InterFase Plus by Klaire Laboratories

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alzheimer disease. Although there is interest in using oral or intravenous chelation therapy products for Alzheimer disease, there is insufficient reliable information about the clinical effects of chelation therapy products for this condition.
• Angina. It is unclear if oral or intravenous chelation therapy products are beneficial for angina. Details: A small clinical trial (Program to Assess Alternative Treatment Strategies to Achieve Cardiac Health; PATCH) in patients with angina shows that 500-mL infusions of a multicomponent disodium ethylenediamine tetraacetic acid (EDTA) chelation solution (Endrate) does not improve exercise capacity or time to ischemia when compared with a placebo containing all components other than EDTA. The dose of EDTA was 40 mg/kg (maximum 3 grams per dose) and was provided over a period of 3 hours. Infusions took place twice weekly for 15 weeks and then monthly for 3 months. Each infusion also provided magnesium sulfate 750 mg, ascorbic acid 5 grams, and sodium bicarbonate 5 grams. All patients also took an oral multivitamin/multimineral product (108104). This study may have been underpowered to detect differences between groups. There is currently no information suggesting that the oral use of chelation therapy products is beneficial.
• Arsenic poisoning. Although there is interest in using topical chelation therapy products for arsenic poisoning, there is insufficient reliable information about the clinical effects of topical chelation therapy products for this condition.
• Atherosclerosis. Although there is interest in using oral chelation therapy products for atherosclerosis, there is insufficient reliable information about the clinical effects of chelation therapy products for this condition.
• Attention deficit-hyperactivity disorder (ADHD). Although there is interest in using oral chelation therapy products for ADHD, there is insufficient reliable information about the clinical effects of chelation therapy products for this purpose.
• Atopic disease. Although there is interest in using oral chelation therapy products for atopic disease, there is insufficient reliable information about the clinical effects of chelation therapy products for this purpose.
• Autism spectrum disorder. It is unclear if oral or topical chelation therapy products are beneficial for autism spectrum disorder. Details: Various chelation therapy products have been investigated in clinical research. One preliminary clinical trial in children aged 3-8 years with autism spectrum disorder shows that taking dimercaptosuccinic acid (DMSA) 10 mg/kg three times daily as chelation therapy does not improve sociability, communication with speech or language, or general stereotypical behaviors when compared with placebo. The DMSA was taken for 3 days and then repeated up to 6 times, with 11 days off between treatment periods. Prior to the initiation of this phase of the study, all children received at least one 3-day round of chelation therapy to ensure the excretion of high amounts of heavy metals; however, heavy metal excretion was not compared between groups . Also, half of the children received topical glutathione for 7 days (21057,108099,108109). Other preliminary clinical research in children aged 3-9 years with autism spectrum disorder shows that taking a single dose of DMSA 10 mg/kg increases urinary excretion of cadmium, mercury, and lead. Taking DMSA monthly for 6 months improves overall behavior when compared with baseline. However, only specific behaviors, such as relating to people, imitation, and communication, were improved; other behaviors, including emotional, visual, auditory, or intellectual responses, were not improved (108110). The validity of these findings is limited by the lack of a comparator group. Small clinical studies have also evaluated other chelation therapy products in children with autism spectrum disorder. These include rectal thiamine tetrahydrofurfuryl disulfide (108111) and oral, intravenous, rectal, or topical 2,3-dimercaptopropane-1-sulfonate (DMPS) (108098). However, there is insufficient reliable information available regarding their effects.
• Cancer. Although there is interest in using oral chelation therapy products for cancer, there is insufficient reliable information about the clinical effects of chelation therapy products for this use.
• Cardiovascular disease (CVD). It is unclear if oral or intravenous chelation therapy products are beneficial for CVD. Details: One large clinical study (the Trial to Assess Chelation Therapy; TACT) in adults with stable coronary disease following a recent myocardial infarction (MI) shows that receiving 500-mL infusions of a multicomponent disodium ethylenediamine tetraacetic acid (EDTA) chelation solution, with or without oral high-dose vitamins, reduces the composite risk of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization by about 18% over 5 years. However, there was no effect of EDTA on the risk of these individual endpoints. A sub-group analysis shows that the risk of this composite outcome is reduced by up to 41% in patients who also have diabetes, with no reduction in patients without diabetes (94983,94985). Also, receiving just the multicomponent disodium EDTA chelation solution without oral high-dose vitamins does not reduce the risk of this composite outcome when compared with placebo, even in the subgroup of patients with diabetes (94986). Each infusion provided EDTA 3 grams over a period of at least 3 hours in combination with ascorbic acid 7 grams, magnesium chloride 2 grams, potassium chloride 2 mEq, sodium bicarbonate 840 mg, pantothenic acid 250 mg, thiamine 100 mg, pyridoxine 100 mg, procaine hydrochloride 100 mg, and heparin 2500 units (94983,94985,94986). Significant limitations of the trial, including missing data and possible unblinding, limit the reliability of these findings (95697).
• Hypertension. Although there is interest in using oral chelation therapy products for hypertension, there is insufficient reliable information about the clinical effects of chelation therapy products for this condition.
• Influenza. Although there is interest in using oral chelation therapy products for influenza, there is insufficient reliable information about the clinical effects of chelation therapy products for this purpose.
• Lead toxicity. Although there is interest in using topical chelation therapy products for lead toxicity, there is insufficient reliable information about the clinical effects of topical chelation therapy products for this condition.
• Mercury toxicity. Although there is interest in topical chelation therapy products for mercury toxicity, there is insufficient reliable information about the clinical effects of topical chelation therapy products for this condition.
• Osteoporosis. Although there is interest in using oral chelation therapy products for osteoporosis, there is insufficient reliable information about the clinical effects of chelation therapy products for this condition.
• Parkinson disease. Although there is interest in using oral chelation therapy products for Parkinson disease, there is insufficient reliable information about the clinical effects of chelation therapy products for this condition.
• Peripheral arterial disease (PAD). It is unclear if oral or intravenous chelation therapy products are beneficial for PAD. Details: Individual preliminary clinical trials included in a systematic review have shown that intravenous disodium ethylenediamine tetraacetic acid (EDTA) has no beneficial effect on blood flow, walking distance, pain-free walking distance, blood lipid levels, or well-being in patients with PAD (5752,5753,5754,108103). Most studies have used EDTA 3 grams twice weekly, usually in combination with vitamins and minerals, over a period of up to 10 weeks (5753,108103). In addition, there is no information suggesting that the oral use of EDTA is beneficial.
• Uterine fibroids. Although there is interest in using oral chelation therapy products for uterine fibroids, there is insufficient reliable information about the clinical effects of chelation therapy products for this purpose. More evidence is needed to rate chelation therapy products for these uses.

