CVC Max Research Articles

Abstract PO4-18-05: Safety and Feasibility of Administration of an Oral Cannabis Preparation in The Preoperative Period in Breast and Oral Cavity Cancer

Abstract Introduction- Cannabis is world’s oldest cultivated medicinal plant. It has potential applications in oncology, in reducing chronic pain, stimulating appetite, alleviating nausea/vomiting, improving overall well-being as well as its anti-cancer properties. We conducted a phase-1 dose escalation study to determine safety of pre-operative oral cannabis in breast and oral cavity squamous cell carcinoma (OC-SCC) with an intent to explore its anticancer potential in the “pre-operative” window. The primary objective was to determine maximum tolerated dose (MTD) and establish dose limiting toxicity (DLT). Secondary objectives were pharmacokinetic profiling and transcriptomic analysis of tumour tissue. Methodology- Primary objective was to determine maximum tolerated dose (MTD) and establish dose limiting toxicity (DLT). Secondary objectives were pharmacokinetic profiling and transcriptomic analysis of tumour tissue. Non-metastatic breast and OC-SCC patients planned for curative surgery were consented after thorough medical and mini-psychiatric evaluation with Brief Psychiatry Rating Scale (BPRS). The investigational product (IP) comprised of a capsule containing 2.5mg of tetrahydrocannabinol (THC) and 2.5mg cannabidiol (CBD) in 100 mg monocrotolyn oil extract of dried leaves of C. sativa. The capsules were manufactured in an Ayurvedic GMP facility. The classical 3+3, phase-1 design used modified Fibonacci sequence for dose escalation, starting with 5mg THC+5mg CBD. Patients received IP once a day for 5 days after breakfast with hemodynamic and psychiatric monitoring and underwent the planned surgery on day-6. Pharmacokinetic samples were collected at predefined time-points and plasma levels of THC, 11-OH-THC, 11-COOH-THC and CBD were determined using a validated LC-MS/MS method. Tumour tissue was collected before 1st dose of cannabis and during surgery for biomarker analysis. Results- A total of 12 patients were enrolled (6-breast, 3-buccal mucosa, and 3-tongue cancers). First 3 patients completed the study without DLT at 5+5mg dose. A DLT was observed at dose level-2 (10+10mg) and therefore additional 3 patients were enrolled at the same dose. Two patients out of six at this dose had DLT (anxiety- grade-3 and somnolence- grade-2) necessitating dose de-escalation in the next cohort. At 7.5+7.5mg dose, all 3 patients tolerated the IP(MTD). Ten patients completed the study protocol. Common adverse effects were headache (2/12, grade-1), heavy head (8/12, grade-1), hypotension (2/12, grade-1 and 3), epigastric discomfort (1/12, grade-1), diarrhoea (1/12, grade-1), hyponatremia (1/12, grade-1), hypertension (1/12, grade-2), anxiety (1/12, grade-2). Pharmacokinetics of both CBD and THC was less than dose proportional. At the MTD (7.5+7.5), day-1 and day-5 AUC0-24 [median (range)] for CBD were 21.75 (12.44–41.44) ng/ml−1*h and 24.85 (13.72–35.93) ng/ml−1*h respectively. Similarly, for THC, day 1 and day 5 AUC0-24 were 11.79 (8.06–70.58) ng/ml−1*h and 68.98 (1.78 – 136.17) ng/ml−1*h, respectively. Significant accumulation of both CBD and THC was observed across all doses from day 1 to 5. A high variability in pharmacokinetics was observed for both constituents (CV Cmax = 101.26% and 117.48%; CV AUC0-24 = 102.50% and 112.37% for CBD and THC respectively. The median half-life of CBD and THC was 2.2 (1.6–10.7) and 1.9 (1.6–2.4) h respectively. There was no correlation observed between drug exposure and toxicity. There was no significant change in BPRS score before and after IP. Conclusion- We report the first phase-1 study of cannabis in breast and OC-SCC cancer in pre-operative setting for its anti-cancer potential. Biomarker analysis is awaited. MTD identified will be further explored in phase 2/3 clinical trials in breast, oral cavity, lung and pancreatic cancer with survival endpoints. Citation Format: Rajendra Badwe, Shalaka Joshi, Shiva Thiagarajan, Vikram Gota, Vaibhav Vanmali, Pallavi Daphale, Jayita Deodhar, Rohan Chaubal, Rohini Hawaldar, Jaya Chitra Aadhi, Saurabh Kumar Gupta, Delzaad Deolaliwala, Anil Bhansali, Siddhant Mistry, Satyajeet Singh, Nita Nair, Vani Parmar, Sudeep Gupta. Safety and Feasibility of Administration of an Oral Cannabis Preparation in The Preoperative Period in Breast and Oral Cavity Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-18-05.

