Table 3.
Clinical Trials of Oxygen-Ozone Therapy
| Author, Year | Aim of the Study | Participants | Ozone Therapy | Results | |
|---|---|---|---|---|---|
| Clavo et al, 200424 | To assess the effect of ozone therapy on the blood flow in the middle cerebral and common carotid arteries |
n = 7 subjects: 2 healthy volunteers + 5 patients with cerebral vascular disease Age: 58 years (34–78 years) |
Autohemotherapy: 200 mL blood + 200 mL O2/O3 mixture (concentration 60 µg/mL) 3 autohemotherapy sessions on alternate days over one week |
Middle cerebral artery: - systolic velocity: t0 = 90.9 ± 6.1 cm/s t1 = 111 ± 7.3 cm/s, p = 0.001 t2 = 104.3 ± 8 cm/s, p = 0.035 - diastolic velocity: t0 = 41.1 ±4.4 cm/s t1 = 54.6 ± 4.6 cm/s, p < 0.001 t2 = 48.6 ± 5 cm/s, p = 0.023 t0 – baseline t1 – after third session t2 – one week later |
Common carotid artery: - blood flow: t0 = 233 ± 19 mL/min t1 = 407 ± 38 mL/min, p < 0.001 t2 = 301 ± 22 mL/min, p = 0.039 The percentage increase in common carotid artery blood flow was directly correlated with age (r = 0.35, p = 0.004) and inversely correlated with the initial values (r = 0.691, p = 0.009). |
| Wu et al, 201325 | To determine the association between major ozonated autohemotherapy and functional recovery of patients with acute cerebral infarction | n = 86 acute cerebral infarction patients GrO3: autohemotherapy GrC: conventional therapy |
10 ± 3 daily autohemotherapy sessions: 100 mL blood + 100 mL O2/O3 mixture (concentration 47 µg/mL) |
Modified Rankin Scale: GrO3: t0 = 4.1 ± 0.8; t1 = 2.5 ± 1.1 GrC: t0= 4.1 ±0.9; t1 = 3.1 ± 1.3 GrO3 vs GrC p < 0.05 National Institutes of Health Stroke Scale (NIHSS): GrO3: t0 = 11.7 ± 3.5; t1 = 5.4 ± 3.5 GrC: t0 = 11.5 ± 3.8; t1 = 7.3 ± 4.1 GrO3 vs GrC p < 0.05 Central motor conduction time: - upper limb: GrO3 significantly shorter time in comparison with GrC (p < 0.05) - lower limb: no significant difference between groups t0 – baseline t1 – after 10 ± 3 sessions |
Cortical potential rise rate: no significant difference between groups Motor-evoked potential amplitude: - upper limb: GrO3: significantly higher in comparison with GrC (p < 0.05) - lower limb: no significant difference between groups Correlation analysis: - positive correlation between NIHSS improvement rate and central motor conduction time improvement rate of the upper limb (r = 0.78, p < 0.005) - positive correlation between NIHSS improvement rate and the improvement rate of motor-evoked potential amplitude of the upper limb (r = 0.85, p < 0.05) |
| Martinez-Sanchez et al, 201226 | Investigation of the therapeutic efficacy of ozone in patients with coronary artery disease, treated with antithrombotic therapy, Aspirin and policosanol. | n = 53 patients with coronary artery disease GrO3: 26 patients, regular anti-thrombotic therapy + ozone therapy GrC: 27 patients, regular anti-thrombotic therapy GrN: reference group of healthy subjects |
20 daily sessions: - rectal insufflation - dose: 200 mL O2/O3 mixture, concentration 40 µg/mL |
