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Biomedical subjects

D L Larson

Publications and source records attributed to D L Larson.

At least 73 records · Page 4Linked to original sources
PubMed1987

Hybrid bivalent ligands with opiate and enkephalin pharmacophores.

Bivalent ligands consisting of oxymorphamine and [D-Glu2]enkephalin pharmacophores linked through a spacer attached to the 6-amino group of the former and D-Glu of the latter were synthesized in an effort to investigate the possible coexistence of mu and delta recognition sites in the same opioid receptor complex. Of the two bivalent ligands (1,2) synthesized, only 1 had substantially greater antinociceptive potency in mice than its monovalent analogues (1a, 1b). Testing of 1, 1a, and 1b in the guinea pig ileum preparation (GPI) revealed a potency profile similar to that found in vivo, whereas no correlation was observed in the mouse vas deferens (MVD). Binding data indicated the same rank-order affinities at delta receptors as the opioid activities in the GPI and in mice. However, mu binding exhibited no relationship with activity. These results are consistent with the simultaneous occupation of mu and delta by a single bivalent ligand 1, but they are also in harmony with the interaction of 1 with an opioid receptor and an accessory binding site.

Analgesics↗
PubMed1987

Topical arachidonic acid: a model for screening anti-inflammatory agents.

Products of arachidonic acid metabolism, prostaglandins and leukotrienes, play an important role in ocular inflammation. In this study, we investigated the efficacies of the cyclo-oxygenase inhibitors (aspirin, indomethacin, and piroxicam) and the lipoxygenase inhibitors (N-hydroxy-arachidonamide (AH) and phenidone) in reducing ocular inflammation induced by arachidonic acid. Administering arachidonic acid topically (0.50% for rabbits and 0.25% for humans) produced a simple model for evaluating the effects of inhibitors on prostaglandins. In rabbits, aspirin, piroxicam and indomethacin all blocked lid closure and chemosis significantly. In humans, aspirin and indomethacin significantly blocked arachidonic acid-induced conjunctival injection. Neither AH nor phenidone blocked any of the signs of ocular inflammation in rabbits or humans. Further testing of phenidone in the presence of the calcium ionophore, ionomycin, also proved negative. Species specificity in arachidonic acid metabolism may account for the different results in humans and rabbits. This model may be a useful tool for comparing the relative efficacies of topical cyclo-oxygenase inhibitors in treating ocular problems.

Administration, Topical↗
PubMed1987

Etiology and treatment of chemotherapeutic agent extravasation injuries: a review.

While extravasation from intravenous (IV) lines is common and usually benign, leakage of certain drugs can cause severe skin ulceration. These ulcerogenic drugs can be conveniently divided into two categories, depending on whether they bind to DNA. Chemotherapeutic agents such as doxorubicin, which bind to DNA, are especially prone to cause severe extravasation skin ulcers. These ulcers are often chronic and progressive. Neither clinical nor experimental studies have shown an antidote to doxorubicin extravasation, which is best prevented by careful technique. If extravasation is suspected, the infusion should be immediately stopped. In the event of extravasation, elevation and ice are the currently recommended treatment. While small ulcerations may on occasion heal, large ulcerations require surgical excision for relief of pain and salvage of underlying tissues.

Antineoplastic Agents↗
PubMed1986

Management of complications of radiotherapy of the head and neck.

It can be seen from this short review that radiation therapy is a double-edged sword--truly life saving and cancer curing but carrying with it the certainty of morbidity. In the majority of patients treated by irradiation, this morbidity is minimal. In the unusual patient in whom there is a significant complication of irradiation, there will be an alteration in quality of life that cannot be documented by words or figures but rather requires caring for this patient. My only request of the reader is that he or she recognizes that the use of irradiation to treat cancer of the head and neck carries with it lifetime implications for both patient and physician and therefore should not be chosen without due thought and indication.

Esophageal Stenosis↗
PubMed1986

Crystal structures of alpha- and beta-funaltrexamine: conformational requirement of the fumaramate moiety in the irreversible blockage of mu opioid receptors.

alpha- and beta-funaltrexamine (alpha- and beta-FNA, 1a and 1b) are naltrexone derivatives differing only in chirality at C(6). Both epimers bind to mu opioid receptors in GPI and MVD preparations, but only the beta-epimer irreversibly blocks these receptors in both preparations. In an effort to investigate the reasons for this difference, we have determined the molecular structures of 1a and 1b by X-ray diffraction techniques. The two epimers have almost identical conformations in the fused ring system except for ring C, which is observed in a twist-boat conformation in alpha-FNA and a chair in beta-FNA. As a result the electrophilic fumaramate moieties are equatorial in both structures and orthogonal to one another when the fused rings are superimposed. In the crystal structure of beta-FNA there is a close intermolecular contact between a phenolic oxygen and the fumaramate double bond that can serve as a model for nucleophilic attack on the fumaramate group. When 1a and 1b are superimposed, the fumaramate double bond of 1a is more than 2 A away from that in its epimer 1b and in the wrong orientation for nucleophilic attack from the proposed direction to take place. The results of this study are consistent with a model that postulates the involvement of two consecutive recognition steps leading to the irreversible blockage by beta-FNA (Sayre, L. M.; Larson, D. L.; Fries, D. S.; Takemori, A. E.; Portoghese, P. S. J. Med. Chem. 1983, 26, 1229) and underscores the importance of the second recognition step in conferring selectivity in the Michael addition of a nucleophile to the fumaramate group.

