Ismigen: Mechanism of Action, Indications, Administration and Studies of the Drug

It is a polyvalent mechanical bacterial lysate (LBMP).

Respiratory tract infections (RTIs) are one of the leading causes of morbidity and are also a cause of death in some parts of the world.

The treatment of respiratory tract infections involves a continuous search for stronger therapies and represents an economic burden for health services and society. In this context, infection prevention is absolutely necessary.

The use of bacterial lysates as immunomodulators to stimulate the immune response is widely debated.

Ismigen is used for recurrent respiratory infections, chronic obstructive pulmonary disease, chronic respiratory infections, and other conditions. Ismigen works by stimulating macrophages and other immune cell responses.

The polyvalent mechanical bacterial lysate (Ismigen) is a lysate administered sublingually that is made through a mechanical process that preserves the structure of bacterial antigens.

It activates T and B cells and causes the in vitro release of macrophage activating cytokines and pro-Th1.

The polyvalent mechanical bacterial lysate induces the expansion of memory B cells, which correlates with the prophylaxis of respiratory tract infection in patients suffering from recurrence and the sIgA response in healthy children and adults.

The use of Ismigen could be effective in reducing the frequency of exacerbation of respiratory tract infections in children and adults at risk.

To date, the efficacy and safety of Ismigen have been demonstrated in several clinical trials, even if systemic analytical reviews underscore the heterogeneity of its study populations.

However, more high-quality studies are needed to better explain the mechanism of action and confirm the beneficial results of Ismigen.

However, prevention strategies are essential both in children and in adult patients affected by respiratory diseases where acute and recurrent infections of the respiratory tract occur. The risk / benefit ratio provided by prevention with Ismigen is favorable.

Additionally, encouraging evidence regarding decreased antibiotic use, symptom relief, and disease duration represents a logical alternative approach to conventional therapy.

Ingredients

Each Ismigen 50 mg tablet contains 7 mg of lyophilized bacterial lysate. Prepared by bacteria (S. aureus, S. pyogenes, S. viridans, K. ozaenae, H. influenzae serotype B, M. catarrhalis and S. pneumoniae) obtained by mechanical lysis.

In any case, it is well known that for S. pneumoniae, nontypeable H. influenzae and M. catarrhalis, recurrent infections occur due to the heterogeneity of the strains.

Therefore, a single or even multiple strain vaccine with a killed whole cell formulation may not be the ideal vaccine.

Furthermore, the inactivation method can affect the immunogenicity of essential antigens through denaturation.

For example, the administration of polyvalent mechanical bacterial lysate (Ismigen), that is, products based on surface bacterial antigens.

The structure of which is not denatured by the use of chemicals, but is obtained by simple mechanical crushing of pathogens, can lead to a more specific antibody response to the surface structure of pathogenic bacteria.

For this reason, the efficacy of bacterial immunostimulants must not only be evaluated but also compared.

Mechanism of action of the Ismigen

Bacterial lysate, being an immunostimulant, works by modulating the immune system to trigger a protective response against bacteria or viruses that cause recurrent respiratory tract infections. This increases immunity against these infections.

Bacterial lysates have recently gained new interest and their use has gained progressively greater consensus in medical practice.

The Polyvalent Mechanical Bacterial Lysate is a bacterial lysate made from a wide range of pathogenic bacteria, including all the most common upper and lower respiratory tract pathogens obtained by mechanical lysis.

The mechanical method is particularly effective since it achieves a lysis of 80-100% of the bacteria.

What is even more interesting, compared to other lysis methods, such as alkaline lysis that produces fragmentation significant enough to cause loss of immunogenicity, mechanical lysis does not alter the structure of antigens: this guarantees excellent preparation. antigenic properties.

In this way, the lysate induces a specific immunostimulation against the seven bacterial strains that compose it, selected from among those most responsible for respiratory infections.

According to the extensive and well-established literature, treatment with polyvalent mechanical bacterial lysate appears to produce several beneficial effects, including a significant increase in antibody titer even after a single course of treatment, in terms of IgM, IgG, and IgA.

This has a positive therapeutic effect on the broad spectrum of immune production and on the production of opsonizing antigens.

In particular, it has been suggested that this polyvalent mechanical bacterial lysate exerts a therapeutic and preventive effect in acute and recurrent infections.

Because it induces the activation and enhancement of both memory IgM lymphocytes (CD24 + / CD27 + cells) and the IL-2 receptor that expresses Lymphocytes (CD25 + cells) involved in humoral or cellular immunity.

