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Biomedical subjects

D W Henry

Publications and source records attributed to D W Henry.

At least 19 recordsLinked to original sources
PubMed1997

The response of anesthetic agent monitors to trifluoromethane warns of the presence of carbon monoxide from anesthetic breakdown.

OBJECTIVE: Trifluoromethane and CO are produced simultaneously during the breakdown of isoflurane and desflurane by dry CO2 absorbents. Trifluoromethane interferes with anesthetic agent monitoring, and the interference can be used as a marker to indicate anesthetic breakdown with CO production. This study tests representative types of gas monitors to determine their ability to provide a clinically useful warning of CO production in circle breathing systems. METHODS: Isoflurane and desflurane were reacted with dry Baralyme at 45 degrees C. Standardized samples of breakdown products were created from mixtures of reacted and unreacted gases to simulate the partial degrees of reaction which might result during clinical episodes of anesthetic breakdown using 1% or 2% isoflurane and 6% or 12% desflurane. These mixtures were measured by the monitors tested, and the indication of the wrong agent or a mixture of agents due to the presence of trifluoromethane was recorded and related to the CO concentration in the gas mixtures. RESULTS: When presented with trifluoromethane from anesthetic breakdown, monochromatic infrared monitors displayed inappropriately large amounts of isoflurane or desflurane. Agent identifying infrared and Raman scattering monitors varied in their sensitivity to trifluoromethane. Mass spectrometers measuring enflurane at mass to charge = 69 were most sensitive to trifluoromethane. CONCLUSION: Monochromatic infrared monitors were unable to indicate anesthetic breakdown via interference by trifluoromethane, but did indicate falsely elevated anesthetic concentrations. Agent identifying infrared and Raman monitors provided warning of desflurane breakdown via the interference of trifluoromethane by displaying the wrong agent or mixed agents, but may not be sensitive enough to warn of isoflurane breakdown Some mass spectrometers provided the most sensitive warnings to anesthetic breakdown via trifluoromethane, but additional data processing by some patients monitor units reduced their overall effectiveness.

Air Pollutants, Occupational↗
PubMed1996

Mass spectrometry provides warning of carbon monoxide exposure via trifluoromethane.

BACKGROUND: The chemical breakdown of isoflurane, enflurane, or desflurane in dried carbon dioxide absorbents may produce carbon monoxide. Some mass spectrometers can give false indications of enflurane during anesthetic breakdown. METHODS: During clinical anesthesia with isoflurane or desflurane, the presence of carbon monoxide in respiratory gas was confirmed when enflurane was inappropriately indicated by a clinical mass spectrometer that identified enflurane at mass to charge ratio = 69. In vitro, isoflurane, enflurane, or desflurane in oxygen was passed through dried carbon dioxide absorbents at 35, 45, and 55 degrees C. Gases were analyzed by gas chromatography and by mass spectrometry. RESULTS: Mass spectrometry identified several clinical incidents in which 30-410 ppm carbon monoxide was measured in respiratory gas. Trifluoromethane was produced during in vitro breakdown of isoflurane or desflurane. Although these inappropriately indicated quantities of "enflurane" correlated (r2 > 0.95) to carbon monoxide concentrations under a variety of conditions, this ratio varied with temperature, anesthetic agent, absorbent type, and water content. CONCLUSIONS: Trifluoromethane causes the inappropriate indication of enflurane by mass spectrometry, and indicates isoflurane and desflurane breakdown. Because the ratio of carbon monoxide to trifluoromethane varies with conditions, this technique cannot be used to quantitatively determine the amount of carbon monoxide to which a patient is exposed. If any warning of anesthetic breakdown results from this technique then remedial steps should be taken immediately to stop patient exposure to carbon monoxide. No warning can be provided for the breakdown of enflurane by this technique.

Anesthetics, Inhalation↗
PubMed1991

Irreversibility of procainamide-dextrose complex in plasma in vitro.

