Tuberculosis Study

Phase III Study of Four Weeks Treatment with Enercel® for New-onset, Presumed Drug-sensitive and Ten Weeks Therapy for Confirmed, Treatment-Refractory, Multi-drug Resistant Pulmonary Tuberculosis at the Regional Antituberculosis Hospital in Chernigov, Ukraine

Dubrov V*, Dubrov T*, Suhareva V*, Christner D**, Baiamonte J**, Laurent D**,

Sanseverino S**

 

* Communal Medical and Preventive Institution, Regional Antituberculosis Hospital, Chernigov, Ukraine

** World Health Advanced Technologies Ltd., Sarasota, Florida/Nassau, Bahamas


ABSTRACT:

Objective: to determine if the complex homeopathic medicine Enercel® is efficacious in short-term treatment of new-onset, presumed drug-sensitive and confirmed multi-drug resistant [MDR-TB] pulmonary tuberculosis [TB].

Materials and Methods: Seven new-onset, presumed drug-sensitive pulmonary TB and eight MDR-TB patients were enrolled. They each had baseline AFB-positive sputum smears. Drug-sensitive patients were treated with Enercel® by intravenous, aerosolized, sublingual and intranasal routes for 30 consecutive days. MDR-TB patients were treated for 10 consecutive weeks. Endpoints included Chest X ray, sputum AFB smears and Quality of Life [QOL] evaluation as assessed by cough, energy, mood, appetite, night sweats, weight and ease of breathing. Safety of Enercel® was evaluated by complete blood count and liver function testing.

Results and Discussion: Seven of seven [100%] presumed drug-sensitive patients were sputum AFB smear negative after 30 days. The 7 patients also had significantly decreased infiltrates and cavitations by Chest X ray. QOL significantly improved in all 7 patients. Four of eight [50%] MDR-TB patients were AFB smear negative and 1 more [12%] had significantly less AFB-positive organisms after 10 weeks. Each of these 5 responders had significantly improved Chest X ray findings. QOL significantly improved in each of the 8 patients. There were no toxicity or side effects associated with Enercel® use.

Conclusions: Enercel® was highly effective in a short time [30 days] for new-onset, presumed drug-sensitive pulmonary TB and 10 weeks for confirmed MDR-TB patients. There were no adverse events associated with Enercel® administration. Enercel® may be useful in improving outcomes, limiting mortality, improving general health, and reducing length of treatment in these populations. Finally, long-term medical costs to public health systems may be significantly reduced.  


INTRODUCTION:

Tuberculosis is the leading cause of infection-related mortality in the world, accounting for some 3 million deaths annually. In 2007 there were an estimated 13.7 million chronic active cases and 9.3 million new cases, mostly in developing countries. TB rates in the Ukraine are very high, especially in persons of low economic status, prisoners and alcoholics. The overall incidence is about 102 cases per 100,000 population [1]. In addition, more people are contracting tuberculosis because their immune systems are compromised by immunosuppressive drugs, substance abuse, or AIDS. The need for effective, inexpensive therapies is essential.

Up to 20% of strains, depending on the area of the world, are multidrug resistant. These infections are especially treatment-resistant and can have a mortality of up to 80%. MDR-TB rates in the Ukraine are very high. One large epidemiological study found that the prevalence of MDR-TB among TB cases in the general population was 15.5% and 41.5% in newly diagnosed and previously treated TB patients, respectively [2]. Among prisoners, MDR-TB rates were 21.8% in new cases and 52.8% in previously treated TB cases. HIV status was significantly associated with MDR-TB as well.

Enercel® is a combination of homeopathics as per the Homeopathic Pharmacopoeia of the United States (HPUS). The preparation has been proven to be completely non-toxic and without side effects in hundreds of patients with a variety of bacterial infections. Enercel® activates intracellular pathways throughout the body. The energy enhancement in the tissues results in improved function, metabolism and resistance to infection and stress. Furthermore, through enhancement of energy pathways, Enercel® has been shown to improve acute and chronic infection-related malaise and fatigue. Finally, it can be hypothesized based upon the principal of dual-therapies in tuberculosis that by providing a second anti-microbial mechanism (immune activation), drug resistance may be limited.

Enercel® has several properties that may make it ideal adjunct therapy for TB infections.  It has been proven for in vitro, animal and human studies to improve cellular immunity; it greatly increases intracellular energy and has antibacterial effects. Animal studies have revealed

enhancement of Natural Killer [NK] cell function and limiting of acute coxsackievirus infections in mice through immune mechanisms [3].

Enercel® has shown broad-spectrum anti-bacterial activity. Enercel® was tested in acute cases of presumptive infectious diarrhea in children less than 5 years of age [4]. The diarrhea was significantly less and of shorter duration in children treated with Enercel® compared to untreated controls.