Furthermore, it is capable of inducing a specific immune response in the salivary fluid of healthy subjects.

Importantly, sublingual administration guarantees effective protection of the respiratory mucosa, which represents the first barrier against infection, making it possible to bypass the gastroenteric tract.

This prevents denaturation of antigens and brings them directly into contact with the cells that best perform the task of antigen-presenting cells, that is, Langherans cells.

Ismigen, a polyvalent mechanical bacterial lysate preparation of 8 different bacterial strains tested in vitro, has been shown to induce dendritic cell activation, leading to significantly higher expression of stimulating membrane molecules (CD80, CD83, CD86).

In addition, another study showed that this multipurpose mechanical bacterial lysate had several immunological effects consisting of:

Activation of the IL-2 receptor (IL-2R-on) in different subsets of lymphocytes (B, CD4 + T and CD8 + T cells) involved in humoral and cellular immune responses (IL-2, in an autocrine manner, is essential for clonal expansion of proliferating cells).

Induction of cytokine synthesis (IL-2, IL-10, IL-12, IFN-ă) in immunocompetent cells, promoting the regulation of immune responses. Generation of CD4 + and CD8 + effector T cells.

Ismigen therapy cost

Researchers and clinicians alike have focused lately on the use of bacterial lysates for a number of reasons.

The adoption of immunomodulators in the treatment of respiratory tract infections in patients with chronic obstructive pulmonary disease could justify an economic benefit.

Since these agents in patients with chronic obstructive pulmonary disease have been shown to reduce the financial burden both for the health system and for patients.

Recurrent infections, particularly in the upper and lower respiratory tract, are frequently observed in pediatric and older ages and represent a relevant problem because they have important socioeconomic implications.

It should be noted that the average cost of antibiotic therapy during the period from September to February of the year prior to the use of Ismigen was € 3459.60, while during the period from September to February of the trial year it was only € 1499.40 (- 57%).

Adding this last amount to the cost of the prophylactic therapy with Ismigen, equal to € 1295.04, the total cost of € 2794.44 was in any case significantly lower (−20%) than the cost for the same period of the previous year (extremely important savings for the management of the health structure.

Indications

Active immunization with Ismigen could reduce hospitalization rates and perhaps overall mortality in high-risk patients

The results of the meta-analyzes suggest that the polyvalent mechanical bacterial lysate is effective in both children and adults in preventing respiratory tract infections.

The current meta-analysis shows that there is a trend with polyvalent mechanical bacterial lysate towards clinically significant results in patients with chronic obstructive pulmonary disease.

At this time, a wide spectrum of different therapeutic options is available, but it is necessary to bear in mind that infectious episodes can derive from various pathophysiological conditions.

The immune system in children, for example, is often relatively ineffective, particularly with regard to antibody responses to infectious stimuli such as viruses or bacteria.

On the other hand, in older subjects, a general process of immune senescence is commonly observed, which consists of an overall reduction in the number and activity of immune cells.

How to take Ismigen

Ismigen tablets are administered sublingually so that antigenic molecules can easily spread into the mucous membrane of the upper respiratory tract and stimulate regional immunity, thus preventing gastric digestion of protein macromolecules that would occur if the tablet were swallowed.

Take this medicine in the dose and duration recommended by your doctor. Swallow it whole and do not chew, crush, or break the capsule. Ismigen can be taken with or without food, but it is best to take it at a certain time.

Ismigen side effects

The following is a list of possible side effects that can occur with all of the constituent ingredients of Ismigen. This is not an understandable list. These side effects are possible, but they don’t always happen.

Some of the side effects can be rare but serious. See your doctor if you notice any of the following side effects, especially if they don’t go away. The most commonly reported side effects of Ismigen are:

  • Problems in urology.
  • Itch.
  • Eruption.

Ismigen can also cause side effects not listed here.

If you notice other side effects not listed above, contact your doctor for medical advice. You can also report side effects to your local food and drug management authority.

Evidence of efficacy and safety of Ismigen in children

Increased specific and non-specific immune responses have been considered a key point in the treatment of recurrent respiratory tract infections.

In this regard, the efficacy of Ismigen in stimulating the immune system and reducing the number of respiratory tract infections has been investigated in several clinical trials and analyzed in systematic reviews.

Most clinical trials conducted in children with respiratory tract infections have demonstrated the efficacy and safety of Ismigen.

In 1993, Collet et al, studied the effect of treatment with Ismigen in nursery children (6 to 36 months of age), there was a 48% reduction in the risk of presenting episodes of upper respiratory infections in the treatment period.