Contrasting Effects of Short-Term Mediterranean and Vegan Diets on Microvascular Function and Cholesterol in Younger Adults: A Comparative Pilot Study.

The Mediterranean diet has been shown to improve cardiovascular health. Vegan diets have demonstrated similar benefits, albeit in fewer studies. In a comparative pilot study, we compared the effects of a short-term Mediterranean Diet (MD) and Vegan Diet (VD) on microvascular function and cholesterol levels in a healthy population. Twenty-four young (aged 18 to 35 years) healthy volunteers followed a four-week intervention (MD = 12; VD = 12) ad libitum. Pre and post-intervention anthropometrics, microvascular function (assessed via LDF and expressed as raw CVC and %CVC MAX), dietary-analysis data (Calories, Protein, Carbohydrates, Total Fat, Saturated Fat, Fibre), Mean Arterial Pressure (MAP), Blood Pressure, Total Cholesterol (TC), High Density Lipoprotein (HDL-C) and TC:HDL-C were compared. MD participants reduced Total Fat intake (p = 0.05). Saturated Fat decreased (MD: p = < 0.001; VD: p = 0.004) and Fibre increased (MD: p = 0.02; VD: p = < 0.001) in both groups. Dietary changes reflected improvements in plateau raw CVC in the MD group (p = 0.005), and a reduction in TC (p = 0.045) and weight loss (p = 0.047) in the VD group. The MD led to improvements in microvascular function; the VD led to reduced TC and weight loss. Although both diets might offer CVD risk-reduction benefits, evidence for the MD appeared to be stronger due to changes in vasodilatory ability and NO bioavailability.