Intranasal Enercel® has been shown to protect respiratory tissues from infection and immune-mediated damage. Respiratory tract allergies and infections both responded to treatment with intranasal Enercel® for 93.2% of cases in one large study [5].

The addition of Enercel® could prove to be beneficial to a regimen for drug-sensitive TB and MDR-TB for several reasons: 1) Enercel® has been proven to have significant, broad-spectrum activity for multiple bacterial organisms, presumably through immune and energy enhancing mechanisms; 2) Enercel® improves immune system function, especially with regard to NK cells; 3) Enercel® may improve outcomes and decrease the length of treatment in drug-sensitive populations; 4) Enercel® may reduce mortality, decrease the number and duration of second lines agents and lessen the length of treatment in MDR-TB; 5) Enercel® has no toxicity or side-effects, including nausea or allergic reactions; 6) Enercel® is cost-effective.

The purpose of this study was to assess the effectiveness of 30-day treatment for new-onset, presumed drug-sensitive and 10 weeks for multi-drug resistant pulmonary TB populations.

MATERIALS AND METHODS:

Patient selection

All patients were selected from within the inpatient population of Communal Medical and Preventive Institution, Regional Antituberculosis Hospital, Chernigov, Ukraine. Patients with active pulmonary tuberculosis infection and age from 18 to 65 were eligible. Dietary supplements other than multivitamins, minerals and protein supplements were not allowed during the study. Hemoglobin levels > 125 g/L, leukocytes > 3.0 cells/nL and serum alanine

4.

aminotransferase [ALT] level < 3x upper limit of normal were required at enrollment. Current active malignancy and positive HIV status were exclusion criteria.

New-onset, Presumed Drug-sensitive

All 7 patients were newly diagnosed and had been on treatment for < 1 month. Baseline sputum AFB smears were required to be positive. Final cultures and sensitivities were not yet available at time of enrollment; therefore, these patients have “presumed” drug-sensitive strains. Chest X rays were required to have infiltrates and/or cavitations consistent with pulmonary tuberculosis.

            Multidrug-resistant

Each patient had positive sputum cultures with tuberculosis resistant to isoniazid and rifampin within 3 months of enrollment. In addition, AFB smears had to remain positive at baseline. Chest X rays were required to have infiltrates and/or cavitations consistent with pulmonary tuberculosis. Each of the 8 patients was considered to be refractory to treatment with second-line agents, and with disease progression, in the opinion of the ward doctors.

Treatment

            Medication:

Each of the 3 Enercel® products used in the study is registered in the Ukraine and manufactured per the Homeopathic Pharmacopoeia of the United States (HPUS) in GMP facilities. Enercel® Plus has the following ingredients: Cactus Grandiflorus 4X ; Aloe Socotrina 4X; Abies Nigra 4X; Arnica 6X; Lachesis 11X; Calcium Carbonate 6X; Lycopodium 4X; Distilled water; and Alcohol (4% by volume). Enercel® Max: Cactus Grandiflorus 4X; Aloe Socotrina 4X; Abies Nigra 4X; Arnica 6X; Lachesis 11X; Calcium Carbonate 6X; Silicea 6X; Distilled water; and Alcohol (5-8% by volume). Enercel® Mist: Cactus Grandiflorus 4X; Aloe Socotrina 4X; Abies

Nigra 4X; Arnica 6X; Lachesis 11X; Calcium Carbonate 6X; Pulsatilla Vulgaris 6X; Distilled water; and Alcohol (5-8% by volume).     

New-onset, Presumed Drug-sensitive

Each patient was on a standard drug-sensitive tuberculosis drug regimen for <1 month per the protocol of the hospital. Enercel® was given for 30 consecutive days on the following schedule:

Enercel® Plus: 50 ml intravenously once daily; Enercel® Mist: 7 cc via nebulizer [Omron CompAir NE-C29-E Nebulizer] once daily; Enercel® Max: 1 ml sublingually once daily; Enercel® Mist: 2 puffs into each nostril once daily.

Multidrug-resistant

Each patient was on a standard drug regimen of second line agents for MDR-TB per the protocol of the hospital and based upon sensitivity testing. Enercel® was given for 10 consecutive weeks on the following schedule:

Enercel® Plus: 50 ml intravenously twice daily for 14 days then once daily; Enercel® Mist: 7 cc via nebulizer [Omron CompAir NE-C29-E Nebulizer] twice daily for 14 days then once daily; Enercel® Max: 1 ml sublingually twice daily for 14 days then once daily; Enercel® Mist: 2 puffs into each nostril twice daily for 14 days then once daily. Treatment non-responders at 1 month were treated with twice daily doses periodically after the first month.

