Dosage & Ingredient Facts

ActRx Treatment...  [Artesunate + Berberine]

Supplement Facts -  PACKET A - Artesunate 50mg (Tablet)

• Serving Size – Two Tablets
• Servings Per Container – 5
• Amount Per Serving:100mg (2 tablets)
• Appearance - White round tablet

Supplement Facts -  PACKET B - Berberine Alkaloid 400mg (Tablet)

• Serving Size – Two Tablets
• Serving Per Container – 5
• Amount Per Serving - 800mg (2 tablets)
• Appearance - Orange/Brown round tablet

Dosage

IMPORTANT: For patients taking the ActRx Professional Malaria Treatment Pack, have a Doctor or qualified medical professional administer the appropriate ActRx Artemether Injection at the start of Treatment, immediately followed by the tablets, as directed on the package or by the medical professional.

Ingredient Facts

ActRx Injectable Artesunate (80 mg) -  [Artemether]

CHEMISTRY

Artemether is a lipid soluble methylether of dihydroartemisinin. Artemisinin is a novel sesquiterpene lactone, extracted from the leaves of the shrub Artemesia annua and possesses an endoperoxide bridge which is a rare feature in natural products. The endoperoxide bridge is essential for its antimalarial activity.

Its chemical formula is 3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro-10-methoxy-3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin. Its molecular formula C16H26O5 and its molecular weight is 298.4.

CLINICAL PHARMACOLOGY

Arthemether is active against all Plasmodia including those which may be resistant to other anti-malarials. Arthemether have very rapid schizontocidal activity. The schizontocidal activity of arthemether is mainly due to destruction of the asexual erythrocytic forms of P. falciparum and P. vivax. Arthemether is concentrated in the food vacuole. It then splits its endoperoxide bridge as it interacts with haem, blocking conversion to haemozoin, destroying existing haemozoin and releasing haem and cluster of free radicals into the parasite. There is inhibition of protein synthesis during growth of trophozoites. There is no cross resistance with chloroquine. Arthemether is not active against hypnozoites. Therefore, 8-amino-quinoline  derivative such as primaquine should be given sequentially after the combination in cases of mixed infections of P. falciparum and P. vivax to achieve hypnozoites eradication. Arthemether reduces gametocyte carriage. There is no rationale at present for using arthemether for chemoprophylaxis.

PHARMACOKINECTICS

The drug is slowly absorbed from intramuscular injection. Peak plasma concentrations have been achieved in about 6 hours after intramuscular injection of arthemether. Arthemether is hydrolyzed after administration to a biologically active metabolite, dihydroartemisinin accounts for most or all of clinical antimalarial activity. Total protein binding is 95.4%. The drug is rapidly and extensively metabolized in the liver. In animal studies, unchanged arthemether has not been detected in both faeces and urine due to its rapid and high first-pass metabolites (unidentified) have been detected in both faeces and urine. The elimination half-life is approximately 1 hour, but following intramuscular administration the elimination phase is prolonged because of continued absorption. The elimination half life of dihydroartemisinin was approximately 2 hours. Arthemether has been reported to clear fever in  severe falciparum malaria within 30-84 hours.

INDICATIONS

Arthemether injection is indicated for treatment of severe and complicated malaria caused by P. falciparum both in adults and children in areas where there is multidrug resistance.

CONTRAINDICATIONS

Arthemether is contraindicated in patients with hypersensitivity to arthemether or other artemisinin compounds. Arthemether is not recommended in the first trimester of pregnancy because of limited data. 

PRECAUTIONS

• Do not exceed the prescribed dose. In case of overdosage, urgent symptomatic treatment in a specialized unit is required.
• Caution is required in patients with Cardiovascular disease, Hepatic impairment, Renal insufficiency

USAGE IN PREGNANCY

As per information available from World Heal Organization, little experience has been gained with the use of this drug in pregnancy but it should not be withheld if it is considered life-saving to the mother. Artemisinin and its derivatives can be used for treatment of uncomplicated malaria during the second and third trimester of pregnancy in areas of multidrug resistance. Owing to lack of data, use in the first trimester of pregnancy is not recommended. Artemisinin and its derivatives have not been measured in the milk to nursing mothers. It is very likely that these are present in milk and nursing mothers should not be given artemisinin if they are suffering from uncomplicated malaria either in multidrug resistance or drug sensitive situations. If the nursing mother is suffering from complicated and serious malaria induced by multidrug-resistant P. falciparum and artemisisn is indicated, breast feeding should be stopped.

DRUG INTERACTIONS

Since electrocardiographics QT prolongation had been reported in some patients treated with artemether, it is recommended to avoid prescription of medications known to produce a prolongation of QT interval or patients receiving such medication: erythromycin, terfenadine, astemizole, probucol, Class 1a anti-arrhythmic agents (quinidine, procainamide, disopyramide), Class III anti-arrhythmic agents (amiodarone, bretylium), bepridil, sotalol, tricyclic, antidepressants, some neuroleptics and phenothiazines are to be monitored closely.

