Joachim Osinski

The safety and efficacy of oral methylnaltrexone in preventing morphine‐induced delay in oral‐cecal transit time

Methylnaltrexone is a quaternary opioid antagonist with limited ability to cross the blood‐brain barrier that has the potential to antagonize the peripherally mediated gastrointestinal effects of opioids. In recent trials in human volunteers, we demonstrated that intravenous methylnaltrexone prevented morphine‐induced changes in gastroin‐testinal motility and transit, without affecting analgesia. In this study, 14 healthy volunteers were first given three ascending oral doses of methylnaltrexone to obtain safety and tolerance data (phase A study). In phase B, these subjects were then given single‐blind oral placebo and intravenous placebo, followed by randomized, double‐blind oral placebo and intravenous morphine (0.05 mg/kg) or oral methylnaltrexone (19.2 mg/kg, an established highest and safe dose based on previous administrations of two smaller doses of 0.64 mg/kg and 6.4 mg/kg in phase A) and intravenous morphine (0.05 mg/kg). Oral‐cecal transit time was assessed by the pulmonary hydrogen measurement technique after lactulose ingestion. Morphine significantly increased oral‐cecal transit time from 114.6 ± 37.0 minutes (mean ± SD) to 158.6 ± 50.2 minutes (p < 0.001). Oral methylnaltrexone (19.2 mg/kg) completely prevented morphine‐induced increase in oral‐cecal transit time (110.4 ± 45.0 minutes; not significant compared with baseline; p < 0.005 compared with morphine alone). These sessions were then followed by single‐blind evaluations of descending doses of methylnaltrexone. We observed that 6.4 mg/kg oral methylnaltrexone significantly attenuated the morphine‐induced delay in oral‐cecal transit time (p < 0.005 compared with morphine alone), and a dose‐dependent response was obtained. There was no correlation between oral methylnaltrexone effects on the transit time and the drug plasma concentration, suggesting direct preferential luminal effects of oral methylnaltrexone. Oral methylnaltrexone may have a clinical value in the prevention and treatment of constipation induced by long‐term opioid use.

Premedication with oral and transdermal clonidine provides safe and efficacious postoperative sympatholysis.

We studied 61 patients undergoing elective major non-cardiac surgery in a randomized, double-blind, placebo-control clinical trial to test the hypothesis that the addition of clonidine to a standardized general anesthetic could safely provide postoperative sympatholysis for patients with known or suspected coronary artery disease. Patients were allocated randomly to receive either placebo (n = 31) or clonidine (n = 30). The treatment group received premedication with a trans-dermal clonidine system (0.2 mg/d) the night prior to surgery, which was left in place for 72 h, and 0.3 mg oral clonidine 60–90 min before surgery. Clonidine reduced enflurane requirements, intraoperative tachycardia, and myocardial ischemia (1/28 clonidine patients vs 5/24 placebo, P = 0.05). However, clonidine decreased heart rates only during the first five postoperative hours; the incidence of postoperative myocardial ischemia (6/28 clonidine vs 5/26 placebo) did not differ between the two groups. Patients who experienced postoperative myocardial ischemia tended to have higher heart rates after surgery. Clonidine significantly reduced the plasma levels of epinephrine (P = 0.009) and norepinephrine (P = 0.026) measured on the first postoperative morning. There were no differences in the need for intravenous fluid therapy or antihypertensive therapy after surgery. The number of hours spent in an intensive care setting and the number of days spent in hospital were not different between the two groups. These results suggest that larger doses of clonidine should be investigated for their ability to decrease postoperative tachycardia and myocardial ischemia. (Anesth Analg 1994;79:1133–40)

Effects of intravenous methylnaltrexone on opioid-induced gut motility and transit time changes in subjects receiving chronic methadone therapy: a pilot study.

