Table 1 Study characteristic animal studies
| Prevention studies (antileukotrienes are administered before inducing lung or systemic damage) | Studies on both prevention and treatment (antileukotrienes are administered before and after inducing lung or systemic damage) | Treatment studies (antileukotrienes are administered after inducing lung or systemic damage) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Demir 2008 | Kertesz 1992 | Cassin 1989 | Phillips 1995 | Schreiber 1985 | Schreiber 1987 | Xiao-Yan 2020 | Chen 2018 | Jouvencel 2003 | Park 2011 | |
| Study design* | Experimental | Experimental | Observational | Experimental | Observational | Observational | Experimental | Experimental | Experimental | Experimental |
| Total number of animals at the very beginning | 47 | Not reported |
24 lambs 10 goats | Not reported | 6 | 16 | 72 | 45 | 24 | Not reported |
| Number of animals which received antileukotrienes |
Montelukast group n = 10 clarithromycin + montelukast + pentoxifylline combination group n = 6 (plus other study groups not relevant in this review) |
Experiment 1: 31 0.1 uM/kg/h: 4 + 1 + 3 + 6 = 14 1.0 uM/kg/h: 8 + 9 = 17 experiment 2: not reported | Not reported |
Prevention (normoxia): 19 (with three different doses) Treatment (hyperoxia): 22 | 5 (we use experiment FPL 57,231 infusion started during hypoxia, so exp 2) | 5 | 24 | Not reported | 12 | Not reported |
| Number of animals in control group |
Clarithromycin n = 8 pentoxifylline n = 8 placebo n = 6 |
Experiment 1: 2 + 2 + 11 + 12 = 27 experiment 2: 60 | No control group, i.e. all animals got antileukotrienes |
Prevention (normoxia): 6 Treatment (hyperoxia): 6 | No control group, i.e. all animals got antileukotrienes | No control group, i.e. all animals got antileukotrienes | 24 | Not reported | 12 | Not reported |
| Number of animals outcome data are reported for | 47 | Not reported |
Sheep: 16 for antileukotrienes (plus 3 for thromboxane receptor antagonist) goats: 6 for antileukotrienes (plus 4 for thromboxane receptor antagonist) | Not reported | Not reported | Not reported | 72 | Not reported | 16 | Not reported |
| Funding | Supported by Dokuz Eylul University and The Scientific and Technological Research Council of Turkey |
Antileuk provided by Stuart Pharmaceuticals Study partly supported by the Dee and Moody Research Fund of Evanston Hospital |
National Hear, Lung and Blood institute Grant Antileukotrienes provided by the pharma |
Supported by the Medical Research Council Drug provided by Upjohn Company | Supported in part by grants from the American Lung Association and U.S.Public Health Service Program Project Grant HL 24,056 | Supported in part by grants from the American Lung Association, HL35518, and US Public Health Service Program Project Grant HL24056 | Funded by Jiangsu Provincial Maternal and Child Health Research Project (F201647 | Funding Project of Bengbu Medical College of Science and Technology Development (No. BYKF1741) | Grant sponsor: Société Française de Médecine Néonatale; Montelukast sodium a gift from Merck, Sharp and Dohme, Whitehouse Station, NJ | Medical Grant Program of Merck Sharp and Dohme Corp. (Rahway, NJ, USA), who also supplied with MK-0591 in powder form |
| Species | Rats | Rabbits | Sheep, goats | Guinea pig | Lambs | Lambs | Rats | Mice | Rats | Mice |
| Strain | Wistar | New Zealand albino | Not reported | Not reported | Mixed-breed | Not reported | Clean level P3 SD | 57BL/6 J | Wistar | FVB/n |
| Age when antileuk/comparator were given | Postnatal days 3–13 | day 7 | Five days. Unclear, but it is likely that the animals were given antileukotrienes and were exposed to hypoxia at the same day | day 3–6 | day 3–7 | day 4–6 | Not reported | day 2–14 | day 4 | Treatment windows were from days 1–4, 5–9 or 10–14 after birth |
