ArticlePDF Available


tericidal activity of ceftazidime could be correlated with the MICvalue for the different strains.Results when the strains were exposed to a concentration of4 × MIC were comparable to those at 8 × MIC, suggesting that nofurther bactericidal effect can be achieved by increasing the cefta-zidime concentration above 4 MIC (no concentration effect). At×2 × MIC, bactericidal activity was seen against all isolates; in general,this activity was comparable to that observed with 4 × and 8 × MIC,even on CTZ-R strains, but in one CTZ-R, one CTZ-I and two CTZ-Sstrains, re-growth at 24 h was observed.CI has been reported to be at least as effective as intermittentadministration in severe infections.
procedure, the patient developed fever (38°C), lethargy and neck
stiffness. Analysis of ventricular CSF revealed 105 white cells/mm
(90% of the white cells were neutrophils), a glucose level of 23 mg/dL
(glucose level in the blood: 106 mg/dL) and protein of 119 mg/dL.
Microscopic examination of the Gram staining showed yeast and no
other microorganisms. Cultures were positive for C. albican s in three
separate samples. The blood culture was sterile. The patient had been
treated with fluconazole 400 mg intravenously (iv) daily, oxacillin 12 g
iv daily, rifampicin 600 mg iv daily, but meningitis persisted. Twenty
days after the stroke, the patient was admitted to our Infectious
Diseases unit. The external shunt was removed and replaced immedi-
ately, and therapy with AmBisome (3 mg/kg/day) and flucytosine
(150 mg/kg/day) was started. In addition, on days 79 of the new
treatment, intraventricular amphotericin B deoxycholate was
injected into the shunt at a dose of 4 mg daily (the shunt was closed for
4 h). Despite this therapy, the patient had a torpid clinical course; his
fluids and clinical condition improved but without complete resolution.
CSF culture was positive until the 7th day of therapy and after this
was negative. Following 23 days of this drug regimen, se rial CSF and
serum samples were taken to check amphotericin B levels. Some
samples were also taken during intraventricular i nfusion. All samples
were stored at 80°C until assay. After 30 days, the patient died as a
result of a second haemorrhagic stroke. Amphotericin B concentrations
in the patients CSF and serum samples were analysed by HPLC,
as described by Bekersky et al.
We performed standard curves for
amphotericin B by regression analysis. The peak serum level of
amphotericin B was 15.61 mg/L and the area under the concentration
time curve (AUC) was 115.5 mg·h/L. Amphotericin B concentrations
in ventricular CSF were between 0.09 and 0.24 mg/L (AUC
3.7 mg·h/L). Concentrations of ventricular amphotericin B taken
after intrathecal administration (range +7, +24 h after intra-shunt
infusion) were between 100.5 and 1.75 mg/L. The concentration of
amphotericin B in lumbar fluid was 0.59 mg/L (the fluid sample was
obtained by single lumbar puncture, 48 h after intra-shunt infusion of
amphotericin B and 22 h after AmBisome iv).
One major concern, for therapy of fungal shunt infections, is CSF
penetration of systemically administered amphotericin B. Currently,
C. albicans is considered susceptible to amphotericin B at a concen-
tration of 1 mg/L (MIC < 1 mg/L).
The minimal drug concentration
achieved at the infection site should be at least equal to the MIC for
the infecting organism, and in vivo, the ratio between the maximum
concentration of the drug (C
) and the MIC value is the best predictor
for outcome.
Conventional amphotericin B deoxycholate is notorious
for its inability to achieve consistently measurable concentrations in
CSF; it ranges from undetectable to no more than 4% of serum con-
A potential strategy for reducing the toxicity and increasing the
therapeutic index of amphotericin B is the use of lipid formulations of
this drug, which allow the administration of a much higher dose.
our case, administration of AmBisome at 3 mg/kg/day did not result
in significantly enhanced amphotericin B concentration in CSF; in
fact a fluid C
of 0.24 is a sub-MIC conc entration, and limited clinical
results were obtained. These data show the po or penetration into CSF
of liposomal amphotericin B at a dose of 3 mg/kg/day (CSF AUC was
equivalent to 3.2% of serum AUC). The intrathecal amphotericin B
therapy, administered only for 3 days in this case, achieved a temporary
elevated concentration in ventricular CSF, but this did not contribute
to the clinical outcome. If CNS penetration is based on C
, an
increased intravenous liposomal amphotericin dosage can be advocated
to treat CNS Candida infections. In clinical situations, the adminis-
tration, at maximal tolerable dosage, of AmBisome (510 mg/kg/day)
may provide more effective therapeutic results.
