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Clinical validation of sublingual formulations of Immunoxel (Dzherelo) as an adjuvant immunotherapy in treatment of TB patients

Yuri V Efremenko1, Olga V Arjanova1, Natalia D Prihoda1, Larisa V Yurchenko1, Nina I Sokolenko1, Igor V Mospan2, Volodymyr S Pylypchuk2, John Rowe3, ai Jirathitikal4, Aldar ourinbaiar5 & Galyna A Kutsyna*
1Lisichansk Tuberculosis Dispensary, Lisichansk, Ukraine 2Ekomed LLC, Kiev, Ukraine 3Island Abbey Foods Ltd, ottetown, Prince Edward Island, da 4Immunitor Thailand Co., LLC, Bangpakong Industrial Park, hoengsao, Thailand unitor USA Inc., College Park, MD, USA
*Author for correspondence: Luhansk State Medical University, k, Ukraine kutsynagalyna@yahoo.com

Immunoxel (Dzherelo) is a water-alcohol extract of medicinal plants used in Ukraine as an adjunct immunotherapy to TB and HIV therapy. Four types of solid sublingual formulations of Immunoxel were made: sugar dragées, sugar-coated pills, gelatin pastilles and dried-honey lozenges. They were administered once-daily along with TB drugs. After 1 month, 84.1 % of TB patients became sputum-negative with rates in individual groups of 89.5, 70, 76.9 and 100%, respectively. The conversion rate was independent of bodyweight, age, gender, differences in chemotherapy regimens or whether subjects had newly diagnosed TB, re-treated TB, multidrug-resistant TB or TB with HIV coinfection. Patients experienced earlier clinical improvement, faster defervescence, weight gain, a higher hemoglobin content and reduced inflammation as evidenced by lower leukocyte counts and erythrocyte sedimentation rate. By contrast, in the placebo group, only 19% of patients had converted. These findings imply that mucosal delivery of solid Immunoxel is equivalent to the original liquid formula given per os twice-daily for 2-4 months.

KEYWORDS: biomarker ■ immunomodulator ■ immunotherapy ■ inflammation ■ mycobacterium ■ phytomedicine

TB is a global killer. Approximately 2 billion people, or a third of the global population, are latently infected with Mycobacterium tuberculosis. Annually, nearly 9 million of these people develop active TB and 2 million die. Current tuberculosis drugs have existed for more than 40 years and must be taken for 6—9 months for drug-sensitive disease and for up to 24 months for drug-resistant strains such as multidrug-resistant (MDR)-TB and extremely drug-resistant TB [1]. As new TB drugs currently under development will be not available in the near future, new approaches are urgently needed [2]. One of these approaches is immunotherapy, which is believed to enhance the efficacy of chemotherapy and can potentially shorten treatment duration [3-5].
The multiherbal immunomodulator Immunoxel (Dzherelo), manufactured by Kiev-based botanical company Ekomed, has been sold in Ukraine for the last 15 years. More than a dozen clinical trials have been published over the past 10 years showing its safety and efficacy in approximately 1200 TB and HIV patients [6]. This extensive experience can be summarized as follows: Dzherelo produced higher levels of IL-2, whereas in the control group given TB drugs alone the levels declined; the production of IL-6 increased in the control group but declined in the immune intervention group; levels ofTNF-a were suppressed in the immunotherapy group, but had risen in control patients; the pattern of production of IFN-g was the opposite to that of TNF-a; moderately decreased levels of IFN-a were observed in both treatment arms, but differences were not significant. These changes in cytokine profile were accompanied by the following clinical changes: the typical sputum conversion rate among MDR-TB, extremely drug-resistant TB and TB with HIV coinfection (TB/HIV) patients after 2—4 months of herbal immunotherapy ranged from 85 to 100%, but in chemotherapy controls it took 6—24 months to reach 48—85%. While these results are clearly in favor of Immunoxel, they are not ideal since the duration of adjunct treatment is still not optimal and faster-acting regimens would be more advantageous. In order to overcome this drawback, the authors have made four types of solid, sublingual formulations of Immunoxel and tested them clinically to see if they performed better than original water—alcohol extract of herbs.