RESVERATROL IMPROVES MICROVASCULAR FUNCTION IN ADULTS WHO REPORTED ADVERSE CHILDHOOD EVENTS

INTRODUCTIONAdversity early in life, referred to as adverse childhood events (ACEs), has been associated with the development of cardiovascular disease (CVDs) during adulthood. Microvascular dysfunction plays a pivotal role in the etiology of CVDs through a reduction in nitric oxide (NO)‐dependent vasodilation. Lower concentrations of sirtuin 1 (Sirt1), an NAD‐dependent protein that increases NO metabolism, have been described in multiple CVDs.PURPOSEThis study sought to test the hypothesis that an acute dose of resveratrol (RES), a natural activator of Sirt1, will improve MVF in adults who reported ACEs.METHODSTen adults (34 ± 3 yrs), with no evidence of overt CVD, participated in the study. Based on the ACE questionnaire, all participants had self‐reported an ACE score of 4 or greater. Two protocols were used to evaluate MVF using Laser Doppler flowmetry: 1) local thermal hyperemia (LTH), with a maximal plateau phase primarily mediated by NO, and 2) post‐occlusive reactive hyperemia (PORH), partly dependent on NO metabolism. MVF assessments were determined before and 90 min after an acute dose of either RES (500 mg) or Placebo (P), separated by at least 7 days and are expressed as cutaneous vascular conductance (CVC; cutaneous flux/mean arterial blood pressure). Maximal dilation capacity was evaluated through LTH. Skin resistance was also calculated for every individual and every treatment using Ohm's law and considered in all the statistical analysis.RESULTSNo differences in resting CVC were observed between days (0.11 ± 0.08 vs. 0.11 ± 0.03 PU/mm Hg; p=0.297) or with the change from either treatment (ΔRES: −0.03 ± 0.03 vs. ΔP: −0.01 ± 0.01 PU/mm Hg; p=0.653). In addition, resveratrol significantly (p=0.005) increased max LTH when compared with P (ΔRES: 0.12 ± 0.24 vs. ΔP: −0.06 ± 0.26, PU/mm Hg). Moreover, RES significantly (p≤0.001) prevented the decrease in PORH relative to the maximal dilation capacity when compared with placebo (ΔRES: −6.4 ± 1.4 vs. ΔP: −18.1 ± 17.8 %CVC max). In addition, the acute dose of RES increased concentrations of Sirt1 (RES: 1.3 ± 0.1 vs. ΔP: −0.4 ± 0.3 ng/ml; p=0.075) which was significantly associated with the max LTH response (r=0.760; p=0.011).CONCLUSIONThese findings document an improvement in MVF after an acute oral dose of resveratrol in adults who have reported ACEs. Future studies are warranted to investigate the long term effects of resveratrol on MVF in adults who have reported ACEs.Support or Funding InformationSupported in part by NIH/NHLBI P01HL069999 (JSP, RAH) and 16POST31080031 (PRM).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Five Nights of Sleep Restriction Attenuates Microvascular Endothelial Function

Adequate sleep is requisite for optimal physiological function, including microvascular endothelial function. Short‐term sleep restriction (5 hours/night) negatively alters glucose metabolism and may also impair microvascular endothelial function via increased sympathetic nervous system activity and inflammatory pathways. The cutaneous microvasculature represents an accessible, well‐described vascular bed to non‐invasively assess the effects of sleep restriction on microvascular function. Our objective was to evaluate cutaneous microvascular endothelial function during baseline sleep replete conditions (10 hours/night time in bed), after 5 nights of sleep restriction (5 hours/night), and again after 2 nights of recovery sleep repletion. This was part of the Sleep Restriction Study (PI: Chang), an 11‐day inpatient study that took place in the Penn State University Clinical Research Center, during which diet and physical activity were controlled. Eight young, healthy men (23.3 ± 3.4 years) participated in the study. Cutaneous microvascular function was measured utilizing a standardized local skin heating protocol to induce endothelial nitric oxide‐synthase‐dependent vasodilation during all three study phases (baseline, sleep restricted, recovery). Red cell flux (laser Doppler flowmetry) was continuously measured on the ventral forearm at thermoneutral temperature (33 °C) and throughout local heating 0.5°C·5 s−1 to 42 °C until a stable (20 min) plateau had been reached. Red cell flux was normalized to cutaneous vascular conductance (CVC: flux·MAP−1) and expressed as a percentage of maximum CVC (43°C: %CVCmax). Compared to the baseline sleep replete state, the response to local heating was attenuated by 10% after 5 nights of sleep restriction (baseline: 89.2 ± 2.0, restricted: 80.4 ± 3.0 %CVCmax; p=0.045) and fully recovered after 2 nights of recovery sleep (88.7 ± 1.8 %CVCmax; p=0.99 compared to baseline). Maximum CVC was not affected by sleep restriction (all p&gt;0.05). These results suggest that 5 nights of sleep restriction impairs microvascular endothelial function, likely through attenuated nitric oxide‐dependent vasodilation, but that 2 nights of recovery sleep restores microvascular endothelial function in young, healthy men.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Acute black tea consumption improves cutaneous vascular function in healthy middle-aged humans

