Salbutamol: comparison of bronchodilating effect of inhaled powder and aerosol in asthmatic subjects.

In the treatment of asthma salbutamol can be administered as an aerosol with a metered-dose inhaler or as a powder with a breath-actuated device (Rotahaler). The two forms of the drug were compared in a double-blind placebo-controlled study involving 10 asthmatic adults who were known to respond to salbutamol. The bronchodilating effect of the aerosol and the powder at doses of 200 micrograms and of the powder at doses of 200 and 400 micrograms was compared, bronchodilation being measured in terms of forced expiratory volume and vital capacity. The response was far greater to salbutamol than to placebo, but there was no significant difference between the two forms of the drug or between the lower and higher doses of powder. No side effects were observed.     

Interaction and dose equivalence of salbutamol and salmeterol in patients with asthma.

OBJECTIVE--To examine the pharmacological interaction of salmeterol and salbutamol and to derive an estimate of dose equivalence of salmeterol for airway and systemic effects in patients with asthma. DESIGN--Randomised double blind crossover study. SUBJECTS--12 patients with mild asthma. INTERVENTION--Placebo or salmeterol 50, 100, 200 micrograms given on separate days followed two hours later by inhaled salbutamol in cumulative doses up to 3600 micrograms. MAIN OUTCOME MEASURES--Change in forced expiratory volume in one second (FEV1), heart rate, plasma potassium concentration, QTc interval, tremor amplitude, and creatine kinase myocardial isoenzyme concentration. RESULTS--Compared with placebo, the mean (95% confidence interval) changes in FEV1 and heart rate after salmeterol 200 micrograms were 0.61 (0.32 to 0.90) l and 7.0 (3.8 to 10.2) beats/min. Adding salbutamol caused a large increase in FEV1 after placebo (0.69 l) with progressively smaller changes after increasing doses of salmeterol (0.19 l after salmeterol 200 micrograms). Heart rate and QTc interval increased and plasma potassium concentration decreased roughly in parallel on the four study days with a suggestion of convergence at higher doses of salbutamol. Geometric mean dose equivalences for salmeterol 50 micrograms and 100 micrograms compared with salbutamol were 4.9 and 7.8 (mean 6.4) for FEV1 and ranged from 7.1 (2.9 to 17.0) to 12.6 (4.4 to 36.4) for heart rate, plasma potassium, and tremor (mean 9.5). CONCLUSIONS--The effect of adding salbutamol to salmeterol is largely additive. Weight for weight salmeterol may be up to 10 times more potent than salbutamol. Considering its longer duration of action salmeterol 50 micrograms twice daily could be equivalent to salbutamol in doses up to 500 micrograms four to six hourly.     

Salbutamol: tablets,inhalational powder,or nebuliser?

A study was carried out to ascertain the most effective method of giving salbutamol. Seventeen children with severe asthma received active salbutamol (4 mg via a nebuliser, 400 micrograms as an inhalational powder, or a 4 mg tablet) together with complementary placebos on a double-blind, triple-dummy randomly allocated basis. The bronchodilatation effect was assessed by measuring the peak expiratory flow rate. The bronchodilatation effect was greatest when patients received nebulised salbutamol (p less than 0.05) but lasted longest when they received the tablet (p less than 0.0001); the onset of the effect was rapid with all forms of administration. These results indicate that nebulised salbutamol gives the best relief in severe asthma; in less severe cases, however, a regimen combining the inhalational powder and tablets is sufficient and more convenient.     

Consideration of inactivated rabies vaccines as oral immunogens of wild carnivores.

