The use of assistants in contact lens practice.
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Contact Lenses↗
Biomedical subjects
L S Harris
Publications and source records attributed to L S Harris.
3H-delta9-tetrahydrocannabinol tissue and subcellular distribution in the central nervous system and tissue distribution in peripheral organs of tolerant and nontolerant dogs.
Tolerant and nontolerant dogs received one i.v. administration of 0.5 mg/kg of 3H-delta9-tetrahydrocannabinol 30 minutes before they were sacrificed. Plasma, peripheral and brain tissues, as well as subcellular fractions of brain tissues from both treatment groups, were analyzed for radioactivity. Throughout the time period before sacrifice, the plasma concentrations of radioactivity in the tolerant and nontolerant dogs were not significantly different. The percentage of radioactivity in brain and plasma that was due to either unchanged delta9-tetrahydrocannabinol or a major metabolite was the same in each group. Of the radioactivity in brain, 46% was identified as delta9-tetrahydrocannabinol. Regardless of treatment, there was a specific accumulation of radioactivity in adrenals, liver, kidney, heart and pancreas. The only significant differences in radioactivity between tolerant and nontolerant peripheral tissues were found in liver, kidney cortex, heart and lymph nodes. Although all brain areas from tolerant dogs contained less radioactivity than the comparable brain areas from nontolerant animals, only pituitary and putamen were significantly less. There was a specific accumulation of radioactivity in some brain areas that could be associated with behavioral effects. The concentration in cerebellar and cerebral gray was significantly greater than that in white, and there was a marked reduction in the concentration in gray after tolerance developed. The mean percentage of radioactivity in each subcellular fraction was as follows: 23% crude nuclei, 44% mitochondria, 8% cholinergic nerve endings, 7% noncholinergic nerve endings, 2% free mitochondria and 6% synaptic vesicles. The quantity of radioactivity in homogenates of brains from tolerant dogs was 17% less than brains of nontolerant animals, which was merely a reflection of the respective plasma concentrations. The distribution of radioactivity was similar in both groups, although most of the subcellular fractions from tolerant dogs contained a lesser amount of radioactivity. The most notable difference was observed in the synaptic vesicle fraction. The synaptic vesicle fraction of tolerant dogs contained 40% less radioactivity than did the same fraction from nontolerant dogs, which implied a possible mechanism of action. A comparison of the remaining subcellular fractions did not appear to explain the development of tolerance.
Animals↗
The inhibition of DNA synthesis by cannabinoids.
Several of the cannabinoids found in marihuana have been shown to inhibit tumor growth and increase the life-span of mice bearing the Lewis lung adenocarcinoma. When trypsin-dispersed isolated Lewis lung cells are incubated in vitro, they maintain their capacity to carry out macromolecular synthesis (RNA, DNA, protein). This process can be inhibited by cytosine arabinoside, actinomycin D, or methyl-1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, whereas cyclophosphamide, an agent that must be bioactivated, was inactive. Inhibition of DNA synthesis as measured by [3H]thymidine uptake into acid-insoluble material was used as an index of cannabinoid activity against isolated Lewis lung cells, L1210 leukemia cells, and bone marrow cells incubated in vitro delta9-, delta8-, 1-hydroxy-3-n pentyl-, and 1-delta8-tetrahydrocannabinol, and cannabinol demonstrated a dose-dependent inhibition of DNA synthesis whereas cannabidiol and 1-hydroxy-3-n-pentylcannabidiol were markedly less inhibitory in our in vitro cell systems. Furthermore, our in vitro observations with these cannabinoids are supported by in vivo tumor inhibition studies. Ring modifications as in cannabichromene or cannabicyclol abolish in vitro activity as does dihydroxylation at the 8beta and 11 positions of 1-delta9-trans-tetrahydrocannabinol. Delta9-trans-tetrahydrocannabinol demonstrated the least toxicity of all inhibitory cannabinoids in vivo; this is supported by its lesser effect on bone marrow DNA synthesis in vitro.
Animals↗
Vasoconstrictor actions of delta8- and delta9-tetrahydrocannabinol in the rat.
Cardiovascular effects of delta8- and delta9-tetrahydrocannabinol (THC) were studied after systemic intravenous administration and intra-arterial administration into a perfused vascular bed in the urethane-anesthetized rat. Intravenous administration of delta8- and delta9-THC produced dose-related transient increases in blood pressure followed by more prolonged hypotensive responses and bradycardia. Intra-arterial administration of delta8- and delta9-THC into the perfused hindquarters of the rat produced an increase in perfusion pressure indicative of vasoconstriction. The vasoconstrictor response to the cannabinoids corresponded temporally to a similar response produced by i.a. norepinephrine and was in contrast to the more prolonged vasoconstrictor responses produced by vasopressin. Phentolamine, in a dose which reduced the vasoconstrictor effect of norepinephrine by 90%, significantly reduced the response to i.a. delta9-THC while having no effect on the actions of i.a. vasopressin. It was demonstrated that reserpine pretreatment significantly reduced vasoconstrictor actions of i.a. tyramine and delta9-THC but did not alter the responses to norepinephrine. These data suggest that delta8- and delta9-THC have peripheral vasoconstrictor activity in the rat which may be mediated, in part, through a tyramine-like action on adrenergic nerve terminals.
