PHARMACEUTICAL COMPOSITION FOR TREATMENT OF ENVELOPED DNA OR RNA VIRUS INDUCED INFECTIONS AND DISORDERS

Abstract

The invention relates to a composition, as well as a dosage, and a medicament for treatment of enveloped DNA or RNA virus induced infections and disorders, such as respiratory tract infection, and lung fibrosis. It has been found that the present composition limits the effects of virus infection on the human body, and contributes to the recovery thereof.

Claims

1. A pharmaceutical composition for use in the treatment of enveloped DNA or RNA virus induced infections and disorders, respiratory tract infections, and lung disorders, comprising (i) at least one first compound comprising at least one carbohydrate and containing more than one sulphate selected from multiple Sulphur containing agents with a molecular weight of <30 kDa, in combination with (ii) at least one second compound selected from the group of non-protein and non-NA-strand compounds, different from (i), that can activate PPAR, wherein the at least one first compound and at least one second compound are provided in a molar ratio of 0.01:1 to 1:0.01.

2. The pharmaceutical composition for use in the treatment of enveloped DNA or RNA virus induced infections and disorders according to claim 1, wherein the use is selected from a use for recovery of lung infection, for recovery of lung disorders, and for recovery of lung fibrosis.

3. The pharmaceutical composition for use in the treatment of enveloped DNA or RNA virus induced infections and disorders according to claim 1, wherein the virus is selected from viruses with a positive-sense single-stranded RNA genome.

4. The pharmaceutical composition for use in the treatment of enveloped DNA or RNA virus induced infections and disorders according to claim 1, , wherein the first compound is selected from pentosan polysulfate (CAS 37300-21-3 N or 116001-96-8, (C.sub.5H.sub.6Na.sub.2O.sub.10S.sub.2).sub.n, n=1-10), Polysulfated glycosaminoglycan, dextran sulphate (CAS 9011-18-1), fucoidan (CAS 9072-19-9), and combinations thereof.

5. The pharmaceutical composition for use in the treatment of enveloped DNA or RNA virus induced infections and disorders according to claim 1, wherein the second compound is selected from indomethacin (CAS 53-86-1), pioglitazone (CAS 112529-15-4), and combinations thereof.

6. The pharmaceutical composition for use in the treatment of enveloped DNA or RNA virus induced infections and disorders according to claim 1, wherein the composition further comprises (iii) at least one pharmaceutically acceptable carrier.

7. The pharmaceutical composition for use in the treatment of enveloped DNA or RNA virus induced infections and disorders according to claim 1, selected from a pharmaceutical composition comprising pentosan sulphate and/or adequan sulphate, and from a pharmaceutical composition comprising indomethacin and/or pioglitazone.

8. The pharmaceutical composition for use in the treatment of enveloped DNA or RNA virus induced infections and disorders according to claim 1, wherein the use is for obese human beings.

9. The pharmaceutical composition for use in the treatment of enveloped DNA or RNA virus induced infections and disorders according to claim 1, for use as a medicament by administering said medicament in an effective amount for a sufficient period.

10. The pharmaceutical composition for use in the treatment of enveloped DNA or RNA virus induced infections and disorders of claim 9, wherein the administration is selected from the administration to a pet and from the administration to a mammal, comprising said virus infection.

11. The pharmaceutical composition according to claim 1 as a medicament selected from the use in the treatment of enveloped DNA or RNA virus induced infections and disorders, and the use in the treatment of fibrosis.

12. The pharmaceutical composition for use in the treatment of enveloped DNA or RNA virus induced infections and disorders according claim 1, wherein the active pharmaceutical ingredients are in one dosage form, comprising 1-10 mg active ingredients/kg body weight.

13. A dosage according to the dosage of claim 12, comprising separate dosage forms for individual pharmaceutical active ingredients, and wherein the composition is in the form selected from a tablet, a capsule, a repository, nanoparticles, and an injectable.

14. The dosage according to claim 12, for a use after chronic inflammation occurred, and/or wherein the dosage is provided during a fibrosis phase, and wherein the dosage is for sub-cutaneous application, wherein a sub-cutaneous dosage comprises 20-100 mg active ingredient per dosage.

15. The dosage according to claim 12, wherein the at least one first compound and at least one second compound are provided in a weight ratio of 1:1 to 10:1, and wherein a total weight of active ingredients is from 1-100 mg per dosage.

