Can an amino acid-based oral rehydration solution be effective in managing immune therapy-induced diarrhea?

Immune checkpoint inhibitor (ICPi) therapy has transformed the way we treat cancer. However, its immune related adverse events (irAEs) can be debilitating and life threatening. Immune therapy-induced diarrhea (ITID) is one of the most commonly encountered irAEs and can lead to expensive and prolonged hospitalizations. The current standard of care for grade 3 or 4 ITID involves ICPi discontinuation, the initiation of steroids, and infliximab for refractory disease. This treatment regimen reverses the desired anti-tumor effect of ICPis, can lead to side effects, and is cost-ineffective. We report the first case of the successful treatment of grade 3 ITID with steroids and an amino acid-based oral rehydration solution (AA-ORS), enterade. Research suggests that AA-ORS may be used to reduce diarrhea and adequately hydrate patients, in contrast to glucose-based oral rehydration solutions, which have been implicated as a contributing factor to diarrhea in cancer patients. We hypothesize that an AA-ORS may mitigate ITID via safer and more economically viable means than the current standard of care, but more controlled trials are needed to test this hypothesis.

Testosterone restores respiratory long term facilitation in old male rats by an aromatase-dependent mechanism.

Steroidal sex hormones play an important role in the neural control of breathing. Previous studies in our laboratory have shown that gonadectomy in young male rats (3 months) eliminates a form of respiratory plasticity induced by intermittent hypoxia, known as long term facilitation (LTF). Testosterone replenishment restores LTF in gonadectomized male rats, and this is dependent on the conversion of testosterone to oestradiol by aromatase. By middle age (12 months), male rats no longer exhibit LTF of hypoglossal motor output; phrenic LTF is significantly reduced, and this persists into old age. We tested the hypothesis that LTF can be restored in old male rats by administration of testosterone. Intact Fischer 344 rats (>20 months) were implanted with Silastic tubing containing testosterone (T), T plus an aromatase inhibitor (T+ADT), or 5α-dihydrotestosterone (DHT), a form of testosterone not converted to oestradiol. One week post-surgery, LTF of hypoglossal and phrenic motor output was measured. By comparison with control rats, hypoglossal LTF was increased in testosterone-treated rats, with levels approaching that of normal young rats. LTF was not restored in T+ADT or DHT-treated rats. Aromatase levels in hypoglossal and phrenic nuclei did not change with age. As serum testosterone levels did not decline with age, local bioavailability of testosterone in old rats may be a limiting factor in the expression of this form of respiratory plasticity. Our findings suggest that testosterone supplementation could potentially be used to enhance upper airway control in the elderly.

Serum and tissue zinc concentrations in patients with endoscopic esophagitis.

Because zinc is an important metabolic requirement for growth and repair of squamous tissue, we questioned whether changes in serum and esophageal tissue zinc were present in patients with reflux esophagitis. To investigate this question, we prospectively studied 49 patients undergoing upper gastrointestinal endoscopy for symptoms of abdominal pain and discomfort; 19 patients were taking H2 antagonists at the time of the study. Blood was obtained to measure serum zinc concentrations prior to endoscopy and tissue zinc levels were obtained from esophageal biopsies from the distal, middle, and proximal esophagus in patients who were either endoscopically normal or who exhibited endoscopic esophagitis. Serum zinc concentrations were significantly lower in patients with endoscopic esophagitis compared to the endoscopically normal group (77 +/- 3.8 micrograms/dl vs 88 +/- 2.4 micrograms/dl, P less than 0.02). Distal esophageal tissue concentrations were significantly higher in patients with endoscopic esophagitis compared to the endoscopically normal group (200 +/- 30 micrograms/liter vs 135 +/- 15 micrograms/liter, P less than 0.05); whereas there were no differences between values obtained in the proximal or middle esophagus. Serum and tissue zinc concentrations in patients with esophagitis receiving H2 antagonists were more similar to values obtained in patients who were endoscopically normal than to patients with endoscopic esophagitis without treatment. This study suggests that in endoscopic esophagitis: (1) greater amounts of zinc are concentrated in the rapidly proliferating distal esophageal epithelium, (2) the serum zinc pool may serve as a major zinc source, and (3) decreasing esophageal mucosal inflammation with H2 antagonists may decrease zinc loss via the esophageal epithelium.

Zinc deficiency decreases the activity of calmodulin regulated cyclic nucleotide phosphodiesterases in vivo in selected rat tissues.

The effect of zinc deficiency on calmodulin function was investigated by assessing the in vivo activity of two calmodulin regulated enzymes, adenosine 3',5'-monophosphate (c-AMP) and guanosine 3',5'-monophosphate (c-GMP) phosphodiesterase (PDE) in several rat tissues. Enzymatic activities in brain, heart, and testis of rats fed a zinc deficient diet were compared with activities in these tissues from pair fed, zinc supplemented rats. In testis, a tissue in which zinc concentration decreased with zinc deficient diet, enzyme activities were significantly decreased over those in rats who were pair fed zinc supplemented diets. In brain and heart, tissues in which zinc concentrations did not change with either diet, enzymatic activities between the groups were not different. These results indicate that zinc deficiency influences the activity of calmodulin-regulated phosphodiesterases in vivo supporting the hypothesis that zinc plays a role in calmodulin function in vivo in zinc sensitive tissues.

In vivo effects of zinc deficiency on calmodulin concentrations in selected rat tissues.

Two groups of male Sprague-Dawley rats, one fed zinc-deficient diet, ad libitum, the other, pair-fed with the same diet, but given supplemental zinc in the drinking water (8 mg Zn++/ml) were studied. After ten weeks of diet, rats were exsanguinated and zinc and calmodulin concentrations in brain and testis were measured. Mean zinc concentration in testis was significantly decreased in rats fed zinc-deficient diet without supplemental Zn++, but mean zinc concentration in brain was not different. Similarly, mean calmodulin concentration in testis was decreased in rats fed zinc-deficient diet without supplemental Zn++ whereas mean calmodulin concentration in brain was not different. Distribution studies of zinc and calmodulin showed that both zinc and calmodulin were released more freely into soluble fractions of testis in rats fed zinc-deficient diet without supplemental Zn++. These results indicate, for the first time in in vivo studies, that zinc influences the calmodulin content of testis.

Hair and serum copper, zinc, calcium, and magnesium concentrations in Alzheimer-type dementia.

Several research groups have reported alterations in mineral concentrations in patients with Alzheimer's disease (AD). A study of serum copper, zinc, magnesium, calcium, and albumin concentrations in outpatients with Alzheimer's disease (in the early-to-middle stages) and in these patients' healthy spouses is reported. Hair concentrations of copper, zinc, magnesium, calcium, and manganese were also measured in these AD patients and controls. No differences in serum of hair concentrations were found, and determinations of these hair and serum mineral concentrations do not appear to be of use in the diagnosis of AD. Significant positive correlations were found between age and hair manganese (Mn) in the control spouses, and a similar (but statistically nonsignificant) trend in the AD patients.