Adrenergic alpha-Antagonists↗
The correlation between antinociceptive activity of narcotics and their antagonists as measured in the mouse tail-flick test and increased synthesis of brain catecholamines.
The effects of several narcotics, narcotic antagonists-analgesics and narcotic antagonists on the synthesis of dopamine and norepinephrine in mouse brain were estimated and related to their activity in the tail-flick test. Catecholamine synthesis was estimated by measuring the accumulation of 3H-dopamine and 3H-norepinephrine formed from an injection of 3H-tyrosine. Morphine produced dose-related increases in both tail-flick activity and catecholamine synthesis. Each of the narcotic analgesics produced a significant increase in catecholamine synthesis 30 minutes after the subcutaneous injection of an antinociceptive dose (ED80). Under these same conditions, drugs which are inactive in the tail-flick test, such as pentazocine, produced a decrease in catecholamine synthesis and cyclazocine; naloxone and naltrexone were without significant effect. However, cyclazocine, which was inactive in the tail-flick test and did not alter catecholamine synthesis 30 minutes after administration, demonstrated tail-flick activity and produced increased catecholamine synthesis 2 minutes after its administration. Morphine was devoid of either activity 2 minutes after administration. Similarly, at 2 hours after the administration of a dose of morphine (10 mg/kg) that was active in the tail-flick test and increased catecholamine synthesis at 30 minutes, neither tail-flick activity nor increased catecholamine synthesis was observed. Naloxone blocked both the antinociceptive action and the increased catecholamine synthesis produced by both morphine and methadone. The results of these studies indicate that a correlation exists between tail-flick activity of narcotic-like drugs and their ability to increase catecholamine synthesis. These data support the hypothesis that brain catecholamines may be involved in the central mediation of the tail-flick response and other actions of the narcotic analgesics.
Analgesics, Opioid↗
Some structural requirements for inhibition of high-affinity synaptosomal serotonin uptake by cannabinoids.
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Animals↗
Structure-activity relationships of enkephalins in the stimulated guinea pig ileum.
A number of analogs and homologs of methionine-enkephalin (H.Tyr. Gly.Gly.Phe.Met.OH) have been synthesized by the Merrifield method of solid phase peptide synthesis. Each peptide was assayed by inhibition of electrically evoked contraction of the guinea pig ileum. The minimum sequence required for biological activity in this preparation was found to be the pentapeptide unit. Methionine was readily replaced by norleucine to give an analog with approximately 50% of the potency of the parent compound. Leucineenkephalin has about 15-20% of the potency of the methionine dervative. Modification of the N-terminal tyrosine moiety (i.e. substitution by phenylalanine or removal of the amino group) practically abolished activity. Incorporation of O-methyl tyrosine into the peptide reduced potency to 1% of the parent compound. The significance of these and other findings in terms of the topography of the guinea pig ileum receptor site is discussed.
Animals↗
Stereospecificity of intraventricularly administered acetylmethylcholine antinociception.
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Acetylcholine↗
Ocular anti-inflammatory effect of fenoprofen. Dose-response study.
An experimental rabbit uveitis model was used to establish a dose response range for topical administration of fenoprofen (dl-2(3-phenoxyphenyl) propionic acid. The 0.3% concentrate group was not distinguishable from the untreated group, and 3% concentrate proved highly irritating. Fenoprofen 1%, pH 6.4, proved most efficacious and had an effect comparable to dexamethasone phosphate 0.1%, seen in a previous study.
Administration, Topical↗
Unsuccessful eccentric perilimbal suction after filtering surgery.
Eccentric suction was applied over the surgical site in 47 eyes thought to have unsuccessful external filtering procedures. Referrals for suction were made either because the postoperative intraocular pressure was uncontrolled or because blebs were becoming progressively flatter. Patients had an average of seven such treatment sessions. No discernible benefit from eccentric suction in failing filtering surgery was noted one year postoperatively.
Epinephrine↗
Antineoplastic activity of cannabinoids.