Dietary flavonoids, such as those present in black tea, are associated with reduced risk of cardiovascular disease (CVD), possibly through improving nitric oxide (NO) mediated vascular function. The aim of this study was to examine the effect of acute black tea ingestion on cutaneous microvascular function. Twenty healthy participants (58±5y, 9 men) attended two experimental trials (tea, placebo), 7-days apart in a randomised, controlled, double-blind, cross-over design. Participants ingested a single dose of 200ml black tea or placebo, followed by assessment of forearm cutaneous perfusion using laser-Doppler flowmetry (LDF) using three distinct heating protocols, enabling us to distinguish between axon- and endothelium-dependent vasodilation: 1. rapid 42°C, 2. rapid 39°C and 3. gradual 42°C. On the contralateral arm, full-field laser perfusion imaging (FLPI) was used to assess forearm perfusion during gradual 42°C. Data were presented as cutaneous vascular conductance (CVC; flux/mean arterial pressure, MAP) and CVC expressed as a percentage of maximal CVC (%CVCmax). Rapid local heating to 39°C or 42°C demonstrated no effect of tea for flux, CVC or %CVCmax (all P>0.05). Gradual local heating to 42°C, however, produced a higher skin blood flow following black tea ingestion for absolute CVC (P=0.04) when measured by LDF, and higher absolute flux (P<0.001) and CVC (P<0.001) measured with FLPI. No effect of tea was found for %CVCmax when assessed by either LDF or FLPI. Acute tea ingestion enhanced cutaneous vascular responses to gradual local heating to 42°C in healthy, middle-aged participants, possibly through a mechanism related to activation of endothelium-derived chemical mediators, such as NO. These improvements may contribute to the cardiovascular health benefits of regular tea ingestion.

Passive heat therapy improves cutaneous microvascular function in sedentary humans via improved nitric oxide-dependent dilation.

Passive heat therapy (repeated hot tub or sauna use) reduces cardiovascular risk, but its effects on the mechanisms underlying improvements in microvascular function have yet to be studied. We investigated the effects of heat therapy on microvascular function and whether improvements were related to changes in nitric oxide (NO) bioavailability using cutaneous microdialysis. Eighteen young, sedentary, otherwise healthy subjects participated in 8 wk of heat therapy (hot water immersion to maintain rectal temperature ≥38.5°C for 60 min/session; n = 9) or thermoneutral water immersion (sham, n = 9), and participated in experiments before and after the 8-wk intervention in which forearm cutaneous hyperemia to 39°C local heating was assessed at three microdialysis sites receiving 1) Lactated Ringer's (Control), 2) N(ω)-nitro-l-arginine (l-NNA; nonspecific NO synthase inhibitor), and 3) 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol), a superoxide dismutase mimetic. The arm used for microdialysis experiments remained out of the water at all times. Data are means ± SE cutaneous vascular conductance (CVC = laser Doppler flux/mean arterial pressure), presented as percent maximal CVC (% CVCmax). Heat therapy increased local heating plateau from 42 ± 6 to 53 ± 6% CVCmax (P < 0.001) and increased NO-dependent dilation (difference in plateau between Control and l-NNA sites) from 26 ± 6 to 38 ± 4% CVCmax (P < 0.01), while no changes were observed in the sham group. When data were pooled across all subjects at 0 wk, Tempol had no effect on the local heating response (P = 0.53 vs. Control). There were no changes at the Tempol site across interventions (P = 0.58). Passive heat therapy improves cutaneous microvascular function by improving NO-dependent dilation, which may have clinical implications.