Quality of Life

QOL was self-assessed on a scale of 0 [complete disability] to 100 [perfect health] at baseline and then at day 30 [drug-sensitive] or week 10 [MDR-TB] based upon the following criteria: cough, energy, mood, appetite, night sweats, weight and ease of breathing.

 

Sputum AFB smears

Sputum was obtained by bronchoscope and examined under light microscopy for the presence and quantity of acid-fast bacterium by established methods.

Chest X ray

Chest X rays were taken at baseline and 21 days to 10 weeks later. In some cases, tomograms were obtained as well. The findings were scored from -1 to 3 as follows: 3 was significant improvement of infiltrates and cavitations; 2 was moderate improvement; 1 was some improvement; 0 was no change and -1 was worsening.

Toxicity monitoring

Patients were clinically monitored during intravenous administrations. Patients were asked to report any adverse effects they thought may be associated with Enercel® use. Laboratory analysis included the following: hemoglobin; red blood cell count; total leukocytes with differential subsets; erythrocyte sedimentation rate; total bilirubin; alanine aminotransferase [ALT] and Thymol turbidity test.

RESULTS:

New-onset, Presumed Drug-sensitive

The results for each individual patient are given in Table 1. All 7 patients had no cough, weight gain, improved energy levels and a better appetite at day 30 as assessed by a significantly improved QOL. Seven of seven [100%] patients converted to AFB smear negative status. Chest X ray findings were significantly improved in each patient. Both cavitations and infiltrates responded. In 3 patients, there was nearly complete resolution of abnormalities. Cough completely resolved in each of these 7 patients.

 

Multidrug-resistant

The results for each individual patient are given in Table 2. Each of the 8 patients improved clinically, with improved QOL scores. All had markedly improved appetites and weight gain. Cough resolved completely in 3 patients and decreased in another 4. 5/6 patients reported improvement in baseline shortness of breath. Two patients had improvement in pleuritic chest pain. Four patients [50%] converted to AFB smear negative status and had marked improvement in Chest X ray abnormalities. One additional patient [12%] had decreased quantity of AFB quantity in the sputum. This patient was 3+ at baseline and only trace positive at day 30. These patients had improved Chest X ray findings—in particular, patient TP had a very large cavitary lesion which decreased in size by > 50%.

Each of the non-responders by Chest X ray and sputum AFB were complicated patients. SB has had tuberculosis for > 12 years and presented with near destruction of his entire left lung and severe right ventricular hypertrophy by EKG. Patient EG has had multiple failed treatment courses for MDR-TB in the past and poorly-controlled diabetes. Patients IC periodically drank alcohol heavily during treatment and missed several doses. All 3 patients improved clinically, however [patient SB had QOL score increase from 35 to 75; patient IC from 50 to 80; and EG from 40 to 65].  

Toxicity monitoring

There were no adverse effects reported by the patients associated with Enercel® administration. Patients were stable during intravenous treatments, with no allergic reactions or phlebitis. The patients had stable or improved laboratory test monitoring: Hemoglobin level; red blood cell count; total leukocytes; erythrocyte sedimentation rate; total bilirubin; alkaline aminotransferase and Thymol turbidity test.

 

 

Table 1: Results for 7 patients with newly-diagnosed, presumed drug-sensitive tuberculosis treated for 30 days with Enercel®

                              Quality of Life score*                                     Chest X ray**                                Sputum AFB smear

Patient                     Baseline                 Day 30                                                                                Baseline                         Day 30

SV 48 y/o ♂                  75                                   100                                 3                                      1+                                   0                                                                 

KI 25 y/o ♀                  80                                   100                                 2                                      1+                                   0

MS 35 y/o ♂                 55                                   90                                   1                                      2+                                   0

PH 27 y/o ♂                 55                                   100                                 3                                      1+                                   0

KV 46 y/o ♂                 60                                   95                                   2                                      1+                                   0

ND 63 y/o ♂                 75                                   100                                 3                                      2+                                   0

VK 52 y/o ♂                 70                                   95                                   2                                      1+                                   0

*  scored from 0 to 100 with 100 being perfect health and 0 complete disability

** scored from -1 to 3 where 3 is significant improvement of infiltrates and cavitations; 2 is moderate improvement; 1 is some improvement; 0 is no change and -1 is worsening

Table 2: Results for 8 patients with treatment-refractory MDR-TB after 10 weeks of treatment with Enercel®

                              Quality of Life score*                        Chest X ray**                      Sputum AFB smear

Patient                     Baseline                               Week 10                                                                Baseline                         Week 10

IL 42 y/o ♂                   50                                   95                                   3                                      2+                                   0                                     

TP 49 y/o ♀                  40                                   80                                   2                                      3+                                   trace