Prothrombin time (s): GrO3: t0 = 11.2 ± 0.6 s; t1 = 24.6 ± 6.6 GrC: t0 = 11.0 ± 0.4 s; t1 = 18.4 ± 4.6 t1: GrO3 vs GrC p < 0.01 Bleeding time: no difference (GrO3 vs GrC) Advanced oxidation protein products (µM): GrO3: t0 = 23.90 ± 0.84; t1 = 18.26 ± 3.61 GrC: t0 = 23.12 ± 5.31; t1 = 24.25 ± 7.18 t1: GrO3 vs GrC p < 0.05 Malondialdehyde (µM): GrO3: t0 = 12.04 ± 0.44; t1 = 8.38 ± 3.63 GrC: t0 = 13.71 ± 3.01; t1 = 10.82 ± 2.52 t1: GrO3 vs GrC p < 0.05 Peroxidation potential (µM): GrO3: t0 = 16.25 ± 3.62; t1 = 6.16 ± 2.51 GrC: t0 = 20.41 ± 8.16; t1 = 19.00 ± 7.03 t1: GrO3 vs GrC p < 0.05 t1: GrO3 vs GrN p > 0.05 t0 – baseline t1 – after 20 sessions |
Ferric reducing ability of plasma (µM): GrO3: t0 = 191.3 ± 57.0; t1 = 471.9 ± 115.8 GrC: t0 = 146.2 ± 62.3; t1 = 386.0 ± 104.3 t1: GrO3 vs GrC p < 0.05 Reduced glutathione (mM): GrO3: t0 = 1.18 ± 0.23; t1 = 1.55 ± 0.63 GrC: t0 = 1.5 ± 0.23; t1 = 1.08 ± 0.45 t1: GrO3 vs GrC p < 0.05 Superoxide dysmutase (U/mL): GrO3: t0 = 37.75 ± 7.13; t1 = 16.27 ± 8.39 GrC: t0 = 40.48 ± 10.12; t1 = 35.27 ± 14.21 t1: GrO3 vs GrC p < 0.05 Catalase (U/l): GrO3: t0 = 839.5 ± 165.3; t1 = 543.4 ± 172.3 GrC: t0 = 880.4 ± 250.1; t1 = 288.0 ± 99.6 t1: GrO3 vs GrC p < 0.05 t1: GrC vs GrN p > 0.05 No difference between GrC and GrO3 for total hydroperoxides. |
| Martinez-Sanchez et al, 200527 | Evaluation of the effectiveness of ozone in the treatment of patients with type 2 diabetes suffering from diabetic foot complications and its effects on oxidative stress, hyperglycaemia and some markers of endothelial damage. | n = 100 patients with diabetic foot GrO3: 51 patients, ozone therapy GrA: 49 patients, antibiotic therapy GrC: 50 healthy subjects, control group |
20 daily sessions: - rectal insufflation (ozone dose 10 mg, concentration 50 mg/l); - local ozone treatment (concentration 60 mg/l, time 1 hour) - Oleozon: ozonised sunflower oil |
Blood glucose concentration: GrO3 > GrA (p < 0.05) Blood glucose within reference range (3.33–8.33 mM): GrO3: t0 = 27%, t1 = 56% patients GrA: t0 = 30%, t1 = 26% patients Lesions area reduction: GrO3: 74.58 ± 0.35% GrA: 50.3 ± 0.17%, GrO3 vs GrA p = 0.017 GrO3: 2.66 ± 0.03 cm2/day GrA: 1.21 ± 0.01 cm2/day, GrO3 vs GrA p = 0.005 t0 - baseline t1 –24 h after the last session |
Total recovery time: GrO3: 21 ± 10 days GrA: 45 ± 11 days, GrO3 vs GrA p = 0.002 Length of hospitalisation: GrO3: 26 days (6–58 days) GrA: 34 days (7–83 days), GrO3 vs GrA p = 0.010 Biomarkers of oxidative damage: GrO3: improvement (t1 vs t0) of the following biomarkers: fructolysine, advanced oxidation protein products, peroxidation potential, superoxide dismutase, catalase. GrO3: improvement to the GrC levels (t1 vs t0) of the following biomarkers: nitrites/nitrates, total hydroperoxides. GrO3: no change for the following biomarkers: reduced glutathione, malondialdehyde, glutathione peroxidase |
| Tafil-Klawe et al, 200228 | Comparison of the effect of ozone and classical balneological methods on health condition of patients with obliterative artheromatosis and on serum activity of three lysosomal enzymes. | n = 94 subjects GrO3: 32 patients with lower limb ischemia Age: 65.9 ± 6.9 years GrB: 32 patients with lower limb ischemia Age: 62 ± 8 years GrC: 30 healthy subjects, control group Age: 60 years |