Materials & methods

■ Patients
The experimental group involved 69 hospitalized patients with TB (76.8%) and TB/HIV (23.2%). They were randomly assigned to four different sublingual formulations of Immunoxel given once per day (Tables 1 & 2).

The significant proportion of patients presented with newly diagnosed TB (37.7%); remaining patients had re-treated TB (RTB), treatment-failed TB, MDR-TB and extra-pulmonary TB at a 31:6:4:2 ratio. Most of the patients were treated with a standard isoniazid, rifampicin, pyrazinamide, ethambu-tol and streptomycin combination (84.9%) or were on individualized chemotherapy regimens (15.1%). The duration of chemotherapy prior to immunotherapy initiation ranged between 1 and 11 months with a mean ± standard deviation (SD) of 2.6 ± 2.4 (median: 2.0) months for the group, comprising 42% of patients who were treated for 1 month or less, and the rest were treated for a mean ± SD of 3.8 ± 2.7 (median: 2.5) months. The study group had 15 females and 54 males between the ages of 20 and 61 years with a mean ± SD age of 38.7 ± 10.5 (median: 36.0) years. The baseline bodyweight and BMI ranged between 40 and 98 kg and 15.2 and 36.0 kg/m2, respectively, with a mean ± SD of 56.9 ± 9.2 (median: 56.0) and 19.1 ± 3 (median: 18.5), respectively. At study initiation, only six out of 69 (8.7%) patients had normal 36.8°C axillary body temperature, with an overall mean ± SD of 38.0 ± 0.7 (median: 38.0)°C.
Twenty one patients in the control chemotherapy group received placebo sugar pills (Tables3 &4). The group had afemale:male ratio of 2:19 with an age range between 21 and 58 years and a mean ± SD of 36.6 ± 9.8 (median: 35.0) years. The baseline bodyweight and BMI ranged between 47 and 72 kg and 16.3 and 22.5 kg/m2 with a mean ± SD of 60.9 ± 6.7 (median: 61.0) and 19.9 ±1.6 (20.5), respectively. The baseline distribution of TB categories was according to the ratio 5:11:5:6 for newly diagnosed TB (first diagnosis), RTB, MDR-TB andTB/HIV, respectively. Most patients (57.1%) received standard first-line TB chemotherapy while the remaining patients were on an individualized TB drug regimen. At the beginning of the study, four out of 21 patients (19%) had normal body temperature with an intragroup mean ± SD of 37.7 ± 0.5 (median: 38.0)°C. Participation in this study was voluntary and patients were eligible to enroll only after signing the written consent. The conduct of the trial was approved by the internal review board of the Lisichansk TB Dispensary [101].

■ Solid formulations of Immunoxel
Four different solid formulations were designed for sublingual absorption:
■ Sugar-based dragees
■ Sugar-coated pills
■ Gelatin pastilles
■ Dried-honey lozenges


Sugar-based dragées were made by Ekomed. Sugar-coated pills were made in collaboration with Immunitor at their manufacturing plant in Chachoengsao, Thailand. The gelatin-based formulation was made by a local confectionery factory specializing in the production of gummy bear-like candies. The dried-honey lozenges were made in collaboration with Island Abbey Foods Ltd (Charlottetown, Prince Edward Island, Canada). This company has a unique proprietary technology for making dried-honey lozenges.
Each sublingual preparation contained either five or ten drops (125 or 250 pl) of Immunoxel, which was administered once per day for a month. Immunoxel, an improved and simplified version of the herbal immunomodulator Dzherelo, contains an aqueous—alcohol cold extract from medicinal plants including aloe (Aloe arborescens), licorice (Glycyrrhiza glabra), dog rose fruit (Rosa canina), oregano (Oreganum majorana), sage (Salvia officinalis), thyme (Thymus vulgaris), fennel (Foeniculum vulgare), purple coneflower (Echinacea purpurea), dandelion (Taraxacum officinale), nettle (Urtica dioica), marigold (Calendula officinalis), greater plantain (Plantago major), wormwood (Artemisia sp.), common knotgrass (Polygonum aviculare), yarrow (Achillea millefolium), cen-taury (Centaurium erythraea), elecampane (Inula helenium), tormentil (Potentilla erecta), cudweed (Gnaphalium uliginosum), three-lobe beggarticks (Bidens tripartita), Siberian golden root (Rhodiola rosea), chaga (Inonotus obliquus), snowball tree berries (Viburnum opulus), seabuckthorn berries (Hippophae rhamnoides) and juniper berries ( Juniperus communis). This multiherbal extract is manufactured by Ekomed according to international Hazard Analysis Critical Control Point (HACCP) standards and has been approved by the Ministry of Health of Ukraine as an immunomodulating herbal supplement belonging to a functional food category.