Thermoregulatory responses to heat stress and hypoxia (1104.19)

The aim of this study was to examine the thermoregulatory responses to combined heat stress and hypoxia. Seven healthy male subjects (22±3 yr, 80±11 kg, 180±7 cm), dressed in a water‐perfused suit, underwent moderate passive heating (Δ core temperature ~0.8 °C) on 2 separate occasions. In 1 trial subjects breathed normoxic air (NORMOXIA) and in the other subjects breathed balanced 13% O2 air (HYPOXIA). Skin blood flow (SkBF; laser Doppler flowmetry), expressed as cutaneous vascular conductance (CVC; flux/blood pressure), and local sweat rate (SR; capacitance hygrometry) were recorded on the forearm. Core (Tcore; intestinal pill) and local skin temperatures (Tsk), as well as blood pressure (BP; automated sphygmomanometry and digital photoplethysmography), heart rate (HR; ECG) oxygen saturation (SpO2; pulse oximetry) were also monitored. Tcore and mean body temperature (Tbody) thresholds for heat stress‐induced elevations in SkBF and SR, as well as the SkBF/SR: Tcore/Tbody slopes were calculated. At normothermic baseline HYPOXIA reduced SpO2 (98±1 vs 90±6 %, P&lt;0.01) and slightly elevated forearm SkBF (9±6 vs 13±12 % CVC max, P=0.10) and HR (67±10 vs 74±7 beats.min‐1, P&lt;0.01). Tcore (37.0±0.3 vs 37.0±0.3 °C, P=0.30) was unchanged. During heating the forearm SkBF Tcore threshold (36.9±0.3 vs 37.0±0.2 °C, P=0.30) and the forearm SR Tbody threshold (36.7±0.3 vs 36.7±0.2 °C, P=0.90) were not different between trials. The forearm SkBF:Tcore slope was slightly reduced during HYPOXIA (1.04±1.17 vs 0.59±1.19 CVC units·°C, P=0.07) whereas the forearm SR:Tbody slope (0.17±0.09 vs 0.22±0.11 ml.cm2.min‐1·°C, P=0.04) was increased by HYPOXIA. These results indicate that moderate hypoxia does not affect central thermoregulatory function but alters peripheral thermoregulatory effector function via blunted skin blood flow and accentuated sweating slopes possibly via baseline hypoxia‐induced cutaneous vasodilation.Grant Funding Source: European Commission FP7

Aging and aerobic fitness affect the contribution of noradrenergic sympathetic nerves to the rapid cutaneous vasodilator response to local heating

Sedentary aging results in a diminished rapid cutaneous vasodilator response to local heating. We investigated whether this diminished response was due to altered contributions of noradrenergic sympathetic nerves by assessing 1) the age-related decline and 2) the effect of aerobic fitness. Using laser-Doppler flowmetry, we measured skin blood flow (SkBF) in young (24 ± 1 yr) and older (64 ± 1 yr) endurance-trained and sedentary men (n = 7 per group) at baseline and during 35 min of local skin heating to 42°C at 1) untreated forearm sites, 2) forearm sites treated with bretylium tosylate (BT), which prevents neurotransmitter release from noradrenergic sympathetic nerves, and 3) forearm sites treated with yohimbine + propranolol (YP), which antagonizes α- and β-adrenergic receptors. SkBF was converted to cutaneous vascular conductance (CVC = SkBF/mean arterial pressure) and normalized to maximal CVC (%CVC(max)) achieved by skin heating to 44°C. Pharmacological agents were administered using microdialysis. In the young trained group, the rapid vasodilator response was reduced at BT and YP sites (P < 0.05); by contrast, in the young sedentary and older trained groups, YP had no effect (P > 0.05), but BT did (P > 0.05). Neither BT nor YP affected the rapid vasodilator response in the older sedentary group (P > 0.05). These data suggest that the age-related reduction in the rapid vasodilator response is due to an impairment of sympathetic-dependent mechanisms, which can be partly attenuated with habitual aerobic exercise. Rapid vasodilation involves noradrenergic neurotransmitters in young trained men and nonadrenergic sympathetic cotransmitters (e.g., neuropeptide Y) in young sedentary and older trained men, possibly as a compensatory mechanism. Finally, in older sedentary men, the rapid vasodilation appears not to involve the sympathetic system.

