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Biomedical subjects

V Knight

Publications and source records attributed to V Knight.

At least 19 recordsLinked to original sources
PubMed1997

Pulmonary delivery of beclomethasone liposome aerosol in volunteers. Tolerance and safety.

STUDY OBJECTIVE: To test the tolerance and safety of single doses of beclomethasone dipropionate (Bec)-dilauroylphosphatidylcholine (DLPC) liposome aerosol in volunteers. DESIGN: Single-dose inhalations of liposome preparations of Bec-DLPC and DLPC alone were administered for 15 min from a jet nebulizer (Puritan-Bennett, modified twin jet; mass median aerodynamic diameter of 1.6 microns) under close clinical and laboratory surveillance. Two dose levels (0.5 mg Bec/12.5 mg DLPC per milliliter, and 1.0 mg Bec and 25 mg DLPC per milliliter in the reservoirs, respectively) were administered. The Bec doses were selected to approximate the dosages of this glucocorticoid used with metered-dose inhalers (MDIs). First, four volunteers were exposed to an initial low dose; the mean (+/-SD) inhaled doses were 0.56 +/- 0.07 mg of Bec and/or 14.0 +/- 1.8 mg of DLPC. Subsequently, a second group of six volunteers was exposed to a higher dose; the mean (+/-SD) inhaled doses were 1.29 +/- 0.14 mg of Bec and/or 34.6 +/- 6.8 mg of DLPC. SETTING: Outpatient and inpatient. PATIENTS: Normal male (n = 6) and female (n = 4) adult volunteers. INTERVENTIONS: Inhalation of Bec-DLPC and DLPC liposome aerosols in a single-dose tolerance study involving 10 normal volunteers. MEASUREMENTS AND RESULTS: Spirometry, clinical observations, clinical chemistry, and hematology were monitored. No adverse clinical or laboratory events were observed. CONCLUSIONS: Bec-DLPC liposome aqueous aerosol was well tolerated in doses equivalent to those currently administered by MDIs and dry powder inhalers for treatment of asthma.

Adult↗
PubMed1996

Synergistic iron reduction and citrate dissimilation by Shewanella alga and Aeromonas veronii

Two bacterial isolates from Great Bay Estuary, New Hampshire, in co-culture carried out anaerobic dissimilation of citric acid with Fe(III) as the terminal electron acceptor. Neither isolate oxidized citrate with Fe(III) anaerobically in axenic culture. The Fe(III) reducer, Shewanella alga strain BrY, did not grow anaerobically with citrate as an energy source. The citrate utilizer, Aeromonas veronii, did not reduce iron axenically with a variety of electron donors including citrate. The onset of iron reduction by the co-culture occurred after initiation of citrate dissimilation and just prior to initiation of growth by either organism (as measured by viable plate counts). Anaerobic culture growth rates and final cell densities of each bacterial strain were greater in co-culture than in axenic cultures. By 48 h of growth, the co-culture had consumed 27 mM citrate as compared with 12 mM dissimilated by the axenic culture of A. veronii. By 48 h the co-culture produced half as much formate (6 mM) and twice as much acetate (40 mM) as did A. veronii grown axenically (12 mM and 20 mM, respectively). Formate produced from citrate by A. veronii appeared to have supported growth and Fe(III) reduction by S. alga.Although not obligatory, nutrient coupling between these two organisms illustrates that fermentative (A. veronii-type) organisms can convert organic compounds such as citrate to those used as substrates by dissimilatory Fe(III) reducers, including S. alga. This synergism broadens the range of substrates available for iron reduction, stimulates the extent and rate of organic electron donor degradation (and that of iron reduction) and enhances the growth of each participant.

Journal Article↗
PubMed1994

Operating characteristics of 18 different continuous-flow jet nebulizers with beclomethasone dipropionate liposome aerosol.

A study of 18 different commercially available continuous-flow, jet nebulizers was performed with a standard liposomal formulation of beclomethasone dipropionate (Bec-DP) prepared with dilauroyl phosphatidylcholine (Bec-DLPC). The analysis compared the total Bec-DP output from aqueous suspensions of Bec-DLPC containing an initial starting reservoir concentration of 0.5 mg/ml. Aerosols from each nebulizer tested were characterized by the mass median aerodynamic diameter, geometric standard deviation, drug output, and the predicted percentage regional deposition of inhaled Bec-DLPC liposomes within the human respiratory tract. These data can provide a basis for the selection of commercially available jet nebulizers for use with glucocorticoid liposome aerosols for treatment of asthma and other inflammatory lung diseases.