Respiratory tract infections often cause missed school days in children aged 6 to 13 years, Jara-Perez et al, have shown the preventive effect of Ismigen in acute respiratory infections in children especially exposed to microbial contamination and, therefore therefore, to recurrent infections of the respiratory tract.

The authors showed that Ismigen treatment significantly reduced the number of missed school days, as well as antibiotic courses and the duration of illness.

The efficacy to prevent respiratory tract infections in preschool and schoolchildren was confirmed in the study by Gutiérrez-Tarango et al, in addition to the decrease in the number and duration of respiratory tract infections, a significant reduction in the number of courses of antibiotics.

Ismigen treatment reduced the incidence of acute respiratory tract infections also in a population of children with recurrent acute respiratory tract infections aged 3 to 8 years, as reported by Schaad et al.

Ismigen significantly reduced the average incidence of respiratory tract infections, again, the efficacy of Ismigen is evident, especially in patients particularly susceptible to recurrent respiratory tract infections.

Despite the fact that the increase in the frequency of exacerbations triggered by infectious agents is an important result in children with wheezing and asthma.

However, clinicians are looking for more appropriate treatments, especially since there is accumulating evidence that the reversibility of severe atopic diseases decreases with time of onset.

Current therapies, including inhaled corticosteroids, have limited efficacy in preventing virus-induced wheezing attacks in young children.

Therefore, primary and secondary prevention strategies are much needed in those children with wheezing attacks induced by respiratory tract infections.

The efficacy of Ismigen in reducing wheezing attacks is an effective secondary preventive strategy in children with respiratory failure and wheezing induced by respiratory tract infection.

The results of clinical studies on Ismigen to prevent respiratory tract infections in asthmatic and atopic children are encouraging. Ismigen increases the levels of secretory IgA, serum IgA, serum IgG and serum IgM in adults.

However, Ismigen in children with recurrent respiratory tract infections has interestingly shown a significant reduction in IgG4 subclass levels after treatment.

Since the active role of the IgG4 subclass has been demonstrated in the type I hypersensitivity reaction, add-on therapy with Ismigen is helpful in reducing recurrent respiratory tract infections in children with allergic respiratory tract diseases.

The antigenic effect of Ismigen has also been tested in children with IgA deficiency, with the intention of evaluating whether Ismigen could induce autoimmunity. The general effect of Ismigen in treating respiratory tract infections has also been examined.

Evidence has also been found in favor of Ismigen for the prevention of acute respiratory tract infection in children, with a trend towards fewer infections.

The efficacy of Ismigen in preventing the occurrence of pediatric respiratory tract infections indicates that the beneficial efficacy of Ismigen is particularly marked in children at high risk of respiratory tract infections.

The magnitude of the effect of Ismigen in reducing the incidence of acute respiratory tract infections is hampered by discrepancies often due to the high heterogeneity of the studies and the poor or moderate quality of the trials.

However, to date, several clinical studies have confirmed the efficacy and safety of Ismigen in preventing and treating respiratory tract infections in children with infections of different origins.

Evidence of efficacy and safety of Ismigen in adults

The Swiss guidelines indicate the use of immunomodulators such as Ismigen among the possible therapeutic options indicated for the treatment of chronic obstructive pulmonary disease in adults.

Furthermore, the use of Ismigen (and other immunostimulants) has been shown to be a useful option in the treatment of chronic obstructive pulmonary disease.

This is in accordance with the recent recommendation of the Global Chronic Obstructive Pulmonary Disease Initiative (GOLD), a collaboration between the World Health Organization and the National Heart, Lung, and Blood Institute (NHLBI). for its acronym in English).

The efficacy of Ismigen in preventing respiratory tract infections in elderly patients has been demonstrated in several clinical studies. An overall reduction in antibiotic prescriptions has also been observed.

Administration of bacterial lysate (Ismigen) was associated with a 28% decrease in the number of patients with lower respiratory tract infections, which was due to a 40% decrease in the number of acute bronchitis episodes.

Treatment with Ismigen significantly reduces the duration of acute episodes of bronchitis and the use of antibiotics. Interestingly, in addition to clinical efficacy, a significant increase in serum levels of:

IgA and T cell counts in patients treated with Ismigen up to 3 months after exacerbation, thus confirming the modulatory role of Ismigen in the immune system.

The preventive role of Ismigen in reducing exacerbations in elderly patients with chronic bronchitis and chronic obstructive pulmonary disease was confirmed in several clinical trials by Collet et al.