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Proteolytic enzymes represent a wide group of enzymes that are used alone or in combination. See specific monographs for effectiveness information.

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INSUFFICIENT RELIABLE EVIDENCE to RATE

• Bronchiectasis. A small clinical study in patients with bronchiectasis shows that taking serrapeptase 30 mg daily for 4 weeks significantly reduces frequency of cough and also seems to decrease sputum viscosity and neutrophil counts in sputum samples when compared with no treatment (13153).
• Chronic bronchitis. A small clinical study in patients with chronic bronchitis shows that taking serrapeptase 30 mg daily for 4 weeks significantly reduces frequency of cough and expectoration and also seems to decrease sputum viscosity and neutrophil counts in sputum samples when compared with no treatment (13153).
• Laryngitis. A clinical study in patients with acute or chronic ear, nose, or throat disorders, including laryngitis, shows that taking serrapeptase 10 mg three times daily reduces pain, secretions, difficulty swallowing, and body temperature after 3-4 days of treatment when compared with placebo (13152).
• Pharyngitis. A clinical study in patients with acute or chronic ear, nose, or throat disorders, including pharyngitis, shows that taking serrapeptase 10 mg three times daily reduces pain, secretions, difficulty swallowing, and body temperature after 3-4 days of treatment when compared with placebo (13152).
• Postoperative swelling. Serrapeptase has been evaluated for reducing facial swelling after a variety of procedures. A clinical study in patients undergoing maxillary antrostomy for empyema shows that taking serrapeptase 10 mg orally three times on the day before surgery, once in the evening after surgery, and three times daily for 5 days after surgery modestly reduces buccal swelling when compared with placebo (13151). In patients requiring removal of impacted mandibular third molars, a small clinical study in healthy adults suggests that taking serrapeptase 10 mg three times daily for 5 days improves postoperative trismus and swelling by the fourth postoperative day when compared with placebo; however, no difference in pain scores was observed (106013). The validity of these findings in limited by a lack of consistent comparison to baseline in both groups. Conversely, two other small studies in patients requiring removal of impacted mandibular third molars suggest that serrapeptase is less effective than dexamethasone or another proteolytic enzyme, consisting of trypsin, bromelain, and the flavonoid rutin, for improving swelling or facilitating wound healing (106011,106012). The validity of these findings is limited due to poor study methodologies.
• Rhinosinusitis. A clinical study in patients with acute or chronic ear, nose, or throat disorders, including rhinosinusitis, shows that taking serrapeptase 10 mg three times daily reduces pain, nasal secretions, nasal obstruction, and anosmia after 3-4 days of treatment when compared with placebo (13152). More evidence is needed to rate serrapeptase for these uses.