In addition, although
a post-antifungal effect on Candida species was disregarded, it may
have been attributable to amphotericin B and flucytosine,
and it
should be the aim of antimicrobial therapy to increase CSF drug con-
centration above the MIC so that there is a greater possibility of com-
pletely eradicating infection.
There exists a direct relationship between peak concentrations of
amphotericin B in plasma, AUCs and cerebral tissue concentrations.
This correlates directly with greater antifungal efficacy.
Thus, if
azole-resistant Candida shunt infections occur, a high dose of
AmBisome (510 mg/kg/day) may be a reasonable option.
1. Bekersky, I., Boswell G. W., Hiles R.
et al
. (1999). Safety and
toxicokinetics of intravenous liposomal amphotericin B (AmBisome) in
beagle dogs.
Pharmaceutical Research
16, 1694701.
2. Ellis, D. (2002). Amphotericin B: spectrum and resistance.
of Antimicrobial Chemotherapy
Suppl. 1
, 710.
3. Andes, D., Stamsted, T. & Conklin, R. (2000). Pharmacodynamics
of amphotericin B in a neutropenic-mouse disseminated-candidiasis
Antimicrobial Agents and Chemotherapy
45, 9226.
4. Patel, R. (1998). Antifungal agents. Part I. Amphotericin B prepar-
ations and flucytosine.
Mayo Clinic Procceedings
73, 120525.
5. Walsh, T. J., Goodman, J. L., Pappas, P.
et al
. (2001). Safety, tol-
erance and pharmacokinetics of high-dose liposomal amphotericin
B (AmBisome) in patients infected with
species and other
filamentous fungi: maximum tolerated dose study.
Antimicrobial Agents
and Chemotherapy
45, 348796.
6. Turnidge, J. D., Gudmundsson, S., Vogelman, B.
et al
. (1994). The
postantibiotic effect of antifungal agents against common pathogenic
Journal of Antimicrobial Chemotherapy
34, 8392.
Journal of Antimicrobial Chemotherapy
DOI: 10.1093/jac/dkh002
Advance Access publication 12 November 2003
Vitamin C and SARS coronavirus
Harri Hemilä*
Department of Public Health, University of Helsinki, Helsinki,
FIN-00014 Finland
Keywords: ascorbic acid, pneumonia, severe acute respiratory
*Tel: +359-0-191-27573; Fax: +358-0-191-2757 0;
Recently, a new coronavirus was identified as the cause of the severe
acute respiratory syndrome (SARS).
In the absence of a specific
treatment for SARS, the possibility that vitamin C may show non-
specific effects on severe viral respiratory tract infections should be
considered. There are numerous reports indicating that vitamin C
may affect the immune system,
for example the function of phago-
cytes, transformation of T lymphocytes and production of interferon.
In particular, vitamin C increased the resistance of chick embryo
tracheal organ cultures to infection caused by an avian coronavirus.
Studies in animals found that vitamin C modifies susceptibility to
various bacterial and viral infections,
for example protecting broiler
chicks against an avian coronavirus.
Placebo-controlled trials have
shown quite consistently that the duration and severity of common
cold episodes are reduced in the vitamin C groups,
indicating that
viral respiratory infections in humans are affected by vitamin C levels.
There is also evidence indicating that vitamin C may affect pneumonia.
In particular, three controlled trials with human subjects reported a
significantly lower incidence of pneumonia in vitamin C-supplemented
suggesting that vitamin C may affect susceptibility to lower
respiratory tract infections under certain conditions. The possibility
that vitamin C affects severe viral respiratory tract infections would
seem to warrant further study, especially in light of the recent SARS
1. Holmes, K. V. (2003). SARS-associated coronavirus.
New England
Journal of Medicine
348, 194851.