ADVERSE EFFECTS

Artemether has been remarkably well tolerated, and appears less toxic than quinine or chloroquine; adverse effects include bradycardia, electrocardiogram abnomalities, gastrointestinal disturbances (nausea, abdominal pain, diarrhoea- oral theraphy only), dizziness, injection site pain, skin reactions, and fever. Transient decreases in neutrophils and reticulocytes have been reported in some patients treated with artemether. Drug induced fever had been observed with artemether. Mild reactions were seen in patients to whom artemether had been administered intramuscularly. These included nausea, hypotension, dizziness and tinnitus. These side effects were also reported: dark urine, sweating, somnolence, and jaundice. There were no deaths or any other side effects. No irreversible side effects seen. Slight rise of SGOT and SGPT may occur in individual cases. Neurological side effects have not yet been observed in clinical use but clinical trials suggests that coma may be prolonged in patients treated with artemether and there was an increased of convulsions in one trial in cerebral malaria. Transient first degree heart block had been documented in three patients receiving artemether. Neurotoxicity has been observed in animal studies but not in humans. Cardiotoxicity had been observed following administration of high doses or Artemether.

DOSAGE AND ADMINISTRATION

Artemether Injection is for intramuscular use only.

The recommendation does is as follows:

3.2 mg/kg by the intramuscular route as a loading does on the first day, followed by 1.6 mg/kg daily until the patient can take oral therapy to complete a 7-day course. The daily dose can be given as a single injection. In children, the use of a tuberculin syringe is advisable since the injection volume will be small.

OVERDOSAGE

There is no experience with overdosage with artemether. There is no specific antidote known for the artemisinin derivatives. However, experimental toxicological results obtained with large doses of artemisinin on the cardiovascular system and the CNS should be considered. Overdose could bring on cardiac irregularities. An ECG should be taken before initiating treatment in cardiac patients. Irregularities in the pulse should be looked for and cardiac monitoring carried out if necessary. The animal results on the CNS suggest that overdose could result in changes in brain stem function. Clinicians treating cases of overdosage should look for changes in gait, loss of balance, or changes in ocular movements and reflexes.

STORAGE

Store in a cool dry dark place.

BERBERINE Alkaloid:

SUPPLEMENTAL FACTS:

Serving Size – See Item #1 (above) for proper dosage of ActRx Treatment or as directed by your healthcare professional, with respect to Malaria.

Other Direction: For general use as a Plant antibiotic-type support. Take 1 capsule every 12 hours for 3 to 5 days or as directed by your healthcare professional until condition is resolved.

Berberine Alkaloid may also sucessfully treat:

Infections caused by Bacteria, Virus, Parasites, and Fungus ranging from Eye Infections, Tooth Infections, Acne Outbreaks, Skin Infections, Intestinal Infections from contaminated Food and Water including UTI (Urinary Tract Infection or Vaginitis) and many others. Works in 1 to 5 days use. No Toxicity… Easy to Consume… and safe to Use. Very Effective Natural  Remedy 100% Plant Derived (Barbary Root).

Introduction

Berberine is a plant alkaloid with a long history of medical use in both Ayurvedic and Chinese medicine. It is present in Hydrastis Canadensis (goldenseal), Coptis chinensis (Coptis of goldenthread), Berberis aquifolium (Oregon grape), Berberis vulgaris (barberry), and Berberis aristata (tree turmeric). The berberine alkaloid can be found in the roots, rhizomes, and stem part of the plants. Berberine extracts and decorations have demonstrated significant antimicrobial activity against a variety of organism including bacteria, viruses, fungi, protozoans, helminths, and chlamydia. Currently, the predominant clinical uses of berberine include bacterial diarrhea, intestinal parasite infections, and ocular trachoma infections.

Pharmacology

The pharmacologic actions of berberine include metabolic inhibition of certain organisms, inhibition of bacterial enterotoxin formation, inhibition of intestinal fluid accumulation and ion secretion, inhibition of smooth muscle contraction, reduction of inflammation, platelet aggregation inhibition, platelet count elevation in certain types of thrombocytopenia, stimulation of bile and bilirubin secretion, and inhibition of ventricular tachyarrhythmias.