An experimental beta-propiolactone (BPL)-inactivated rabies virus vaccine was evaluated for the oral immunization of captive raccoons (Procyon lotor) and red foxes (Vulpes vulpes). None of 10 red foxes administered a single 1.0 ml dose of BPL-inactivated rabies virus vaccine (PM strain; 100 or 500 micrograms protein) per os developed detectable anti-rabies virus-neutralizing antibodies (VNA) at any time over 8 wk of observation. Foxes were excluded from further study. In two different groups of five to six raccoons, each administered a single 1.0 ml dose of BPL-inactivated rabies virus vaccine (ERA strain) per os, at concentrations of 100 or 400 micrograms protein, only a single animal in each group demonstrated evidence of seroconversion within 4 wk. In contrast, instillation of a single dose (500 micrograms protein) of BPL-inactivated rabies virus vaccine (ERA strain), directly into the small intestine via fiberoptic endoscope, or ERA vaccine (800 micrograms protein) instillation to the buccal cavity by needle-less syringe, resulted in the production of rabies-specific VNA and protection against lethal rabies infection in three of six, and in four of six raccoons, respectively; all seven control raccoons succumbed to street virus challenge. These preliminary challenge studies, while somewhat encouraging, demonstrate that considerable quantities of purified viral antigen are required for even minimal oral efficacy against lethal rabies infection. At the present time, therefore, potent, self-replicating, attenuated, or recombinant viruses offer the most versatile, economic, efficacious, and safe solutions to terrestrial rabies control of free-ranging carnivores.     

Minoxidil-induced changes in the contraction of collagen lattices by human skin fibroblasts.

This investigation has studied the effect of minoxidil on the contraction of hydrated collagen lattices by human dermal fibroblasts. Type I collagen was mixed with a fibroblast suspension and polymerized, and minoxidil 10 to 800 micrograms/ml (0.05 to 4 mM) was added at the time the lattices were released. Minoxidil at concentrations from 100 to 600 micrograms/ml inhibited contraction in a dose-dependent manner, whereas 800 micrograms/ml prevented contraction completely, most cells remaining rounded. Considerable inhibition was already evident within 24 hours. Visualization of living cells with MTT and cell counts showed that inhibition in the first 48 hours was not due to fibroblast death. Exchange of minoxidil to normal medium led to a resumption of contraction and a return to an elongate morphology. Minoxidil at 10 micrograms/ml had no significant effect on lattice contraction, whereas at 100 micrograms/ml it slowed contraction without affecting proliferation or morphology, as observed under the light microscope. The inhibitory effect of minoxidil should be investigated further in relation to the control of contraction of wounds in vivo.     

Intravenous beta agonist in severe acute asthma.

STUDY OBJECTIVE--To determine whether salbutamol is more effective in treating severe asthma when given intravenously or by inhalation. DESIGN--Randomised trial of short term response to intravenous versus nebulised salbutamol in acute severe asthma. SETTING--District general hospital (secondary care centre). PARTICIPANTS--76 patients aged 16-70 admitted to hospital with acute severe asthma (peak expiratory flow rate less than 50% of predicted) during study period. Five withdrawn because of adverse effects of treatment or non-response. Of remaining 71, 34 allocated to nebuliser group and 37 to intravenous treatment group. Patients with history of cardiovascular disease or recent corticosteroid or intravenous bronchodilator treatment excluded. Admission characteristics similar in the two groups. INTERVENTIONS--All patients given 5 mg nebulised salbutamol on admission before randomisation plus 200 mg hydrocortisone bolus intravenously and 35% inspired oxygen throughout. Nebuliser group received two more 5 mg doses of nebuliser salbutamol at 30 minutes and 2 hours; intravenous group received 4 hours'' continuous salbutamol infusion (12 micrograms/min) starting at 30 minutes plus supplementary intravenous potassium chloride. No other bronchodilators used. ENDPOINT--Change in peak expiratory flow rate over 4 hours. MEASUREMENTS and MAIN RESULTS--Peak expiratory flow rate improved more in intravenous group (25.2%) than in nebuliser group (14.3%) (p less than 0.01, 95% confidence interval 2.4 to 19.1%). Tachycardia caused two withdrawals from intravenous group; non-response caused three withdrawals from nebuliser group. CONCLUSIONS--Intravenous salbutamol is more effective than nebulised salbutamol in acute severe asthma but may have unacceptable cardiovascular effects.     

Prolonged blood pressure reduction by orally active renin inhibitor RO 42-5892 in essential hypertension.