The extent to which the procainamide-dextrose complex reverts to free procainamide hydrochloride in plasma was studied in vitro. The procainamide-dextrose species was formed, isolated using preparative liquid chromatography, and then added to six different lots of pooled plasma that were maintained at physiological temperature (37 +/- 0.1 degrees C). At zero, four, and eight hours after preparation of the samples, 1-mL portions were removed from each sample, extracted, and assayed for procainamide hydrochloride using high-performance liquid chromatography. The mean procainamide hydrochloride concentrations at zero, four, and eight hours after preparation were 2.67, 4.81, and 1.38 g/mL, respectively. Each lot of pooled plasma was statistically analyzed to determine if a significant amount of procainamide hydrochloride reappeared. Analysis of variance showed significant difference between the concentrations of free procainamide hydrochloride in the samples at zero, four, and eight hours (p less than 0.02). Follow-up with Duncan's multiple comparisons test determined that the mean procainamide hydrochloride concentrations immediately after preparation were not significantly different from those at eight hours, but the mean procainamide hydrochloride concentrations at four hours were significantly different from those at eight hours (p less than 0.01). A paired Student's t test comparing the data from zero and eight hours showed a significant reduction in mean procainamide hydrochloride concentrations with time (p less than 0.05). The procainamide-dextrose complex in vitro does not revert to free procainamide hydrochloride in plasma at physiological temperature during the first eight hours.

Drug Compounding↗
PubMed1991

Determination of sedative and amnestic doses of lorazepam in children.

An open-label, dose-escalation study was conducted to determine doses of lorazepam required to induce anterograde amnesia and sedation in children without producing excessive toxicity. Oncology patients 4 to 17 years of age undergoing lumbar puncture or bone marrow aspiration were eligible; a patient could be entered in the study for a second procedure at a different lorazepam dose. A single oral dose of lorazepam was administered 45-60 minutes before the procedure. Starting with 0.02 mg/kg, the same dose was given to three patients; if no dose-limiting effects occurred, dose was increased by 0.01 mg/kg. Before the procedure the patient was shown a toy that he or she was later asked to identify. Immediately after the procedure (usually 60-75 minutes after the lorazepam dose), sedation was assessed on a scale of 0 (alert) to 4 (coma), and the clinician performing the procedure was asked to subjectively evaluate sedation. Patients were rated for amnesia 24 hours after the procedure; a scale of 0 (recalls procedure and toy without prompting) to 4 (recalls nothing since procedure) was used. Twenty patients received 28 doses of lorazepam. The study was terminated when two patients who received 0.10 mg/kg had excessive ataxia. Sedation was subjectively considered adequate for 24 of the procedures. Sedation and amnesia scores were not well correlated with increased dose. Amnesia occurred in some patients with doses as low as 0.03 mg/kg. In children undergoing lumbar puncture or bone marrow aspiration, premedication with oral lorazepam 0.02-0.09 mg/kg generally produced adequate sedation for the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1986

Stability of propranolol hydrochloride suspension compounded from tablets.

The stability of a propranolol hydrochloride suspension compounded from commercially available tablets was studied. Propranolol hydrochloride 10-mg tablets were triturated to a powder and incorporated into a commercially available suspension vehicle to yield a suspension with a theoretical propranolol hydrochloride concentration of 1 mg/mL. The suspension was divided into portions and stored in amber glass bottles at either room (25 degrees C) or refrigerated (2 degrees C) temperature for four months. The concentration of propranolol hydrochloride in the samples was determined by a stability-indicating, high-performance liquid chromatographic (HPLC) assay at 0, 30, 60, 90, and 120 days. Also at these times, the pH of the samples was measured, and the samples were inspected visually for evidence of microbial growth and ease of resuspension. The concentration of propranolol hydrochloride in the samples remained within 90% of the initial concentration throughout the study period. No important changes in the pH of the samples and no visible evidence of microbial growth were noted. This extemporaneous suspension of propranolol hydrochloride compounded from commercially available tablets is stable for at least four months when stored at room or refrigerated temperature.

Chromatography, High Pressure Liquid↗
PubMed1983

A simplified high-pressure liquid chromatography method for determining lipophilicity for structure-activity relationships.

A highly deactivated octadecyl-bonded silica column and a mobile phase consisting of an water-methanol mixture in the range of blood pH and ionic strength are used to correlate log kappa' with biological activity for a series of sulfonamides and barbiturates. The results were compared to literature methods by using retention volume (VR) and retention indexes (I). For the nine sulfonamides tested, log VR and log kappa' were used with and without correction for ionization. For each biological end point (protein binding and minimum inhibitor concentration against Eschericia coli from two sources) and each independent variable (log kappa' and log VR) the residual standard derivation for the regression was determined. the standard derivations were compared in an F test for each of 12 relevant regressions. Log kappa' was statistically superior in for cases, while log VR was superior in one case. Overall, the methods were statistically indistinguishable. Log kappa' values and I values for 15 barbiturates were regressed against three biological end points [hypnotic activity (the minimum effective dose in rabbits), inhibition of Arbacia egg cell division, and inhibition of rat brain respiration]. Standard deviations were compared by an F test, and the two methods were indistinguishable as far as the goodness of biological correlations are concerned. Procedures for controlling the column's activity are presented. Choices for an appropriate mobile phase are discussed, and a method of calculating pH and ionic strength in a methanol-aqueous mobile phase is presented.

