To date, several therapeutic trials with IP have been designed for various infections and diseases, among which herpes infections, SSPE, HIV infections, AIDS and PGL, type B and C viral hepatitis, HPV infections and autoimmune diseases. The drug has been compared with placebo in several cases or versus other available treatments. The usual oral daily dosage of IP has ranged from 25 to 100 mg/kg, totalling 1–6 g, in single or divided doses (4–6).

Herpes Virus Infections

Human HSV types 1 and 2, commonly known as HSV-1 and HSV-2, belong to the Alphaherpesvirinae subfamily of AIDS Herpesviridae family. HSV-1 usually causes orofacial infection, whereas HSV-2 is transmitted mainly sexually and is more often associated with genital infection. However, HSV-1 is an increasing cause of genital infection [47, 48]. Both viruses can establish latent infection and there can be a recurrence affecting the same dermatome.

HSV-1, transmitted primarily by oral–oral contact, causes orolabial herpes (“cold sores”) in those infected. HSV-1 infections occur principally during childhood and they are not eliminated from the human body. HSV-1 is the most common identified causal agent of sporadic encephalitis in children and adults. For 2012, the average worldwide prevalence of HSV-1 infection was estimated to be 67%, while there was approximately a total of 118 million new infections reported [48].

The clinical presentation of HSV-2 infection is variable, and the majority of individuals are unaware that they are infected. In 2012, worldwide estimated prevalence and incidence of HSV-2 infection were 11.3 and 0.5%, respectively. Affected people had an age range of 15–49 years, and more than half were women [49]. Although rare, infection in the neonate is associated with a high risk of severe morbidity and mortality [50].

Several double-blind, placebo-controlled studies of IP in herpes infections (labialis or genitalis) and other types of herpetic infections, such as zoster, have shown encouraging results which are summarized in Table 2.

Table 2 Summary of studies investigating the clinical efficiency of IP in alphaherpesvirus infections Full size table

In a recent study by You et al. [3], the efficacy and safety of oral IP was compared with acyclovir in the treatment of recurrent herpes labialis (RHL) and recurrent herpes genitalis (RHG). IP was as equally effective as acyclovir in treating RHL and RHG with significantly greater reduction of the short-term recurrence rate of herpes genitalis at 3-month follow-up. The main limitations of this study are the single follow-up at 3 months after treatment discontinuation, which cannot reflect the long-term recurrence rate of RHG, and the lack of a control group with placebo treatment.

Subacute Sclerosing Panencephalitis (SSPE)

SSPE is a progressive and fatal neurodegenerative encephalitis owing to infection by the measles virus and its persistence in the cerebral nervous system. The prevalence of SSPE is inversely connected to measles vaccination and dependent on the patient’s age. The estimated incidence of SSPE ranges from 4 to 11 cases per 100,000 cases of measles and involves mostly children younger than 5 years old [51, 52]. There is an average of 4–10 years between the measles infection and the onset of the disorder, and prevalence is higher in males [53].

Several case reports have suggested that IP may provide beneficial therapeutic effects in patients with SSPE (reviewed in Campoli-Richards et al. [31]; Gadoth [54]) contrary to Noetzel and Dodson [55] who reported unabated progression of cerebral pathology in a patient with SSPE despite continuous treatment with IP (70 mg/kg/day) and periods of considerable clinical improvement or stabilization. In another case report, improvement was observed after a combination of IFN-α, ribavirin and IP therapy between 6 and 10 months; however, the patient suddenly deteriorated, and died [56].

Long-term studies, with or without a control group, have tested the impact of IP as a monotherapy in SSPE patients. Moreover, combined treatment regimens including IP were compared between them and against controls as to their effects in SSPE (Table 3). In most of the studies, it was suggested that the drug both increased survival and decreased neurological deficiencies [57,58,59,60,61].