OBJECTIVE--To investigate the effects of a novel specific renin inhibitor, RO 42-5892, with high affinity for human renin (Ki = 0.5 x 10(-9) mol/l), on plasma renin activity and angiotensin II concentration and on 24 hour ambulatory blood pressure in essential hypertension. DESIGN--Exploratory study in which active treatment was preceded by placebo. SETTING--Inpatient unit of teaching hospital. PATIENTS--Nine men with uncomplicated essential hypertension who had a normal sodium intake. INTERVENTIONS--Two single intravenous doses of RO 42-5892 (100 and 1,000 micrograms/kg in 10 minutes) given to six patients and one single oral dose (600 mg) given to the three others as well as to three of the patients who also received the two intravenous doses. RESULTS--With both intravenous and oral doses renin activity fell in 10 minutes to undetectably low values, while angiotensin II concentration fell overall by 80-90% with intravenous dosing and by 30-40% after the oral dose. Angiotensin II concentration was back to baseline four hours after the low and six hours after the high intravenous dose and remained low for at least eight hours after the oral dose. Blood pressure fell rapidly both after low and high intravenous doses and after the oral dose and remained low for hours. With the high intravenous dose the daytime (0900-2230), night time (2300-0600), and next morning (0630-0830) systolic blood pressures were significantly (p less than 0.05) lowered by 12.5 (95% confidence interval 5.6 to 19.7), 12.2 (5.4 to 19.3), and 10.7 (3.2 to 18.5) mm Hg respectively, and daytime diastolic pressure was lowered by 9.3 (2.2 to 16.8) mmHg. With the oral dose daytime, night time, and next morning systolic blood pressures were lowered by 10.3 (5.5 to 15.4), 10.5 (4.2 to 17.2), and 9.7 (4.0 to 15.6) mm Hg, and daytime and night time diastolic pressures were lowered by 5.8 (0.9 to 11.0) and 6.0 (0.3-12) mm Hg respectively. CONCLUSIONS--The effect of the inhibitor on blood pressure was maintained over a longer period than its effect on angiotensin II. RO 42-5892 is orally active and has a prolonged antihypertensive effect in patients who did not have sodium depletion. This prolonged effect seems to be independent, at least in part, of the suppression of circulating angiotensin II.     

Effects of ethinyl estradiol on isoproterenol-induced death in ventricular fibrillation in DOCA-salt pretreated male and female rats

To assess the effects of ethinyl estradiol on the incidence of death in ventricular fibrillation induced by isoproterenol in DOCA-salt pretreated rats we implanted male and female rats simultaneously with a 20 mg DOCA pellet and pellets containing either ethinyl estradiol or vehicle (wax). Rats drank saline after implantation. After 6 days rats were challenged with a single, sc dose of 150 micrograms of isoproterenol. The average daily dose of estradiol per rat was estimated on the basis of the quantity of pellet lost during 6 days. In male rats the average daily dose of 61.2 +/- 20.2 micrograms/rat of ethinyl estradiol decreased the incidence of mortality by 80%, from 73.3% (11/15) in vehicle treated to 13.3% (2/15) in estradiol treated rats. Death occurred within 19.2 +/- 8.0 minutes from the injection of isoproterenol and was due to ventricular fibrillation. Serum levels of magnesium and potassium were comparable in the two groups both before and after isoproterenol. Isoproterenol induced death in 9 of 11 DOCA-salt pretreated, ovariectomized rats within 22.3 +/- 9.8 minutes. Only 3 of 11 DOCA-salt ovariectomized rats receiving the average daily dose of 28.4 +/- 12.1 micrograms/rat of ethinyl estradiol died. None of 10 ovariectomized untreated rats died from isoproterenol challenge. Serum levels of magnesium and potassium were comparable in the estradiol and vehicle treated groups. The average daily dose of 2.8 +/- 0.42 micrograms/rat of ethinyl estradiol elicited uterine growth but did not influence the incidence of mortality, since 9 out of 16 and 10 out of 16 rats died following isoproterenol in vehicle and estradiol treated DOCA-salt ovariectomized rats. We conclude that only pharmacological doses of estradiol exert protective effects against DOCA-salt induced myocardial sensitization to isoproterenol and that this protection is not associated with relevant changes in serum potassium or magnesium.     