In this preliminary study, we evaluated the effects of methylnaltrexone, a peripheral opioid-receptor antagonist, on chronic opioid-induced gut motility and transit changes in four subjects with chronic methadone-induced constipation. Subjects participated in this single blind, placebo controlled study for up to 8 days. We gave placebo the first day; for the remainder of the study, we gave intravenous methylnaltrexone (0.05-0.45 mg/kg) twice daily. During the study period, we recorded oral-cecal transit time and opioid withdrawal symptoms, as well as laxation response based on the frequency and consistency of the stools. Subjects 1 and 2 who were administered methylnaltrexone 0.45 mg/kg, a dose previously administered in normal volunteers, showed immediate positive laxation. Subject 2, after positive laxation response, had severe abdominal cramping, but showed no opioid systemic signs of withdrawal. The subject was discontinued due to the cramping. In Subjects 3 and 4, we reduced the methylnaltrexone dose to 0.05-0.15 mg/kg. The latter two subjects also had an immediate laxation response during and after intravenous medication without significant side effects. The stool frequency of these four subjects increased from 1-2 times per week before the study to approximately 1.5 stool per day during the treatment period. Oral-cecal transit times of Subjects 1, 3, and 4 were reduced from 150, 150 and 150 min (after placebo) to 90, 60 and 60 min (with methylnaltrexone), respectively. Our preliminary results demonstrate that low dose intravenous methylnaltrexone effectively reversed chronic methadone-induced constipation and delay in gut transit time. Thus, we anticipate that cancer patients receiving chronic opioids may also have increased sensitivity to methylnaltrexone, and that low dose methylnaltrexone may have clinical utility in managing opioid-induced constipation in chronic-pain patients.

Effects of enteric‐coated methylnaltrexone in preventing opioid‐induced delay in oral‐cecal transit time

Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated methylnaltrexone prevented morphine‐induced delay in gastrointestinal transit time.

Measurement of purine nucleoside concentration in the intact rat retina

Adenosine, produced from the decomposition of adenosine triphosphate, is believed to provide protective effects during ischemia. On the other hand, adenosine metabolites may serve as precursors for oxygen free radical formation. These substances have not been previously measured in intact vertebrate retina, where adenosine and its metabolites may play a role in the pathogenesis of ischemic injury. The small tissue mass of the retina, particularly in rats, renders these measurements challenging. Furthermore, accurate measurement of purine nucleosides requires immediate cessation of ongoing adenosine metabolism. Concentrations of adenosine and its purine nucleoside metabolites inosine, hypoxanthine, and xanthine in the retina of ketamine/xylazine-anesthetized rats were measured after in situ freezing using high-performance liquid chromatography. The retina was removed from the frozen eyes and analyzed. Quantitative measurements were made possible through the use of an internal standard. Ischemia was induced by ligation of the central retinal artery. Retinal purine nucleoside concentrations did not differ between the two eyes of the rat under control conditions, and there was no effect of placement of the ligating suture itself compared to completely unmanipulated eyes. Use of two different in situ freezing methods yielded comparable results. To evaluate the impact of a period of ischemia, one retina of each rat was ischemic for 30 min, and the other, non-ischemic. Our measurements were associated with a high degree of reproducibility and minimal variability, and significant changes in purine nucleoside concentrations were detectable in the retina after 30 min of ischemia. Our method may be used to assess the role of adenosine and its metabolites in the pathogenesis of ischemic neuronal injury, including in the retina.

Determination of polyphenolic compounds in grape seed extracts using reverse-phase high performance liquid chromatography

Oxidative stress is associated with many kinds of chronic diseases. Antioxidants such as polyphenols are compounds that protect cells against the damaging effects of reactive oxygen species. Grape seeds are considered good resources of polyphenols, and grape seed extracts have a very strong antioxidant effect. In the present study, we established a simple gradient reverse-phase high performance liquid chromatography method to determine polyphenol content from three different grape seed resources. An ODS (2), column has been employed, and six polyphenols have been determined: gallic acid, protochatechuic acid, (+)-catechin, (-)-epicatechin, procyanidin B2, and epicatechin gallate. Catechin and epicatechin were the main polyphenol compounds in all three extracts. The amount of procyanidin B2 was higher in Extract 1 (from a company of China), while Extract 2 (extracted in our lab) and Extract 3 (from a company of USA) contained higher proportions of epicatechin gallate. For the total polyphenol content, Extract 1 was much higher than that of Extract 2 and 3. The results suggest that the dietary dose of grape seed extracts from different resources should be adjusted according to polyphenol content.