2. Leibovitz, B. & Siegel, B. V. (1981). Ascorbic acid and the immune
Advances in Experimental Medicine and Biology
135, 125.
3. Hemilä, H. & Douglas, R. M. (1999). Vitamin C and acute respiratory
International Journal of Tuberculosis and Lung Diseases
4. Atherton, J. G., Kratzing, C. C. & Fisher, A. (1978). The effect of
ascorbic acid on infection of chick-embryo ciliated tracheal organ cultures
by coronavirus.
Archives of Virology
56, 1959.
5. Davelaar, F. G. & Bos, J. (1992). Ascorbic acid and infectious
bronchitis infections in broilers.
Avian Pathology
21, 5819.
6. Hemilä, H. (1997). Vitamin C intake and susceptibility to pneumonia.
Pediatric Infectious Diseases Journal
16, 8367.
... It modulates the migration of neutrophils to the site of infection and regulates phagocyte cells and NK cells [116]. In addition, it can mitigate the symptoms of respiratory infections [153]. Vitamin C is also able to promote intrauterine growth and childbirth [154]. ...
Full-text available
The immune system is highly dynamic and susceptible to many alterations throughout pregnancy. Since December 2019, a pandemic caused by coronavirus disease 19 (COVID-19) has swept the globe. To contain the spread of COVID-19, immediate measures such as quarantine and isolation were implemented. These containment measures have contributed to exacerbate situations of anxiety and stress, especially in pregnant women, who are already particularly anxious about their condition. Alterations in the psychological state of pregnant women are related to alterations in the immune system, which is more vulnerable under stress. COVID-19 could therefore find fertile soil in these individuals and risk more severe forms. Normally a controlled dietary regimen is followed during pregnancy, but the use of particular vitamins and micronutrients can help counteract depressive-anxiety states and stress, can improve the immune system, and provide an additional weapon in the defense against COVID-19 to bring the pregnancy to fruition. This review aims to gather data on the impact of COVID-19 on the immune system and psychological condition of pregnant women and to assess whether some micronutrients can improve their psychophysical symptoms.
... Most of the products mentioned above contain natural vitamins (such as vitamins A, C, and D) and minerals (like Zn, Fe, and Se) and other phenols that are particularly immunoprotective due to their antioxidant and anti-inflammatory effects. 10,50 Innate immunological responses are improved, immune-modulatory effects are achieved by boosting T cell activities, and immunoglobulin synthesis is increased due to vitamin C intake. 51,52 According to Rayman,53 Se deficiency is linked to reduced immunological activity. ...
Full-text available
Due to the absence of successful therapy, vaccines for protection are continuously being developed. Since vaccines must be thoroughly tested, viral respiratory tract infections (VRTIs), mainly coronaviruses, have seriously affected human health worldwide in recent years. In this review, we presented the relevant data which originated from trusted publishers regarding the practical benefits of functional foods (FFs) and their dietary sources, in addition to natural plant products, in viral respiratory and COVID-19 prevention and immune-boosting activities. As a result, FFs were confirmed to be functionally active ingredients for preventing COVID-19 and VRTIs. Furthermore, the antiviral activity and immunological effects of FFs against VRTIs and COVID-19 and their potential main mechanisms of action are also being reviewed. Therefore, to prevent COVID-19 and VRTIs, it is critical to identify controlling the activities and immune-enhancing functional food constituents as early as possible. We further aimed to summarize functional food constituents as a dietary supplement that aids in immune system boosting and may effectively reduce VRTIs and COVID-19 and promote therapeutic efficacy.
... Vitamin C may possess effects on viral infections of the respiratory tract especially when specific therapy for COVID-19 is absent. It is noteworthy that vitamin C increases the resistance to coronavirus and under certain conditions reduce the risk of infections of the lower respiratory tract (Hemilä 2003;Hemilä and Douglas 1999). ...
