penate E, Bertaccini C.
2. Immunomodulatory Effects of a Homeopathic Agent. J Nat Med 1997. See DM, Tilles JG, Bertacchini C.
3. Diverse In Vitro Optimization of Enercel®. Abstract. July 2006. See DM
4. Effect of a New Alternative Medicine in Acute Diarrheas, including those caused by rotavirus, in children less than 5 years of age consulting at the emergency ward of Benjamin Bloom Hospital in San Salvador, between August 2003 and April 2004. Abstract. Rafael Ruiz Izaguirre, MD, Miguel Reyes Guzmán, MD, Rafael Chacón Fuentes MD, Carlos E. Mena MD, Emilio Peñate, MD.
5. Clinical Trial Involving ENERCEL® Nasal Spray in the Treatment of Recurrent Allergic Disease of the Upper Respiratory Tract: A Preliminary Communique by Rafael Ruiz, M.D., FAAP (October 1999)
6. "Can Wasted Muscle be Rehydrated and Functionally Enhanced?" Utilizing
ENERCEL®, as presented by Carlton F. Hazlewood, Ph.D. and Zsolt Kereszti, M.D. (Abstract; March 1997)
7. A Clinical Study of Cases of "Allergic-Origin Othorhinological Diseases", Utilizing ENERCEL®. Gedeon O. Kereszti, M.D., Ph.D., Department of Otolaryngology and Audiology, Magyar Inre Hospital, Ajka, Hungary (December 1996)
8. Determination of the Toxicity of Enercel® in Mice. Abstract, August 1995. See, MD
9. Study of Selective Aspects of the Quality of Life of Patients with Advanced Pancreatic Cancer, Utilizing ENERCEL®. Cesar Bertacchini, M.D., Instituto de Medicina Integracion, Buenos Aires, Argentina (1992)
10. The Statistical "In Vivo" Study on Experimental Tumors in Rats, Utilizing ENERCEL®. Rose M. Bergoc, M.D. and Elena S. Rivera, M.D. (1992)
11. The Analysis of the Mechanisms of Action of ENERCEL® Therapeutics, performed by Cesar Bertacchini, M.D., Buenos Aires, Argentina (July 1991)