Lewis lung adenocarcinoma growth was retarded by the oral administration of delta9-tetrahydrocannabinol (delta9-THC), delta8-tetrahydrocannabinol (delta8-THC), and cannabinol (CBN), but not cannabidiol (CBD). Animals treated for 10 consecutive days with delta9-THC, beginning the day after tumor implantation, demonstrated a dose-dependent action of retarded tumor growth. Mice treated for 20 consecutive days with delta8-THC and CBN had reduced primary tumor size. CBD showed no inhibitory effect on tumor growth at 14, 21, or 28 days. Delta9-THC, delta8-THC, and CBN increased the mean survival time (36% at 100 mg/kg, 25% at 200 mg/kg, and 27% at 50 mg/kg, respectively), whereas CBD did not. Delta9-THC administered orally daily until death in doses of 50, 100, or 200 mg/kg did not increase the life-spans of (C57BL/6 times DBA/2)F1 (BDF1) mice hosting the L1210 murine leukemia. However, delta9-THC administered daily for 10 days significantly inhibited Friend leukemia virus-induced splenomegaly by 71% at 200 mg/kg as compared to 90.2% for actinomycin D. Experiments with bone marrow and isolated Lewis lung cells incubated in vitro with delta9-THC and delta8-THC showed a dose-dependent (10(-4)-10(-7)) inhibition (80-20%, respectively) of tritiated thymidine and 14C-uridine uptake into these cells. CBD was active only in high concentrations (10(-4)).
Administration, Oral↗
Corneal anesthesia induced by soaps and surfactants, lack of correlation in rabbits and humans.
Five commonly marketed bath and facial soaps and four commercially available hair shampoos were studied for their anesthetic effect on human and rabbit corneas. These compounds all produced anesthesia comparable to that induced by tetracaine hydrochloride 0.5 percent but lasting several hours longer in rabbits. None of the soaps or shampoos produced corneal anesthesia in humans. Studies of corneal anesthesia in rabbits may not be extrapolated to the human eye.
Anesthesia↗
Pump infusion of pilocarpine.
Pilocarpine was infused into the conjunctival sac of glaucoma patients with the Sage Model 216 pump. Doses as high as 20 mg were given in 30 min without ocular or systemic toxicity. The ocular hypotension effect, in the same group of patients, was doubled over 4-percent pilocarpine drops given four times daily. In addition to increased efficacy the duration of the ocuoar hypotensive effect was markedly prolonged. Return of ocular pressure to baseline values after a single pump infusion of 20 mg required an average of 33.9 h.
Drug Administration Schedule↗
Effect of narcotic drugs on ribonucleic acid and nucleotide metabolism in mouse brain.
Mice either were administered 10, 30 or 100 mg/kg of morphine sulfate acutely or were chronically implanted with pellets containing morphine, naloxone or pentazocine. They were then injected intraperitoneally or intracerebroventricularly with [5-3H] uridine or [5-3H] orotic acid either 30 minutes, 24 hours of 48 hours before sacrifice. The incorporation of the 3H into brain total homogenate, ribonucleic acid (RNA) and uridine nucleotides was measured. The RNA content of brain and liver was also assayed. When [3H] uridine was injected. i.p. 30 minutes before sacrifice, acute injection of 30 or 100 mg/kg of morphine sulfate or chronic implantation of morphine pellets decreased the incorporation of the [3H] uridine into brain RNA. However, neither the acute administration of 10 mg/kg of morphine sulfate, nor the chronic administration of naloxone or pentazocine, altered the amount of radioactivity incorporated into RNA. Chronic morphine treatment decreased the incorporation of 3H into uridine nucleotides and nucleotide sugars due partially to increased catabolism of the [3H] uridine. The brain and liver RNA concentration was unchanged by chronic morphine administration. Thus, chronic morphine treatment alters the metabolism of uridine nucleotides but does not appear to alter the net synthesis of the total brain RNA.
Animals↗
Determination and characterization of the antinociceptive activity of intraventricularly administered acetylcholine in mice.
Antinociceptive activity of intraventricularly administered acetylcholine was quantitated in mice by the tail-flick and phenylquinone tests. Acetylcholine was administered intraventricularly under light ether anesthesia in a 5 mul volume of sterile saline and mice were retested 10 minutes after the operation. A dose-response curve was established for acetylcholine (ED50 equals 7.3 mug) which was potentiated by intraventricular neostigimine and blocked by intraperitoneal atropine, but not by atropine methyl nitrate or mecamylamine. The antinociceptive effect of morphine was potentiated by intraventricularly administered acetylcholine. The acetylcholine-induced antinocieption was blocked by five narcotic antagonists in the same rank order of potency in which they antagonized the effects of morphine. However, the stereo-specificity of two narcotic antagonists, pentazocine and cylcazocine, was reversed in blocking acetylcholine and morphine-induced antinociception. The results of this study have established a phenomenon of acetylcholine-induced antinociception and identified the central, muscarinic nature of this response. In addition, several experiments have demonstrated similarities between this phenomenon and morphine-induced antinociception. These data implicate the possible involvement of central cholinergic mechanisms in the antinociceptive action of morphine.
