S. Fred Brunk

The analgesic properties of delta-9-tetrahydrocannabinol and codeine

The administration of single oral doses of delta‐9‐tetrahydrocannabinol (THC) to patients with cancer pain demonstrated a mild analgesic effect. At a dose of 20 mg, however, THC induced side effects that would prohibit its therapeutic use including somnolence, dizziness, ataxia, and blurred vision. Alarming adverse reactions were also observed at this dose. THC, 10 mg, was well tolerated and, despite its sedative effect, may have analgesic potential.

Morphine metabolism in man

Morphine metabolism was studied in 6 normal men at weekly intervals after intravenous, intramuscular, subcutaneous, and oral administration. Morphine was rapidly absorbed after intramuscular and subcutaneous iniection, producing plasma levels of free morphine, from 15 minutes to 3 hours, which are significantly higher than levels after intravenous administration. Intravenous morphine, while initially higher, undergoes more rapid distribution, metabolism, and excretion. Morphine is well absorbed from the gastrointestinal tract, but is so rapidly coniugated with glucuronide in the cells of the intestinal mucosa and liver that significant levels of free morphine are not found in either the plasma or urine, whereas the levels of coniugated morphine are high. N‐demethylation of morphine is greater after oral than after parenteral administration. While route of administration alters plasma levels of free morphine, it does not alter plasma half‐life.

Analgesic Effect of Delta‐9‐Tetrahydrocannabinol

A preliminary trial of oral delta-9-tetrahydrocannabinol (THC) demonstrated an analgesic effect of the drug in patients experiencing cancer pain. Placebo and 5, 10, 15, and 20 mg THC were administered double blind to ten patients. Pain relief significantly superior to placebo was demonstrated at high dose levels (15 and 20 mg). At these levels, substantial sedation and mental clouding were reported.

Comparison of intensive versus moderate chemotherapy of lymphocytic lymphomas. A progress report

In an Eastern Cooperative Oncology Group trial, Cytoxan‐prednisone (CP) Induction was compared to BCNU‐prednisone (BP) in 273 patients with lymphocytic lymphoma. Response rates were comparable, with 21% achieving complete response and 40%, partial response. Patients with a nodular pattern responded better. Maintenance phase comparing cyclic intensive therapy (BCVP) with intermittent chlorambucil revealed the superiority of BCVP as demonstrated by improvement of the quality of response and somewhat longer remissions. The value of the Rappaport classification in the evaluation of lymphoma chemotherapy results is discussed. It is suggested that NHL be separated into “favorable” and “unfavorable” groups, based on the presence or absence of nodularity and treatment schedules devised accordingly.

Effect of propranolol on morphine metabolism

Morphine metabolism was studied in 12 normal subjects. Six were studied before and while receiving propranolol, 20 mg every 6 hr, and 6 were studied before and while receiving propranolol, 40 mg every 6 hr. The study was performed to determine whether propranolol affects morphine metabolism or morphine‐induced respiratory depression. Plasma and urinary levels of free morphine and conjugated morphine when propranolol and morphine were given together were similar to the levels after morphine alone. Respiratory minute volumes, while breathing a 4% CO2 in air mixture, were also unchanged from control. The findings indicate that propranolol does not affect morphine metabolism or morphine‐induced respiratory depression in man.

Effects of Hypothyroidism and Hyperthyroidism on Dipyrone Metabolism in Man

A LTERATIONS in thyroid function may affect drug metabolism. A number of different drug metabolizing enzyme systems have been studied in animals and varying effects of thyroid hormone have been found.17 The purpose of the study was to investigate the effects of hypothyroidism and hyperthyroidism on dipyrone metabolism in man. Dipyrone is an aminopyrine derivative which undergoes oxidative N-demethylation to 4-aminoantipyrine in the liver. In studying dipyrone metabolism, both the disappearance of dipyrone from the plasma and the urinary excretion of 4-aminoantipyrine may be determined. This provides an indirect assessment of the effects of altered thyroid function on the hepatic microsomal enzyme, aminopyrine N-demethylase.

Morphine metabolism in man: Effect of aspirin

Morphine metabolism was studied in 12 normal subjects. Six were studied before and while receiving aspirin, 0.6 gm every 6 hours, and 6 were studied before and while receiving aspirin, 1.2 gm every 6 hours. The study was performed to determine whether aspirin decreases the conjugation of morphine with glucuronide. When aspirin and morphine were given together, plasma levels of free morphine were lowered slightly; after the high dosage of aspirin, the plasma levels of conjugated morphine were slightly higher than control. The urinary excretion of conjugated morphine was decreased by aspirin. Total radioactivity excreted in the urine was similar in all studies. These findings can best be explained by changes in renal clearance of free and conjugated morphine. The clearance of free morphine (organic calion system) tends to be either unchanged or increased by aspirin while the clearance of conjugated morphine (organic anion system) is decreased. These changes appear to be sufficient to explain the changes in plasma and urinary ffee and conjugated morphine levels. Aspirin, at these dosage levels, therefore, does not decrease the conjugation of morphine with glucuronide and does not affect N‐demethylation.

Morphine Metabolism in Man: Effect of Guanethidine

November-December, 1974 581 SOME of the pharmacological effects of morphine may be mediated in part by catecholamine-containing neurons. Reduction of whole-brain eatecholamincs in mice and rats has been shown to enhance morphine-induced analgesia in some studics3 but not in others.4-5 Cicero, Meyer, and Smithloff,2 using Holtzman strain rats, found that the aipha-adrenergic blocking agents phenoxybenzamine and phentolamine enhanced morphineinduced analgesia as measured by the hotplate reaction time. Contreras and Tamayo,4 using electrical stimulation of the genital papilla in albino rats, found that morphine-induced analgesia was unaffected by phenoxybenzamine but was enhanced by methyldopa if this agent was given 4.5 hours or 24 hours before morphine. If methyldopa was given 48 hours prior to the morphine there was antagonism of morphine analgesia. Contreras and Tamayo,4 in the same study, found that guanethidine eliminated the analgesia effect of morphine and would also block the effect of methyldopa. Since methyldopa acts centrally as well as peripherally and may have several mechanisms and sites of action, we elected in this investigation to study guanethidine, an adrenergic neuron blocking agent which does not cross the bloodbrain barrier and acts only peripherally. The purpose of the study was to determine whether guanethidine affects morphine metabolism and whether it produces any change in niorphinc-induced respiratory depression.

The distribution of radioactivity from uracil mustard-2-14C in the hepatic subcellular particulates and nucleic acids of the rat.

Abstract The concentration of radioactivity in the liver particulates and in the nucleic acids of the liver, kidney, spleen, and small intestine of rats was measured after intravenous uracil mustard-2- 14 C. Of the injected radioactivity 2.6% was localized in the liver at 30 minutes; the level gradually declined to 0.26% at 96 hours. The cell sap: particulate ratio was 1.5 at 30 minutes and 0.4 at 96 hours. At most time periods the concentration of radioactivity in the renal nucleic acids was significantly higher than that in the nucleic acids of the liver, spleen, and small intestine. At 1 and 3 hours the concentration of radioactivity in duodenal and jejunal RNA was not significantly different from that in renal RNA and was also higher than the concentration in the liver and spleen. Based upon the concentration of radioactivity, uracil mustard appeared to have reacted with the various nucleic acids in the range of 16,400 to 65,000 nucleotide units per molecule of uracil mustard at 1 2 hour. Only 2–3% of the radioactivity present in the liver cell was localized in nucleic acids. There was, therefore, widespread association of the radioactivity with other cellular constituents.