Prevention of recurrent respiratory infections : Inter-society Consensus.

Recurrent respiratory infections (RRIs) are a common clinical condition in children, in fact about 25% of children under 1 year and 6% of children during the first 6 years of life have RRIs. In most cases, infections occur with mild clinical manifestations and the frequency of episodes tends to decrease over time with a complete resolution by 12 years of age. However, RRIs significantly reduce child and family quality of life and lead to significant medical and social costs.Despite the importance of this condition, there is currently no agreed definition of the term RRIs in the literature, especially concerning the frequency and type of infectious episodes to be considered. The aim of this consensus document is to propose an updated definition and provide recommendations with the intent of guiding the physician in the complex process of diagnosis, management and prevention of RRIs.

Pidotimod and Immunological Activation in Individuals Infected with HIV.

BACKGROUND: The improvements in HIV infection therapy and the large availability of antiretroviral drugs have led to an increased survival among HIV infected people, and simultaneously to a raised morbidity and mortality due to not-AIDS-related events in this group compared to the general population. An increased systemic inflammation and a persistent immune activation play a pivotal role in determining high rates of non-AIDS comorbidities. In the last years, many natural or synthetic immunomodulatory molecules acting by different mechanisms have been conceived. Pidotimod is a synthetic dipeptide molecule showing immunomodulatory properties. The aim of this pilot study was to evaluate the effects of Pidotimod supplementation on residual inflammation in HIV infected population. METHODS: Forty HIV positive individuals under cART were enrolled: 30 were treated with Pidotimod supplementation (study group) and 10 served as control group (without Pidotimod supplementation). For all participants, Cystatin C, PCR, ESR, microalbuminuria, TNF-α, INF-γ, IL-4, IL-10, IL1ß, IL-18 and IL-2 were measured at enrolment (T0), 4 weeks after of Pidotimod supplementation (T1), and 4 weeks after completing supplementation (T2). RESULTS: In HIV positive participants treated with Pidotimod, the evaluation of cytokine levels showed that IL-10, IFN gamma, and IL-4 were significantly higher at enrolment compared to the control group. The increase under Pidotimod treatment persisted after supplementation suspension, while the pro-inflammatory cytokines levels were reduced. Salivary IgA also increased during 4 weeks of supplementation and persisted at 4 weeks after completing supplementation. On the other hand, the Cystatin C and microalbuminuria levels decreased over time, at a greater extent the Cystatin C serum levels. CONCLUSION: The study findings showed that the HIV population receiving Pidotimod achieved a rebalancing of pro-inflammatory and anti-inflammatory cytokines as well as a significant reduction in cystatin C levels. The treatment further allowed for an increase in salivary IgA levels at all the analyzed times, as a secondary event to a remodulation of the immunological status obtained with pidotimod. This approach could represent a new way to design new intervention strategies aimed at improving the persistent immune activation status in the virologically suppressed HIV population.

Neurotherapeutic and antioxidant response of D-ribose-L-Cysteine nutritional dietary supplements on Alzheimer-type hippocampal neurodegeneration induced by cuprizone in adult male wistar rat model.

INTRODUCTION: Cuprizone is a neurotoxicant causing neurodegeneration through enzymes inhibition and oxidative stress. D-Ribose-L-Cysteine (DRLC) is a powerful antioxidant with neuroprotective properties. This study explored the antioxidant response of DRLC against cuprizone-induced behavioral alterations, biochemical imbalance and hippocampal neuronal damage in adult wistar rats. MATERIALS AND METHODS: Thirty two (32) adult male wistar rats (150-200g) were divided into four groups (n = 8). Group A received normal saline only as placebo; Group B received 0.5% cuprizone diet only; Group C received a combination of 0.5% cuprizone diet and 100 mg/kg bw of DRLC and Group D received 100 mg/kg bw of DRLC only. The administration was done through oral gavage once daily for 45 days. After the last treatment, neurobehavioral tests (Morris Water Maze and Y maze) was conducted; animals sacrificed and brain harvested for histological analysis and biochemical estimations of levels of antioxidants, oxidative stress markers, neurotransmitters and enzyme activitties. RESULTS: The results showed significant memory decline, hippocampal alterations, decrease levels of antioxidant markers, enzyme and neurotransmitters activities with concomitant increase in norepinephrine and oxidative stress markers in cuprizone induced rats relative to normal but was attenuated with DRLC administration. CONCLUSION: Cuprizone causes cognitive impairment and neurodegeneration through oxidative stress; however, administration of DRLC ameliorated neuropathological alteration induced by cuprizone.

Pidotimod in allergic diseases.

The rising incidence of allergic disease requires more specific, effective and safe therapeutic strategies. In this regard, several kinds of biologically active substances, commonly known as immunostimulants, have been introduced for the prevention and treatment of allergic diseases in pediatric population. Among the heterogeneous group of biologically active molecules to date available, pidotimod (Axil, Valeas S.p.A, Milan) is proved to be able to ameliorate both innate and adaptive immunity and enhances the immune system properties often impaired in patients with allergic disorders.

Pidotimod enhanced the anti-growth effect of cisplatin on lung cancer in mice via promoting anti-tumor immune response.