Overcoming beta-agonist tolerance: high dose salbutamol and ipratropium bromide. Two randomised controlled trials

Background

Asthmatics treated with long-acting beta-agonists have a reduced bronchodilator response to moderate doses of inhaled short acting beta-agonists during acute bronchoconstriction. It is not known if the response to higher doses of nebulised beta-agonists or other bronchodilators is impaired. We assessed the effect of long-acting beta-agonist treatment on the response to 5 mg nebulised salbutamol and to ipratropium bromide.

Methods

Two double-blind, placebo-controlled, crossover studies of inhaled formoterol 12 μg twice daily in patients with asthma. High-dose salbutamol: 36 hours after the last dose of 1 week of formoterol or placebo treatment, 11 subjects inhaled methacholine to produce a 20% fall in FEV₁. Salbutamol 5 mg was then administered via nebuliser and the FEV₁ was monitored for 20 minutes. Ipratropium: 36 hours after the last dose of 1 week of formoterol or placebo treatment, 11 subjects inhaled 4.5% saline to produce a 20% fall in FEV₁. Salbutamol 200 μg or ipratropium bromide 40 μg was then inhaled and the FEV₁ was monitored for 30 minutes. Four study arms compared the response to each bronchodilator after formoterol and placebo. Analyses compared the area under the bronchodilator response curves, adjusting for changes in pre-challenge FEV₁, dose of provocational agent and FEV₁ fall during the challenge procedure.

Results

The response to nebulised salbutamol was 15% lower after formoterol therapy compared to placebo (95% confidence 5 to 25%, p = 0.008). The response to ipratropium was unchanged.

Conclusion

Long-acting beta-agonist treatment induces tolerance to the bronchodilator effect of beta-agonists, which is not overcome by higher dose nebulised salbutamol. However, the bronchodilator response to ipratropium bromide is unaffected.     

Proteins of the kininogen-kinin system

Rat passive cutaneous anaphylaxis (PCA) was inhibited in a dose-related manner by disodium cromoglycate (DSCG) given in one intravenous injection with antigen challenge. When administered in advance of challenge, a single high dose of DSCG lost its efficacy against the subsequent PCA reaction within 20 minutes.Pretreatment with one or several intravenous injections of DSCG showed a self-suppressive effect on the anti-PCA activity of DSCG injected later, at the time of antigen challenge. This suppression of activity consistently occurred only when a high first dose of DSCG preceded a normally-effective secondary dose by a period of less than 2 hours.At no time did DSCG-pretreatment significantly increase the PCA-inhibitory effect of subsequent DSCG doses.     

Growth of asthmatic children during treatment with budesonide: a double blind trial.

OBJECTIVE--To determine whether the inhaled glucocorticosteroid budesonide has any adverse effect on short term linear growth in children with mild asthma. SETTING--Outpatient clinic in secondary referral centre. PATIENTS--15 children aged 6-13 years with normal statural growth velocity during the previous year, no signs of puberty, and no use of systemic or topical steroids in the two months before the study. DESIGN OF INTERVENTIONS--Double blind, randomised crossover trial with two active periods in which budesonide was given in divided daily doses of 200 micrograms and 800 micrograms. During run in and two washout periods placebo was given. After the second washout period the children received open treatment with 400 micrograms budesonide daily. All periods were of 18 days'' duration. MAIN OUTCOME MEASURE--Growth of the lower leg as measured twice a week by knemometry. RESULTS--Mean growth velocity of the lower leg was 0.63 mm/week during run in and during washout 0.64 mm/week. Budesonide treatment was associated with a significant dose related reduction of growth velocity: the mean reduction in growth velocity during treatment was 0.11 (95% confidence interval -0.15 0.36 (0.13 to 0.59) mm/week with 800 micrograms budesonide (p less than 0.05; Page''s test). During treatment with 400 micrograms budesonide a reduction of 0.17 (-0.10 to 0.45) mm/week was found. CONCLUSIONS--Treatment with inhaled budesonide is associated with a dose related suppression of short term linear growth in children with mild asthma.     