Full-text available
The immune system protects human health from the effects of pathogenic organisms; however, its activity is affected when individuals become infected. These activities require a series of molecules, substrates, and energy sources that are derived from diets. The consumed nutrients from diets help to enhance the immunity of infected individuals as it relates to COVID-19 patients. This study aims to review and highlight requirement and role of macro- and micronutrients of COVID-19 patients in enhancing their immune systems. Series of studies were found to have demonstrated the enhancing potentials of macronutrients (carbohydrates, proteins, and fats) and micronutrients (vitamins, copper, zinc, iron, calcium, magnesium, and selenium) in supporting the immune system’s fight against respiratory infections. Each of these nutrients performs a vital role as an antiviral defense in COVID-19 patients. Appropriate consumption or intake of dietary sources that yield these nutrients will help provide the daily requirement to support the immune system in its fight against pathogenic viruses such as COVID-19.
... It also increases the quantity of antibodies in the blood and aids lymphocytes differentiation, both of which are necessary for resistance to viral infection (110). Vitamin C strengthens the immune system (Supplementary Table 2) and protects against coronavirus infection (128). For example, it enhanced the resistance of chick embryo tracheal organ cultures to infection and protected broiler chicks against an avian coronavirus as well as can ameliorate flu-like symptoms (sneezing, a running nose, and swollen sinuses) as a mild antihistaminic agent (124,129,130). ...
Full-text available
SARS-CoV-2, a novel Corona virus strain, was first detected in Wuhan, China, in December 2019. As of December 16, 2021, almost 4,822,472 people had died and over 236,132,082 were infected with this lethal viral infection. It is believed that the human immune system is thought to play a critical role in the initial phase of infection when the viruses invade the host cells. Although some effective vaccines have already been on the market, researchers and many bio-pharmaceuticals are still working hard to develop a fully functional vaccine or more effective therapeutic agent against the COVID-19. Other efforts, in addition to functional vaccines, can help strengthen the immune system to defeat the corona virus infection. Herein, we have reviewed some of those proven measures, following which a more efficient immune system can be better prepared to fight viral infection. Among these, dietary supplements like- fresh vegetables and fruits offer a plentiful of vitamins and antioxidants, enabling to build of a healthy immune system. While the pharmacologically active components of medicinal plants directly aid in fighting against viral infection, supplementary supplements combined with a healthy diet will assist to regulate the immune system and will prevent viral infection. In addition, some personal habits, like- regular physical exercise, intermittent fasting, and adequate sleep, had also been proven to aid the immune system in becoming an efficient one. Maintaining each of these will strengthen the immune system, allowing innate immunity to become a more defensive and active antagonistic mechanism against corona-virus infection. However, because dietary treatments take longer to produce beneficial effects in adaptive maturation, personalized nutrition cannot be expected to have an immediate impact on the global outbreak.
... The authors suggest that the combined use of ribavirin, telbivudine, cyanocobalamin and nicotinamide could be tested as a potential treatment for SARS-CoV-2. A study that investigated the effects of cyanocobalamin in hepatitis C patients showed a sustained virological response (SVR) when this vitamin was added to standard antiviral therapy, suggesting that cyanocobalamin supplementation may be an independent factor associated with SVR in difficult-to-treat genotype (genotype 1) hepatitis C and in those with a higher baseline viral load [77]. ...