Table 3 Clinical studies of the effectiveness of IP (monotherapy or in combination) in subacute sclerosing panencephalitis treatment Full size table

The combination of IP and IFN-α appeared to be an effective treatment of SSPE (Table 3). In general, the beneficial effect of this combined regimen was observed in patients with slowly progressive SSPE, in contrast to patients with an acutely progressive course. Differences between studies could be attributed to the natural history of the disease, the disease stage at the time of IFN-α administration, the scope of each study, the limited number of patients, the use of historical controls, and the duration of treatment and of follow-up. Albeit with limited data, IFN-β has been suggested as an alternative to IFN-α, due to fewer side effects and an easier route of administration [62, 63].

Various other kinds of drugs, such as amantadine, antivirals and DNA polymerase inhibitors [64,65,66,67], have been tested for treatment or to control disease progression. The efficacy of IFN-α, amantadine, and IP in the treatment of SSPE was compared and all three drugs were found to be relatively effective in either ceasing or slowing down progression of the disease. Nonetheless, the efficacy of IP outweighed that of amantadine and IFN-α by an order of four and two, respectively [65]. Patients were also found to benefit from either the combination of IP with IFN and lamivudine [67] or with IFN and antivirals [66].

The results from a multinational survey on actual diagnostics and treatment of SSPE, incorporating the experience of contributing physicians, revealed that IP monotherapy and combined oral IP plus ribavirin were applied frequently, as opposed to any combinations of IP with the following: IFN-α either subcutaneously or via an implanted pump, ribavirin plus IFN-α via an implanted pump, intraventricular IFN-α plus ribavirin, amantadine, and subcutaneous IFN-β [68]. Clinical and demographics characteristics along with commonly applied treatments were reviewed in a retrospective study including 43 children. IP was apparently the mainstay treatment either as a monotherapy (51% of patients) or in combination with IFN-β (4.7%) [69].

No cure exists for SSPE, which can only be prevented by a timely vaccination against measles. Nevertheless, the efficacy of IP on disease progression and patient survival rate, especially at early stages of SSPE, is evident by the obtained results (Table 3). Combined administration of IP and interferons has been supported by the majority of studies to achieve clinical improvement and prolonged survival. It should be noted that treatment shorter than 2 months was not found to be effective, and administration of relevant drugs should be continued even after apparent remission [65].

Human Papilloma Virus Infections

In early studies, comparing the efficacy of IP to conventional treatments (podophyllin, cryotherapy, electrocautery, CO 2 laser and surgery), a combined use of oral IP plus conventional non-surgical treatment of genital warts was found to produce more increased cure rates that conventional treatment alone [70, 71]. The authors concluded that the advantage of oral or topical treatment over hospitalisation and anaesthesia make IP a valid therapy. However, these studies had certain limitations, such as lack of placebo controls. In a multicentre, prospective, randomised, placebo-controlled study by Davidson-Parker et al. [72] it was suggested that IP may be worth considering as adjunct to conventional treatment (primary podophyllin or trichloroacetic acid) of patients with refractory genital warts.

A randomized, double-blind, placebo-controlled study demonstrated a significant pharmacological activity of oral IP in subclinical HPV infection of the vulva [73]. Moreover, involvement of HPV in chronic vulvodynia is suspected, based on identifications of acetowhite vulval lesions. Although limited data exists on this topic, it was suggested that oral IP could also serve as a non-invasive alternative for the treatment of young women with chronic vulvodynia [74].

The efficiency and toxicity of IP has been investigated in the combined treatment of patients infected with HPV 16 and 18, manifesting epithelial dysplasia and preinvasive cancer of the cervix uteri [75]. Following a course of IP treatment, HPV 16 and 18 were undetectable in 77.8% and 50% of treated patients, respectively. A second or third course of treatment was required for only a small proportion of patients.

Of the 17 treated individuals registered in a randomised, placebo-controlled study on the efficacy and safety of IP in the treatment of cervical condylomata acuminata, four responded to the treatment completely, seven responded partially and six did not respond at all. The therapeutic difference between treated women and placebo group was statistically significant. No recurrences were observed during the 12-month follow up in the complete responders. Adverse effects were mild and resolved upon completion of therapy [76].