Aerosols↗
PubMed1993

Characterization and administration of cyclosporine liposomes as a small-particle aerosol.

Systemically administered CsA has not consistently suppressed the pulmonary immunoreactivity that leads to rejection in lung transplant patients. Pulmonary T cells from patients given CsA systemically still retain their immunoreactivity, which can be suppressed with added CsA. Direct application of CsA by aerosol to the respiratory epithelium should achieve high lung concentrations with minimum systemic effects. In the present study, CsA was most efficiently incorporated into liposomes composed of egg yolk phosphatidylcholine at a molar ratio of CsA to egg yolk phosphatidylcholine of 1:20. These CsA liposomes retained their biological activity and were as effective as free CsA in the suppression of anti-CD3-stimulated [3H]thymidine incorporation by mouse spleen cells. The generation of a small-particle aerosol of CsA liposomes had no effect on this biological activity. CsA liposome aerosol particles have a mass median aerodynamic diameter of 2 microns, which allows for distribution of drug throughout the respiratory tract. Quantitation of CsA in the lungs and blood of mice exposed to CsA liposome aerosols for 4 days showed that as little as 15 min daily (0.11 mg/kg/day) was sufficient to achieve an estimated concentration of CsA in respiratory secretions of 6 micrograms/ml without detectable blood levels. Thus, CsA liposomes can be produced and aerosolized that achieve pulmonary concentrations with sufficient immunosuppressive activity to be effective in the treatment of lung diseases.

Aerosols↗
PubMed1992

Further studies with short duration ribavirin aerosol for the treatment of influenza virus infection in mice and respiratory syncytial virus infection in cotton rats.

Ribavirin aerosol administration has been shown to be effective in the treatment of respiratory syncytial virus (RSV) infections in infants and in influenza A and B virus infections in young adults. Long treatment schedules and potential for environmental contamination have stimulated the search for alternative dosing schedules. Thus, we attempted to determine the length of time of ribavirin aerosol necessary for effective treatment of influenza and RSV. In RSV-infected cotton rats, aerosolization for just 30 min with high-dose ribavirin (HDR:60 mg ribavirin/ml in reservoir), 3 times daily, reduced viral lung titers/gm of tissue by 1.1 log10. In influenza virus-infected mice, 15 min of aerosolized HDR, 3 times daily, was effective in reducing both mortality and pulmonary virus titers (1.1 log10 reduction). When the intervals between aerosol administration each day were equally divided (i.e., q.8 h), the treatments were most effective. Treatment for 45 min, once daily, was not as effective as divided doses. Calculations of ribavirin concentrations in respiratory secretions following 15 min treatment in mice with HDR indicated that drug levels dropped below the ED50 for influenza viruses after about 9 h. A daily dosage of ribavirin, estimated to be 8-15 mg/kg, was effective for the treatment of influenza and RSV infections.

Aerosols↗
PubMed1990

Aerosol treatment of respiratory viral disease.

We have described a reasonably accurate method of predicting ribavirin small-particle aerosol dosage administered by nasal inhalation or endotracheal tube adjusted for age, sex, weight, and fever. Regional distribution of inhaled small particles was also presented according to age. This methodology will predict dosage for many other drugs given in this way as long as they are water-soluble and their density in solution does not differ materially from unity. A standardized method of estimating dosage should make possible quantitative comparisons of treatment in different studies. Also presented were studies in which triple the usual dose of ribavirin aerosol was administered, but in one third of the usual dosage period. Aged patients with chronic obstructive pulmonary disease tolerated the treatment with little difficulty, and a group of infants and children with RSV disease recovered promptly with no evidence of intolerance to the treatment. This modification of dosage offers increased accessibility for patient care, and the therapeutic benefits seem as good as the longer regimen. Higher respiratory secretion concentrations with the high-dose regimen may conceivably improve therapeutic results over current methods.

Administration, Inhalation↗
PubMed1989

Liposomes of enviroxime and phosphatidylcholine: definition of the drug-phospholipid interactions.

Interaction of the antiviral compound, enviroxime (E), with natural and synthetic phosphatidylcholines in organic and aqueous media was studied. Although insoluble in chloroform, E dissolved in chloroform solutions containing phosphatidylcholines. Solvation was directly related to the length of the fatty acid chains of the phospholipid. Proton spin resonance studies suggested an interaction of the fatty acid chains with the aromatic rings of E. Suspension of E-phosphatidylcholine mixtures of molar ratios up to 0.7:1.0 in aqueous media resulted in the formation of multilamellar liposomes. Liposomes containing E were more stable permeability barriers than those prepared with phospholipid alone, a property previously observed with cholesterol. Competition experiments suggested that E bound to the same sites in lipid bilayers as does cholesterol. These data indicate that E is incorporated into lipid bilayers of liposomes and that it alters the physical properties of the liposomes in a manner similar to that of cholesterol.