Acetylcholine↗
Relationship of brain morphine levels to analgesic activity in acutely treated mice and rats and in pellet implanted mice.
The relationship of brain morphine concentration, determined fluorometrically, to tail-flick activity was investigated after acute and chronic morphine treatment of mice and acute treatment of rats. Brain morphine levels were quantitatively related to the analgesic effect on acute administration, with levels of 100 and 140 ng/g of tissue corresponding to the ED50 in mice and rats, respectively. Over a 90-minute time course after acute s.c. injection, the analgesic effect of morphine in the tail-flick test lagged slightly behind morphine brain level in both species. In mice implanted s.c. with morphine pellets, significant analgesia and appreciable morphine brain levels appeared as early as 20 to 30 minutes after implantation. Increased brain morphine corresponded to increased analgesia at 1 and 4 hours after implantation. Tolerance was evident by 24 hours after implantation and was maximal at 72 hours. Brain morphine remained elevated up to 144 hours after implantation even though substantial encapsulation of the pellet occurred within 72 hours. If pellets were removed at 72 hours, brain morphine declined to control levels with 6 hours, but significant tolerance persisted for at least 24 hours after pellet removal. These results demonstrate that morphine is absorbed from the pellet up to 6 days after implantation and that the decreased analgesic activity observed in the latter times is due to tolerance to the narcotic and not to a decrease in absorption from the pellet.
Analgesics↗
Schedule-induced oral narcotic self-administration: acute and chronic effects.
A pattern of lever pressing was maintained in rats by presenting a food pellet following the first lever press to occur after at least 90-seconds had elapsed (fixed-interval 90-second schedule of food presentation, FI 90-second). With a drinking solution available, a pattern of excessive postpellet drinking (schedule-induced polydipsia) developed and was used to induce rats to drink solutions containing varying concentrations of narcotics. During acute exposure to morphine HCl, morphine SO4 or methadone HCl in the drinking solution, drinking decreased as a function of increasing drug concentration (from 0.3-1 mg/ml), but the total dose of narcotic ingested increased as a function of increasing drug concentration. The highest average dose of morphine HCl consumed in tap water was 30 mg/kg within an hour session. When morphine HCl was presented in an isotonic saline solution, drinking was increased and the highest average dose of morphine HCl ingested was 60 mg/kg within an hour session. The use of an isotonic saline solution did not appreceiably enhance the ingestion methadone HCl (about 30 mg/kg/hr). After chronic exposure to drug solutions for daily 4-hour sessions, the doses ingested averaged between 150 and 250 mg/kg/4 hr for 1 mg/ml solutions of morphine HCl and morphine SO4. The stable pattern of drinking exhibited by rats on the 0.5 mg/ml morphine HCl solution was characterized by a dissociation of drinking from pellet presentation. Chronic exposure to methadone HCl solutions (1 mg/ml) produced less drinking and lower doses ingested (approximately 100 mg/kg) than was obtained with either morphine HCl or morphine SO4 at an equal concentration.
Administration, Oral↗
Effects of narcotic agonists and antagonists on schedule-induced water and morphine ingestion.
A pattern of lever pressing and schedule-induced polydipsia was maintained in rats by a fixed-interval 90-second of food presentation. The effects of acute morphine, methadone, nalorphine, naloxone, pentazocine and cyclazocine were studied in control rats (morphine-free rats) and rats maintained on 200 mg/kg daily oral infections of morphine (morphine-maintained rats). The effects of morphine, nalorphine and naloxone also were studied in rats that were drinking a 0.5 mg/ml of morphine solution (morphine-drinking rats) in the experimental apparatus. All six drugs decreased drinking in the morphine-free rats. Pentazocine and naloxone increased lever-pressing rates in the morphine-free rats, while morphine, methadone, nalorphine and cyclazocine only decreased lever-pressing rates. In the morphine-maintained rats, the dose-effect curves for both lever-pressing and drinking measures were shifted to the left for naloxone, nalorphine, pentazocine and cyclazocine, indicating an increased sensitivity to the antagonists, while the dose-effect curves for morphine and methadone were shifted to the right, indicating that the morphine-maintenance regimen had produced tolerance to these drugs. Morphine and methadone injections increased drinking in the morphone-maintained rats, but none of the drugs increased lever-pressing rates in the morphine-maintained rats. In the morphine-drinking rats, morphine decreased lever pressing at doses that left licking rates unaffected. Since the effects of morphine in the morphine-drinking rats differed from those in the morphine-free rats or the morphine-maintained rats, the effects of morphine on the self-ingestion of morphine in the experimental setting cannot be attributed entirely to the schedule of pellet delivery or to the effect of chronic morphine dosing.
Animals↗