Full-text available
Obesity, diabetes, cardiovascular and respiratory diseases, cancer and smoking are risk factors for negative outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can quickly induce severe respiratory failure in 5% of cases. Coronavirus disease-associated liver injury may occur during progression of SARS-CoV-2 in patients with or without pre-existing liver disease, and damage to the liver parenchyma can be caused by infection of hepatocytes. Cirrhosis patients may be particularly vulnerable to SARS-CoV-2 if suffering with cirrhosis-associated immune dysfunction. Furthermore, pharmacotherapies including macrolide or quinolone antibiotics and steroids can also induce liver damage. In this review we addressed nutritional status and nutritional interventions in severe SARS-CoV-2 liver patients. As guidelines for SARS-CoV-2 in intensive care (IC) specifically are not yet available, strategies for management of sepsis and SARS are suggested in SARS-CoV-2. Early enteral nutrition (EN) should be started soon after IC admission, preferably employing iso-osmolar polymeric formula with initial protein content at 0.8 g/kg per day progressively increasing up to 1.3 g/kg per day and enriched with fish oil at 0.1 g/kg per day to 0.2 g/kg per day. Monitoring is necessary to identify signs of intolerance, hemodynamic instability and metabolic disorders, and transition to parenteral nutrition should not be delayed when energy and protein targets cannot be met via EN. Nutrients including vitamins A, C, D, E, B6, B12, folic acid, zinc, selenium and ω-3 fatty acids have in isolation or in combination shown beneficial effects upon immune function and inflammation modulation. Cautious and monitored supplementation up to upper limits may be beneficial in management strategies for SARS-CoV-2 liver patients.
... Being an antioxidant, vitamin C is reported to protect macrophages against free radicals thereby helping host cells to combat bacteria, viruses, and tumor cells (Castellani et al., 2010). Clinical evidence suggests that vitamin C (Table 2) is beneficial against SARS coronavirus (Hemilä, 2003) and SARS-CoV-2 is 82% comparable with SARS-CoV . Active vitamin D metabolite signaling pathways control various interleukin factors including IL-6, CRP, and TLR (Calton et al., 2015). ...
Full-text available
Cytokine storm is a phrase used to refer to an abrupt upsurge in the circulating levels of various pro-inflammatory cytokines, causing increased stimulation and activity of immune cells during disease conditions. The binding of pattern recognition receptors to pathogen-associated molecular patterns during COVID-19 infection recruits response machinery involving the activation of transcription factors and proteins required for a robust immune response by host cells. These immune responses could be influenced by epigenetic modifications as evidenced by significant variations in COVID-19 pathophysiology and response to therapy observed among patients across the globe. Considering that circulating levels of interleukin 1, tumor necrosis factor-α, and interleukin 6 are significantly elevated during cytokine storm in COVID-19 patients, genetic and epigenetic variations in the expression and function of these proteins could enhance our understanding of the disease pathogenesis. Treatment options that repress the transcription of specific cytokine genes during COVID-19 infection could serve as possible targets to counteract cytokine storm in COVID-19. Therefore, the present article reviews the roles of cytokines and associated genes in the COVID-19 cytokine storm, identifies epigenetic modifications associated with the disease progression, and possible ameliorative effects of some vitamins and minerals obtained as epigenetic modifiers for the control of cytokine storm and disease severity in COVID-19 patients.
... In this context, vitamin C may have positive outcomes on this acute viral infection. Moreover, vitamin C may alter susceptibility to respiratory tract infections by promoting coronavirus resistance [14,30]. In fact, vitamin Cdeficient people are prehensile to severe respiratory infections [3,31], and supplementation with vitamin C may reduce this infection [31]. ...
Full-text available
Background The outbreak of coronavirus infectious disease-2019 (COVID-19) is globally deemed a significant threat to human life. Researchers are searching for prevention strategies, mitigation interventions, and potential therapeutics that may reduce the infection’s severity. One such means that is highly being talked in online and in social media is vitamin C. Main text Vitamin C is a robust antioxidant that boosts the immune system of the human body. It helps in normal neutrophil function, scavenging of oxidative species, regeneration of vitamin E, modulation of signaling pathways, activation of pro-inflammatory transcription factors, activation of the signaling cascade, regulation of inflammatory mediators, and phagocytosis and increases neutrophil motility to the site of infection. All of these immunological functions are required for the prevention of COVID-19 infection. Conclusion Considering the role of vitamin C, it would be imperative to administrate vitamin C for the management of severe COVID-19. However, there is no specific clinical data available to confirm the use of vitamin C in the current pandemic.
... Despite all mentioned immune-boosting properties of folic acid and beneficial effects of vitamin C against SARS coronavirus and even 82% comparability between SARS-CoV-2 and SARS, we have to wait for the elucidation of ongoing investigations. 115,[204][205][206][207][208][209][210][211] Cai et al. conducted a study to investigate the effects of vitamin C on influenza virus infection and pneumonia in a restraint-stressed mouse model. Fulminant viral pneumonia, severe inflammation, and considerable damage were detected in the restraint stress-loaded infected mouse model. ...