■ Laboratory evaluation
The sputum microscopy on acid-fast bacilli smears was conducted in a blinded fashion at baseline and 1 month later. TB drug resistance was determined by a commercially available kit (Tulip Diagnostics, Goa, India) in approximately a third of the patients. The failure to test every patient for drug resistance was due to a temporary lack of funds for laboratory services. MDR-TB status was assigned when resistance to both isoniazid and rifampicin, with or without resistance to other drugs, was present.
The hematology parameters such as hemoglobin content, leukocyte counts and erythrocyte sedimentation rate (ESR) were evaluated by standard routine techniques at baseline and repeated 1 month later.

■ Statistical analysis
The obtained results were analyzed with commercially available statistical software (GraphPad Software Inc., La Jolla, CA, USA). The paired Student's t-test was used to compare before and after mean values by assuming that the distribution of the differences was in accord with the Gaussian distribution. Side-by-side comparison between two independent populations was performed by an unpaired t-test or by a Mann-Whitney U test. The Wilcoxon ranking test was used to compare paired before and after nonparametric values such as conversion rates arranged in a 'yes' or 'no' binary manner. Fisher's exact two-tailed test was employed for analysis of data arranged in a contingency table. Comparison across multiple groups was tested either by analysis of variance or a categorical Kruskal-Wallis test. All statistical analyses were performed on an intent-to-treat basis, involving all initially enrolled patients including fatalities. The resulting probability values were considered significant at p < 0.05.

Results
■ Sugar dragées
The first trial of a solid form of Immunoxel involved small-size (~4 mm) sugar dragées to which gradually increasing doses of Immunoxel were added, so that ten of them contained a total of ten drops of Immunoxel. The test involved 21 patients who were instructed to place dragées under the tongue until fully absorbed. Half of the patients received five drops and the other half a dose of ten drops. After 1 month, every measured end point had improved significantly (p < 0.0001). These and other results described below are summarized in Tables 1 & 2 and Figure 1. The percentage of patients with negative sputum conversion was 81% — results from which the authors did not exclude the three patients who died. In two of these patients post-treatment sputum samples were not analyzed and were assumed to remain positive at the time of death. One, a female patient, was in a very unfavorable condition and died a few days after checking into the hospital. Another female patient was obese (BMI = 36 kg/m2) and had a fatal stroke before her sputum could be analyzed. The third patient, whose sputum had converted to negative, unfortunately died from an alcohol overdose after the 1-month study was concluded. If the two female patients without post-treatment sputum results are excluded, then the conversion rate in this group stands at 89.5%. No difference was seen in sputum outcome between five- and ten-drop doses.
■ Sugar-coated pills
Following the initial trial with sugar dragées, which were found to be inconvenient owing to the high moisture absorption property and cumbersome dosing procedure, conventional sugar-coated, oval-shaped pills were made, each containing the same ten-drop dose of Immunoxel and standard excipients such as lactose, talc, magnesium stéarate and menthol flavoring. Ten patients were enrolled to evaluate the effect. Of these ten patients, seven became negative after 1 month (p < 0.0001). Bodyweight and temperature, as well as BMI, demonstrated statistically significant improvements. Other end points, such as hemoglobin content, ESR and leukocyte counts, had improved as well, but statistical significance was not reached owing to sample size (Tables 1 &2 & Figure 1). This formulation had no additional active ingredients that could have biased the outcome and was essentially the same as the sugar dragées described above. If sugar-coated pill results are combined with the outcome from sugar dragées, then the overall conversion rate for sugar-based formulations is 79.8%.