Animals↗
PubMed1979

5-Iminodaunorubicin. Reduced cardiotoxic properties in an antitumor anthracycline.

Treatment of daunorubicin with methanolic ammonia affords 5-iminodaunorubicin, the first quinone-modified analogue of either daunorubicin or adriamycin. This product retains antileukemic activity in mice, is less cardiotoxic by electrocardiographic measurements in rats, and is nonmutagenic in Salmonella typhimurium (Ames test).

Animals↗
PubMed1979

Synthesis of daunorubicin analogues with novel 9-acyl substituents.

Synthetic approaches to anthracyclines bearing novel 9-acyl substituents were investigated. Reaction of the lithium enolate of N-(trifluoroacetyl)daunorubicin (9) with methyl iodide in tetrahydrofuran afforded only the 9-propionyl derivative 10 in high yield. Reaction of 10 under identical conditions cleanly afforded the 9-isobutyryl derivative 11. Extension of this procedure to other alkylating agents (ethyl iodide, benzyl bromide, and heptyl iodide) required hexamethylphosphoramide as cosolvent and afforded mixtures of mono- and dialkylated products as well as recovered 9. The amino group was deblocked with NaOH in aqueous tetrahydrofuran, except in the case of the dibenzyl derivative 13 which was inert under these conditions. The 9-formyl analogue 23 was prepared via NaIO4 cleavage of 13-dihydroadriamycin (21). Antitumor evaluation against P388 leukemia in mice showed 23 to have activity comparable to the parent compounds, while the C-alkylated analogues were less active.

Animals↗
PubMed1979

Improved antitumor effects in 3'-branched homologues of 2'-deoxythioguanosine. Synthesis and evaluation of thioguanine nucleosides of 2,3-dideoxy-3-(hydroxymethyl)-D-erythro-pentofuranose.

The 3-(hydroxymethyl) branched homologue of 2-deoxyribofuranose was synthesized from the corresponding branched ribofuranose 2-O-(S-methyl dithiocarbonate) with tributyltin hydride in the first direct, one-step deoxygenation at C-2 of a ribofuranose. Nucleoside coupling afforded the corresponding 3'-branched 2'-deoxyribonucleosides of thioguanine. The alpha- and beta-nucleosides were equally inhibitory to growth of WI-L2 human lymphoblastoid cells, were phosphorylated and incorporated into the DNA of Mecca lymphosarcoma in mice to the same degree, and were more effective in these tests than the parent analogue alpha-2'-deoxythioguanosine. These results indicate that the hydroxy functions at the 3' and 5' positions of 2'-deoxynucleosides are interchangeable and that acceptance by the that the furanose ring oxygen and 2'-methylene are corresponding interchangeable, and that acceptance by the enzymes is improved if primary hydroxyls are provided at both the 3' and 5' positions.

Animals↗
PubMed1979

Adriamycin analogues. 3. Synthesis of N-alkylated anthracyclines with enhanced efficacy and reduced cardiotoxicity.

Reaction of daunorubicin (1) and adriamycin (2) with aldehydes and ketones in the presence of NaCNBH3 afforded N-alkyl- and N,N-dialkylanthracyclines along with their 13-dihydro derivatives. Product ratios depended upon the nature of the carbonyl reagent and the starting drug. The majority of these analogues retained in vivo antitumor activity comparable to 1 and 2. However, unlike the parent compounds, which inhibit DNA and RNA synthesis at comparable concentrations, several of these analogues inhibit RNA synthesis at markedly lower concentrations than required to inhibit DNA synthesis. In addition, in some cases the ability to bind to DNA in vitro was reduced while antitumor activity was retained. N,N-Dibenzyldaunorubicin was especially notable for increased efficacy (T/C 259, qd 1--9) against P388 leukemia in mice, despite reduction of DNA binding in vitro. It showed almost complete loss of mutagenicity vs S. typhimurium (Ames test) and it was tenfold less cardiotoxic by electrocardiographic measurements (Zbinden test) in the rat.

Alkylation↗
PubMed1979

7-(Aminoethyl) ether and thioether of daunomycinone.