The efficacy of this immunomodulatory agent has also been confirmed by Solèr et al, in a slightly younger population with mild chronic obstructive pulmonary disease or chronic bronchitis.

They reported a significantly higher probability that Ismigen-treated patients remain free from acute exacerbation events.

The effect of Ismigen was also tested in a group of HIV positive patients, a patient population for whom immunostimulatory therapies were actively sought.

These patients have a high prevalence of chronic obstructive pulmonary disease and are at high risk of developing seasonal respiratory tract infections. Ismigen was administered with satisfactory results, extending the treatment for 2 years.

The number of events in the year before administration and the year after administration was compared, and there were fewer cycles of antibiotics and hospitalizations.

The effect of purified bacterial lysates such as Ismigen, administered orally in chronic bronchitis and chronic obstructive pulmonary disease, produces improvements in symptoms, and shortens the average duration of exacerbation.

Studies with the Ismigen

The effects of bacterial lysates as immunostimulating agents have become the focus of many studies.

Over the past 20 years, the efficacy of bacterial lysates as immunostimulating agents has become the focus of many clinical trials.

The goal of these studies was to understand and evaluate the ability of these types of treatments to create a powerful immune system response against microbial infections, ultimately leading to a reduction in their number.

These studies are quite heterogeneous.

There are many differences between enrollees regarding their age (pediatric versus adult patients) and their conditions, including recurrent upper and lower airway infections, acute and chronic bronchitis, rhinosinusitis, and chronic obstructive pulmonary disease.

First study

In an Italian study conducted in 57 patients older than 75 years with chronic obstructive bronchitis and affected by at least one exacerbation in the last 12 months.

Ismigen significantly reduced the absolute number of exacerbations, their duration and severity.

As well as the need to use antibiotic treatments and the general cost of treating these patients during the treatment period compared to the same period last year, during which antibacterial prophylaxis had not been administered.

Second study

In another multicenter study, 178 patients were randomized into two different groups: one group was treated with Ismigen (the first 10 days of each month for 3 consecutive months) and the other with placebo. The trial was double blind.

At the end of the treatment, the patients were followed up for a further 9 months. Selected clinical end points were seen as significantly lower in the lysate group than in the placebo group.

Ismigen treatment led to a highly significant reduction in the frequency (215 versus 248 cases) and duration (10.6 days versus 15.8 days) of exacerbations, as well as a decrease in the use of antibiotics (−270 dose) and length of hospitalization (275 days versus 590 days).

Third study

As for pediatric trials, the earliest example, and one of the most cited, is a 1980 study by Oehling et al. That showed a reduction in symptom severity when using bacterial lysates.

Other studies, on the other hand, revealed the benefits of using bacterial lysates.

In a randomized controlled trial where children with rhinosinusitis underwent treatment with bacterial lysate, a decrease in the incidence and duration of infectious episodes, their number and the duration of concomitant treatments.

Furthermore, the clinical response showed a correlation with an increase in serum IgA levels.

Another randomized controlled trial with 188 pediatric patients showed that the infection rate was reduced by 50% in treated patients, and this protection was maintained for half a year after the termination of drug administration.

Pharmacological reactions were few, transitory, expected and not serious.

Conclution

In both pediatric and adult trials, a positive trend in the results can be found: a reduction in infection rates and the duration and use of antibiotics, as well as a beneficial effect on symptoms.

It should be noted that there are also new clinical perspectives and approaches on the potential use of bacterial lysates in different pathologies, in addition to common respiratory diseases, with the possibility of improving the quality of life of the patient in several different diseases.

Observations made in particular patient populations, such as those infected with HIV, are promising and should be encouraging for further extensive research.

Currently, the exact mechanisms of action of Ismigen and its individual components are not yet well defined. Additional studies are required to define these issues.

In particular, randomized trials recruiting a large population with a well-defined diagnosis of respiratory disease could confirm the beneficial results seen with Ismigen treatment and better define optimal doses, dosing regimens, and population target.

In conclusion, although these findings are encouraging, more randomized controlled trials are needed to further clarify the mechanism of action of Ismigen (bacterial lysates).

According to Braido et al, further trials including a larger number of selected patients and well-designed trials in terms of blinding and randomization procedures are needed.

These studies will help to find more solid evidence of the beneficial effects of Ismigen (bacterial lysates) in improving symptoms, preventing infections and, above all, in the quality of life of our patients.

Further analysis of the mechanism of action of bacterial lysates in animals and humans is ongoing and necessary.