Comparison of nifedipine and diltiazem with salbutamol for prevention of preterm delivery in the ovariectomized, oestrogen-treated late pregnant rat

The ovariectomized, oestrogen-treated, late pregnant rat has been used to compare the ability of two calcium antagonists, diltiazem and nifedipine, with an agonist at beta-adrenoceptors, salbutamol, to prevent the development of uterine contractions, prolong gestation and maintain fetal survival in utero. Preterm delivery of the fetuses was not prevented in the animals infused with salbutamol (2 micrograms/kg/min), occurring at the same time, 30-40 h after ovariectomy, as in the saline-infused rats. The overall integral of uterine contractions was significantly reduced in the salbutamol-treated compared with the saline-treated animals due to decreased contractions after abortion. Both diltiazem (100 micrograms/kg/min) and nifedipine (3.1 and 6.2 micrograms/kg/min) produced significant inhibition of uterine contractions and in contrast to salbutamol prolonged gestation and improved fetal survival in utero as assessed at post mortem on Day 21. However, maternal survival was low (57%) with the higher dose of nifedipine, possibly reflecting the relaxant effect of this compound on vascular smooth muscle with consequent underperfusion of vital organs.     

Evaluation of the immunogenicity of meningococcal vaccines in experiments on mice]

The immunogenicity of 2 meningococcal vaccines, multicomponent vaccine produced at the Mechnikov Research Institute for Vaccines and Sera in Moscow and polysaccharide vaccine obtained from Merck Sharp & Dohme (USA), was evaluated on experimental meningococcal sepsis in mice, produced by the injection of meningococcal culture in mucin suspension. The protective effect of these 2 vaccines, expressed in terms of ED50, was 0.28 +/- 0.12 for the multicomponent vaccine and 0.25 +/- 0.24 for the polysaccharide vaccine; the challenge dose used in the test was 10 LD50 of the culture. The multicomponent vaccine gave the maximum immunological effect in a dose of 8 micrograms, while higher or lower doses induced a lesser increase in antibody titer and thus gave lower protection to mice against infection.     

Further evidence of the inhibitory role of perifornical hypothalamic beta-adrenergic receptors in the feeding behaviour of hungry rats

The reduction of food intake in hungry rats induced by salbutamol (10 mg/kg/i.p.) was prevented by IPS 339 (5 mg/kg, i.p.) a selective beta 2 adrenergic antagonist, but not by metoprolol (10 mg/kg i.p.), a blocker of beta 1 adrenergic receptors. Similarly, bilateral injections of IPS 339 (32 micrograms/1 microliter) but not metoprolol (80 micrograms/1 microliter) in the perifornical hypothalamic area completely antagonized the anorectic effect of intraperitoneal salbutamol, suggesting an involvement of beta 2 adrenergic receptors in this brain area. Clenbuterol, a beta 2 adrenergic agonist which readily crosses the blood-brain barrier, was 10-100 times more potent than salbutamol in inhibiting feeding consumption of deprived rats when injected intraperitoneally and this effect was also selectively antagonized by pretreatment with IPS 339. Neither IPS 339 nor metoprolol injected in the perifornical hypothalamus significantly modified the anorectic effect of diethylpropion (5 mg/kg i.p.) whereas it was partially prevented by intraperifornical injection of 1-propranolol (52 micrograms/2 microliter), a non-selective beta antagonist, suggesting that both beta 1 and beta 2 adrenergic receptors in the hypothalamus contribute to the mechanism by which diethylpropion causes anorexia.     

Effects of garlic preparations on superoxide production by phorbol ester activated granulocytes.

