Biomedical subjects

K L Meyer

Publications and source records attributed to K L Meyer.

32 records · Page 2Linked to original sources

PubMed1991

Synthesis and biological evaluation of a series of 1,1-dichloro-2,2,3-triarylcyclopropanes as pure antiestrogens.

A series of 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs) was synthesized and evaluated as pure antiestrogens. Addition of 4-methoxy- or 4-(benzyloxy)phenyl Grignard reagents to p-methoxy, p-benzyloxy, or unsubstituted deoxybenzoins, followed by dehydration of the resulting carbinols produced a mixture of E and Z olefins, which were reacted with dichlorocarbene to give O-protected DTACs. The E and Z isomers were separated by fractional crystallization and the central or geminal phenyl ring was deprotected to provide phenolic DTACs. Alkylation with (N,N-dimethylamino)ethyl chloride yielded basic cyclopropanes. Two chlorodiarylindenes were isolated as thermolysis products of the DTACs, and one was converted to a phenol by hydrogenolysis. All DTACs and indenes were competitive inhibitors of [3H]estradiol binding in the immature rat uterine cytosol receptor assay, with relative binding affinities of 0.1-3.6% of estradiol. None of the new compounds were estrogenic in the 3-day immature mouse uterotrophic assay at doses up to 750 micrograms. In the 3-day immature mouse antiuterotrophic assay, five DTACs with either a methoxy (5a), benzyloxy (4d, 5c), or (dimethylamino)ethoxy (7a, 7b) central ring side chain produced significant decreases in uterine weight at doses up to 750 micrograms. One compound, (Z)-1,1-dichloro-2-[4-[2-(dimethylamino)ethoxy]-phenyl]-2-(4- methoxyphenyl)-3-phenylcyclopropane (7b), elicited a dose-dependent decrease in vivo comparable to MER 25. These same five compounds, as well as the lead compound Analog II, were active in vitro against the estrogen-dependent MCF-7 human breast tumor cell line in a dose-dependent fashion.

Animals↗

PubMed1991

In vitro evaluation of phosphocholine and quaternary ammonium containing lipids as novel anti-HIV agents.

A series of synthetic lipids containing a two- or three-carbon backbone substituted with a thio, oxy, or amidoalkyl functionality and either a phosphocholine or quaternary ammonium moiety was evaluated as potential anti-HIV-1 agents. Several analogues were identified as possessing activity with the most promising compound being rac-3-octadecanamido-2-ethoxypropylphosphocholine (8). Compound 8 exhibited an IC50 for the inhibition of plaque formation of 0.16 microM which was 84-fold lower than the IC50 value determined for CEM-SS cell growth inhibition. Initial mechanistic studies have indicated that these compounds, unlike AZT, are not reverse transcriptase (RT) inhibitors, but instead appear to inhibit a late step in HIV replication involving virus assembly and infectious virus production. Since these lipids are acting via a different mechanism, they represent an alternative approach to the chemotherapeutic treatment of AIDS as well as candidates for combination therapy with AZT.

Antiviral Agents↗

PubMed1991

Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIV-1 activity.

Combinations of an amidoalkylphosphocholine, 8, and AZT have been found to cause an apparent synergistic action in suppressing infectious HIV-1 replication. In addition, amidoalkyl, oxyalkyl, and thioalkyl ether lipids have been chemically linked to anti-HIV-1 nucleosides (AZT and DDI) through phosphate and phosphonate linkages. These conjugates have shown promising in vitro anti-HIV-1 activity. Also, the conjugates have a 5-10-fold reduction in cell cytotoxicity compared to AZT alone. The most active compound, an amidoalkyl ether lipid-AZT conjugates, 4A, was found to have a differential selectivity of 1793 in a syncytial plaque assay. In comparison, AZT alone has a value of 1281.

Antiviral Agents↗

PubMed1990

Synthesis and biological activity of novel quaternary ammonium derivatives of alkylglycerols as potent inhibitors of protein kinase C.

Alkylglycerols such as rac-1-O-octadecyl-2-O-methylglycerophosphochocholine (Et-18-OMe) have shown an inhibitory effect on the metastasis and growth of various cancer cell lines. Alkyl phospholipids have been shown to accumulate at the surface in several cell lines, the selectivity of which is still not clearly understood. A consequence of this action may lead to the inhibition of cell membrane related protein kinase C (PKC). The goal of this research was to develop ether lipid inhibitors of PKC to augment antineoplastic activity. This led to the synthesis and in vitro testing of a series of novel quaternary ammonium derivatives of alkylglycerols. The biological testing of these analogues on PKC stimulated with rac-1-O-oleoyl-2-O-acetylglycerol showed several analogues with inhibition comparable to that of Et-18-OMe.

