Alleviation of severe chronic arthritic pain using polyvalent immunoglobulins (KMP01): Two case reports.

BACKGROUND: Treatment of arthritis is carried out using corticosteroids, methotrexate, sulfasalazine-like agents, and TNF-α-blocking agents such as infliximab and adalimumab. The disadvantages of these agents are high-cost, severe side effects including leucopenia, and in some cases the necessity of administration by injection. Polyvalent immunoglobulin formulations derived from bovine colostrum and marketed as a standardized formulation for oral application, are reported to be efficacious in chronic pain syndromes but are rarely, if ever, used as an alternative medication in such patients. AIMS: To treat arthritis in a real-world setting using polyvalent immunoglobulins in 2 patients, in one case where no alternative treatment modality was available and in another patient in whom the use of polyvalent immunoglobulins appeared to be a suitable option. MATERIALS AND METHODS: Two male subjects aged 46 and 82 years with confirmed diagnosis but not well-controlled arthritis/polyarthritis receiving either high-dose NSAIDS, corticosteroids, methotrexate injections, with previous use of, or recommendations for treatment with monoclonal antibodies (etanercept and adalimumab) were treated with oral polyvalent immunoglobulins (KMP01; dose range 10 - 20 g daily) in real-world settings, in one case during a field excursion in Peru. RESULTS: The treatment produced a rapid alleviation of pain in both patients, in one patient where the symptoms were severe and debilitating. In the second patient methotrexate SC injections could be discontinued, and there was a progressive reversal of leucopenia (leucocyte count 3.9 × 103/µL) over a period of ~ 3 months. DISCUSSION: Polyvalent immunoglobulins have been shown previously to reduce the expression of interleukin-6 and C-reactive protein in peripheral blood monocytes, events attributed to the neutralization of gut-derived endotoxin ligands lipopolysaccharides (LPS) driving the basal immune response. The mode of action of KMP01 on cytokine expression is therefore similar to the TNF-α-blocking agents etanercept and adalimumab. CONCLUSION: Findings from two case reports support the rationale for using polyvalent immunoglobulins as an effective and safe alternative in arthritis patients receiving standard treatments, in particular, methotrexate and TNF-α-blocking agents.

Evidence that oral immunoglobulins (KMP01) suppress pro-tumor inflammation in rectal carcinoma: Case report and treatment concept.

BACKGROUND: A female patient aged 49 years with a rectal adenocarcinoma underwent tumor resection and multiple follow-up surgical operations whilst receiving compassionate therapy with polyvalent immunoglobulins derived from bovine colostrum (KMP01), a potential modulator of the pro-tumor inflammatory response. AIMS: Assessment of safety of the treatment, effect on tumor recurrence, and effect on parameters associated with the pro-tumor inflammatory response. MATERIALS AND METHODS: The dose of KMP01 varied from 72 g daily in the perioperative period to 12 - 24 g daily thereafter. The pro-tumor inflammatory response was measured using changes in C-reactive protein (CRP) and the lymphocyte-monocyte ratio (LMR). RESULTS: Surgical intervention caused large increases in CRP (up to 400 mg/L) and decreases in the LMR (below target levels of 2.83). However, such changes rapidly returned to normal, where they remained during prolonged treatment with immunoglobulins. Despite the generally poor prognosis associated with a stenotic tumor, cachexia, and multiple surgery, there was no tumor recurrence during the 3-year follow-up. The condition of the patient is good, albeit with a reduced quality of life due to the stoma. CONCLUSION: Polyvalent immunoglobulins constitute a potential and safe prophylactic agent against the pro-tumor inflammatory response. This is the first time that polyvalent immunoglobulins have been used in a colorectal carcinoma patient. The findings can be a basis for further investigations.

COVID-19: Effect-modelling of vaccination in Germany with regard to the mutant strain B.1.1.7 and occupancy of ICU facilities.

BACKGROUND: The characteristics of the COVID-19 pandemic in Europe have changed since the initial outbreak in 2019 due to the emergence of more contagious mutant strains, notably the B.1.1.7 variant. This has resulted in the rapid implementation of vaccination programs in an effort to control the spread of the disease. AIMS: To model the effect of vaccination on the course of the pandemic in Germany taking into account observational data and the appearance of viral mutant B.1.1.7. MATERIALS AND METHODS: An effect model based on the Batman-SIZ algorithm was developed, taking into account both the parent and the B.1.1.7 mutant strains of the SARS-CoV-2 coronavirus and using input parameters obtained from observational data for January - March 2021. RESULTS: Effect-modelling using 3 different vaccination scenarios with different rates of vaccination involving 67 million persons (priority groups 1 - 5) and completed within 134 days compared to 318 days beginning February 24, 2021, showed a reduction in the number of infected persons from ca. 12.5 million to ca. 4.5 million with quantitively similar benefits regarding the occupancy and a critical burden on ICU facilities. CONCLUSION: The effect of vaccination in reducing the daily number of new infections, the total number of infections and the occupancy of intensive-care facilities in hospitals is proportional to the speed with which the target population are vaccinated.