16. The pharmaceutical composition for use in the treatment of enveloped DNA or RNA virus induced infections and disorders according to claim 1, wherein the at least one second compound is selected from PPARγ, thiazolidinediones, NSAIDs, sulphonylureas, and indoles, and a salt thereof.

17. A method for treating enveloped DNA or RNA virus induced infections and disorders, respiratory tract infections, or lung disorders in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 1.

18. The method of claim 17 wherein the virus is selected from viruses with a positive-sense single-stranded RNA genome.

Description

SUMMARY OF THE FIGURES

[0082] FIG. 1 shows a schematic structure of Thiazolidinedione and FIG. 2 of sulfonylurea.

[0083] FIG. 3 shows Polysulfated glycosaminoglycan.

[0084] FIG. 4 shows schematics of bleomycin induced fibrosis and FIG. 5 effects thereof on lung tissue, showing H&E and SMA staining.

EXPERIMENTAL SET-UP

[0085] The inducement of fibrosis and the mouse model used largely follow the procedure as described in Ruscitti et al. Multi-disciplinary Respiratory Medicine (2017) 12:8, DOI 10.1186/s40248-017-0089-0.

[0086] The present first and second compound, such as pentosan, is typically provided in the drinking water, such as at a dosage of 20-25 mg/kg/day, and/or sub-cutaneous of e.g. 50 mg/kg/week.

[0087] Experiment:

[0088] Day 1 baseline blood draws and intra tracheal injection of 80 μl of physiological saline (control for bleomycin) with Isoflurane anesthesia.

[0089] Day 7 baseline blood draws

[0090] Day 7 start treating with compounds (n=28, n=4 per group)

[0091] 1 compound B (second compound, e.g. indomethacin) 4 mg/kg (DMSO and trapsol) drinking water

[0092] 2 compound C (alternative/additional second compound) 40 mg/kg (DMSO and trapsol) drinking water

[0093] 3 compound A (first compound) 20 mg/kg and B 4 mg/kg (DMSO and trapsol) drinking water

[0094] 4 compound A 20 mg/kg and C 40 mg/kg (DMSO and trapsol) drinking water

[0095] 5 compound A 50 mg/kg/week subcutaneously weekly and B 4 mg/kg (DMSO and trapsol) drinking water

[0096] 6 compound A 50 mg/kg/week subcutaneously weekly and C 40 mg/kg (DMSO and trapsol) drinking water

[0097] 7 control (DMSO and trapsol) saline subcutaneous weekly+drinking water (added because we need a control group without compounds to compare with given FACS BAL dif staining and activation markers on the alveolar macrophages)

[0098] Day 14 change drinking water and subcutaneous injections with A

[0099] Day 21 sacrifice mice.

[0100] Collection of:

[0101] Blood divided into 3 portions (Acrp30 (5 μl), cytokines (50 μl) and remainder); measure at regular intervals, typically 5 times, whereof 2 times after treatment starts; measure e.g. adiponectin levels. Adipocyte complement-related protein of 30 kDa (Acrp30, adiponectin, or AdipoQ) is a fat-derived secreted protein that circulates in plasma. Acrp30 is lower in insulin-resistant states and it is implicated in the regulation of in vivo insulin sensitivity. Plasma Acrp30 levels from two diabetic mouse models were increased in response to treatment.

[0102] Results suggest that induction of Acrp30 may represent a key mechanism that contributes to the beneficial metabolic effects of the present compounds and that measurement of Acrp30 levels prove to be a valuable biomarker that can be used to gauge the extent of in vivo activation.

[0103] FACS analysis (fluorescence activated cell sorting) of cells in BAL (bronchoalveolar lavage), a ELISA (enzyme-linked immunosorbent assay) in bronchoalveolar fluid (BALF).

[0104] Lung histology (freeze) and left lobe for hydroxyproline assay.

[0105] Results

[0106] From the experiments it follows that first of all a positive effect was observed in the treatment of (bleomycin) induced fibrosis. In addition, the combined pharmaceutical composition of the present invention showed a synergistic effect over the individually applied first and second compounds, respectively. The synergistic effect of the present composition was typically at least 2 times the summed individual effects, mostly at least 10 times, and often at least 20 times, hence at least a factor higher. Also, (bleomycin-induced) fibrosis was largely or fully mitigated, that is e.g. lung tissue preserved at least partly.