Antineoplastic Agents↗

PubMed1990

Synthesis of quaternary amine ether lipids and evaluation of neoplastic cell growth inhibitory properties.

Novel quaternary amine ether lipids have been synthesized and tested for inhibition of neoplastic cell proliferation with the HL-60 promyelocytic leukemia cell line. These compounds contain a positively charged quaternary amine functional group attached either directly to the glycerol backbone or at the end of an alkoxy chain. The biological testing has identified several analogues with activity equivalent to or greater than that exhibited by the reference compound in this assay, ET-18-OMe (1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine). Among the most active analogues are compounds 11, [N,N,N-triethyl-3-(hexadecyloxy)-2-ethoxy-1-propylammonium bromide] and 22 [N-[4-[3-(hexadecyloxy)-2-ethoxypropoxy]-1-butyl]pyridinium bromide], which are approximately 3 times as active as the reference standard.

Antineoplastic Agents↗

PubMed1990

Tumor visualization with a radioiodinated phospholipid ether.

The known ability of phospholipid ethers to accumulate in certain tumors prompted the synthesis and evaluation of a radioiodinated phospholipid ether analog as a potential tumor imaging agent. Tissue distribution studies with [125I]-rac-1-0-[12-(m-iodophenyl)dodecyl-2-0-methylglycero-3- phosphocholine in rats bearing the Walker 256 carcinosarcoma showed the tumor to contain the highest concentration of radioactivity at 24 hr (15% of the dose) and a tumor-to-blood ratio of 13. Scintigraphic images taken at 24 hr compared favorably with those obtained with (67Ga)-citrate. In contrast with the latter, however, the phospholipid ether showed little propensity to accumulate in an inflammatory lesion in the rat. Tumor visualization was also accomplished in a rabbit bearing the V x 2 adenocarcinoma. We conclude that phospholipid ethers may represent a new class of carrier molecules for the transport of radionuclides to tumors.

Adenocarcinoma↗

PubMed1989

Potential tumor or organ-imaging agents. 30. Radioiodinated phospholipid ethers.

A radioiodinated analogue of a naturally occurring alkyl lysophospholipid (ALP) was synthesized for evaluation as a potential tumor-localizing imaging agent. rac-1-[12-(m-Iodophenyl)dodecyl]-2-methylglycero-3-phosphocholine (ET-12IP-OMe, 14) was radiolabeled with iodine-125 via an isotope-exchange procedure. Tissue distribution studies with [125I]ET-12IP-OMe in tumor-bearing rats revealed an immediate tumor uptake of radioactivity. Although radioactivity was also present in nontarget tissues at this time, clearance of tracer from the tumor was much slower and thus provided a suitable tumor to nontarget tissue ratio at 24 h. As a result of this selective accumulation, it was possible to clearly delineate the tumor with gamma-camera scintigraphy.

Animals↗

PubMed1987

Hematology, blood chemistry and selenium values of captive pronghorn antelope, white-tailed deer and American bison.

Pronghorn were observed to have a significantly higher whole blood selenium concentration than either the white-tailed deer or bison. Pronghorn colloid values were significantly less than those of the bison, and approached statistical significance for the white-tailed deer. Differential white blood cell counts for the white-tailed deer were markedly different from those of the pronghorn and bison. The American bison had significantly higher cortisol values and lower T3 values than either the white-tailed deer or pronghorn.

Animals↗

PubMed1986

Cell-cooling in flow cytometry by Peltier elements.

We have built a cooling device for cell suspensions in flow cytometry that makes use of the Peltier effect (Barnard RD, Thermo electricity in Metals and Alloys, Taylor and Francis, London; Siemens-Z 34:383-88, 1963). The prototype described here is used for cooling collection tubes during long-duration cell sorting and is capable of maintaining a temperature of 2-5 degrees C in a cell suspension of up to 3 ml. In general, Peltier element-based cooling is useful for equilibrating the temperature of small volumes of fluids. Furthermore, Peltier element-based cooling devices are easy to build and handle.

Animals↗

PubMed1985

Somatosensory evoked potentials as a measure of experimental cerebral ischemia.