Crystallography↗
PubMed1986

Activity of N-methyl-alpha- and -beta-funaltrexamine at opioid receptors.

The N-methyl analogues (2a, 2b) of the nonequilibrium mu opioid receptor antagonist beta-funaltrexamine (1b) were synthesized and evaluated in the guinea pig ileum preparation (GPI). These analogues are highly potent, reversible opioid agonists and possess no nonequilibrium antagonist activity. The ineffectiveness of 2b in protecting against irreversible blockage of mu opioid receptors by 1b and the fivefold lower reactivity of 2b with cysteine suggest that N-methyl substitution adversely affects both the first and second recognition steps that are essential for effective covalent blockage of opioid receptors.

Animals↗
PubMed1986

Synthesis and opioid antagonist potencies of naltrexamine bivalent ligands with conformationally restricted spacers.

Bivalent ligands 1-4 with naltrexamine pharmacophores and spacers of different lengths containing a fumaryl moiety were synthesized and evaluated for mu and kappa opioid antagonist activity on the electrically stimulated guinea pig ileal longitudinal muscle (GPI). The fumaryl moiety was incorporated into the spacer in order to determine the effect of conformational restriction of the spacer on the relationship between spacer length and opioid antagonist potency. While it was found that the fumaryl and succinyl series (11) possessed a very similar structure-potency profile with respect to antagonism at mu opioid receptors, the interaction of these two series at kappa receptors differed substantially from one another. This difference was manifested by the longer spacer requirement for peak kappa antagonist potency in the fumaryl relative to the succinyl series. It is concluded that the conformational restriction imposed by the fumaryl group in a short spacer (n = 0) prevents effective interaction of both pharmacophores with vicinal recognition sites of the kappa receptor system; as the spacer is lengthened (n = 2) and becomes more flexible, the simultaneous occupation of vicinal recognition sites occurs with greater facility.

Animals↗
PubMed1986

Opioid agonist and antagonist bivalent ligands. The relationship between spacer length and selectivity at multiple opioid receptors.

Bivalent ligands containing the oxymorphamine or naltrexamine pharmacophores connected to spacers of varying length were synthesized and evaluated for their selectivity at mu, kappa, and delta opioid receptors. The oxymorphamine bivalent ligands (1-8) behaved as mu agonists on the electrically stimulated guinea pig ileum longitudinal muscle preparation (GPI). The spacer that conferred peak agonist activity in these series contains a total of four glycyl units (n = 2). Binding studies with guinea pig brain membranes showed a qualitatively similar profile at mu receptors as a function of spacer length. Also, delta receptor selectivity increased as the spacer was lengthened. The naltrexamine bivalent ligands (9-13) effectively antagonized the mu receptor agonist morphine in the GPI at the same optimal spacer length (n = 2) as in the agonist series. However, the peak antagonism of ethylketazocine, a kappa receptor agonist, occurred with the bivalent ligand 9 containing the shortest spacer (n = 0), and it was found that 9 is the most selective kappa antagonist in the series. While receptor binding roughly parallels that of kappa antagonist activity in the GPI, no correlation between binding and antagonist activity was observed at mu opioid receptors. The possible significance of these results is discussed.

Animals↗
PubMed1986

Skeletal suspension in the management of severe burns in children. A sixteen-year experience.

From 1966 to 1983, skeletal suspension was used at the Shriners Burns Institute, Galveston, Texas, for the treatment of 626 burned pediatric patients who had 1128 affected extremities. Skeletal suspension was used for 863 acutely burned extremities (76.5 per cent) to facilitate skin-grafting and in 265 extremities (23.5 per cent) for functional positioning in the surgical correction of burn-acquired deformities. In a retrospective examination of these patients, there were fifty complications (4.4 per cent) related to the skeletal suspension, of which forty-five (4.0 per cent) were infections. All infections resolved with removal of the pins or the administration of antibiotics, or both. With this established low rate of complications, skeletal suspension continues to be a useful adjunct in the care of the severely burned pediatric patient.