AV 43 y/o ♂                 35                                   90                                   1                                      2+                                   0

SB 25 y/o ♂                  35                                   75                                   1                                      2+                                   2+

IC 35 y/o ♂                  50                                   80                                   0                                      3+                                   3+

EG 56 y/o ♂                 40                                   65                                   0                                      2+                                   2+

NN 26 y/o ♂                 55                                   95                                   3                                      1+                                   0

LK 46 y/o ♀                 75                                   100                                 2                                      1+                                   0

*  scored from 0 to 100 with 100 being perfect health and 0 complete disability

** scored from -1 to 3 where 3 is significant improvement of infiltrates and cavitations; 2 is moderate improvement; 1 is some improvement; 0 is no change and -1 is worsening

 

DISCUSSION:

Enercel® was effective in eliminating AFB in sputum smears for 100% of cases of newly-diagnosed, presumed drug-sensitive TB patients after just 30 days. Confirmation of improvement in pulmonary anatomy was achieved by Chest X ray. These are rapid results with a high success rate compared to data from comparable patients with newly-diagnosed pulmonary TB treated with standard anti-tuberculosis regimens [6]. The treatment success rate is 50%-60% in these reports, but is rare in such a short time span as in this study [30 days]. This data suggests that Enercel® may be useful in this population of TB in several ways. The number of TB cases resulting in microbiological cures may be increased. Rapid elimination of AFB in the sputum may decrease the need for the use of multiple drugs for an extended period of time. This effect may also dramatically lower treatment costs, improve patient compliance and decrease risk to the public. Public health funds in the Ukraine are severely strained due to the high incidence of TB, and reducing treatment costs may free up resources to treat more patients, improve facilities and use funds for other epidemic diseases like HIV.

Enercel® also showed significant benefit after 10 weeks in chronically ill patients with long-standing MDR-TB. In particular, patients had decreased cough, improved appetite and weight gain. These may be useful signs that such patients may benefit even more with longer treatment courses of Enercel®. 62% of patients had decreased quantities or elimination of AFB in the sputum smears and improved Chest X ray abnormalities. This data is remarkable in such a relatively short time period, given the refractory and long-standing MDR-TB that these patients have. Standard treatment courses with 4 or more second-line agents run for 18 months and <50% of these cases result in permanent cures. Mortality in these patients can be up to 60% and the data from this study suggests that Enercel® may impact mortality in a very positive way. Clinical improvements in such chronically ill patientsmay also result in better outcomes by reinforcing the notion that they are improving.

 

Antituberculosis drugs are associated with toxicity and side effects, especially the second line agents. Enercel® has been shown in multiple studies to be free of adverse events, a finding confirmed in these patients. Longer studies are needed to prove that Enercel® can shorter the course of treatment and perhaps decrease the number of drugs used. However, this study suggests that these goals may be possible, eliminating potential adverse drug effects and reducing cost of treatment and need for monitoring.

Thus, a 30-day course of Enercel® was effective for new-onset, presumed drug-sensitive pulmonary TB. MDR-TB patients received an additional 6 weeks and also improved. Final cultures to definitively prove microbiological cures in AFB smear negative patients are in progress. Larger cohorts and more prolonged treatment data are in process to determine the more long-term ramifications of Enercel® use in terms of improved outcomes and cost-reduction. Longer studies may also reveal the optimal time period in which Enercel® should be administered to TB patients.

REFERENCES:

1.     WHO Tuberculosis profile, Ukraine. www.who.int/tb/data. Accessed 21/12/11.

2.     Vassall A, Chechulin Y, Raykhert I, Osalenko N, Svetlichnaya S, Kovalyova A, van der Werf MJ, Turchenko LV, Hasker E, Miskinis K, Veen J, Zaleskis R. Reforming tuberculosis control in Ukraine: results of pilot projects and implications for the national scale-up of DOTS. Health Policy Plan. 2009 Jan;24(1):55-62.

3.     See DM, Tilles JG, Bertacchini C. Immunomodulatory effects of a homeopathic agent. Amer J Nat Med1998; 5(6): 10-14.

  1. Izaguirre R, Reyes M, Christner D, Laurent D.Effect of Enercel® on Acute Documented or Presumed Infectious Diarrhea in Children Less Than 5 Years of Age at the Emergency Ward of B. Bloom Hospital in San Salvador [submitted 2011].
  2. Izaguirre RR. Enercel: A New Homeopathic Immune Enhancer Nasal Spray For Recurrent Allergic Disease Of The Upper Respiratory Tract: A Preliminary Communique [2002].
  1. USAID Ukraine. Tuberculosis profile.

http://www.vitapol.com.ua/user_files/pdfs/tubvil/16PagesfromTuberkulez1i2012.pdf

 

 

 

 

 

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