Benzimidazoles↗
PubMed1988

Antiviral therapy with small particle aerosols.

The generation and use of small particle aqueous aerosols (1.23 microns aerodynamic mass median diameter, GSD = 2.0 microns) containing ribavirin is described. Administered via aerosol, ribavirin will be deposited rather uniformly on the surface of the nasopharynx, the tracheobronchial tree and in the pulmonary area. Examples of aerosol-delivered dosages found to be effective in the treatment of respiratory syncytial virus infection and influenza A and B virus infections are as follows: 12.8 mg of ribavirin/hour for a 6-month-old infant weighing 7.5 kg, and 56.2 kg of ribavirin/hour for a 25-year-old adult weighing 62.5 kg. Drugs which are relatively insoluble in aqueous solutions can also be administered in small particle aerosol by using liposomes as a vehicle. The preparation of enviroxime, a potent anti-rhinovirus drug, in liposomes for aerosol use is reported here. Its antiviral activity in liposomes was found to be undiminished, but its cellular toxicity was greatly reduced. It was well-tolerated by normal volunteers and studies are planned to determine its clinical efficacy.

Aerosols↗
PubMed1988

Small particle aerosols of enviroxime-containing liposomes.

Enviroxime inhibits the replication of all rhinoviruses tested in vitro at very low concentrations (10-100 ng/ml), but evaluations in humans have not consistently shown efficacy. Lack of an appropriate method for administering this water-insoluble drug may have contributed to the latter result. The present report describes the characteristics and utilization of small particle aerosols to continuously deliver enviroxime-containing liposomes (LE) throughout the respiratory tract. The enviroxime content of liposomes and biological fluids of exposed individuals was quantified by high performance liquid chromatography using C18 resin, a mobile phase of 60:40 acetonitrile:water, and monitoring at 215 nm. Small particle aerosols of LE generated by Puritan-Bennett nebulizers had mass median diameters ranging from 2.4 to 3.1 microns. The concentration of enviroxime in aerosol particles was proportional to the reservoir concentration; during the first hour of operation, the mean concentration was 20 micrograms of enviroxime/l of aerosol. Liposome particles in the reservoir, although initially heterogeneous in size (less than 0.1 to greater than 1 micron), were processed by passage through the nebulizer to smaller, more homogeneous particles; the majority were less than 0.2 micron. In a preliminary study to evaluate short term tolerance and toxicity, five volunteers were exposed to small particle aerosol of LE for 1 h. At 1 h post-treatment, large amounts of enviroxime were still present in the nasal wash as determined both by HPLC and biological assay. Enviroxime was not detected in any urine sample and was detected in only 1 of 5 serum samples. No side effects were noted. This data suggest that liposome aerosols offer a method for the delivery of hydrophobic compounds for the treatment of respiratory diseases.

Adult↗
PubMed1988

Estimating the dosage of ribavirin aerosol according to age and other variables.

We describe a method for estimating the dosage of aerosolized ribavirin according to age. The calculations were determined by using a computer model of particle deposition, and corrections are described for sex, body weight, fever, and tracheal intubation. Respiratory tract deposition in infants, after they inhaled an aerosol containing 200 micrograms of ribavirin/L, was 1.8 mg/kg per hour; in adults the deposition was 0.9 mg/kg per hour. Adolescent females and older women have less (7%/kg) respiratory tract deposition than do males. Fever will increase deposition about 9%/degree Centigrade (5%/degree Fahrenheit) for each degree of increase above normal temperature. Tracheal intubation will deliver relatively more drug to the lung and no drug to the nasopharynx. Our report shows the regional and total deposition of inhaled ribavirin aerosol in the respiratory tracts of persons in different age-groups from three months to 25 y.

Adolescent↗
PubMed1988

Activity against rhinoviruses, toxicity, and delivery in aerosol of enviroxime in liposomes.

Enviroxime has been shown to inhibit the replication of rhinoviruses and other enteroviruses in concentrations as low as nanograms per milliliter in in vitro assays but is markedly less effective in clinical trials. The marked hydrophobicity and water insolubility of this compound may be a factor for this disparity. To overcome this handicap, we incorporated enviroxime into liposomes and then tested the antirhinovirus activity and toxicity of the liposome-incorporated enviroxime (LE) in cell culture and studied its administration by small-particle aerosol. Free enviroxime and LE were found to have equivalent efficacies against rhinovirus strains 1A and 13 in in vitro assays; however, preparations of LE were 10- to greater than or equal to 50-fold less toxic to tissue culture cells than was free enviroxime. In contrast to free enviroxime, which could not be delivered by small-particle aerosol because of its water insolubility, LE (4 mg/ml) was readily and successfully delivered by small-particle aerosol to the upper and lower respiratory tracts of mice; after just 20 min, significant levels of enviroxime were detected in the lungs and noses of exposed mice. Moreover, mice exposed to aerosols of liposomes containing both enviroxime and fluorescein isothiophosphatidylethanolamine showed accumulations of the fluorescent marker in the lungs, particularly in or around the tall columnar epithelial cells lining the bronchi and bronchioles.

Aerosols↗
PubMed1987

Ribavirin aerosol treatment of influenza.

In this article we have described the clinical and laboratory features of uncomplicated influenza in college students and its treatment with ribavirin aerosol. The disease presents as an acute febrile systemic illness of short duration that varies little from patient to patient. Peripheral blood cell changes in the infection are also quite specific and very consistent. Polymorphonuclear cell counts are slightly increased above normal early in infection at a time when lymphocyte counts were greatly reduced. As lymphocyte numbers increase at the third day of illness, polymorphonuclear cell counts diminish substantially. Eosinophil counts fluctuate in a pattern similar to that of lymphocytes. Basophil, monocyte, and band cell counts are increased at admission and thereafter decline in numbers. Reticulocytes and platelets are reduced during acute illness. We assume that changes in peripheral white blood cell counts during influenza result from migration of cells to the inflamed respiratory tract and subsequent resupply of the various types of cells to the circulation from other sites in the body. The cellular alterations in the circulation and at the site of infection are of fundamental importance in the pathogenesis of infection, and a better knowledge of them should open new avenues for prevention and treatment. Aerosol treatment was shown to alleviate the symptoms of influenza and to reduce the shedding of influenza virus from the respiratory tract. No evidence of untoward effect of ribavirin treatment on peripheral white or red blood cells was found, and a wide range of clinical chemical tests revealed no toxic effects of treatment. There was no pulmonary irritation detected from the treatment. Reference was made to prompt recovery of four patients with influenzal pneumonia treated with ribavirin aerosol. Ribavirin aerosol must produce its major therapeutic effect through inhibition of virus replication at the sites of infection in the respiratory epithelium. This appears to result mainly from interference with viral messenger RNA initiation and elongation. This is best demonstrated by the prompt decline in viral shedding in treated patients. The associated prompt clinical improvement suggests that illness results from continued virus replication, and when virus replication is retarded, improvement follows. Although treatment promptly reduces illness and virus shedding, antibody response is not reduced in treated patients. We emphasized that ribavirin aerosol had a major therapeutic effect on infections caused by both influenza A and B viruses, and the picture of illness with these types of influenza was not clinically distinguishable.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1986

Influenza virus infection induces functional alterations in peripheral blood lymphocytes.

This report describes alterations in functional responses to lectin-induced stimulation of peripheral blood lymphocytes and in the natural killer cell (NKC) activity, of college students, obtained during an outbreak of influenza A/Philippines/2/82(H3N2) virus infection. These results are compared with similar observations in college students with an acute, febrile, noninfluenzal respiratory illness that occurred during the same outbreak. The lymphopenia typical of influenza during acute illness was shown to be due to a reduction in both T and B cells without alteration in the CD4:CD8 ratio. In addition, phytohemagglutinin and concanavalin A responses were reduced and NKC activity was increased, while pokeweed mitogen reactivity was unaltered at the time of admission to the study. Patients with noninfluenzal illness showed early polymorphonuclear leukocytosis and a similar lymphopenia. Lymphocyte functions were virtually unchanged during acute illness in noninfluenza patients. The relatively specific alterations in lymphocyte responses to lectin-induced stimulation in influenza patients may indicate that the peripheral T cells are incapable of activation via the CD3 or CD2 activation pathways. In addition, increased NKC activity in the periphery may be reflective of increased NKC activity in the lung. Influenza-infected individuals with higher NKC activity at the time of admission to the study also took longer to recover. Finally, the early lymphopenia and the later neutropenia in the influenza-infected patient may represent migration of these cells from the circulation to the infected respiratory tract as a consequence of infection.

Concanavalin A↗
PubMed1986

Effects of selenazofurin and ribavirin and their 5'-triphosphates on replicative functions of influenza A and B viruses.

We studied the effects of selenazofurin alone and in combination with ribavirin on replication of influenza A and B viruses. These drugs showed little cytotoxicity as measured by leucine incorporation into protein in MDCK cells, although they were potent inhibitors of viral replication in the same cells. Selenazofurin inhibited growth of influenza A and B viruses at concentrations (50% inhibitory dose = 25 and 19 microM, respectively) which were similar to those at which growth was inhibited by ribavirin (50% inhibitory dose = 50 and 30 microM, respectively). The inhibition of replication of either influenza A or B virus was additive for any combination of ribavirin and selenazofurin. The effects of the 5'-triphosphate of selenazofurin on two replicative functions associated with the influenza virus RNA-dependent RNA polymerases, primer generation (initiation of transcription) and its subsequent elongation, were measured. Elongation was more sensitive to selenazofurin 5'-triphosphate than was primer generation, and the effects of this drug on these functions were approximately the same as those of ribavirin 5'-triphosphate. The activities of ribavirin triphosphate and selenazofurin triphosphate were additive, and combinations did not potentiate the individual inhibitory effects of these drugs on elongation.

Animals↗
PubMed1986

Chemotherapy of respiratory viruses.

We have described positive clinical effects of seven different anti-viral drugs in the treatment of viral respiratory diseases; three of these agents are approved for clinical use--amantadine, acyclovir, and vidarabine. Of the remaining four, the most consistent and broadest range of effect was observed with ribavirin while rimantadine was similar to amantadine in its effect. Interferon and enviroxime, under the conditions in which they were tested, showed a range of effect from moderate to no effect. A feature of the use of ribavirin was its administration by inhalation over several hour periods as a small-particle aerosol. This allowed a total dosage not much less than might have been given by other routes, but with the advantage that it was evenly deposited over the surface of the infected respiratory tract beginning within seconds of the start of treatment and reached higher concentration in nasal secretions than in serum. It may be that aerosol administration can be used with other drugs, as suggested by preliminary results with amantadine. We regard the results presented in this chapter as very encouraging, but just a beginning. Effective therapy will set in motion a reexamination of many problems of viral respiratory tract infection, including how to develop more rapid and more precise viral diagnosis, the need for further characterization of both short- and long-term consequences of infection in the untreated host and their modification by treatment. The structure for rapid progress in treatment of viral diseases is in place, and with it should come a resolution of many long-standing problems in this area of medicine.

Acyclovir↗
PubMed1985

Effect of repeated intraperitoneal injections of soman on schedule-controlled behavior in the rat.

Intraperitoneal (IP) administration of the acetylcholinesterase inhibitor, soman (10-40 micrograms/kg), suppressed in a dose-related manner response rates in rats maintained under a multiple fixed-interval 50-s fixed-ratio 25 schedule of food delivery. Chronic administration of soman at weekly intervals resulted in tolerance to the response. When soman administration was separated by 2-5 weeks in individual rats, the suppressive effects of the agent again became apparent. Analysis of acetylcholinesterase activity revealed that enzyme inhibition was limited to gastrointestinal areas near the site of injection. There was no significant effect on brain acetylcholinesterase even following IP injection of doses which completely suppressed responding. The IP route may be useful for studying tolerance and other chronic effects of soman without producing generalized toxicity.

Acetylcholinesterase↗
PubMed1985

Mode of action of ribavirin: effect of nucleotide pool alterations on influenza virus ribonucleoprotein synthesis.

Ribavirin, a guanosine analogue, is a broad spectrum antiviral agent which is effective in the treatment of influenza. In this study, the effect of ribavirin on influenza virus ribonucleoprotein (RNP) synthesis and nucleotide pool sizes was simultaneously measured. Ribavirin (100 microM) reduced viral RNP synthesis 94% as measured by UTP incorporation. Intracellular GTP pools, measured by high performance liquid chromatography, were reduced approximately 45% in ribavirin treated cells, while other nucleotides remained near control values. Attempts to reverse ribavirin's inhibitory effects on viral RNP synthesis by addition of exogenous guanosine (50 microM) resulted in only a partial restoration of viral RNP synthesis, despite full restoration of the GTP pool. Dose-response experiments indicated that the GTP pool was significantly reduced (65% of control) at 25 microM ribavirin, and increasing concentrations of the drug caused only a small further reduction in the GTP pool (5-10% at 100 microM). In contrast, RNP synthesis was inhibited by 50% at 25 microM ribavirin and was further decreased to 5% of control at 100 microM ribavirin. Thus, ribavirin's antiviral activity may result from a reduction of the GTP pool size combined with direct effects on viral replicative enzymes.

Guanosine↗