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POSSIBLY UNSAFE ...when unregulated chelation therapy products are used orally or parentally or when prescription chelation therapy products are used for unproven indications and/or in unapproved doses or routes of administration. The American College of Medical Toxicology and The American Academy of Clinical Toxicology recommend against the unapproved use of chelation therapy products (108106). Chelation therapy products can result in severe side effects including dehydration, hypocalcemia, kidney failure, neurodevelopmental toxicity, and death (107700,108095,108096,108105,108106,108107). Also, infusion of the disodium form of EDTA over less than 3 hours can cause severe, life-threatening adverse effects including hypocalcemia and death (5737).

CHILDREN: POSSIBLY UNSAFE
when unregulated chelation therapy products are used orally or parentally or when prescription chelation therapy products are used for unproven indications and/or in unapproved doses or routes of administration. The American College of Medical Toxicology and The American Academy of Clinical Toxicology recommend against the unapproved use of chelation therapy products (108106). Chelation therapy products can result in severe side effects including dehydration, hypocalcemia, kidney failure, neurodevelopmental toxicity, and death (107700,108095,108096,108105,108106,108107).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when unregulated chelation therapy products are used orally or parentally or when prescription chelation therapy products are used for unproven indications and/or in unapproved doses or routes of administration. The American College of Medical Toxicology and The American Academy of Clinical Toxicology recommend against the unapproved use of chelation therapy products (108106). Chelation therapy products can have teratogenic effects and result in severe side effects including dehydration, hypocalcemia, kidney failure, neurodevelopmental toxicity, and death (107700,108095,108096,108105,108106,108107).

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POSSIBLY SAFE ...when used orally and appropriately. Various proteolytic enzymes have been safely used orally in clinical research (716,964,965,968,969,6252,6253,10622,11457,18281,18284) (91104,91105,91106,91111,96449). Side effects are typically mild to moderate and most often include gastrointestinal effects. See specific monographs for more detailed information related to the safety of individual proteolytic enzymes. ...when used topically and appropriately. Various proteolytic enzymes have been safely used topically in clinical research (67835,67843,67845,91113). Some proteolytic enzymes might cause allergic reactions when used topically. See specific monographs for more detailed information related to the safety of individual proteolytic enzymes.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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POSSIBLY SAFE ...when used orally and appropriately, short-term. Serrapeptase seems to be safe when used in clinical trials lasting up to 4 weeks (13151,13152,13153). There is insufficient reliable information available about the safety of serrapeptase when used long-term.

PREGNANCY AND LACTATION:
Insufficient reliable information available; avoid using.

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DIURETIC DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Concomitant use of ethylenediamine tetraacetic acid (EDTA) and potassium-depleting diuretics might increase the risk for hypokalemia.  Details EDTA can decrease serum potassium levels and increase excretion of potassium (15).

INSULIN Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Ethylenediamine tetraacetic acid (EDTA) can decrease the activity of insulin and increase the risk for hypoglycemia.  Details Concomitant use of disodium EDTA with insulin can cause severe decreases in blood glucose concentrations (5737,5771). Additionally, EDTA chelates zinc in insulin products (15) and might interfere with the onset and duration of activity of various insulin preparations.