COVID-19: Predictions for SARS-CoV-2 vaccination on the course of the pandemic and critical occupancy of intensive-care facilities in Germany.

AIMS OF THE STUDY: To obtain predictions using the Modified Bateman SIZ Model for the effects of vaccination on the course of the COVID-19 pandemic in Germany. MATERIALS AND METHODS: Start parameters for the model were obtained from observational data after data-smoothing to reduce between-day variation. Three scenarios, 1) no vaccination, 2) vaccination of 60% of the population over 12 months, 3) vaccination of 60% of the population over 7 months were examined. The effects of changes in tα (doubling-time for the spread of infection, known to be slower in the summer months) and tß (half-life of recovery from infection) on the daily number of infectious persons, the cumulative number of infected persons, and the duration of critical occupancy of intensive-care units were also determined. RESULTS: Vaccination produced a marked and rapid reduction in the number of infectious persons (up to -60%) and the total number of infected persons (up to -70%). A 7-month vaccination strategy was significantly more effective than a 12-month strategy. The summer effect came too late to have an additional effect on the spread of infection. Vaccination was predicted to reduce the duration of critical occupancy of intensive-care facilities by ~ 70%. DISCUSSION: The predictions are based on the assumptions that lockdown conditions are maintained and vaccine availability is not limiting. CONCLUSION: Predictions made using the model show that vaccination with a SARS-CoV-2 vaccine can markedly reduce the spread of the COVID-19 disease and the period of critical occupancy of intensive-care facilities in Germany.

COVID-19: Cytokine storm modulation/blockade with oral polyvalent immunoglobulins (PVIG, KMP01D): A potential and safe therapeutic agent (Primum nil nocere).

Although medication treatment in COVID-19 patients would have no direct effect on the spread of the disease, a shortening of the period of hospitalization by only a few days would release 25 - 30% of critical-care resources. However, there appears to be no well-established medication treatment available that can do this reliably at the present time. Anti-malarials currently being evaluated, i.e., chloroquine and hydroxychloroquine, are not yet established as effective medications, and antiviral agents, including remdesivir, are only weakly active. This position paper report is focused on the modulation of the cytokine storm since it appears to be a major cause of the multi-organ failure in COVID-19. Whereas corticosteroids are not recommended in patients not on mechanical ventilation, immunotherapy with convalescent plasma and intravenous immunoglobulin (IVIG) have been used with some success in COVID-19. There is emerging new evidence that polyvalent immunoglobulins (PVIG) from bovine colostrum given orally can also modulate the immune response. Research using lipopolysaccharide-stimulated peripheral blood mononuclear cells from colorectal cancer patients (a so called micro-cytokine storm) has shown that PVIG block the expression of pro-inflammatory cytokines and stimulate the expression of anti-inflammatory cytokines. We have been able to confirm these results in a similar model using mononuclear cells from healthy subjects and could demonstrate that the modulations produced by PVIG are quantitatively and qualitatively similar to those obtained using human immunoglobulin (IVIG). Both immunoglobulins reduce the lipopolysaccharide-induced increase in inflammatory cytokines, interleukin (IL-) 12/23p40 (-90%), IL-6 (-75%) and TNF-α (-60%) and increased the levels of the anti-inflammatory cytokine, IL-10 (+75%). Evidence is presented that PVIG can produce anti-inflammatory effects similar to these after oral application in patients. Its use is contraindicated in patients with lactose intolerance but is otherwise safe and free of complications in clinical studies including the treatment of infants with gastrointestinal disorders. Conclusion: PVIG appears to be a potential and safe anti-inflammatory agent and can be recommended as a candidate medication for studies in COVID-19 patients.

Predictions for the COVID-19 pandemic in Germany using the modified Bateman SIZ model.

AIMS OF THE STUDY: To obtain predictions for the course of the COVID-19 pandemic in Germany using the modified Bateman SIZ model and input variables based on the status quo in July 2020. To predict the effect of a change in tα on the course of the pandemic. To evaluate the robustness and sensitivity of the model in response to a change in the input parameters. MATERIALS AND METHODS: Start parameters for the modified Bateman SIZ model were obtained from observational data published by the Robert-Koch-Institute in Berlin for the period June 1 to July 13, 2020. The robustness and sensitivity of the model were determined by changing the input parameter for the doubling-time (tα) by ± 5% and ± 10%. RESULTS: The predictions show that small changes, ± 5%, in the doubling-time, tα for the rate of increase in the number of new infections, can have a major effect, both positive and negative, on the course of the pandemic. The model predicted that the number of persons infected with the virus would reach 1 million within 8 years. A 5% longer tα would reduce the number of infected persons by ~ 75%. In contrast, a 5% shorter doubling-time would increase the number of infections over 8 years to ~ 9 million when the number of infectious persons would exceed 100,000 at the end of 2022. The pandemic is predicted to have disappeared by the end of 2024. DISCUSSION: Predictions for the course of the COVID-19 pandemic in Germany based on the status quo up to July 13, 2020 have been obtained using the modified Bateman SIZ model. There are several important assumptions necessary to apply the model and thus the results must be interpreted with caution. The model, previously used to predict the course of the COVID-19 pandemic in the city of Heidelberg (pop. 166,000) gives comparable predictive data for the whole of Germany (pop. 83 million) and thus appears to be both sensitive and robust. CONCLUSION: Since a shorter doubling-time for the number of infectious persons by only 5% would result in a major clinical emergency, interventional measures such as vaccination are urgently needed. Taking into consideration that a SARS-CoV-2 vaccine is not yet available and the efficacy of the Corona-Warn-App has yet to be shown, a relaxation in the lockdown conditions in Germany in 2020 appears premature.