GrO3: everyday ozone therapy for 10 days: - intravenous infusions: 500 mL of normal saline satiated with ozone (60 µg O3/mL) - 30-minute aerosol oxygen-ozone baths: ozone concentration in a chamber was 19 µg/l GrB: whirlpool massage therapy and carbonic acid baths, everyday therapy for 10 days |
GrO3: - arylsulphatase: t1 = 1.71 ± 0.40; t2 = 1.88 ± 0.42 (p < 0.05 vs t1), t3 = 2.71 ± 0.68 - acid phosphatase: t1 = 14.11 ± 2.56; t2 = 12.21 ± 1.9 (p < 0.05 vs t1), t3 = 9.97 ± 1.48 - cathepsin D: t1 = 1.75 ± 0.38; t2 = 3.41 ± 0.69 (p < 0.05 vs t1), t3 = 5.39 ± 1.19 - alfa-1-antitrypsin: t1 = 1.62 ± 0.22; t2 = 1.39 ± 0.22 (p < 0.05 vs t1), t3 = 1.19 ± 0.15 (p > 0.05 vs GrC: 1.07 ± 0.12) t1 – 24 h hours before first therapy t2 – one hour following therapy t3 – on 10th day of therapy |
GrO3: - BMI reduction by 2.4% - ankle arm index (right extremity): improved by 13.8% - ankle arm index (left extremity) improved by 14.9% - intermittent claudication distance in the corridor: improve by 34.2% - intermittent claudication distance on a track: improvement by 50.6% - total cholesterol: reduction by 5.0% - HDL: no change - LDL: reduction by 7.2% - triglycerides: reduction by 11.1% |
| Marfella et al, 200931 | Analysis of ozone therapy effect on TNF-α level, endothelial progenitor cells (EPCs) level and on limb perfusion. | n = 151 patients with critical limb ischemia, candidates not appropriate for standard revascularization. Age > 40 years GrO3: 77 patients, ozone therapy GrC: 74 patients receiving injections with 10 mL sterile saline |
Intragluteal injection of autologous blood exposed to oxygen/ozone gas mixture (ozone concentration: 15.35 g/m;3 flow rate: 240 mL/min) Two treatments were given on consecutive days, followed by a third one on day 7. Subsequent treatments given at 1-week intervals for a least 22 weeks. |
Pain perception: GrO3: reduced pain perception in 36 patients GrC: reduced pain perception in 12 patients Wound healing: GrO3: deterioration in wound size t1 vs t0 (p<0.05), at t1 GrO3 vs GrC (p<0.05) GrO3: complete ulcer healing in 32 patients at 6 months Ankle-Branchial Index: No difference among groups at any of the time points t0 – baseline t1 – 22 weeks |
TcPO2: GrO3: significant increase at t1 vs t0 (p<0.01), GrO3 vs GrC (p<0.001) GrO3: higher number of patients with TcPO2> 30 mmHg (t0 = 31.1%, t1 = 84.4%) GrC: lower number of patients with TcPO2> 30 mmHg (t0 = 35.1%, t1 = 15.1%) TNF-α level: GrO3: t0 = 225.5±28.2 ng/l, t1 = 114.8±23.1 ng/l (p<0.001) GrC: no difference EPCs: GrO3: increase of CD34/KDR(+); No difference in CD34(+), CD133(+) or total number of mononuclear cells |
| Zhang et al, 201430 | Assessment of effectiveness of ozone therapy on the healing and the expression of growth factors of the wounds at the early stage after treatment of diabetic foot ulcer. | n = 50 patients with type II diabetes mellitus, as well as with diabetic foot ulcer of Wagner classification stages 2, 3, 4 GrO3: 25 patients, ozone therapy GrC: 25 patients, standard treatment including debridement, wound dressing, moisture maintenance of the wound |