WARFARIN (Coumadin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, disodium ethylenediamine tetraacetic acid (EDTA) can decrease the anticoagulant effects of warfarin.  Details Disodium EDTA has been reported to decrease international normalized ratio (INR) in a patient taking warfarin (4611).

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General ...The use of chelation therapy products for unproven indications, or in unapproved doses or routes of administration, is generally considered to be unsafe.
Most Common Adverse Effects:
Orally: Gastrointestinal upset, nausea.
Intravenous: Abdominal cramps, anorexia, burning and pain at infusion site, diarrhea, headache, nausea, vomiting.
Serious Adverse Effects (Rare):
Orally: Allergic reactions, Stevens-Johnson syndrome.
Intravenous: Allergic reactions, arrhythmias, convulsions, death, heart failure, hypercalcemia, hypocalcemia, insulin shock, kidney failure, paresthesia, respiratory arrest, tetany, thrombophlebitis.

Cardiovascular ...Intravenously, chelation therapy products such as 2,3-dimercaptopropane-1-sulfonate (DMPS) or ethylenediamene tetraacetic acid (EDTA) have been associated with hypotension and irregular heartbeat (5737,5771,5772,108105,108106). Intravenously, EDTA can also cause thrombophlebitis (108099,108103). Disodium EDTA, when given as a rapid infusion or highly concentrated solution, can cause hypocalcemia, severe cardiac arrhythmias, respiratory arrest, and death (15,108102).
There are at least three case reports of intravenous chelation therapy-related hypocalcemia resulting in cardiac arrest. Two cases involved the use of disodium EDTA in children and one involved the unapproved use of an unknown type of EDTA over a 10- to 15-minute infusion in an adult (107700,108095,108096,108097,108105). At least in part because of these cases, disodium EDTA is no longer FDA-approved (108105). In a large clinical trial in patients with a previous myocardial infarction, the rate of hypocalcemia was 6.2% in patients given disodium EDTA, compared with 3.5% of those given placebo; however, disodium EDTA did not increase the risk of heart failure or death (94985).

Dermatologic ...There is a case report of Stevens-Johnson syndrome after two weeks of oral 2,3-dimercaptopropane-1-sulfonate (DMPS) chelation therapy in a child with chronic mercury exposure. Symptoms included a widespread eruption of red, itchy macules which gradually improved after discontinuation of DMPS therapy (108112). Rash has also been reported in patients given intravenous DMPS or oral dimercaptosuccinic acid (DMSA) (108099).
Intravenously, ethylenediamene tetraacetic acid (EDTA) can commonly cause exfoliative dermatitis (15,108103) and a burning sensation and pain at the site of infusion (5744,108103).

Endocrine ...Intravenously, calcium disodium ethylenediamene tetraacetic acid (EDTA) can cause zinc deficiency (5771,5772) and hypercalcemia (5771,5772). Disodium EDTA can occasionally reduce magnesium and potassium serum concentrations (5771,5772), and rarely cause insulin shock (5737).
Disodium EDTA, when given as a rapid infusion or highly concentrated solution, can cause hypocalcemia, leading to tetany, convulsions, cardiac arrhythmias, cardiac failure, respiratory arrest, and death. This has occasionally occurred when the disodium form of EDTA was used in error, instead of the calcium disodium form (15,94984,94985,107700,108095,108096,108097,108099,108105).

Gastrointestinal ...Intravenously, ethylenediamene tetraacetic acid (EDTA) can commonly cause abdominal cramps, anorexia, nausea, vomiting, and diarrhea (15). EDTA can also sometimes cause thirst (15).
When given orally or intravenously, 2,3-dimercaptopropane-1-sulfonate (DMPS) has caused nausea and dysgeusia.
Orally, dimercaptosuccinic acid (DMSA) has caused gastrointestinal upset and diminished appetite (108099).

Hematologic ...Intravenously, ethylenediamene tetraacetic acid (EDTA) can sometimes cause anemia (15), prolonged prothrombin time (5737) and transient bone marrow suppression (5737,5772).