Sulfur containing constituents of garlic are considered responsible for conveying the antioxidative properties of garlic preparations. The radical scavenging properties of garlic preparations against oxygen radicals, specifically their ability to inhibit the formation of superoxide anions, were investigated using human granulocytes activated with 10 nM phorbol myristyl acetate (PMA). A garlic powder preparation inhibited the production of superoxide with a calculated IC50 of 390 micrograms/ml. An 8-10% alliin enriched garlic extract (alliinase inactivated) did not inhibit superoxide production even at concentrations as high as 1000 micrograms/ml. When the extract was mixed with garlic powder (90% garlic powder, 10% garlic extract), there was a clear inhibition of superoxide production with an IC50 value of 295 micrograms/ml. An even stronger inhibitory effect could be achieved when garlic powder was added to garlic extract (10% garlic powder, 90% extract, IC50 = 160 micrograms/ml). These experimental results suggest that the alliin metabolite allicin may be responsible for the oxygen radical scavenging properties of garlic.     

Immune response to a new hepatitis B vaccine in healthcare workers who had not responded to standard vaccine: randomised double blind dose-response study.

OBJECTIVE: To evaluate the immunogenicity and reactogenicity of a new triple S recombinant hepatitis B vaccine in a cohort of healthy people in whom currently licensed hepatitis B vaccines had persistently not induced an immune response. DESIGN: Single centre, randomised, double blind, dose-response study. SETTING: Research vaccine evaluation centre at a teaching hospital. SUBJECTS: 100 healthcare workers aged 18-70 years with a history of failure to seroconvert after at least four doses of a licensed hepatitis B vaccine containing the S component. INTERVENTION: Each subject was randomly allocated two doses of 5, 10, 20, or 40 micrograms of a new hepatitis B vaccine two months apart. MAIN OUTCOME MEASURES: Immunogenicity of the four doses. Seroconversion and seroprotection were defined as an antibody tire > 10 IU/l and > 100 IU/l respectively against an international antibody standard. RESULTS: 69 subjects seroconverted after a single dose of the vaccine. After the booster vaccination one other subject seroconverted, bringing the overall seroconversion rate to 70%. Fifteen subjects given 5 micrograms of vaccine, 19 given 10 micrograms, 16 given 20 micrograms, and 20 given 40 micrograms seroconverted. Seroconversion rates in the four antigen dose groups were 60% (15/25), 76% (19/25), 64% (16/25), and 80% (20/25). After the booster dose there was no significant dose-response effect on the overall seroconversion rate, although the small sample size meant that a clinically important dose-response could not be ruled out. CONCLUSION: A single dose of 20 micrograms of the vaccine was as effective as two doses of either 40 micrograms or 20 micrograms of this vaccine formulation in terms of seroconversion, seroprotection, and geometric mean titres.     

Leukotriene C4-induced radioprotection: the role of hypoxia.

Pretreatment of mice with leukotriene C4 (LTC4), a biological mediator that can cause marked contraction of vascular, tracheal, and bronchial smooth muscles, enhances radiation survival. Optimal protection is observed with 10 micrograms LTC4 per mouse (400 micrograms/kg body wt) administered subcutaneously 5 to 10 min prior to irradiation. Pretreatment with 10 micrograms LTC4 increases the LD50/30 from 8.36 Gy in mice receiving saline to 15.7 Gy, providing a dose reduction factor of 1.9. Enhanced survival of mice was observed with doses of 50 micrograms LTD4/mouse, but not with LTE4. Fifteen minutes after administration of 10 micrograms LTC4, the breathing rate is reduced by 33%, the blood paO2 by 20%, the paCO2 by 29%, and the HCO3- by 43%. Whole blood lactate increased by 288% at this same time. The period over which the elevation in blood lactate occurs is similar to the times for optimal radioprotection. These data coupled with the finding that protection was eliminated when irradiation occurred in an enriched oxygen atmosphere indicate that hypoxia plays a role in leukotriene C4-induced animal radiation survival. High-performance liquid chromatography and tissue distribution analyses support a role for an indirect mechanism since the highest levels of LTC4 in the tissues do not correlate with the peak time for radioprotection.     