One-step treatment of daunomycinone with excess 2-aminoethanethiol and 2-aminoethanol in trifluoroacetic acid afforded at C-7 the thioether (77% yield) and ether (30% after recycling), respectively. Stereoselectivity for the natural 7S over the 7R configuration was greater for the ether (97:3) than for the thioether (2.5:1). Esterification of daunomycin at C-7 with beta-alanine was accomplished through the mixed anhydride of Z(OMe)-beta-alanine. Preliminary biological tests suggests that the antitumor and DNA interactive properties of the anthracyclines can be retained in such structures.

Animals↗
PubMed1979

Experimental antitumor activity of aminoanthraquinones.

The activity of a number of substituted alkylaminoanthraquinones was compared in transplanted murine tumor systems including P388 and L1210 leukemias, B16 melanoma, and colon carcinoma 26. The structure-activity relationships among this class of compounds are discussed. Several derivatives had very high antitumor activity in several tumor systems. Two of the most active derivatives, namely, 1,4-bis(2-[(2-hydroxyethyl)amino]ethylamino)-9,10-anthracenedione (bisalkylAAD) and 1,4-dihydroxy-5,8-bis(2-[(2-hydroxyethyl)amino]ethylamino)-9,10-anthracenedione (dihydroxybisalkylAAD), which had curative activity in the above-mentioned tumors, were compared in considerable detail. DihydroxybisalkylAAD showed distinct advantages over bisalkylAAD in several tumor systems and is tenfold more potent with respect to effective dose range. This last difference is important for two reasons. First, these aminoanthraquinones are strong and persistent blue dyes and the administration of lower doses would minimize a potential cosmetic drawback of these compounds. Second and most important, iv administration of dose levels of bisalkylAAD which are within the therapeutic dose range on intermittent dose schedules produced convulsions and immediate death. IV administration of dihydroxybisalkylAAD also caused acute toxicity, but, because of its increased potency relative to antitumor activity and delayed toxicity, this acute toxicity was apparent only at doses well above the therapeutic dose range. All of the aminoanthraquinones evaluated, regardless of their activity as antitumor agents in vivo, proved to be potent inhibitors of DNA and RNA synthesis in vitro and bound strongly to DNA as evidenced by deltaTm values (deltaTm = upward shift in DNA melting temperature). Thus, the strong antitumor activity of aminoanthraquinones would appear to be due to some mechanism other than, or in addition to, DNA binding and inhibition of nucleic acid synthesis.

Animals↗
PubMed1979

Structure-activity relationships among daunorubicin and adriamycin analogs.

Structural characteristics of Adriamycin and daunorubicin analogs are discussed in terms of three antitumor activity classifications: compounds with potency and efficacy equivalent to or superior to the parent antibiotics, compounds displaying high efficacy but with decreased potency, and compounds in which a key structural change has destroyed all in vivo antitumor activity. It is first concluded that analogs possessing efficacy and potency comparable to the parent antibiotics are quite similar to the parents in structural terms, ie, their hydrophilic character, functional groups, and stereochemistry. Within this group there is suggestive evidence that altered electronic character of the aglycones may be associated with improved cardiotoxicity characteristics. The second general conclusion is that high efficacy accompanied by decreased potency is compatible with a much wider array of structural variants than is high efficacy accompanied by high potency. Thus, analogs with substantially higher or lower lipophilicity than the parent antibiotics, as well as those with an array of ionic characteristics differing from the parents, retained significant efficacy. These characteristics are compatible with the concept of multiple mechanisms of action for the anthracycline antibiotics. In general, structural changes in the sugar side chain are appreciably more compatible with retention of in vivo antitumor efficacy than are changes in the aglycone, both in terms of functional groups and stereochemistry.

Animals↗
PubMed1978

Adriamycin analogues. 2. Synthesis of 13-deoxyanthracyclines.

The syntheses of several 13-deoxyanthracyclines are described. Koenigs-Knorr condensation of epsilon-rhodomycinone (12) with the protected daunosaminyl chloride 15 afforded 14 after deprotection. Efforts to decarbomethoxylate 12, as well as attempts to selectively deoxygenate the 13 position of daunomycinone and adriamycinone, were unsuccessful as approaches to 13-deoxyanthracyclines. However, reaction of the readily available tosylhydrazones 4 and 5, of daunorubicin and adriamycin with NaCNBH3 in acidic MeOH, afforded the 13-deoxy analogues 6 and 7 in satisfactory yield. These compounds retained antitumor activity, being comparable to the parent compounds in both efficacy and potency in the P-388 mouse leukemia screen. The epsilon-rhodomycinone glycoside 14 was less active than 6 and 7.

Animals↗