Comparison of Publications on Heated Tobacco Products With Conventional Cigarettes and Implied Desirability of the Products According to Tobacco Industry Affiliation: A Systematic Review.

INTRODUCTION: Heated tobacco products (HTPs) have been advertised as "reduced-harm" tobacco products compared to conventional cigarettes (CC); however, no direct evidence supporting HTPs being desirable for human health exists. A previous systematic review reported that evidence on HTPs published in 2017 or earlier was primarily drawn from industry-related papers. We aimed to investigate whether tobacco industry-affiliated studies are more likely to conclude that HTPs are more desirable than CC. METHODS: PubMed and Ichushi-Web were searched up to March 15, 2022, for studies on HTPs published in 2017 or after. We selected studies that assessed any measures of HTPs and CC, including secondary analyses using gray literature in English or Japanese. We excluded review articles except for a meta-analysis that met the aforementioned criteria. Data on the authors' affiliations, grant, conflict of interest, category of research subjects, and interpretation were extracted. Research members in two groups independently assessed the papers; discrepancies were solved by discussion between the groups. RESULTS: Overall, 134 studies met the criteria. Eighty-seven (64.9%) of them were affiliated with the tobacco industry. Of the 134 studies, 56.3% (49/87) of the industry-affiliated studies versus 19.1% (9/47) of nonindustry-affiliated studies concluded that HTPs were more desirable than CC (p < .01). No study investigated clinically relevant outcomes, such as disease occurrence. CONCLUSIONS: Publications on HTPs in the biomedical literature from January 2017 to March 2022 were dominated by tobacco industry-affiliated studies. More than half of them concluded that HTPs were more desirable than CC compared to independent studies. IMPLICATIONS: Tobacco industry advertises HTPs as "reduced-harm" tobacco products compared to CC. HTP users tend to consider HTPs as alternative tobacco products less harmful than CC (ie, products for "harm reduction"). Our results demonstrated that papers written by tobacco industry-affiliated authors concluded that HTPs were more desirable than CC compared to papers by independent authors. However, all their judgments were based on surrogate outcomes. Surrogate outcomes are not necessarily linked to clinically relevant outcomes such as disease occurrence. Further studies on HTPs using clinically relevant outcomes are warranted by independent authors from tobacco industry.

Effects of nitric oxide synthase inhibition on cutaneous vasodilation in response to acupuncture stimulation in humans.

OBJECTIVES: The aim of the present study was to elucidate the mechanism of cutaneous vasodilation following acupuncture stimulation by investigating the roles of nitric oxide (NO) and axon reflex vasodilation. METHODS: The subjects were 17 healthy male volunteers. The role of NO was investigated by administering N(G)-nitro-l-arginine methyl ester hydrochloride (L-NAME, 20 mM), an NO synthase inhibitor or Ringer's solution (control site), via intradermal microdialysis (protocol 1; n=7). The role of axon reflex vasodilation by local sensory neurones was investigated by comparing vasodilation at sites treated with 'eutectic mixture of local anaesthetics' (EMLA) cream (2.5% lidocaine and 2.5% prilocaine) with untreated sites (control site) (protocol 2; n=10). After 5 min of baseline recording, acupuncture was applied to PC4 and a control site in proximity to PC4 for 10 min and scanning was performed for 60 min after acupuncture stimulation. Skin blood flow (SkBF) was evaluated by laser Doppler perfusion imaging. Cutaneous vascular conductance (CVC) was calculated from the ratio of SkBF to mean arterial blood pressure. RESULTS: In the first protocol, sites administered L-NAME showed significant reductions in CVC responses following acupuncture stimulation compared to control sites (administered Ringer's solution) (p<0.05). In the second protocol, changes in CVC responses after acupuncture stimulation did not differ significantly between treated sites with EMLA cream and untreated sites (p>0.05). CONCLUSIONS: These data suggest that cutaneous vasodilation in response to acupuncture stimulation may not occur through an axon reflex as previously reported. Rather, NO mechanisms appear to contribute to the vasodilator response.

Inhibition of nitric oxide synthase attenuates cutaneous vasodilation during warm moxibustion-like thermal stimulation in humans.

OBJECTIVES: This study investigated if nitric oxide (NO) and/or prostaglandin (PG) are responsible for cutaneous vasodilation during warm moxibustion-like thermal stimulation (WMTS). DESIGN: For two protocols, two microdialysis membranes were placed in the medial forearm skin. In the first protocol (n=8), the sites were randomly assigned and perfused with N(G)-nitro-l-arginine methyl ester hydrochloride (l-NAME), an NO synthase inhibitor or Ringer's solution (control site). Similarly, two microdialysis membranes were placed in the medial forearm skin in the second protocol (n=6). One site was perfused with ketorolac (Keto), the cyclo-oxygenase (COX) pathway inhibitor, and the other site was perfused with Ringer's solution (control site). In both protocols, cutaneous vasodilation was induced using WMTS with an electronic warm moxibustion treatment appliance. After 10 minutes of baseline recording, WMTS was applied to the forearm skin for 20 minutes and recovery was monitored over a period of 20 minutes. Skin blood flow (SkBF) at each site was measured using laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial blood pressure (BP). SETTINGS/LOCATION: The study was conducted in a laboratory at the Kansai University of Health Sciences. SUBJECTS: The subjects were 14 healthy male volunteers. INTERVENTIONS: WMTS was applied to the medial forearm skin using an electronic warm moxibustion treatment appliance. OUTCOME MEASURES: SkBF, skin temperature (Tsk), core body temperature (Tc), heart rate (HR), and BP were outcome measures. RESULTS: In the first protocol, peak CVC values during WMTS at the site perfused with l-NAME were significantly decreased, compared to those at the control site (p<0.05). In the second protocol, peak CVC values during WMTS did not differ between the control site and the Keto site (p>0.05). CONCLUSIONS: These data demonstrate that NO is involved in the mechanism of cutaneous vasodilation induced by WMTS. Furthermore, increases in CVC despite inhibition of the COX pathway suggest that PG does not contribute to cutaneous vasodilation during WMTS.