Somatosensory evoked potentials (SEP's) reflect the integrity of the central neuronal pathway, and as such may be used to assess function that remains during a variety of cerebral insults. To evaluate the natural history and utility of SEP's during experimental cerebral ischemia and infarction, SEP's were measured in 17 adult cats at 24 hours and 1 hour prior to right middle cerebral artery (MCA) occlusion, and again immediately afterward and at either 6 hours (five cats) or 24 hours (six cats) post-occlusion. Before occlusion of the right MCA, the SEP's were identical in the right and left hemispheres. After occlusion, there was a significant slowing of the interpeak latency of the first positive peak (P1) in the right hemisphere (3.53 +/- 0.6 msec before compared to 3.99 +/- 0.6 msec after occlusion, p less than 0.001). Maximal slowing in right hemisphere P1 latency was seen in those animals in which the stroke extended into the thalamus (4.38 +/- 0.1 msec). This was significantly slower than left hemisphere values (3.92 +/- 0.32 msec, p less than 0.01). The ipsilateral cortical components of the SEP's, the second positive peak (P2), and the major negative deflection (MN) were slowed in all cats immediately after right MCA occlusion compared to preocclusion measurements (p less than 0.001). Severe infarcts in the mid-suprasylvian and posterior ectosylvian gyri (including the somatosensory cortex) resulted in a greater slowing of the latency of MN compared to less severe infarcts in that region (20.6 +/- 3.9 msec versus 16.4 +/- 1.1 msec, p less than 0.05). There was a precipitous decrease in the amplitude or voltage of the ipsilateral P2-MN complex immediately after occlusion (5.32 +/- 0.4 microV before compared to 0.98 +/- 0.3 microV after occlusion, p less than 0.001). Therefore, the central latencies and cortical amplitudes of the SEP's are sensitive experimental tools as indicators of the onset and extent of a cerebral ischemic insult.

Animals↗

PubMed1985

Indomethacin-mediated improvement following middle cerebral artery occlusion in cats. Effects of anesthesia.

Focal cerebral ischemia initiates multiple detrimental effects in the brain. Chief among these are the regional development of ischemic edema, decreased local perfusion, altered neuronal function, and eventual infarction. To determine if pretreatment with the cyclo-oxygenase inhibitor, indomethacin, would result in improvement in these parameters, adult cats were given indomethacin or control solvent (4 mg/kg intraperitoneally twice daily) and were studied for periods up to 24 hours after right middle cerebral artery occlusion. The interaction of anesthetic agents with indomethacin was also examined in separate groups of experimental animals using pentobarbital and ketamine. In cats allowed to recover from pentobarbital anesthesia, indomethacin reduced gray and white matter edema at 6 and 24 hours after occlusion (p less than 0.05). This was noted in densely areas (indomethacin = 84.3%, control = 87.5%), "penumbra" regions (indomethacin = 82.5%, control = 85.3%), and in nonischemic zones (indomethacin = 81.5%, control = 82.3%) at 24 hours. Somatosensory evoked potential amplitude and central latency were also improved in the indomethacin group (p less than 0.05), as was cerebral perfusion (p less than 0.05). In animals anesthetized with continuous ketamine administration, cerebral edema and perfusion as well as evoked potentials were not significantly improved in any region by indomethacin. Regional cerebral blood flow in the group was increased by indomethacin in the nonischemic opposite hemisphere (indomethacin = 64.7 cc/100 gm/min, control = 48.5 cc/100 gm/min, p less than 0.05), but not in the penumbra region of the ischemic hemisphere (indomethacin = 15.0 cc/100 gm/min, control = 18.6 cc/100 gm/min, p less than 0.05), when measured 4 hours after occlusion. This suggested a steal phenomenon. Beneficial effects of indomethacin were evident in the presence of pentobarbital, but not after ketamine anesthesia. This suggests a synergism dependent on decreased arachidonic acid production from pentobarbital-stabilized membranes coupled with diminished production of cyclic endoperoxides from available arachidonate due to inhibition of cyclo-oxygenase with indomethacin.

Animals↗

PubMed1985

Effects of verapamil and diltiazem on acute stroke in cats.