■ Gelatin pastilles
The batch of Immunoxel formulated into so-called 'gummy candies' contained a ten-drop dose per pastille, also containing in addition sugar, glucose syrup, starch, food coloring, citric acid and porcine gelatin, according to their standard procedure. Out of 20 patients, 13 were smear-positive at baseline, of whom ten (76.9%) became negative after 1 month (p < 0.0001). All other end points except leukocyte counts had improved in a statistically significant manner (Tables 1 & 2 & Figure 1).

■ Dried-honey lozenges
This preparation was made by Island Abbey Foods Ltd. This company has a unique proprietary technology for slowly drying liquid honey into solid dried-honey lozenges. Two batches were manufactured, one with four drops and another with ten drops of Immunoxel per lozenge, which were then given to two equal groups of patients (n = 18). After 1 month, every smear-positive patient in both groups had converted. All other measured end points were also improved in a statistically significant manner (Tables 1 & 2 & Figure 1).


■ Comparison of outcomes from different Immunoxel formulations
The baseline characteristics of four groups of patients were tested by the analysis of variance or Kruskal—Wallis test, as appropriate, and were found to be matched by age (p = 0.25), BMI (p = 0.83), and hematological parameters such as hemoglobin (p = 0.36) and ESR (p = 0.12), but not by gender distribution (p = 0.03) or leukocyte counts (p = 0.03). The primary end point of the study is sputum conversion (Figures 1 & 2). When results from the four formulations were compared by the nonparametric Kruskal—Wallis test, the outcomes were not different from each other (p = 0.15), even though, at baseline, there were differences between individual groups (p = 0.02). This indicates that solid formulations have an equivalent biological activity (Tables 1 & 2 & Figure 1). The effective dose was equivalent to ten drops of liquid Immunoxel. However, it is possible that smaller doses could be equally effective, since sugar-based dragées and dried-honey lozenges tested at five- and four-drop doses produced the same favorable outcome. The stratified analysis of data comparing outcomes between newly diagnosed TB (n = 26), RTB (n = 31), TB/HIV (n = 16) and MDR-TB (n = 4) also failed to reveal any difference (p = 0.17). Similar results were obtained when outcomes of patients on standard isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin chemotherapy (n = 57) were compared with the conversion of patients receiving individualized drug regimens (n = 12). The Mann-Whitney U test shows that the two treatment regimes produced identical favorable outcomes (p =0.83). The duration of chemotherapy prior to immunotherapy also had no impact on outcome. Those who were treated for 1 month or less were converting as readily as those who were treated for longer; for example, 1 versus 3.8 months (p = 0.67). The same Mann-Whitney U test failed to reveal gender- or age-dependent differences. Males and females, as well as younger or older patients (the age threshold was equal to highest mean age + highest SD, i.e., > 48 years), converted at the same rate without any gender or age preference (p = 0.5 and p = 0.29, respectively). A baseline BMI higher or lower than the normal 18.5 kg/ m2 value had no effect on conversion rate either (p = 0.6). However, when these data were compared with outcomes from control patients, there was an obvious and highly significant difference (p < 0.0001) irrespective of formulation type, discrepancies in baseline diagnosis, gender, age, BMI or treatment regimen.

■ Treatment outcome in the placebo group
As a control, the authors used sugar-coated pills without Immunoxel, which were administered to 21 randomly chosen patients who were concurrently receiving TB drugs. Despite a sufficient sample size that was equivalent to or larger than any of the Immunoxel-treated populations, the only statistically significant results were obtained with ESR and sputum smear conversion (Tables 3 & 4). As can be seen from Figure 1, the proportion of patients responding to chemotherapy was adequate; however, the magnitude of response was smaller. For example, control group patients gained less weight than those who received various Immunoxel formulations; the mean weight and BMI accruals were 0.5 kg and 0.2 kg/m2 versus 1.9 kg and 0.6 kg/m2 in the immune intervention arm. Similar trends were observed with other end points indicating that, even though chemotherapy alone has been beneficial to TB patients, its potency was lower than that of chemotherapy with adjunct immunotherapy.