Clinical Applications

Bacterial Diarrhea

Diarrhea caused by Vibrio Cholera and Escherichia coli has been the focus of numerous berberine studies, and results indicate several mechanisms which may explain its ability to inhibit bacterial diarrhea. An animal study found berberine reduced the intestinal secretion of water and electrolytes induced by cholera toxin. Other studies have shown berberine directly inhibits some V.cholera and E. coli enterotoxins, significantly reduces smooth muscle contraction and intestinal motility, and delays intestinal transit time in humans. Berberine sulfate was  has been found to be directly bacteriodical to V. cholera. In case of E. coli, in vitro research indicated berberine sulfate was capable of inhibiting bacterial adherence to mucosal or epithelial surfaces, the first step in the infective process. This may be a result of berberine’s inhibitory effect on fimbrial structure on the surface of the treated bacteria.

Intestinal Parasites

Berberine extracts and salts have demonstrated growth inhibition of Giardia lamblia, Entamoeba histolytica, Trichomonas vaginalis, and Leishmania donovani, with crude extracts being more effective than berberine salts. In tropical climates Giardia lamblia infestation (giardiasis) is a common occurrence, particularly in pediatric populations. Clinical trials conducted in India showed berberine administration improved gastrointestinal symptoms and resulted in a marked reduction in Giardia-positive stools. In comparison to metronidazole (Flagyl), another popular gardiasis medication, berberine was nearly as effective at half the dose. Both in vivo and in vitro studies of berberine’s effects on E. histolytica indicated berberine sulfate was rapidly amoebicidal and caused encystation, degeneration, and eventual lysis of the trophozoite forms. Berberine sulfate rapidly inhibited the growth of Trichomonas vaginalis via formation of large autophagic vacuoles that eventually result in lysis of the trophozoite forms. Studies have shown berberine markedly decreased parasitic load and rapidly improved hematologic parameters in infected animals. In vitro results indicated berberine inhibited multiplication, respiration, and macromolecular biosynthesis of amastigote forms of the parasite interfered with the nuclear DNA of the promastigote form, and inhibited organism maturation.

Ocular Trachoma Infections

A clinical study of aqueous berberine versus sulfacetamide for the treatment of Chlamydia trachomatis infection was conducted in 51 subjects in an outpatient eye clinic. It was determined that while sulfacetamide eye drops produced slightly better clinical results, conjunctival scrapings of these patients remained positive for the infective agent and relapses occurred. In contrast, the conjunctival   scrapings of these patients receiving the berberine chloride eye drops were negative for C. trachomatis and there were no relapses, even one year after treatment. It was also concluded that, while berberine chloride had no direct anti-chlamydial properties, it seemed to cure the infection by stimulating some protective mechanism in the host. A second clinical study found berberine chloride superior to sulfacetamide in both the clinical course of trachoma and in achieving a drop in serum antibody titers against C. trachomatis.

Cardiovascular Effects

Both clinical trials and animals research have indicated berberine administration prevented ischemia induced ventricular tachyarrhythmia, stimulated cardiac contractility, and lowered peripheral vascular resistance and blood pressure. The mechanism for berberine’s antiarrhythmic effect is unclear, but an animal study indicated it may be due to suppression of delayed after-depolarization in the ventricular muscle. An animal study suggested, in addition to affecting several other parameters of cardiac performance, berberine may have a vasodilatory/hypotensive effect attributable to its potentiation of acetycholine.

Anti-Inflammatory Effects

In vitro studies utilizing human cell lines demonstrated that berberine inhibited activator protein 1 (AP-1), a key transcription factor in inflammation and carcinogenesis. Another study, utilizing human peripheral lymphocytes, showed berberine to exert a significant inhibitory effect on lymphocyte transformation, concluding that its anti-inflammatory action may be due to inhibition of DNA synthesis in activated lymphocytes. A third study concluded that during platelet activation in response to tissue injury, berberine had a direct affect on several aspects of the inflammatory process. It exhibited dose-dependent inhibition of arachidonic acid release from cell membrane phospholipids, inhibition of thromboxane A 2 from platelets, and inhibition of thrombus formation.

Other Effects

Berberine has demonstrated a number of other beneficial effects, including immunostimulation via increased blood flow to the spleen, macrophage activation, elevation of platelet counts in cases of primary and secondary thrombocytopenia, and increased  excretion of conjugated bilirubin in experimental hyperbilirunemia. In addition, berberine may possess anti-tumor promoting properties as evidenced by inhibition of COX-2 transcription and N-acetyltransferase activity in colon and bladder cancer lines, and transient, but marked, inhibitory action on the growth of mouse sarcoma cells in culture.

Dosage and Toxicity

Berberine is not considered toxic at doses used in clinical situations, nor has it been shown to be cyto-toxic or mutagenic. Side-effects can result from high dosages and may include gastrointestinal discomfort, dyspnea, lowered blood pressure, flu-like symptoms, and cardiac damage. Berberine usage should be avoided in pregnancy due to potential for causing uterine contractions and miscarriage, and in jaundiced neonates because of its bilirubin displacement properties. The therapeutic dosage for most clinical situations is 200 orally two to four times daily. 