Ozone gas bath: - concentration: 52 mg/mL - time: 30 min/day, 20 days |
Effective rate of wound healing: GrO3: 92% GrC: 64%, GrO3 vs GrC p = 0.037 Wound size reduction: GrO3: 6.84 ± 0.62 cm2 GrC: 3.19 ± 0.65 cm2, GrO3 vs GrC p < 0.001 Collagen contents of the wound (a.u.): GrO3: 4.48 ± 0.43 GrC: 3.07 ± 0.23, GrO3 vs GrC p = 0.012 VEGF levels in wound exudates at 7 day following up (pg/mL): GrO3: 27.89 ± 5.53 GrC: 22.25 ± 4.05, GrO3 vs GrC p < 0.05 PDGF levels in wound exudates at 7 day following up (pg/mL): GrO3: 21.31 ± 3.08 GrC: 13.39 ± 2.33, GrO3 vs GrC p < 0.05 TGF-β in wound exudates at 11 day following-up (pg/mL): GrO3: 9.81 ± 2.61 GrC: 8.45 ± 1.74, GrO3 vs GrC p < 0.05 |
VEGF levels in tissues at 11 day following up (pg/mL): GrO3: 34.86 ± 3.00 GrC: 26.44 ± 2.02, GrO3 vs GrC p = 0.032 PDGF levels in tissues at 11 day following up (pg/mL): GrO3: 31.44 ± 3.33 GrC: 20.78 ± 2.69, GrO3 vs GrC p = 0.023 TGF-β in wound tissues at 11 day following-up (pg/mL): GrO3: 14.95 ± 1.39 GrC: 10.45 ± 1.07, GrO3 vs GrC p = 0.019 Expression of VEGF proteins in tissues at 11 day following up (a.u.): GrO3: 3.34 ± 0.27 GrC: 2.03 ± 0.16, GrO3 vs GrC p < 0.001 Expression of PDGF proteins in tissues at 11 day following up (a.u.): GrO3: 4.09 ± 0.14 GrC: 3.06 ± 0.13, GrO3 vs GrC p < 0.001 Expression of TGF-β proteins in tissues at 11 day following-up (a.u.): GrO3: 7.83 ± 0.49 GrC: 6.10 ± 0.45, GrO3 vs GrC p = 0.018 |
| Zhou et al, 201632 | Comparison of the effectiveness of standard endovenous laser therapy with endovenous laser therapy combined with ozone gas bathing in patients with lower limb venous ulcers. | n = 92 patients with lower limb venous ulcers GrO3: 50 patients Age: 61.1 years ± 11.2 GrC: 42 patients, control group Age: 60.2 years ± 9.7 |
Preconditioning with ozone gas bath: - concentration: 60 mg/l - time: 1 hour, once a day until the necrosis and infection were improved an suitable for skin puncture (mean: 8.6 days, range: 8–13 days) |
Ratio of complete occlusion of the treated vein: no significant difference at any of time point (1, 3, 6, 12 months of follow-up) Ratio of recovery at the 12 months following up: GrO3: 92.00% GrC: 76.19%, GrO3 vs GrC p = 0.03 |
Ratio of ulcer recur at the 24 months following up: GrO3: 6.52% GrC: 25.00%, GrO3 vs GrC p = 0.03 Patient’s satisfaction assessment: GrO3: 90.00% GrC: 71.43%, GrO3 vs GrC p = 0.03 |
Note: p values above 0.05 are shown in bold.
Abbreviations: BMI, body mass index; EPCs, endothelial progenitor cells; Gr, study group; HDL, high-density lipoprotein; KDR, kinase-insert domain-containing receptor; LDL, low-density lipoprotein; n, number of subjects; p, statistical difference; PDGF, platelet-derived growth factor; t, time point; TcPO2, transcutaneous oxygen pressure; TGF-β, transforming growth factor-beta; TNF-α, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor.