Small-particle Aerosol Research Articles

The realities of biodefense vaccines against Rickettsia

Rickettsia prowazekii, R. rickettsii, R. conorii, and R. typhi are serious biologic weapon threats because of high infectivity of low dose aerosols, stable small particle aerosol infectivity, virulence causing severe disease, difficulty in establishing a timely diagnosis, ineffectiveness of usual empiric treatments, potential for engineered complete antimicrobial resistance, lower level of immunity, availability of the agents in nature, and feasibility of propagation, stabilization, and dispersal. Infection induces long-term immunity, killed rickettsial vaccines stimulate incomplete protection, and a live attenuated mutant stimulates strong immunity but reverts to virulence. Prospects for rational development of a safe, effective live attenuated vaccine are excellent.

Optical attenuation in fog at a wavelength of 1.55 micrometers

As part of a series of studies on laser propagation for terrestrial free space optical (FSO) telecommunications or laser telecommunications, an experiment was conducted to determine the relationship between visibility in fog and optical attenuation (dB/km) at a laser wavelength of 1.55 μm. In the telecommunications industry, a semi-empirical equation, called the Kruse formula [Kruse, P.W., McGlauchlin, L., McQuistan, R.B., 1962. Elements of infrared technology: generation, transmission, and detection. John Wiley and Sons, New York] is typically used to calculate expected attenuation for a given meteorological visibility. The Kruse formula, however, was developed to relate meteorological visibility to optical attenuation over wavelengths from the visible to the near infrared (IR), and for dust and small particle aerosols with dimensions much smaller than the wavelength. Typically, suspended small aerosols have diameters that average about 0.1 μm while fog droplets have diameters that range upward from 2.5 μm with mean diameters that exceed 10 μm in some fogs. Therefore, application of the Kruse formula to attenuation in fog is not appropriate since fogs consist mainly of particles much larger than the laser wavelength. As part of the experiment, a transmissometer with an 85-m baseline and a dynamic range of 60 dB operated for thirteen months in an area prone to radiation fog. A commercial visibility sensor, similar to those used at airports, was located near the middle of the optical path of the transmissometer and operated over the same period. The largest attenuation measured at this site was just over 300 dB/km, corresponding to a visibility of 32 m. The key finding of the study is that the generally accepted Kruse formula relating visibility and optical attenuation may be too pessimistic at low visibilities, and actual attenuation values for a given visibility may be more than 20% lower than previously thought. At visibilities exceeding about 650 m, the Kruse formula gives a good estimate of optical attenuation.

Efficacy of therapeutic intervention with an oral ether–lipid analogue of cidofovir (CMX001) in a lethal mousepox model

In the 21st century we are faced with the potential use of natural or recombinant VARV and MPXV as biological weapons, and the emergence of human MPXV. Such an occurrences would require therapeutic and prophylactic intervention with antivirals. Cidofovir, an antiviral approved for the treatment of cytomegalovirus retinitis in AIDS patients, has activity against poxviruses, but must be administered intravenously and is associated with nephrotoxicity. An ether–lipid analogue of CDV, CMX001 (HDP-CDV), has potent antiviral activity against a range of DNA viruses including poxviruses, excellent oral bioavailability and minimal nephrotoxicity. CMX001 and CDV are equally efficacious at protecting mice from mortality following high ectromelia virus doses (10,000 × LD 50) introduced by the intra-nasal route or small particle aerosol. Using CMX001 at a 10 mg/kg dose followed by 2.5 mg/kg doses every other-day for 14 days provided solid protection against mortality and weight loss following an intra-nasal challenge of (100–200) × LD 50 of ectromelia virus. Furthermore, complete protection against mortality was achieved when administration was delayed until as late as 5 days post-infection, which is 3–4 days prior to the death of the untreated controls. This therapeutic window would be equivalent to intervening during the rash stage of ordinary smallpox.

Vaccines Against Francisella Tularensis

Francisella tularensis is one of the most pathogenic pathogens known, especially when disseminated as a small particle aerosol. Because of this, it was developed into a biological warfare agent by several states during the 20th century. Nowadays, concerns remain about the potential of this pathogen to cause widespread disease, tularemia, in the hands of terrorists. This has resurrected interest in methods to combat it. This article reviews the current status of vaccine development efforts against tularemia. To date most of our understanding of tularemia vaccine efficacy has been derived from the clinical and experimental use of a pragmatically attenuated live vaccine strain of F. tularensis subspecies holarctica. However, this vaccine which has been in existence for more than 50 years is still beset by regulatory issues that continue to hamper its licensure. These issues and possible solutions are highlighted, along with more modern molecular approaches to vaccine development against this highly virulent pathogen.

Respiratory syncytial virus fusion inhibitors. Part 3: Water-soluble benzimidazol-2-one derivatives with antiviral activity in vivo

The introduction of acidic and basic functionality into the side chains of respiratory syncytial virus (RSV) fusion inhibitors was examined in an effort to identify compounds suitable for evaluation in vivo in the cotton rat model of RSV infection following administration as a small particle aerosol. The acidic compounds 2r, 2u, 2v, 2w, 2z, and 2aj demonstrated potent antiviral activity in cell culture and exhibited efficacy in the cotton rat comparable to ribavirin. In a BALB/c mouse model, the oxadiazolone 2aj reduced virus titers following subcutaneous dosing, whilst the ester 2az and amide 2aab exhibited efficacy following oral administration. These results established the potential of this class of RSV fusion inhibitors to interfere with infection in vivo following topical or systemic administration.

Community-acquired respiratory viruses

Community-acquired respiratory viruses

Ribavirin, viramidine and adenosine-deaminase-catalysed drug activation: implication for nucleoside prodrug design.

The epidemics caused by pathogenic viruses, such as HIV, hepatitis C virus (HCV) and most recently the severe acute respiratory syn- drome (SARS) by a new coronavirus, represent major global health hazards, which demand novel broad-spectrum antiviral intervention. Although discovered 40 years ago, ribavirin (1-β-D-ribofuranosyl- 1,2,4-triazole-3-carboxamide) remains the only approved small mol- ecule drug that is active against both DNA and RNA viruses. 1 The unique antiviral profile of ribavirin deserves a brief review of its dis- covery. Back in the 1960s, two five-membered ring nucleoside anti- biotics, showdomycin and pyrazomycin, were isolated from bacterial culture, and both (Figure 1) showed significant activity against a broad series of viruses in cell culture. The novel properties of these nucleoside antibiotics prompted synthesis and testing of a number of imidazole- and triazole-based ribonucleosides. 2 Among them, riba- virin (originally termed Virazole) stood out as the most promising broad-spectrum antiviral agent. Structurally, ribavirin is a ribo- nucleoside with an unconventional triazole base (Figure 1). X-ray crystallographic studies indicated that the five-membered triazole ribonucleoside is capable of mimicking the conformation of several canonical purine ribonucleosides with its 3-carboxamide oxygen and nitrogen spatially eclipsing the O6 and N1 atoms of inosine and guanosine. By rotating the C3-C6 bond by 180°, ribavirin also resembles the conformation of adenosine. The multiple conforma- tions adopted by ribavirin make it possible to target both viral and host enzymes that utilize purine ribonucleosides/nucleotides as a substrate or a cofactor, and may hold the key for its broad-spectrum antiviral activity. Current data support the notion that ribavirin acts by pleiotropic modes of action. 3 Ribavirin itself is a prodrug that is metabolized to the active 5'-monophosphate, -diphosphate and -tri- phosphate in vivo. Ribavirin 5'-monophosphate (RMP) inhibits cel- lular inosine monophosphate dehydrogenase (IMPDH), thereby depleting intracellular pools of GTP for viral replication. Ribavirin 5'-triphosphate (RTP) is the major metabolite accumulated in vivo. It is an effective inhibitor of viral RNA guanylyl transferase and (gua- nine-7N-)-methyl transferase, contributing to the defective 5'-cap structure of viral transcripts and insufficient translation. All the 5'-phosphate forms of ribavirin have been implicated as direct inhibitors of viral RNA polymerases. As a nucleotide analogue, RTP can also be incorporated into a viral genome and induces virus error catastrophe by mutations. 4 In a recent study of poliovirus replication in cell culture, a single mutation in the poliovirus RNA-dependent RNA polymerase was shown to confer resistance to ribavirin. 5 This is the first report of viral resistance to ribavirin. This study reinforces the notion that the transition mutations caused by incorporation of ribavirin as a mutagen are responsible for antiviral activity, at least in the case of poliovirus. On the other hand, consistent with the broad-spectrum antiviral property, ribavirin is also a small molecule immunomodulator and is capable of eliciting immuno-based anti- viral activities by shifting the host immune response to 'type 1', thereby enhancing T cell mediated immunity that favours elimin- ation of intracellular viral pathogens. The fact that no ribavirin resist- ance has been convincingly identified in the clinical setting supports the notion that ribavirin exerts its effect through non-specific or pleiotropic mechanisms. Despite its success as an effective antiviral in cell culture and in animal infection models, the clinical application of ribavirin has so far met with mixed results. One factor that may limit its clinical potential is the dose-limiting haemolytic anaemia when high doses are administered. Ribavirin formulated as small particle aerosol is currently approved for treatment of the respiratory syncytial virus (RSV) infection. In capsule or tablet form it is used as a part of combination therapy for chronic HCV infection. Notably, the com- bination therapy of ribavirin with interferon-α (both native and pegylated forms) has become the 'gold' standard for anti-HCV chemotherapy.

Final Report on the Safety Assessment of Stearoxy Dimethicone, Dimethicone, Methicone, Amino Bispropyl Dimethicone, Aminopropyl Dimethicone, Amodimethicone, Amodimethicone Hydroxystearate, Behenoxy Dimethicone, C24–28 Alkyl Methicone, C30–45 Alkyl Methicone, C30–45 Alkyl Dimethicone, Cetearyl Methicone, Cetyl Dimethicone, Dimethoxysilyl Ethylenediaminopropyl Dimethicone, Hexyl Methicone, Hydroxypropyldimethicone, Stearamidopropyl Dimethicone, Stearyl Dimethicone, Stearyl Methicone, and Vinyldimethicone

Dimethicone is a fluid mixture of fully methylated linear siloxane polymers end-blocked with trimethylsiloxy units. Methicone is a linear monomethyl polysiloxane. The other dimethicones and methicones covered in this review are siloxane polymers of Dimethicone and Methicone. Most of these ingredients function as conditioning agents in cosmetic formulations at current concentrations of use of ≤ 15%. Clinical and animal absorption studies reported that Dimethicone was not absorbed following oral or dermal exposure. Dimethicone, Methicone, and Vinyldimethicone were not acutely toxic following oral exposure. No adverse reactions were found in rabbits following short-term dermal dosing with 6% to 79% Dimethicone, yet adverse effects were noted with a hand cream formulation containing 1% Dimethicone, suggesting something else in the preparation was toxic. Mice and rats were dosed for 90 days with up to 10% Dimethicone without adverse effect. Dimethicone did not produce adverse effects in acute and short-term inhalation-route studies, Methicone and Vinyldimethicone were negative in acute exposure studies using rats, but Hexyl Methicone was toxic to rats at 5 mg/L delivered in small particle (mean diameter of 0.29 μ) aerosols. Most dermal irritation studies using rabbits classified Dimethicone as a minimal irritant. Dimethicone (tested undiluted and at 79%) was not a sensitizer in four assays using mice and guinea pigs. It was not a sensitizer at 5.0% in a clinical repeated insult patch test using 83 panelists. Most ocular irritation studies using rabbits classified Dimethicone as a mild to minimal irritant. Dimethicone was tested in numerous oral-dose (using rats) and dermal-dose (using rats, rabbits, and monkeys) reproductive and developmental toxicity studies. In a few studies, treated males had significantly decreased body weight and/or decreased testes or seminal vesicles weights. No treatment-related adverse findings were noted in dosed pregnant females or fetuses. Dimethicone was negative in all genotoxicity assays. It was negative in both an oral (tested at 91%) and dermal (tested at an unknown concentration) dose carcinogenicity assay using mice. The Cosmetic Ingredient Review (CIR) Expert Panel considered it unlikely that any of these polymers would be significantly absorbed into the skin due to their large molecular weight. Although adverse effects were noted in one inhalation study with small aerosol particles, the expected particle sizes for cosmetic products would primarily be in the range of 60 to 80 μ, and less than 1% would be under 10 μ, which is an upper limit for respirable particles. Overall, the safety test data support the safety of these ingredients at the concentrations they are known to be used in cosmetic formulations. Accordingly, the CIR Expert Panel was of the opinion that Stearoxy Dimethicone, Dimethicone, Methicone, Amino Bis-propyl Dimethicone, Aminopropyl Dimethicone, Amodimethicone, Amodimethicone Hydroxystearate, Behenoxy Dimethicone, C24–28 Alkyl Methicone, C30–45 Alkyl Methicone, C30–45 Alkyl Dimethicone, Cetearyl Methicone, Cetyl Dimethicone, Dimethoxysilyl Ethylenediaminopropyl Dimethicone, Hexyl Methicone, Hydroxypropyldimethicone, Stearamidopropyl Dimethicone, Stearyl Dimethicone, Stearyl Methicone, and Vinyldimethicone are safe as used in cosmetic formulations.

Final Report on the Safety Assessment of Stearoxy Dimethicone, Dimethicone, Methicone, Amino Bispropyl Dimethicone, Aminopropyl Dimethicone, Amodimethicone, Amodimethicone Hydroxystearate, Behenoxy Dimethicone, C24-28 Alkyl Methicone, C30-45 Alkyl Methicone, C30-45 Alkyl Dimethicone, Cetearyl Methicone, Cetyl Dimethicone, Dimethoxysilyl Ethylenediaminopropyl Dimethicone, Hexyl Methicone, Hydroxypropyldimethicone, Stearamidopropyl Dimethicone, Stearyl Dimethicone, Stearyl Methicone, and Vinyldimethicone

Dimethicone is a fluid mixture of fully methylated linear siloxane polymers end-blocked with trimethylsiloxy units. Methicone is a linear monomethyl polysiloxane. The other dimethicones and methicones covered in this review are siloxane polymers of Dimethicone and Methicone. Most of these ingredients function as conditioning agents in cosmetic formulations at current concentrations of use of <15%. Clinical and animal absorption studies reported that Dimethicone was not absorbed following oral or dermal exposure. Dimethicone, Methicone, and Vinyldimethicone were not acutely toxic following oral exposure. No adverse reactions were found in rabbits following short-term dermal dosing with 6% to 79% Dimethicone, yet adverse effects were noted with a hand cream formulation containing 1% Dimethicone, suggesting something else in the preparation was toxic. Mice and rats were dosed for 90 days with up to 10% Dimethicone without adverse effect. Dimethicone did not produce adverse effects in acute and short-term inhalation-route studies, Methicone and Vinyldimethicone were negative in acute exposure studies using rats, but Hexyl Methicone was toxic to rats at 5 mg/L delivered in small particle (mean diameter of 0.29 μ) aerosols. Most dermal irritation studies using rabbits classified Dimethicone as a minimal irritant. Dimethicone (tested undiluted and at 79%) was not a sensitizer in four assays using mice and guinea pigs. It was not a sensitizer at 5.0% in a clinical repeated insult patch test using 83 panelists. Most ocular irritation studies using rabbits classified Dimethicone as a mild to minimal irritant. Dimethicone was tested in numerous oral-dose (using rats) and dermal-dose (using rats, rabbits, and monkeys) reproductive and developmental toxicity studies. In a few studies, treated males had significantly decreased body weight and/or decreased testes or seminal vesicles weights. No treatment-related adverse findings were noted in dosed pregnant females or fetuses. Dimethicone was negative in all genotoxicity assays. It was negative in both an oral (tested at 91%) and dermal (tested at an unknown concentration) dose carcinogenicity assay using mice. The Cosmetic Ingredient Review (CIR) Expert Panel considered it unlikely that any of these polymers would be significantly absorbed into the skin due to their large molecular weight. Although adverse effects were noted in one inhalation study with small aerosol particles, the expected particle sizes for cosmetic products would primarily be in the range of 60 to 80 μ, and less than 1% would be under 10 μ, which is an upper limit for respirable particles. Overall, the safety test data support the safety of these ingredients at the concentrations they are known to be used in cosmetic formulations. Accordingly, the CIR Expert Panel was of the opinion that Stearoxy Dimethicone, Dimethicone, Methicone, Amino Bispropyl Dimethicone, Aminopropyl Dimethicone, Amodimethicone, Amodimethicone Hydroxystearate, Behenoxy Dimethicone, C24-28 Alkyl Methicone, C30-45 Alkyl Methicone, C30-45 Alkyl Dimethicone, Cetearyl Methicone, Cetyl Dimethicone, Dimethoxysilyl Ethylenediaminopropyl Dimethicone, Hexyl Methicone, Hydroxypropyldimethicone, Stearamidopropyl Dimethicone, Stearyl Dimethicone, Stearyl Methicone, and Vinyldimethicone are safe as used in cosmetic formulations.

Pharmacokinetics of a benzodithiin (RD3-0028) following aerosol treatment in rat

1. RD3-0028, a benzodithiin compound, has potent antiviral activity against respiratory syncytial virus (RSV) in cell culture. The compound also inhibits growth of RSV and improves pathologic changes of interstitial pneumonia in the immunosuppressed mouse when delivered by small-particle aerosol. 2. In the present study, the absorption, distribution and excretion of 14C-RD3-0028 were compared in rat following either a single aerosol treatment or oral administration. 3. The plasma concentration was maintained at the same level from 5 min to 1 h, and decreased with a half-life of 2.2 ± 0.1 h for 1-8 h. 4. The excretion of radioactivity in the urine and faeces at 24 h after aerosol treatment was 89.3 and 4.5%, respectively, indicating that almost all the radioactivity was rapidly excreted in the urine. The excretion of total radioactivity was 98.9% within 168 h. 5. The concentrations of radioactivity in the lung and trachea following aerosol treatment were higher than those in other tissues, and were detected even at 72 h. 6. These results suggest that the aerosol treatment might be useful for delivering RD3-0028 to the respiratory tract of RSV-infected patients.

9-NITROCAMPTOTHECIN LIPOSOME AEROSOL: LACK OF SUBACUTE TOXICITY IN DOGS

9-Nitrocamptothecin (9-NC) dilauroylphosphatidylcholine (DLPC) liposome aerosol was evaluated for potential toxicity in an 8-wk, subacute toxicity study in dogs. Fourteen adult dogs were divided into 2 groups with 10 animals in the 9-NC-DLPC treatment group and 4 animals in the DLPC-only vehicle control group. 9-NC-DLPC was administered to the animals using an Aerotech II nebulizer flowing at 10 L/min. Fullface exposures for 60 min were conducted for 5 consecutive days a week for 8 wk. The estimated deposited aerosol dose was 24.7 µg/kg/day. Animals in the vehicle control group received aerosolized DLPC only. Body weight, food consumption, urinalysis, in-life observations, hematology, plasma chemistry, and necropsy and histopathology were monitored before and during the treatment period and in a subset of animals for 2 wk following the end of treatment. Animals were observed for signs of pharmacologic and/or toxicologic effects three times on days of dosing and once daily on nondosing days. 9-NC-DLPC liposomes administered as a small-particle aerosol were determined to be nontoxic to dogs when given for 5 days/wk, for a duration of 8 wk. DLPC-only liposome also had no toxic effects.

Treatment of aerosolized cowpox virus infection in mice with aerosolized cidofovir

The Brighton strain of cowpox virus causes lethal bronchopneumonia when delivered as a small-particle (1 μm) aerosol to weanling BALB/c mice. We showed previously that this disease can be prevented or cured with one subcutaneous injection of cidofovir (HPMPC, Vistide®). To determine whether even better results could be obtained by delivering the drug directly to the respiratory tract, we administered cidofovir by small-particle aqueous aerosol before or after aerosolized cowpox infection. In a series of five experiments, aerosol doses of 0.5–5 mg/kg were always more effective than 25 mg/kg and sometimes more effective than 100 mg/kg injected subcutaneously, as measured by changes in body and lung weight, lung viral titers, pulmonary pathology and survival. A cyclic analog ((1-[( S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl] cytosine) (cHPMPC) was less protective. The results suggest that aerosolized cidofovir would be effective for prophylaxis or early post-exposure therapy of human smallpox or monkeypox virus infection.

Nosocomial viral infections revisited

In 1980 and 1981, Valenti et al. (l-4) published a series of ground-breaking articles that addressed, for the first time in a comprehensive manner, the epidemiology and control of nosocomial viral infections. Since then, significant advances have been made in viral diagnosis, prophylaxis, and treatment of viral infections. Moreover, these guidelines were published before the recognition of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) and before the implementation of “standard” precautions in the health care setting. The following, then, is an overview and an update on the detection and prevention of nosocomial viral infections. Nosocomial viral infections can be separated into different categories based on their mode of transmission. Bloodborne viruses, such as cytomegalovirus (CMV), hepatitis B virus (HBV), HCV, hepatitis D virus, HIV1 and -2, parvovirus, HTLV-I, and HTLV-II, are transmitted by transfusion and blood and blood products. In addition, undergoing dialysis or organ-transplantation and contact with certain body fluids have also been shown as routes of transmission for some of these viruses (5). Airborne transmission by smallparticle aerosol nuclei ( Gum in size) has been implicated for influenza, measles, and varicella-zoster (VZV) viruses. Large-droplet (>5pm) aerosol transmission occurs with adenovirus, influenza virus, mumps virus, parainfluenza virus, parvovirus B 19, rhinovirus, respiratory syncytial virus, and rubella virus. Enteric adenoviruses, enteroviruses, hepatitis A virus (HAV), rotavirus, and other gastroenteritis viruses are transmitted by the fecal-oral route or by contact with contaminated objects or surfaces in the patient’s environment. Herpes simplex virus (HSV) and VZV are spread by direct contact with patient lesions; CMV and HSV are spread by intimate contact with infectious secretions (2,6,7).

Precautions against biological and chemical terrorism directed at food and water supplies.

Deliberate food and water contamination remains the easiest way to distribute biological or chemical agents for the purpose of terrorism, despite the national focus on dissemination of these agents as small-particle aerosols or volatile liquids. Moreover, biological terrorism as a result of sabotage of our food supply has already occurred in the United States. A review of naturally occurring food- and waterborne outbreaks exposes this vulnerability and reaffirms that, depending on the site of contamination, a significant number of people could be infected or injured over a wide geographic area. Major knowledge gaps exist with regard to the feasibility of current disinfection and inspection methods to protect our food and water against contamination by a number of biological and chemical agents. However, a global increase in food and water safety initiatives combined with enhanced disease surveillance and response activities are our best hope to prevent and respond quickly to food- and waterborne bioterrorism.

Pharmacological evaluation of aerosolized cannabinoids in mice

The reemergence on the debate of the use of marijuana for medicinal purposes has been the impetus for developing an acceptable delivery form of aerosolized cannabinoids. The goals of the present study were to: (1) develop and characterize the physical properties of an aerosolized form of Δ 9-tetrahydrocannabinol (Δ 9-THC), the major psychoactive constituent present in marijuana; and (2) assess the pharmacological effects of cannabinoid inhalation in mice. A Small Particle Aerosol Generator (SPAG) nebulizer, used to generate the aerosol, had an output of approximately 0.154 mg/l of aerosolized Δ 9-THC with a 2.0 μm mass median aerodynamic diameter and a 2.2 geometric standard deviation (GSD). Virtually all the particles were less than 5.0 μm in diameter suggesting that they were sufficiently small to penetrate deeply into the lungs. Inhalation exposure to aerosolized Δ 9-THC in mice elicited antinociceptive effects that were dependent on concentration and exposure time with an estimated Δ 9-THC dose of 1.8 mg/kg. On the other hand, inhalation exposure to Δ 9-THC failed to produce two other indices indicative of cannabinoid activity, hypothermia and decreases in spontaneous locomotor activity. The antinociceptive effects occurred within 5 min of exposure and lasted approximately 40 min in duration. The cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H-pyrazole-3-carboxamide HCl (SR 141716A), but not naloxone, blocked these antinociceptive effects (AD 50=0.09 mg/kg) indicating a cannabinoid receptor mechanism of action. Similarly, inhalation exposure to a water soluble cannabinoid analog, 3-(5′-cyano-1′,1′dimethylheptyl)-1-(4- N-morpholinobutyrloxy)-Δ 8-tetrahydrocannabinol (O-1057), produced antinociception that was blocked by SR 141716A. These results demonstrate that the development of an aerosolized form of cannabinoids for human medicinal use is feasible.

Aerosolised liposomal hamycin for treatment of systemic Candida infections in mice.

Mice lethally infected with Candida albicans were exposed to small-particle aerosols containing hamycin liposomes. The drug, when administered twice daily for 2 h (0.68 mg kg(-1) body weight per day) on days 1, 2 and 3 post inoculation, significantly reduced the numbers of Candida organisms in the kidneys. Aerosol treatment increased the survival time of mice given two 2-h treatments once a week for 4 weeks. A twice weekly 2-h small particle aerosol administration of hamycin for 1, 2, or 3 weeks significantly increased both the mean time of survival and percent survival.

Measures for control of influenza.

Influenza viruses cause recurring illnesses among individuals and recurring epidemics among populations. The major effective control measure for preventing infection and illness is inactivated vaccine, which can prevent influenza illnesses and their complications when given before exposure to the virus. While inactivated vaccine is effective for preventing influenza in most individuals, recommendations for its use focus on the prevention of severe disease and death among those who are at high risk of complications. Live attenuated cold-adapted influenza vaccines are nearing availability. They are given by nasal spray and are particularly effective for preventing influenza among young children, but also for preventing influenza among young adults, and enhancing protection against influenza when given with inactivated vaccine to elderly persons. The antiviral agents amantadine and rimantadine are related compounds that are effective for the prevention and treatment of influenza A virus infections and illnesses. Disadvantages are the rapid development of resistance during treatment and CNS adverse effects with amantadine. These drugs are also effective for outbreak control. Ribavirin is an antiviral given by small particle aerosol that is approved for the treatment of respiratory syncytial virus disease; it is also effective for the treatment of influenza. Two new antiviral agents inhibit influenza viral neuraminidase activity; one is given by inhalation or intranasally (zanamivir) and the other orally (GS4104). The former is free of adverse effects, while the latter induces nausea and vomiting in some individuals. Both are effective for the prevention as well as the treatment of influenza A and B illnesses. Thus, various measures for preventing and treating influenza are nearing availability. Their optimal use should further improve the control of influenza in individuals and populations as well as permit efforts to prevent community epidemics.

Vaccinator device for delivering propellant-driven aerosols of Streptococcus suis bacterin into the respiratory tracts of swine

Metered-dose propellant-driven small particle aerosols of a killed whole bacterium, Streptococcus suis, were produced and characterized for their aerodynamic particle sizes and antigenicity as potential respiratory mucosal vaccines against S. suis infections in swine. To facilitate the efficient delivery of such vaccine aerosols to large animals, an electro-mechanical device was developed to synchronize aerosol release to an animals inhalation cycles. The device was tested for its capacity to deliver a fluorescein conjugate of this bacterin (FITC- S. suis) into the respiratory tracts of 18 pigs. Results showed that FITC- S. suis could be detected in the lungs of swine as small as 4.5 kg with as few as two aerosol actuations. Metered-dose propellant-driven aerosols of bacterin vaccines delivered by this respiratory vaccinating device are discussed as a new approach for stimulated mucosal immunity against respiratory infections in animals

Tetrafluoroethane (HFC 134A) propellant-driven aerosols of proteins.

Develop metered-dose propellant-driven aerosols of proteins using tetrafluoroethane (HFC 134A) as propellant. Proteins were lyophilized with the propellant-soluble surfactants Triton X-100, Triton X-405, Laureth-9, Brij-30, Nonidet-40, and diethylene glycol monoethylether and then charged with propellants. Small particle aerosols of the experimental protein bovine gamma globulin were produced. The fraction of aerosolized respirable-sized protein particles (< 4-5 microns) increased after dispersion of particles in propellant with agitation by shaking. Scanning electron microscopy of respirable-sized protein aerosols demonstrated bead-like particles in grape-like clusters. Vigorous shaking of propellant-suspended particles for 2 minutes or more reduced the size of clusters and reduced the diameters of the protein-containing subparticles that constituted the clusters. A 50:50 ratio of HFC 134A and dimethylether (DME) propellants improved the respirability of protein aerosols compared to HFC 134A as the sole propellant. Protein/surfactant particles first dispersed in DME and then diluted in HFC 134A propellant most efficiently produced respirable-sized, propellant-driven, protein aerosols.

Inhibitory effects of recombinant manganese superoxide dismutase on influenza virus infections in mice.

The oxygen free-radical scavenger recombinant human manganese superoxide dismutase (MnSOD) was studied for its effects on influenza virus infections in mice when used alone and in combination with ribavirin. Mice challenged with influenza A/NWS/33 (H1N1) virus were treated parenterally in doses of 25, 50, and 100 mg/kg of body weight per day every 8 h for 5 days beginning at 48 h post-virus exposure. An increase in mean day to death, lessened decline in arterial oxygen saturation, and reduced lung consolidation and lung virus titers occurred in the treated animals. To determine the influence of viral challenge, experiments were run in which mice were infected with a 100 or 75% lethal dose of virus and were treated intravenously once daily for 5 days beginning 96 h after virus exposure. Weak inhibition of the mortality rate was seen in mice receiving the high viral challenge, whereas significant inhibition occurred in the animals infected with the lower viral challenge, indicating that MnSOD effects are virus dose dependent. To determine if treatment with small-particle aerosol would render an antiviral effect, infected mice were treated by this route for 1 h daily for 5 days beginning 72 h after virus exposure. A dose-responsive disease inhibition was seen. An infection induced by influenza B/Hong Kong/5/72 virus in mice was mildly inhibited by intravenous MnSOD treatment as seen by increased mean day to death, lessened arterial oxygen saturation decline, and lowered lung consolidation. MnSOD was well tolerated in all experiments. A combination of MnSOD and ribavirin, each administered with small-particle aerosol, resulted in a generally mild improvement of the disease induced by the influenza A virus compared with use of either material alone.