COVID-19 pandemic predictions using the modified Bateman SIZ model and observational data for Heidelberg, Germany: Effect of vaccination with a SARS-CoV-2 vaccine, coronavirus testing and application of the Corona-Warn-App.

AIMS OF THE STUDY: Published data show that the current progression of the COVID-19 pandemic in Heidelberg, Germany, despite the current lockdown, could continue into 2021 and become more severe. We have used the modified Bateman SIZ algorithm to predict the effects of interventional measures to control the COVID-19 pandemic. MATERIALS AND METHODS: Model parameters, e.g., doubling time and rate of decrease in the number of infectious persons were obtained from published reports. Predictions were made for the status quo on June 1, 2020, and for interventional measures obtained for 4 scenarios. These included vaccination of the whole population using a SARS-CoV-2 vaccine having an efficacy of 50% and 100%, mass-testing for COVID-19 coronavirus and application of the Corona-Warn-App. RESULTS: The principle findings were 1) without new measures to control the pandemic, the daily number of infectious persons could reach a peak of > 4,500 daily within 18 months when > 67,000 persons would have been infected. This could be prevented by using a vaccine with 50% efficacy which was almost equally effective as a vaccine with 100% efficacy. Application of the Corona-Warn-App was the most effective method and more effective than testing for COVID-19. The methodology used has been described in detail to enable other researchers to apply the modified Bateman SIZ model to obtain predictions for COVID-19 outbreaks in other regions. Application of the model has been verified by independent investigators using different commercial software packages. CONCLUSION: The modified Bateman SIZ model has been verified and used to predict the course of the COVID-19 pandemic in Heidelberg. Lockdown measures alone are insufficient to control the pandemic during 2021. Vaccination, diagnostic tests, and use of the Corona-Warn-App with quarantine could successfully control the spread of the coronavirus infection in the community. The Corona-Warn-App applied correctly may be the most effective. The model showed that vaccination with 50% efficacy is almost as effective as vaccination with 100% efficacy.

Risk of tumor progression in colon carcinoma resection and perioperative prophylaxis with polyvalent immunoglobulins - per aspera ad astra.

There is strong evidence that tumor progression in the postoperative period is attributable to the influx of lipopolysaccharides (LPS) into the blood from the gastrointestinal (GI) lumen. Although several research groups have emphasized the need to neutralize LPS antigens from the GI tract to prevent tumor progression and reduce the inflammatory response, a therapeutic option to achieve this has not been put forward hitherto. Enterally applied immunoglobulins (IgG) in the form of colostrum concentrates are able to neutralize LPS antigens from the GI tract and to reduce the inflammatory response during abdominal surgery. Thus, the perioperative oral application of IgG appears to be an interesting and safe therapeutic option during colon carcinoma resection. A treatment strategy suitable for routine use at low cost in such patients and based on polyvalent immunoglobulins containing IgG is described.
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Polyvalent immunoglobulins with vitamin D3 and vitamin B12 in the treatment of Sjogren's syndrome in a vegetarian with stomatitis, glossodynia, xerostomia, and elevated antinuclear antibodies: Case report
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BACKGROUND: Sjogren's syndrome, involving sicca symptoms with xerostomia, stomatitis, and considerable pain is a difficult-to-treat autoimmune disease where the treatment options are limited and, as in the case of methotrexate, have a low therapeutic index. CASE REPORT: This case report concerns a male patient, aged 75 years and vegetarian, with Sjogren's syndrome subsequently confirmed by salivary gland biopsy. Serum antinuclear antibodies (ANA) were elevated (1 : 320). Low serum vitamin B12 and iron levels could be improved after 20 days using vitamin B12 and iron oral supplements. Despite symptomatic treatment, xerostomia, glossitis, and glossodynia were still present, at times marked, after 12 months when the ANA titer was unchanged. Following treatment with an anti-inflammatory polyvalent immunoglobulin formulation (Lactobin®N, 7 g daily), a bovine colostrum concentrate given orally in combination with oral vitamin D3 (2,000 IU daily), sicca symptoms and xerostomia progressively decreased and at day 750 were confined to occasional and minor glossitis of the upper lip. CONCLUSION: This case report demonstrates the satisfactory control of Sjogren's syndrome using oral polyvalent immunoglobulins with vitamin D3. In contrast to treatment options involving antimalarial drugs and methotrexate, there are no safety issues in patients tolerant to milk products.
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