An open trial compared the results of combined therapy using surgery and IP in a group of 25 patients with oral HPV-positive proliferative verrucous leucoplakia (PVL) against a group of 25 patients that underwent only surgery. Six months postoperatively there was a significant difference, with 18 recurrences in the patients treated by surgery alone compared to only two recurrences in those treated also with IP. Eighteen months postoperatively there were no further recurrences in the patients treated by surgery alone but two new recurrences in those treated with IP. Overall, by 18 months follow-up, there were 18 recurrences in the surgery-treated group, and only four in the IP group. The use of this antiviral agent appeared to offer a significant enhancement to the surgical management of PVL [77].

Studies of the effect of IP in patients with HPV infections are summarised in Table 4. Considerable efficacy with insignificant and reversible adverse effects and with low rate of recurrences is supported, hence IP may represent an efficacious and safe alternative therapy for HPV infections.

Table 4 Summary of studies on the efficacy of IP administration in patients with HPV infections Full size table

Influenza and Rhinovirus Infections

While treatment with IP in a total daily dose of 6 g had no statistically significant effect on the clinical course and serology of experimental infection due to rhinovirus 44 or rhinovirus 32 [78], a total daily dose of 4 g effected a significantly lower incidence and severity of rhinovirus 21 infection (vs. placebo) [79].

A study in volunteers challenged intranasally with influenza virus has shown significantly reduced symptomatology for the treated group [80]. Additively to them, the efficacy and safety of IP have been supported in a recent Phase 4 randomized, placebo-controlled, double-blind study [81] in subjects with clinically diagnosed influenza-like illness, including subjects with laboratory-confirmed acute respiratory viral infections due to influenza A or B virus, RSV, adenovirus, or parainfluenza virus 1 or 3 [81]. The study results indicate the safety of IP for the treatment of subjects with laboratory-confirmed acute respiratory viral infections and confirm the efficacy of IP versus placebo in healthy non-obese subjects less than 50 years of age with clinically diagnosed influenza-like illnesses [81]. Statistically significant differences in time to resolution of influenza-like symptoms were obtained for the IP subgroups containing subjects less than 50 years of age who were without related ongoing disease and subjects of less than 50 years of age who were non-obese.

Type B and C Viral Hepatitis

IP was considered ineffective for patients in the acute phase of classical acute viral hepatitis [82]. In a double-blind, placebo-controlled study, 30 patients with HBsAg-positive acute hepatitis were administered 6 g/day of IP for a mean duration of 28 days [83]. Treatment and placebo groups were comparable as to clinical symptoms and signs, and hematological and immunological parameters. After 4 weeks of therapy, the IP group had significantly less asthenia, anorexia and splenomegaly, lower total bilirubin, transferases and alkaline phosphatase concentrations, and greater well-being. There was no statistically significant difference in abdominal malaise, nausea or hepatomegaly. Within 90 days from therapy initiation, a significantly greater number of treated patients were HBsAg-negative.

Immunomodulation therapy for patients with hepatitis C virus infection has been addressed only in individual cases or small groups of people [84, 85]. Use of IP, as monotherapy or in combination with ribavirin, had no impact on viral load. Similarly, the increase in levels of alanine aminotransferase were not considered important. However, normalization of alanine aminotransferase levels was observed in patients non-responsive to IFN treatment [85]. In addition, concomitant use of IP with ribavirin improved disease severity and liver inflammation, evidenced by a reduction in the levels of the IFN-γ-inducible protein 10 [84]. If similar results are obtained in the future in controlled studies with larger numbers of patients, the beneficial role of IP, especially in the case of patients non-responsive to mainstay treatments, could be established.

Persistent Generalised Lymphadenopathy, HIV, and Acquired Immunodeficiency Syndrome

Evidence from early studies suggested that IP may improve some of the clinical symptoms associated with PGL in immunosuppressed males. In a placebo-controlled study in immunologically suppressed homosexual males with PGL, a total oral daily dosage of 3 g IP administered for 28 days also appeared to stimulate positive clinical effects [18, 86]. A greater percentage of drug-treated than placebo patients had an improvement in qualitatively assessed clinical symptoms, i.e., well-being, increased appetite, weight gain, night sweats, fever, skin rashes and lymph node pain.