Hepatic ...Intravenously, the calcium disodium form of ethylenediamene tetraacetic acid (EDTA) can cause mild elevations of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and decreased alkaline phosphatase (ALP) levels (15,108102).
Orally, dimercaptosuccinic acid (DMSA) has been associated with mild elevations in liver transaminase levels (108105).

Immunologic ...Intravenously, disodium ethylenediamene tetraacetic acid (EDTA) can rarely cause histamine-like reactions (5737). There are rare reports of allergic reactions to EDTA given as a nasal provocation, topically, intradermally, and subcutaneously (94992). In one case report, a 57-year-old male presented with pruritus on the hands and feet, as well as urticaria and swelling of the face, following subcutaneous injection with a local anesthetic containing EDTA. Allergy to other ingredients in the anesthetic was ruled out, and intradermal and subcutaneous testing with calcium disodium EDTA confirmed the allergic response. The patient also reacted to radio-contrast medium containing EDTA (94992).
Topically, application of EDTA in cosmetics, shampoos, and other products has rarely been reported to cause contact dermatitis (94992).
Orally, dimercaptosuccinic acid (DMSA) has been associated with allergic reactions (108105).

Musculoskeletal ...Intravenously, disodium ethylenediamene tetraacetic acid (EDTA) can occasionally cause muscle cramps, back pains, muscle weakness, and myalgias (15). In a large clinical trial in patients with a previous myocardial infarction, the rate of hypocalcemia was 6.2% in patients given disodium EDTA, compared with 3.5% of those given placebo; however, only one patient had associated muscle cramping leading to a hospital visit (94985).

Neurologic/CNS ...Intravenously, ethylenediamene tetraacetic acid (EDTA) can commonly cause headache and faintness (15,108103). EDTA can also sometimes cause fever, chills, fatigue, and malaise (15,108099). Disodium EDTA can occasionally cause tremors, tingling, and paresthesias (15).
Orally, dimercaptosuccinic acid (DMSA) was associated with lethargy in one child in a clinical trial. Other possible adverse effects associated with DMSA included sleep problems (108099).

Pulmonary/Respiratory ...Intravenously, ethylenediamene tetraacetic acid (EDTA) can sometimes increase sneezing and nasal congestion (15). Inhalation of disodium EDTA contained in nebulizer solutions has been reported to cause dose-related bronchoconstriction (5765).

Renal ...Intravenously, ethylenediamene tetraacetic acid (EDTA) can sometimes cause urinary urgency and frequency (5772). However, the most serious adverse effect of EDTA is kidney toxicity (5772,108095,108099,108102) for doses greater than 3 grams daily (15). In a clinical trial in patients with angina, intravenous disodium EDTA has resulted in an elevation of serum creatinine (108104). EDTA can cause nocturia, hyperuricemia, polyuria, dysuria, oliguria, proteinuria, glycosuria, hematuria. and distal tubule and glomeruli changes (15). EDTA can also cause acute renal tubular necrosis, renal insufficiency, and renal failure (5772).

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General ...Orally, proteolytic enzymes are generally well tolerated. See specific monographs for detailed safety information related to individual proteolytic enzymes.
Most Common Adverse Effects:
Orally: Gastrointestinal upset.
Serious Adverse Effects (Rare):
Topically: Allergic reactions.

Gastrointestinal ...Orally, some patients taking proteolytic enzymes may have gastrointestinal complaints (101517).

Immunologic ...Proteolytic enzymes are commonly found in laundry detergents and pre-spotter products. Rarely, protease specific IgE positive tests possibly related to these products have occurred. Exposure may be airborne or topical (102705). In addition, in case reports, occupational exposure to the airborne proteolytic enzyme pepsin has resulted in allergic rhinoconjunctivitis or asthma (102706,102707).

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General ...Orally, serrapeptase seems to be well-tolerated. Some patients have reported epigastric pain, gastrointestinal upset, and nausea; however, these side effects appear to occur at the same rate as placebo (13152).

Gastrointestinal ...Orally, some patients have reported experiencing epigastric pain, gastrointestinal upset, and nausea; however, these side effects appear to occur at the same rate as placebo (13152).

Immunologic ...There is a case report of bullous pemphigoid, an autoimmune subepidermal dermatosis, in an elderly man who took serrapeptase (13154).

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