Acute Disease↗
PubMed1985

Opioid receptor binding characteristics of the non-equilibrium mu antagonist, beta-funaltrexamine (beta-FNA).

beta-Funaltrexamine (beta-FNA) bound to mouse brain membranes in a reversible and an irreversible (not removed by washing of the membrane) manner, and a portion of each type of binding was opioid-specific. Addition of 100 mM NaCl to the incubating medium enhanced the binding of beta-FNA to membranes. Using membranes preincubated with beta-FNA (1 microM) and then washed three times, the maximum number of binding sites available to [3H]morphine was markedly diminished whereas the affinity of morphine for binding sites was not significantly altered. The binding of [3H]naltrexone was also reduced markedly by beta-FNA pretreatment. In similarly pretreated membranes, the binding of [3H]methionine enkephalin [3H][D-Ala2,D-Leu5]enkephalin (DADLE) or [3H]ethylketazocine was reduced to a smaller extent. Using brain membranes from mice pretreated with a single subcutaneous injection of beta-FNA (100 mg/kg) 48 h prior to use, the binding of [3H]methionine enkephalin was unaffected whereas the number of binding sites available to [3H]morphine was significantly reduced. The inhibition by various ligands of the reversible binding of [3H] beta-FNA resembled the relative ability of the same ligands to inhibit the binding of [3H]ethylketazocine. It was concluded that the irreversible portion of the binding of beta-FNA demonstrates a selectivity for mu over delta binding sites, and that the reversible portion of the binding of beta-FNA demonstrates a selectivity for kappa binding sites over mu or delta binding sites. As such, the binding characteristics of beta-FNA are consistent with its profile in vivo and in isolated tissue studies in vitro.

Animals↗
PubMed1985

What is the appropriate management of tissue extravasation by antitumor agents?

Review of 175 patients sustaining extravasation of an antitumor agent showed that most (89 percent) can be managed immediately with intermittent application of ice (15 minutes four times daily for 3 days) and close wound observation. We consider pain, usually associated with varying degrees of skin involvement, to be the only indication for surgery. Such a procedure should consist of wide, three-dimensional excision of all involved tissue, temporary coverage with a biologic dressing, and simultaneous harvesting and storage of a split-thickness skin graft. Once the wound is clean, delayed application of the graft is performed (usually at 2 to 3 days). Not only will this result in immediate pain relief and provide safe wound coverage, but it also will not interrupt the patient's chemotherapy schedule. Most patients were able to be restarted on their chemotherapy shortly after surgery, and none demonstrated a "recall phenomenon."

Adult↗
PubMed1984

Skin grafts in intraoral reconstruction. A new stenting method.

The results of skin graft reconstruction in intraoral cancer in 65 consecutive cases were uniformly good. There were only 11 wound complications and all resolved spontaneously without additional surgery. Skin grafts were used successfully in conjunction with coronal resections of the mandible, incontinuity modified neck dissections, and composite resections. Postoperative radiation therapy had no ill effects on the grafts or oral hygiene. A new stenting method with a dental tissue conditioner was employed. When used to immobilize intraoral skin grafts, it improved oral hygiene and patient deglutition, thereby hastening rehabilitation. The success of grafts performed with the new stent was equal to (if not better than) the success of grafts performed with the traditional stent.

Adult↗
PubMed1984

Surgical stents for the head and neck cancer patient.

Split-thickness skin graft reconstruction following intraoral cancer surgery maintains functional mobility within the oral cavity and gives excellent support for the final intraoral rehabilitative prosthesis. We describe the use of a dental material, called tissue conditioner, for skin graft immobilization as an alternative to the usual gauze bolus and thermoplastic materials following surgery in various intraoral anatomic sites.

Dentures↗
PubMed1984

Lymphoma of the head and neck. A diagnostic dilemma.

The surgeon should remember that lymphoma may involve any tissue in the head and neck region. By maintaining a high level of suspicion when evaluating a tumor that appears to be more aggressive than expected (that is, multiple primary sites), the head and neck surgeon will expedite treatment of the patient with lymphoma. Aids in early diagnoses center around providing sufficient tissue to the pathologist by avoiding needle biopsy and piecemeal removal of the regional lymph nodes or obtaining undistorted representative tissue from extranodal sites. We stress the need for a continuing dialogue between the head and neck surgeon and the pathologist regarding early identification of the potential lymphoma patient, thereby preventing a diagnostic dilemma.

Adolescent↗
PubMed1984

A reliable rat model of the delayed hypersensitivity skin test response.

A model of the delayed type hypersensitivity response (DTH) has been developed in Sprague-Dawley rats. The sensitizing and skin test antigen is keyhole limpet hemocyanin (KLH). This antigen produces 99% sensitization and the response is maintained in 98% of the animals for up to 3 months. In four animals the DTH response was maintained greater than 1 year. The response can be abrogated with protein deprivation and restored with refeeding. The skin test method of DTH assessment correlates with an alternate technique of radiolabeled cell accumulation in the ear (r = 0.95, P less than 0.001). This model should prove useful in evaluating the role of the DTH response in measuring host resistance to infection.

Animals↗