Effects of intranasal administration of atrial natriuretic hormone on spontaneously hypertensive rats

The effects of the intranasal administration of synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) were investigated in 14 anesthetized spontaneously hypertensive rats (SHR; Okamoto-Aoki strain). They were given intranasally synthetic alpha-hANP in distilled water at doses of 10 micrograms/kg, 50 micrograms/kg and 100 micrograms/kg. Intranasal application of 200 microliter of distilled water as a control was also performed in 3 anesthetized SHR. Sixteen anesthetized SHR were examined for the effects of intravenous administration of alpha-hANP at doses of 4 micrograms/kg, 10 micrograms/kg, 20 micrograms/kg and 40 micrograms/kg. Urinary volume and the urinary excretion of sodium increased 2- to 3-fold during the 50 minutes following intranasal administration of a single dose of 50 micrograms/kg or 100 micrograms/kg, although neither the urinary volume nor the urinary excretion of sodium increased after intranasal administration of 10 micrograms/kg of alpha-hANP or 200 microliter of distilled water. There were no significant changes in arterial pressure or heart rate after the intranasal administration of synthetic alpha-hANP or distilled water. In contrast, arterial pressure was decreased and urinary volume and urinary excretion of sodium were increased, in a dose dependent manner, within 5 minutes after intravenous bolus-injection of alpha-hANP and returned to their baseline levels within 20 minutes. These results indicate that intranasal administration of synthetic alpha-hANP exerts its diuretic effect without concomitant changes in arterial pressure or heart rate in SHR.     

Adenovirus vectored IFN-α protects mice from lethal challenge of Chikungunya virus infection

Chikungunya virus (CHIKV) is a mosquito-borne pathogen that is responsible for numerous large and geographical epidemics, causing millions of cases. However, there is no vaccine or therapeutics against CHIKV infection available. Interferon-alpha (IFN-α) has been shown to produce potent antiviral responses during viral infection. Herein we demonstrated the use of an adenovirus-vectored expressed mouse IFN-α (mDEF201) as a prophylactic and therapeutic treatment against CHIKV in vivo. 6-day-old BALB/c mice were pre- or post-treated intranasally with single dose of mDEF201 at 5 x 10⁶ PFU per mouse and challenged with lethal dose of CHIKV. Complete survival protection was observed in mice upon a single dose of mDEF201 administration 1 days prior to virus challenge. Viral load in the serum and multiple organs were significantly reduced upon mDEF201 administration in a dose dependent manner as compare with adenovirus 5 vector placebo set. Histological analysis of the mice tissue revealed that mDEF201 could significantly reduce the tissue morphological abnormities, mainly infiltration of immune cells and muscle fibre necrosis caused by CHIKV infection. In addition, administration of mDEF201 at 6 hours post CHIKV challenge also showed promising inhibitory effect against viral replication and dissemination. In conclusion, single-dose of intranasal administration with mDEF201 as a prophylactic or therapeutic agent within 6 hours post CHIKV infection is highly protective against a lethal challenge of CHIKV in the murine model.     

The immunogenic and serological properties of the O-specific polysaccharide (L-hapten) in Shigella]

O-specific polysaccharide (L-hapten) was isolated earlier (Zh. mikrobiol. epidemiol. immunobiol., 1989, No. 11, pp. 8-11). In this paper L-hapten was shown to be unable, even at high concentrations (up to 2,000 micrograms/ml), to sensitize sheep red blood cells for passive hemagglutination by O-antibodies. At the same time classical LPS and heat-activated LPS were active at concentrations ot 32 and 8 micrograms/ml respectively. The O-antibody-neutralizing activity of L-hapten was lower than that of LPS 10(3)-10(4) times in the passive hemagglutination test and 25-50 times in competitive ELISA. The immunogenicity of isolated L-hapten was very weak: primary response in mice to the i.v. injection of 1-10 micrograms of L-hapten was similar to the effect produced by 10(-3)-10(-4) micrograms of LPS. No protective activity of L-hapten was noted in mice when the challenge dose of virulent shigellae was 16 LD50 or more, and only a weak protective effect was observed with a low challenge dose (8 LD50). The molecular basis of low serological and biological activity of L-hapten is discussed. The most probable explanation of the results obtained in this study is that L-hapten contains some nonspecific carbohydrates, inserted in or complexed with the O-side chain. Despite its low immunogenicity, L-hapten can be an important component of effective bacterial vaccines provided it is included into a suitable delivery system as is the case with Shigella ribosomal vaccine.