| Presence and degree of prematurity | Full term | Full term | Not reported | Pre-term | Not reported | Not reported | Likely Full term | Likely Full term | Likely Full term | Full term |
| Mode of delivery | Naturally delivered | Not reported | Not reported | Caesarean section | Not reported | Not reported | Not reported | Not reported | Not reported | Naturally delivered |
| Type of lung damage/insult | Hyperoxia | Hyperoxia > 95% O2 | Hypoxia, ventilation | Hyperoxia 95%O2 | Hypoxia | LTD4 injection | Hypoxia | Hyperoxia | Hyperoxia 50% O2 from P0 to P15 | Hyperoxia 85% O2 |
| Age at lung damage | Days 3–13 | Day 7 | Five days. Unclear, but it is likely that the animals were given antileukotrienes and were exposed to hypoxia at the same day | days 1–3 | Days 3–7 | Days 4–6 | Not reported | 12 h, hyperoxia for 7 consecutive days | Within 24 h of birth | Within 24 h of birth |
| Type of control group |
Clarithromycin Pentoxifylline Placebo | Vehicle | No control group, i.e. all animals got antileukotrienes | Vehicle | No control group, i.e. all animals got antileukotrienes | No control group, i.e. all animals got antileukotrienes | Saline for periventricular leukomalacia group | Saline (0.9% NaCl) | Saline |
Vehicle (5% ethanol; 1% Tween 80) |
| Name of antileuk/name of comparator |
Antileuk: Montelukast, Montelukast + pentoxifylline + clarithromycin combination Comparator: clarithromycin pentoxifylline |
INTERVENTION ICI 198,615 (leukotriene receptor antagonist) CONTROL vehicle consisting of polyethylene glycol 400 (PEG 4OO), 1 M NaOH, and phosphate buffered saline (PBS) |
Leukotriene receptor antagonist L 649923 Dual cyclooxygenease and lipoxygenase inhibitor BW 755C | U-75302 (LTB4 antagonist) | FPL57231 (leukotriene receptor antagonist) | FPL57231 (leukotriene receptor antagonist) |
INTERVENTION Pranlukast CONTROL Saline |
Antileuk: montelukast sodium Control: Saline |
INTERVENTION Montelukast sodium CONTROL Normal saline |
INTERVENTION MK-0591 (5-lipoxygenase-activating protein inhibitor) CONTROL vehicle |
| Dose |
INTERVENTION montelukast: 1 mg/kg/day one dose combination: clarithromycin 100 mg/kg in two doses per day, montelukast 1 mg/kg/day, pentoxifylline 150 mg/kg in two doses per day CONTROL clarithromycin: 100 mg/kg/day in two doses pentoxifylline: 150 mg/kg/day in two doses saline: not reported |
INTERVENTION experiment 1: two groups group 1: 0.1 uM/kg/h ICI group 2: 1.0 uM/kg/h ICI Experiment 2: 0.1 uM/kg/h CONTROL not reported |
L 649,923: prepared in saline daily (10 mg/ml) and injected (5,86 mg/kg) over a 2 min period BW 755C: prepared in saline (8,8 mg/ml) and administered (30 mg/kg) over a 2- to 5-min period | 3.0 mg/100 g body wt** | 2 mg/kg/min (total 20 mg/kg) | 2 mg/kg/min (total 20 mg/kg) | 0.1 mg/kg |
Montelukast 10 mg/kg Saline not reported |
INTERVENTION 1 mg/kg/day (diluted in normal saline to 200mcg/ml—injected 5 mcg/g) CONTROL 5 mcg/g |
INTERVENTION 40 mg/kg ** |
| Frequency |
INTERVENTION montelukast: 1 dose per day combination: clarithromycin in two doses per day, montelukast 1 dose per day, pentoxifylline in two doses per day CONTROL clarithromycin: in two doses per day pentoxifylline: in two doses per day saline: once daily | Continuous by micro-pump pumping 0.5 uL/h | We suspect that the drugs were only given once, but this cannot be extracted from the text with complete certainty | Every 12 h over a 72 h period | Once for 10 min | Once for 10 min | once every 12 h, for 3 consecutive days | Once every other day | 1/day, from days 4–14 | Once daily during the treatment window |
| Route of administration |
INTERVENTION subcutaneously CONTROL clarithromycin: subcutaneously pentoxifylline: injected intraperitoneally saline: not reported | Subcutaneous pump |
L 649,923: injected directly into the pulmonary circulation BW 755C: administered via femoral artery | Not reported | Infusion | Intravenous infusion | Intraperitoneal injection | Intraperitoneally | Subcutaneously | Subcutaneously |