References

1.       Birdsall TC, Kelly GS. Berberine: Therapeutic potential of an alkaloid found in several medicinal plants. Altern Med Rev 1997;2:94-103.

2.       Akhter MH, Sabir M, Bhide NK. Possible mechanism of antidiarrhoel effect of berberine.  Indian J Med Res  1979;70:233-241.

3.       Swabb EA, Tai YH, Jordan L. Reversal of cholera toxin-induced secretion in rat ileum by luminal berberine.  Am J Physiol 1981;241: G248- G252.

4.       Sack RB, Froelich JL. Berberine inhibits intestinal secretory response of Vibrio cholera and Escherichia coli enteroxins.  Infect Immin 1982;35:471-475.

5.       Yuan J, Shen XZ, Zhu XS. Effect of berberine on transit time of human small intestine. Chung Kuo Chung His I Chieh Ho Tsa Chih 1994.14:718-720.

6.       Amin AH, Subbaiah TV, Abbasi KM. Berberine sulfate: antimicrobial activity, bioassay, and mode of action. Can J Microbiol 1969:15:1067-1076.

7.       Sun D, Abraham SN, Beachey EH. Influence of berberine sulfate on synthesis and expression of Pap fimbrial adhesin in uropathogenic Escherichia coli.  Antimicrob Agents  Chemother  1988;32:1274-1277.

8.       Kaneda Y, Torii M, Tanaka T, Aikawa M. In vitro effects of berberine sulfate on the growth and structure of Entamoeba histolytica, Giardia lamblia, and Trichomonas vaginalis.  Ann Trop Med Parasitol  1991;85:417-425.

9.       GhoshAK, Bhattacharyya FK, Ghosh DK. Leismania donovani: amastigote inhibition and mode of action of berberine.  Exp Parasitol 1985;60:404-413.

10.    Kaneda Y, Tanaka T, Saw T. Effects of berberine, a plant alkaloid, on the growth of anaerobic protozoa in axenic culture. Tokai J Exp Clin Med  1990;15:417-423.

11.    Nair KP. Giardiasis in children.   Pediatric Clinics India  1970;5:45.

12.    Choudhry VP, Sabir M, Bhide VN. Berberine in giardiasis.   Indian Pediatrics  1972;9:143-146.

13.    Subbaiah TV, Amin AH. Effect of berberine sulphate on Entamoeba histolytica.   Nature  1967;215:527-528.

14.    Babbar OP, Chhatwal VK, Ray IB, Mehra MK. Effect of berberine chloride eye drops on clinically positive trachoma patients.Indian J Med Res  1982;76:S83-S82.

15.    Khosla PK, Neeraj VI, Gupta SK, Satpathy G. Berberine, a potential drug for trachoma.    Rev Int Trach Pathol Ocul Trop Subtrop Sante Publique  1992;69:147-165.

16.    Chun YT, Yip TT, Lau KL, Kong YC. A biochemical study on the hypotensive effect of berberine in rats.   Gen Pharmac  1978;10:177-182.

17.    Marin-Neto JA, Maciel BC, Secches AL, Gallo L. Cardiovascular effects of berberine in patients with severe congestive heart failure.  Clin Cardiol  1988;11:253-260.

18.    Wang YX, Yao XJ, Tan YH. Effects of berberine on delayed afterdepolarizations in ventricular muscles in vitro and in vivo.  J. Cardiovasc Pharmacol  1994;23:716-722.

19.    Fukuda K, Hibiya Y, Mutoh M, et al. Inhibition of activator protein 1 activity by berberine in human hepatoma cells.Planta Med 1999;65:381-383.

20.    Ckless K, Schlottfeldt JL, Pasqual M, et al. Inhibition of in-vitro lymphocyte transformation by the isoquinoline alkaloid berberine. J Pharm Pharmacol  1995;47:1029-1031.

21.    Huang CG, Chu ZL, Yang ZM. Effects of berberine on synthesis of platelet TXA2 and plasma PGI2 in rabbits.   Chung Kuo Yao Li Hsueh Pao  1991;12:526-528.

22.    Wu JF, Liu TP. Effects of berberine on platelet aggregation and plasma levels of TXB2 and 6-keto-PGF1 alpha in rats with reversible middle cerebral artery occlusion.  Yao Hsueh Hsueh Pao  1995;30:98-102.

23.    Lin JG, Chung JG, Wu LT, et al. Effects of berberine on arylamine N-acetyltransferase activity in human colon tumor cells.  Am J Chin Med 1999;27:265-275.

24.    Fukuda K, Hibiya Y, Mutoh M, et al. Inhibition by berberine of cyclooxygenase-2 transcriptional activity in human colon cancer cells.  JEthnopharmacol  1999;66:227-233.

25.    Creasey WA. Biochemical effects of berberine.    Biochem Pharmacol  1979;28:1081-1084