■ Discussion
This study reveals that all tested solid formulations of Immunoxel produced similar favorable outcomes. The conversion rates in patients were identical regardless of their baseline diagnosis, such as first diagnosis, RTB, MDR-TB or TB/HIV. The success of therapy was not affected by concomitant chemotherapy regimens, and both standard and individualized treatments had comparable favorable outcomes. Similarly, the duration of chemotherapy prior to immunotherapy had no impact either. Those who were treated for 1 month or less converted at the same rate as those who were receiving TB drugs for 4 months on average. Neither gender nor age was a significant factor influencing sputum conversion. Underweight patients converted at the same rate as those in the normal weight range. In addition to bacterial clearance, Immunoxel has shown clear improvement in clinical manifestations, weight gain, defervescence, reduction of inflammation such as leukocytosis and ESR, and increase in hemoglobin content. All these benefits were described in prior studies of liquid Immunoxel, except that solid formulations acted faster and much smaller and less frequent doses were required.
A bewildering range of botanical supplements, especially in traditional Chinese and Ayurvedic medicine, is used today with the intention of boosting immunity and curing various diseases including tuberculosis [7]. However, the clinical or experimental evidence is lacking in most cases [8]. To the best of the authors' knowledge, clinical results from only three plant-derived preparations with anti-TB properties have been reported in peer-reviewed literature [9-11]. The oldest known is umck-aloabo - a traditional South African medicine from the roots of Pelargonium sidoides — used to treat TB and respiratory tract infections since the late 19th century [9]. Another report concerns inhaled tea tree oil from Australian Melaleuca alternifolia, which has produced remarkable recovery in a few cases of advanced TB [10]. Finally, a multiherbal water-infusion cocktail based on Russian folk medicine has been reported to reduce the duration of TB treatment to 6.4 months, instead of 8.6 months in controls [11]. For other phytomedicines, there is only anecdotal evidence without any systematic clinical studies [12,13]. Immunoxel stands out in this crowd since more than a dozen clinical trials involving a total of 1200 patients have been published by the authors and their colleagues [14-26]. During the past couple of years the authors have attended several conferences on TB topics and Immunoxel has become quite familiar in professional circles. While the TB research community outside of Ukraine has been slow to embrace this approach, Immunoxel clinical data have attracted genuine interest and calls have been made at various venues to test it independently [3,4].


In the course of the present study several advantages of solid Immunoxel were uncovered. First, sublingual formulations appeared to act very quickly, producing, within 1 month, the conversion rate that usually occurs after 2—4 months of dosing with liquid formulas. Second, the effective dose was equivalent to ten drops and possibly even less, given once-daily as opposed to 30—60 drops of liquid immunomodulator given twice-daily, showing at least six- to 12-fold enhancement in activity. Third, sublingual administration as opposed to liquid formulation was simple and convenient; there was no need to count drops and mix them in drinking water, which can be an issue in countries without ready access to clean water. Fourth, the elimination of an alcohol component from the preparation has improved patient compliance. Many of the authors' patients have a tendency to abuse alcohol and were often inclined to overdose with a herbal tincture containing 50% ethanol. As a result, the monthly supply of Immunoxel was consumed at once causing treatment default. Finally, another advantage of solid formulations relates to shipping cost and logistics, especially for export purposes. These issues are now defunct owing to the elimination of bulky glass bottles and potentially flammable liquid, which complicated clearing procedures with cargo airlines and customs. In summary, the solid form of Immunoxel has major advantages over the original formulas and is more appealing as the next generation of botanical immunomodulator from Ukraine.

The evaluation of clinical results in the context of commercial feasibility of product manufacture leads us to two choices; one is sugar-based tablets and the other dried-honey lozenges. Even though Immunoxel pastilles performed no worse than other formulations they have limited appeal owing to the presence of gelatin from animal sources. Sugar-based tablets are the cheapest and simplest delivery vehicle, and in two separate tests produced reliable conversion results. However, this formulation needs to be improved, which will be achieved by adding appropriate excipients such as those found in slow-release tablets. On the other hand, dried-honey lozenges, which produced 100% conversion, may be more attractive than sugar-coated pills. We do not know whether this outcome was random or if the higher efficacy was due to synergy with honey. The antimycobacterial activity of honey has been known since ancient times and it is used as a folk medicine even today. Several in vitro studies have demonstrated the direct inhibition of tubercle bacilli growth with honey [27-30]. Although inhibitory doses of honey were rather high, there are clinical studies showing its benefit in healing tuberculous lesions and counteracting the toxicity of TB drugs [31,32]. The only drawback in this approach is the price of honey. If Immunoxel lozenges can be made at a low cost, this, perhaps, will be an ideal formulation, especially considering the beneficial antimycobacterial and hepatoprotective properties of honey [27-32]. Both formulations will be pursued in future clinical studies expanding on these preliminary findings.