The efficacy and safety of IP in patients infected with HIV and with no manifestation of AIDS was investigated within a placebo-controlled study, including a total of 831 male and female patients. Use of IP was found to be safe, as no serious side effects were reported. In addition, an effective delay in the progression to AIDS has been observed in the treated group [87]. Kovacs et al. [88] investigated the mechanism through which IP prevents Pneumocystis jiroveci (formerly P. carinii) pneumonia in patients infected with HIV, thus decreasing progression to AIDS. The plausible explanation provided was inhibition of the metabolism of P. jiroveci, in particular of dihydropteroate synthetase by p-acetamidobenzoic acid, one of IP’s components [88].

Besides the positive results emerging from these studies, showing that IP can both improve clinical symptoms and delay progression of HIV infection, it has also been described that its concomitant administration with zidovudine may have advantageous effects in HIV-infected patients [89].

Autoimmune Diseases

Positive immunomodulating effects of IP have been demonstrated in several studies on patients with autoimmune diseases, such as alopecia, rheumatoid arthritis or aphthous stomatitis, but further investigation is warranted to determine the efficacy of IP in the treatment of specific autoimmune diseases. In therapeutic studies, positive clinical effects of IP, at doses of 25–50 mg/kg daily (1.5–3 g), have been reported in the majority of treated patients with aphthous stomatitis [41] and alopecia [39, 40, 90].

In a randomized, placebo-controlled, double-blind study in patients with rheumatoid arthritis, a daily dose of 3 g IP failed to produce any positive therapeutic results [4]. Notably, the same treatment regimen has been found to be beneficial in terms of morning stiffness, tender joints, proximal interphalangeal joint circumference, sedimentation rate and fibrinogen level [91,92,93]. Consequently, use of IP as a second-line activity in rheumatoid arthritis would need more supportive evidence.

Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) is characterised by symptoms such as severe fatigue, exercise intolerance, myalgia, cognitive deficit, dizziness and problems in sleep, thinking and concentration. It is most common in people between 40 and 60 years old, but it can also affect children, adolescents, and adults of all ages, with women being more susceptible. Its pathogenicity has not been yet defined, and it remains undiagnosed in approximately 90% of affected people. It is speculated that changes in the immune system, such as chronic production of cytokines, decreased NK activity and differences in markers of T-cell activation, may contribute to the onset of CFS. There is no cure or established treatment for CFS, and healthcare professionals are mainly trying to cure the symptoms rather the disease itself [94].

The safety and efficacy of IP in CFS were investigated in a single-blind, placebo-controlled study of 16 CFS patients, with a mean age of 45.6 years [17]. Ten patients were randomly assigned to a regimen of IP for 12 weeks, consisting of 3 g/day on the odd weeks and 1 g/day on the even weeks, and six patients received methylcellulose placebo tablets. Following the 12 weeks of treatment, patients from both the treatment and the placebo groups received IP for 16 more weeks. Immune measures as well as responses of the patients to three tests, i.e., the Activities of Daily Living Questionnaire, the Cognitive Deficit Subset of the Symptom Checklist Questionnaire and the Karnofsky Performance Score, were evaluated.

Of the ten patients treated initially with IP, six reported improvement in their symptoms (improved group) and the median percentage reduction in cognitive symptoms for this group was 16%. The results from this study suggest that patients with CFS could benefit from treatment with IP. Nevertheless, further studies are warranted, with an adequate sample size and a longer follow-up period, in order to extract firm conclusions as to the efficacy of IP.

Multiple Sclerosis

Multiple sclerosis (MS) is one of the most common neurological disorders and causes of disability in young adults. Most people with MS have a normal or near-normal life expectancy. It may happen that some people with MS will experience little disability during their lifetime; nonetheless, up to 60% are no longer fully ambulatory 20 years after onset, with major implications for their quality of life. In rare cases, MS can be terminal. Globally, the median estimated prevalence of MS is 30 per 100,000, with the greatest prevalence in Europe (80 per 100,000), followed by the Eastern Mediterranean (14.9), the Americas (8.3), the Western Pacific (5), South-East Asia (2.8) and Africa (0.3). MS is more frequent in high-income countries (89 per 100,000). The global median estimated incidence of MS is 2.5 per 100 000 per year, with Europe ranking first (3.8 per 100,000), followed by the Eastern Mediterranean (2), the Americas (1.5), and the Western Pacific [95].