Human cutaneous reactive hyperaemia: role of BKCa channels and sensory nerves

Reactive hyperaemia is the increase in blood flow following arterial occlusion. The exact mechanisms mediating this response in skin are not fully understood. The purpose of this study was to investigate the individual and combined contributions of (1) sensory nerves and large-conductance calcium activated potassium (BKCa) channels, and (2) nitric oxide (NO) and prostanoids to cutaneous reactive hyperaemia. Laser-Doppler flowmetry was used to measure skin blood flow in a total of 18 subjects. Peak blood flow (BF) was defined as the highest blood flow value after release of the pressure cuff. Total hyperaemic response was calculated by taking the area under the curve (AUC) of the hyperaemic response minus baseline. Infusates were perfused through forearm skin using microdialysis in four sites. In the sensory nerve/BKCa protocol: (1) EMLA cream (EMLA, applied topically to skin surface), (2) tetraethylammonium (TEA), (3) EMLA + TEA (Combo), and (4) Ringer solution (Control). In the prostanoid/NO protocol: (1) ketorolac (Keto), (2) NG-nitro-l-arginine methyl ester (L-NAME), (3) Keto + l-NAME (Combo), and (4) Ringer solution (Control). CVC was calculated as flux/mean arterial pressure and normalized to maximal flow. Hyperaemic responses in Control (1389 +/- 794%CVC max s) were significantly greater compared to TEA, EMLA and Combo sites (TEA, 630 +/- 512, P = 0.003; EMLA, 421 +/- 216, P < 0.001; Combo, 201 +/- 200, P < 0.001%CVC max s). Furthermore, AUC in Combo (Keto + l-NAME) site was significantly greater than Control (4109 +/- 2777 versus 1295 +/- 368%CVC max s). These data suggest (1) sensory nerves and BKCa channels play major roles in the EDHF component of reactive hyperaemia and appear to work partly independent of each other, and (2) the COX pathway does not appear to have a vasodilatory role in cutaneous reactive hyperaemia.

Cyclooxygenase and nitric oxide synthase dependence of cutaneous reactive hyperemia in humans

We tested the hypothesis that cyclooxygenases (COXs) or COX products inhibit nitric oxide (NO) synthesis and thereby mask potential effects of NO on reactive hyperemia in the cutaneous circulation. We performed laser-Doppler flowmetry (LDF) with intradermal microdialysis in 12 healthy volunteers aged 19-25 yr. LDF was expressed as the percent cutaneous vascular conduction (%CVC) or as the maximum %CVC (%CVC(max)) where CVC is LDF/mean arterial pressure. We tested the effects of the nonisoform-specific NO synthase inhibitor nitro-L-arginine (NLA, 10 mM), the nonspecific COX inhibitor ketorolac (Keto, 10 mM), combined NLA + Keto, and NLA + sodium nitroprusside (SNP, 28 mM) on baseline and reactive hyperemia flow parameters. We also examined the effects of isoproterenol, a beta-adrenergic agonist that causes prostaglandin-independent vasodilation to correct for the increase in baseline flow caused by Keto. When delivered directly into the intradermal space, Keto greatly augments all aspects of the laser-Doppler flow response to reactive hyperemia: peak reactive hyperemic flow increased from 41 +/- 5 to 77 +/- 7%CVC(max), time to peak flow increased from 17 +/- 3 to 56 +/- 24 s, the area under the reactive hyperemic curve increased from 1,417 +/- 326 to 3,376 +/- 876%CVC(max).s, and the time constant for the decay of peak flow increased from 100 +/- 23 to 821 +/- 311 s. NLA greatly attenuates the Keto response despite exerting no effects on baseline LDF or on reactive hyperemia when given alone. Low-dose NLA + SNP duplicates the Keto response. Isoproterenol increased baseline and peak reactive flow. These results suggest that COX inhibition unmasks NO dependence of reactive hyperemia in human cutaneous circulation.