To test the effect of verapamil and diltiazem in acute stroke, three groups of mongrel cats of either sex underwent occlusion of the middle cerebral artery (MCA) via a transorbital approach under ketamine anesthesia. The first group served as controls, the second received an intravenous infusion of verapamil (0.1 microgram/kg/min), and the third received an intravenous infusion of diltiazem (0.1 to 1.0 microgram/kg/min). All drug infusions began 2 hours before MCA occlusion and continued for the remainder of the experiment. Before and for up to 24 hours after MCA occlusion, regional cerebral blood flow (rCBF), somatosensory evoked potentials (SSEP's), arterial blood gases, blood pressure, temperature, and hematocrit were measured at least every 2 hours. At the experiment's end, brains were perfused with India ink, removed, sliced, photographed for determination of nonperfused brain area, and weighed, dried, and reweighed for H2O content determination. In these studies, verapamil was associated with worsening of rCBF in ischemic regions and inappropriate increases in rCBF in nonischemic regions, indicating intracerebral steal. Diltiazem increased rCBF in marginally ischemic regions. Changes in SSEP's paralleled blood flow changes, with verapamil decreasing amplitude and conduction velocity while diltiazem slightly improved conduction in the ischemic brain. Verapamil increased the area of nonperfused brain and the content of cerebral H2O. Diltiazem-treated animals had decreased cerebral H2O content, but had a marked increase in the area of nonperfused brain, a finding associated with the high incidence of transtentorial herniation in the diltiazem-treated animals. These findings agree with in vitro studies demonstrating high sensitivity of cerebral blood vessels to calcium channel blockers. These studies further support the notion that calcium channel blockers probably affect several different classes of calcium channels, at different brain sites.

Animals↗

PubMed1985

The surgical approach to primary malignant melanoma.

Surgical excision is the only curative treatment for malignant melanoma. Excisional biopsy of the suspected lesion allows for adequate tissue diagnosis and microstaging and does not alter ten year survival periods. Wide local excision with a resection margin of 3 centimeters is recommended for all but the most superficial (less than 0.76 millimeters) lesions. Nodal and systemic metastases and long term survival are unaffected by the size of the resection margin. The role of prophylactic lymphadenectomy for Stage I melanoma remains controversial. The results of both prospective and retrospective studies have demonstrated an improved survival after prophylactic lymphadenectomy for patients with intermediate thickness (0.76 to 3.9 millimeters or Clark's level III to IV, or both) lesions. Patients with ulcerated lesions and lesions in the BANS distribution, even when superficial, might benefit from elective lymphadenectomy. At least quarterly follow-up examination is recommended for those patients who undergo wide excision alone. Therapeutic lymphadenectomy is indicated for the treatment of Stage II melanoma. The results of ongoing prospective randomized studies will clarify the role of fascia removal, resection margins and prophylactic lymphadenectomy in the treatment of malignant melanoma.

Biopsy↗

PubMedDate not supplied

Synthesis and characterization of a new 5-thiol-protected deoxyuridine phosphoramidite for site-specific modification of DNA.

A new nucleotide analogue was developed for site-specific incorporation of a reactive thiol group into DNA. This creates a unique site for the post-synthetic modification of that nucleotide with a variety of molecular tags, such as photo-cross-linkers and fluorescent or spin-label moieties. 5'-O-(4,4'-Dimethoxytrityl)-5-[S-(2,4-dinitrophenyl)thio]-2'-deoxyuridin e 3'-O-(2-cyanoethyl N,N'-diisopropylphosphoramidite) was synthesized and incorporated at internal positions in several oligonucleotides using automated DNA synthesis and standard phosphoramidite chemistry. The coupling yield of the analogue was comparable to the coupling yield for a standard phosphoramidite, and no significant differences were observed in the overall yields of the dinitrophenyl-labeled oligonucleotides compared to the corresponding unmodified oligonucleotides. Characterization of the dinitrophenyl-modified oligonucleotides included enzymatic degradation, HPLC chromatography, and gel electrophoresis. Deprotection of the mercaptan group with beta-mercaptoethanol yielded an oligonucleotide containing 5-mercaptodeoxyuridine which was then selectively modified, without purification, by reaction with 5-(iodoacetamido)fluorescein. Incorporation of the dinitrophenyl-modified oligonucleotide into double-stranded DNA was achieved using the polymerase chain reaction. CHaracterization of the dinitrophenyl-labeled product by immunodetection with anti-dinitrophenyl antibodies confirmed the stability of the protecting group to the thermocycling and thus established the use of this thiol-protected mercaptodeoxyuridine phosphoramidite for preparation of site-specifically modified DNA.

Alkylation↗