Use of IP in the treatment of MS has been investigated in several studies (see Hommes and Comi [96] and references therein). Significant beneficial changes were observed in patients with relapsing–remitting MS treated with IP, in regard to the mean annual relapse rate, the Kurtzke Disability Status Scale values, and the mean period of standard corticosteroid therapy [97]. In contrast to that, no significant difference in the clinical course of the disease between IP-treated patients and the control group were observed in 11 patients over a treatment period of 60 days [98].

The immunological and clinical beneficial effects of IP therapy in patients with exacerbating remitting MS were supported in the study by Pompidou et al. [99]; however, no firm conclusions could be drawn as to the long-term effectiveness of IP. A total of 52 patients with relapsing–remitting and relapsing–progressing MS were included in a double-blind, randomized, and placebo-controlled study, during which they were administered 3 g of IP or placebo for 2 years following a single, pulsed, intravenous administration of methylprednisolone. No benefit was demonstrated in the relapse rate, yet the expanded disability status scale and ambulation index show increased favor for the IP group, especially in the relapsing–remitting MS patients [100].

It is evident that outcomes from different studies are conflicting. Methodological bias makes it difficult to evaluate a potential benefit. There were major differences between the dosages, treatment regimens, patient selection and number, follow-up, and errors in randomization of patients in the treated and placebo groups.

Other Diseases and Infections

Worldwide, tuberculosis (TB) is one of the top ten causes of death, and it strikingly ranks above HIV/AIDS. The global incidence of TB for 2017 was approximately 10 million. Prevalence is higher in male adults. In 2017, the proportion of people who died from TB was 16%. Among HIV-negative and HIV-positive people, TB is estimated to have caused 1.3 and 0.3 million deaths, respectively. About 23% of the world’s population is estimated to have a latent TB infection [101] which, together with the length of treatment, malnutrition and weak immunity, are the major obstacles in controlling the TB epidemic [102]. The bacille Calmette–Guérin vaccine has been shown to prevent severe forms of TB in children, yet no such vaccine exists for adults, either before or after exposure to TB infection. The currently recommended treatment for cases of drug-susceptible TB is a 6-month regimen of four first-line drugs, i.e., isoniazid, rifampicin, ethambutol and pyrazinamide. However, drug-resistant TB continues to be a public health crisis. Approximately 600,000 people worldwide in 2017 developed TB resistant to rifampicin, the most effective first-line drug, and, of these, 82% had multidrug-resistant TB [101].

The efficacy of IP against Mycobacterium tuberculosis has not so far been tested. IP enhances TNF-α and IFN-γ (Th1 cytokines), stimulates T-lymphocyte differentiation into T-cytotoxic cells and T-helper cells and potentiates lymphoproliferation, both in vitro and in vivo. This resembles crucial responses of the host immune system during early stages of M. tuberculosis infection used to evade the pathogen. Based on this, Mishra et al. [103] suggested that the use of IP as an adjunct anti-tuberculosis chemotherapy should be considered, as potentiation of innate immunity by IP in combination with the direct inhibitory activity of the anti-TB drugs could help fight the infection while at the same time allowing for the reduction of drug doses and side effects [103]. Mishra et al. [103] have also outlined a strategy for evaluating repurposed IP for the treatment of tuberculosis.

Conclusions from a randomized, double-blind study on 22 children, aged 2.7–16.8 years with early dengue infection, suggest that IP could be used along with standard approved fluid and anti-pyretic therapy [104].

In vivo studies of the effect of IP on Echinococcus multilocularis and E. granulosus metacestodes (Cestoda), the causal agents of hydatid disease, have been performed, using jirds and mice as experimental hosts. Short- and long-term treatments with different doses (ranging from 0.5 to 4 g/kg) were tested. Marked ultrastructural damage with metabolic perturbations was observed in a dose-dependent mode [105, 106]. Evidence for direct interaction of IP with Echinococcus has been provided by Lawton et al. [107].