The coronavirus disease 2019 (COVID-19) outbreak has caused a public health crisis worldwide. However, data regarding the protective factors of the disease is limited. Consequently, preventive health measures that can decrease the risk of infection, progression, and severity are dreadfully required. It is well-documented that people with immunodeficiency, such as the elderly, people who already have comorbidities (e.g., diabetes mellitus, hypertension, respiratory and cardiovascular disorders), and underrepresented minorities, are placed in a group with a higher risk of getting infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A diet rich in vitamins, minerals, and antioxidants plays an essential role in strengthening the immune system and fighting against invading pathogens. The present comprehensive review has discussed published literature regarding the potential role of vitamins in strengthening the immune system and managing viral infections, particularly SARS-CoV-2 infection. Although there are controversial data regarding the plasma level of vitamin D and the severity of the disease, according to the limited evidence, vitamin D may lower the mortality rate. Moreover, vitamin C could reduce the development of inflammatory response; however, the results of ongoing clinical trials are required to confirm these primary findings.
Full-text available
World Health Organization (WHO) declared a global public health emergency due to the recent spread of COVID-19 throughout the world. Millions of people are affected daily and thousands died. Almost all countries are now paying attention to control this pandemic outbreak. Therefore, researchers are trying to identify the pathophysiology of the disease, appropriate prognosis, effective management and prevention of COVID-19. Based on current published evidence, this review article specifies the role of different nutrients in the possible prevention and management of COVID-19 and viral infections. Balanced nutrition including adequate vitamin C, vitamin A, vitamin D, magnesium, selenium, zinc and phytonutrients have shown promising immune-boosting roles in COVID-19 and other respiratory infections due to their potential anti-inflammatory and antioxidants properties. These micronutrients act against COVID-19 infections both individually and synergistically.
Background: According to the Global Burden of Disease Study 2015, lower respiratory tract infection is the leading cause of infectious disease death, and the fifth most common cause of death overall. Vitamin C has a role in modulating resistance to infectious agents, therefore vitamin C supplementation may be important in preventing and treating pneumonia. Objectives: To assess the impact of vitamin C supplementation to prevent and treat pneumonia in children and adults. Search methods: We searched CENTRAL, MEDLINE, Embase, PubMed, CINAHL, LILACS, Web of Science, and two trials registers to 4 March 2020. We also checked references to identify additional studies. We did not apply any publication status or language filters. Selection criteria: We included randomised controlled trials (RCTs) and quasi-RCTs (studies using allocation methods that are not random, e.g. date of birth, medical record number) assessing the role of vitamin C supplementation in the prevention and treatment of pneumonia in children and adults compared to control or placebo. Data collection and analysis: We used standard methodological procedures expected by Cochrane. Main results: We included five studies in the review and identified two ongoing studies. The five included studies involved a total of 2655 participants; two studies were RCTs and three were quasi-RCTs. The included studies were conducted in one high-income country (USA) and three lower-middle-income countries (Bangladesh and Pakistan). Three studies were conducted in hospital inpatient settings, one in school, and one in a military training centre. Three studies included children under five years of age, one study included school-aged children, and one study included adult participants. Two studies assessed the effect of vitamin C supplementation for pneumonia prevention; and three studies assessed the effect of vitamin C supplementation as an adjunct to pneumonia treatment. For pneumonia prevention, the included studies provided supplementation in doses of 1 g daily for 14 weeks, 2 g daily for 8 weeks, and 2 g daily for 14 weeks. For pneumonia treatment, the included studies provided vitamin C supplementation in doses of 125 mg daily and 200 mg daily until the symptoms resolved or discharge, as an adjunct to the pneumonia treatment. Overall, the included studies were judged to be at either high or unclear risk of bias for random sequence generation, allocation concealment, and blinding; and the evidence certainty was very low. Two studies assessed the effect of vitamin C supplementation for pneumonia prevention; we judged the certainty of the evidence as very low. We are uncertain about the effect of vitamin C supplementation on pneumonia incidence and adverse events (urticaria). None of the included studies reported other primary outcomes (pneumonia prevalence and mortality) or any of the secondary outcomes. Three studies assessed the effect of vitamin C supplementation as an adjunct to pneumonia treatment; we judged the certainty of the evidence as very low. We are uncertain of the effect of vitamin C supplementation on duration of illness and hospitalisation. None of the included studies reported other primary or secondary outcomes. Authors' conclusions: Due to the small number of included studies and very low certainty of the existing evidence, we are uncertain of the effect of vitamin C supplementation for the prevention and treatment of pneumonia. Further good-quality studies are required to assess the role of vitamin C supplementation in the prevention and treatment of pneumonia.