Executive summary
Four different versions of solid Immunoxel were tested: sugar dragées, sugar-coated pills, gelatin pastilles and dried-honey lozenges, which produced negative sputum conversion equal to 89.5% (n = 21), 70% (n = 10), 76.9% (n = 20) and 100% (n = 18) of patients, respectively. The differences in outcome were not statistically significant.
Concurrent administration of various solid forms of Immunoxel with first- or second-line TB drugs resulted in the clearance of Mycobacterium tuberculosis in sputum smears in a mean 84.1% of patients versus 19% among placebo recipients. Sputum conversion occurred very fast - only 1 month of treatment was needed.
No difference was seen when first-diagnosed TB was compared with re-treated TB, multidrug-resistant TB or TB with HIV coinfection; the proportion of converted patients and time to conversion were the same. Differences in gender, age and bodyweight had no influence on conversion rates.
A 1-month pretreatment time with chemotherapy had the same favorable outcome as a 3.8-month pretreatment time.
One sublingual dose of Immunoxel given once-daily produced the same effect as six- to 12-times higher doses of liquid formula
administered for 2-4 months.
Immunoxel reversed TB-associated wasting; the average weight gain was 1.9 kg in 89.8% of Immunoxel-treated patients versus 0.5 kg in 61.9% of placebo recipients.
Immunoxel eliminated TB-associated fever in 97.5% of patients versus 42.9% of placebo recipients.
Immunoxel demonstrated marked anti-inflammatory effects. Erythrocyte sedimentation rate and leukocyte counts reverted back to normal over 1 month. However, patients on TB drugs alone also experienced reduced inflammation. Immunoxel is affordable, easy to administer and made from renewable sources. Immunoxel is safe; it has not produced any adverse effects or caused reactivation of TB.

Conclusion
Many medicinal plants have been identified as having antimycobacterial activity, but they have to go through lengthy development processes before, and if, they are made available to patients [33]. The integration of herbal medicines into modern medical practice has to be validated through rigorous scientific and clinical research in order to be accepted by the medical establishment. Ekomed started developing herbal immune modulators in the late 1980s and today both Dzherelo and Immunoxel are commonly found in Ukrainian pharmacies. Present findings further support the value of Immunoxel and may allow us to persuade public opinion and health authorities that new sublingual formulations are worth being considered as an integral part of TB management strategy. As a result, lives of many thousands of individuals may be saved in Ukraine and elsewhere. Our dream of contributing to the reduction of the global TB burden may then materialize.

Future perspective
Despite increasing attention, the future for TB immunotherapy is uncertain. We cannot predict whether, in the next 5 years, solid forms of Immunoxel will be used widely as an adjunct to immune therapy for TB or will remain outside of mainstream TB management and control strategies, without adequate funding or interest. However, the emergence of drug-resistant TB and TB/HIV has become a great concern to TB caregivers and policymakers. If this trend continues we may see changes that will be constructive and may result in adoption of immune interventions on a larger scale than exists today.

Acknowledgements
We thank all patients who participated in this study. The assistance of Ekomed in generously providingfree supplies of Immunoxel is very much appreciated.

Financial & competing interests disclosure
This work was supported in part by the STEP Business Partnership Grant UKB1-9017-LK-09 awarded by the US Civilian Research and Development Foundation (CRDF), a nonprofit organization authorized by the US Congress and established in 1995 by the National Science Foundation. This study was conducted under the auspices of the regional health authorities of Ukraine as a part of the routine clinical care at the TB Dispensary (Lisichansk, Ukraine). IV Mospan, VS Pylypchuk, J Rowe, VJirathitikal and AS Bourinbaiar are employees of their respective companies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research
The authors have obtained the Institutional Review Board approval of Lisichansk TB Dispensary and have followed the principles of the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved. Participation in this trial was voluntary and participants were free to withdraw from this study at any time. This study is registered with ClinicalTrials.gov, identifier NCT01061593.

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101 Adjunct Immunotherapy With Immunoxel in
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