Full-text available
So far over 60 studies have examined the effects of vitamin C on the common cold. No effect on common cold incidence was observed in the six largest studies, indicating that vitamin C has no preventive effects in normally nourished subjects in the Western countries. There are, however, smaller studies reporting benefit. In three trials of subjects under heavy acute physical stress, common cold incidence decreased by on average 50%, and in four trials of British males common cold incidence decreased by on average 30% in the vitamin C groups. The dietary vitamin C intake in the UK is low, and consequently the benefit may be due to the correction of marginal deficiency, rather than high vitamin doses. Regular vitamin C supplementation (> or =1 g/day) has quite consistently reduced the duration of colds, but the size of the benefit has varied greatly. In the four largest studies the duration of colds was reduced only by 5%. In two of these studies, however, absence from school and work was reduced by 14-21% per episode, which may have practical importance. Three controlled studies recorded a reduction of at least 80% in the incidence of pneumonia in the vitamin C group, and one randomised trial reported substantial treatment benefit from vitamin C in elderly UK patients hospitalized with pneumonia or bronchitis. It seems that the preventive effects of supplementation are mainly limited to subjects with low dietary vitamin C intake, but therapeutic effects may occur in wider population groups. Further carefully designed trials are needed to explore the effects of vitamin C.
Full-text available
Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1, 4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18-94 microg/mL.
Full-text available
We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (C(max)) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 microg/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC(24)) changed to 692, 1,062, 860, and 554 microg x h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of >or=7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n = 43) and in 52 and 13% of the patients in the 7-day evaluable population (n = 31). These findings indicate that L-AMB at dosages as high as 15 mg/kg/day follows nonlinear saturation-like kinetics, is well tolerated, and can provide effective therapy for aspergillosis and other filamentous fungal infections.
Full-text available
Amphotericin B is a polyene macrolide antibiotic derived from the actinomycete Streptomyces nodosus. Of the 200 known polyene agents, amphotericin B is the only one with toxicities that are sufficiently limited to permit intravenous administration. All polyenes have a common mechanism of action in that they preferentially bind to ergosterol, the primary sterol in the fungal cell membrane. The consequence of this binding includes disruption of the osmotic integrity of the membrane, with leakage of intracellular potassium and magnesium, and also the disruption of oxidative enzymes in target cells. Amphotericin B has a relatively broad spectrum of action and is useful in treating cases of candidosis, cryptococcosis, histoplasmosis, blastomycosis, paracoccidioidomycosis, coccidioidomycosis, aspergillosis, extracutaneous sporotrichosis and mucormycosis, and some cases of hyalohyphomycosis and phaeohyphomycosis. Resistance (MIC > 2 mg/L) tends to be species-dependent and emerges uncommonly and slowly in isolates from patients treated with amphotericin B. These include some individual strains of Candida albicans, Candida tropicalis, Candida parapsilosis and Candida lusitaniae, which may acquire resistance during treatment. Some isolates of Scedosporium apiospermum, Fusarium spp. and Sporothrix schenckii also show primary resistance, whereas all strains of Scedosporium prolificans demonstrate resistance. The main problems associated with the use of conventional amphotericin B have always been due to its poor aqueous solubility and toxicity rather than antifungal resistance.
The effect of supplementing the feed of broiler chicks with different levels of ascorbic acid on the resistance against infectious bronchitis virus was investigated. Resistance was measured by the severity of tracheal lesions and the development of airsacculitis after challenge. The effect of ascorbic acid was dose dependent. Addition of 300 to 330 ppm ascorbic acid to the feed gave the best results. High concentrations (>600 ppm) had a less beneficial effect.
Chick embryo tracheal organ cultures showed increased resistance to infection by a coronavirus after exposure to ascorbate, while chick respiratory epithelium and allantois-on-shell preparations showed no increase in resistance to infection by an influenza virus or a paramyxovirus.
Since the introduction of ascorbic acid as an antiviral and antibacterial agent (Klenner, 1951; McCormick, 1952; Klenner, 1974) interest has focused on the possible immunologic mechanisms involved in its protective effect. The role of ascorbic acid in the immune response is reviewed here with regard to cellular and humoral functions, and experiments pertaining to the role of ascorbic acid in autoimmunity and anaphylaxis are discussed.
In vivo pharmacodynamic parameters have been described for a variety of antibacterials. These parameters have been studied in correlation with in vivo outcomes in order to determine which dosing parameter is predictive of outcome and the magnitude of that parameter associated with efficacy. Very little is known about pharmacodynamics for antifungal agents. We utilized a neutropenic mouse model of disseminated candidiasis to correlate pharmacodynamic parameters (percent time above MIC [T > MIC], area under the concentration time curve [AUC]/MIC ratio, and peak serum level/MIC ratio) for amphotericin B in vivo with efficacy, as measured by organism number in homogenized kidney cultures after 72 h of therapy. Amphotericin B was administered by the intraperitoneal route. Drug kinetics for amphotericin B in infected mice were nonlinear. Serum half-lives ranged from 13 to 27 h. Infection was achieved by intravenous inoculation with 10(6) CFU of yeast cells per ml via the lateral tail vein of neutropenic mice. Groups of mice were treated with fourfold escalating total doses of amphotericin B ranging from 0.08 to 20 mg/kg of body weight divided into 1, 3, or 6 doses over 72 h. Increasing doses produced concentration-dependent killing, ranging from 0 to 2 log(10) CFU/kidney compared to the organism number at the start of therapy. Amphotericin B also produced prolonged dose-dependent suppression of growth after serum levels had fallen below the MIC. Nonlinear regression analysis was used to determine which pharmacodynamic parameter best correlated with efficacy. Peak serum level in relation to the MIC (peak serum level/MIC ratio) was the parameter best predictive of outcome, while the AUC/MIC ratio and T > MIC were only slightly less predictive (peak serum level/MIC ratio, coefficient of determination [R(2)] = 90 to 93%; AUC/MIC ratio, R(2) = 49 to 69%; T > MIC, R(2) = 67 to 85%). The total amount of drug necessary to achieve various microbiological outcomes over the treatment period was 4.8- to 7.6-fold smaller when the dosing schedule called for large single doses than when the same amount of total drug was administered in 2 to 6 doses. Given the narrow therapeutic window of amphotericin B and frequent treatment failures, these results suggest the need for a reevaluation of current dosing regimens.
Ralph A. Tripp, Lia M. Haynes, Deborah Moore, Barbara Anderson, Azaibi Tamin, Brian H. Harcourt, Les P. Jones, Mamadi Yilla, Gregory J. Babcock, Thomas Greenough, Donna M. Ambrosino, Rene Alvarez, Justin Callaway, Sheana Cavitt, Kurt Kamrud, Harold Alterson, Jonathan Smith, Jennifer L. Harcourt, Congrong Miao, Raj Razdan, James A. Comer, Pierre E. Rollin, Thomas G. Ksiazek, Anthony Sanchez, Paul A. Rota, William J. Bellini, Larry J. Anderson. (2005) Monoclonal antibodies to SARS-associated coronavirus (SARS-CoV): Identification of neutralizing and antibodies reactive to S, N, M and E viral proteins. Journal of Virological Methods 128, 21-28 CrossRef