Cisplatin-based chemotherapeutics represent a mainstay of lung cancer therapy, but resistance limits their curative potential. In the current study, we reported that Pidotimod, which is an immunostimulant and used for the prevention of acute respiratory infections, elevated cisplatin sensitivity, leading to the synergistic attenuation of tumor growth in mouse lewis lung cancer (LLC) model. With further exploration, we found that Pidotimod enhanced the anti-growth effect of cisplatin on LLC via promoting anti-tumor response, such as increased infiltration of dendrite cells (DCs) and CD8+ T cells as well as enhancement of IFN-γ and Granzyme B expression. In summary, Pidotimod affects the anti-tumor function of cisplatin via promoting anti-tumor immune response and these findings provide a novel approach for the development of therapeutic strategies for lung cancer.

Effects of Pidotimod on recurrent respiratory infections in children with Down syndrome: a retrospective Italian study.

BACKGROUND: Children with Down syndrome (DS) show a high susceptibility to recurrent infections (RI), caused by immune defects and abnormalities of the airways. Our goal was to investigate the effects of Pidotimod on RI prevention in children with DS, comparing immune and clinical parameters before (T0) and after (T1) the treatment with Pidotimod. METHODS: The study was conducted at the Down syndrome outpatient Center of Bambino Gesù Children's Hospital, in Rome. We reviewed the medical records of all children with a positive history for RI and who received oral prophylaxis of Pidotimod from September 2016 to February 2017. RESULTS: Thirty-three children met the inclusion criteria (males: 51.5%; average age: 6 years ±SD: 3). We found a significant decrease in the number of children with upper respiratory infections (82% at T0 vs 24% at T1; p = 0,0001) and with lower respiratory infections (36% at T0 vs 9% at T1; p = 0.003) after treatment with Pidotimod. We also demonstrated a significant decrease in the number of children hospitalized for respiratory infections (18% at T0 vs 3% at T1; p = 0.03). We measured T and B cells in the peripheral blood and B cell function in vitro at T0 and T1. We found that the response to CpG improved at T1. A significant increase of B cell frequency (p = 0.0009), B cell proliferation (p = 0.0278) and IgM secretion (p = 0.0478) were observed in children with DS after treatment. CONCLUSIONS: Our results provided evidence that Pidotimod may be able to prevent RI in children with Down syndrome.

Effects of pidotimod and bifidobacteria mixture on clinical symptoms and urinary metabolomic profile of children with recurrent respiratory infections: a randomized placebo-controlled trial.

BACKGROUND: Many preschool children develop recurrent respiratory tract infections (RRI). Strategies to prevent RRI include the use of immunomodulators as pidotimod or probiotics, but there is limited evidence of their efficacy on clinical features or on urine metabolic profile. OBJECTIVE: To evaluate whether pidotimod and/or bifidobacteria can reduce RRI morbidity and influence the urine metabolic profile in preschool children. MATERIALS AND METHODS: Children aged 3-6 years with RRI were enrolled in a four-arm, exploratory, prospective, randomized, double-blinded, placebo-controlled trial. Patients were randomly assigned to receive pidotimod plus bifidobacteria, pidotimod plus placebo, bifidobacteria plus placebo or double placebo for the first 10 days of each month over 4 consecutive months. Respiratory symptoms and infections were recorded with a daily diary by parents during the study. Metabolomic analyses on urine samples collected before and after treatment were performed. RESULTS: Compared to placebo, children receiving pidotimod, alone or with bifidobacteria, had more symptom-free days (69 versus 44, p = 0.003; and 65 versus 44, p = 0.02, respectively) and a lower percentage of days with common cold (17% versus 37%, p = 0.005; and 15% versus 37%, p = 0.004, respectively). The metabolomic analysis showed that children treated with Pidotimod (alone or in combination with bifidobacteria) present, respect to children treated with placebo, a biochemical profile characterized by compounds related to the pathway of steroids hormones, hippuric acid and tryptophan. No significant difference in the metabolic profile was found between children receiving bifidobacteria alone and controls. CONCLUSIONS: Preschool children with RRI treated with pidotimod have better clinical outcomes and a different urine metabolomic profile than subjects receiving placebo. Further investigations are needed to clarify the connection between pidotimod and gut microbiome.

Pidotimod, an immunostimulant in pediatric recurrent respiratory tract infections: A meta-analysis of randomized controlled trials.

OBJECTIVES: Recurrent respiratory tract infections (RRTIs) remain a great challenge to pediatricians, because they can increase the risk of various complications and there is no confirmed effective treatment. In the present study, we aimed to assess the effectiveness and safety of pidotimod (PDT), an immunostimulant, in treatment of RRTIs in children aged 14 years and under. METHODS: PubMed, EMBASE, Web of Science, Cochrane Library, ClinicalTrials.gov, CBM and CNKI were searched from their inception up to February 2018. All randomized controlled trials (RCTs) using PDT with various treatment durations and enrolling participants <14 years of age were included in the present review. The interventions were PDT plus conventional treatment (e.g. anti-bacterial and antiviral therapy) or PDT alone versus the conventional treatment plus placebo or conventional treatment alone. RESULTS: A total of 29 RCTs consisting of 4344 pediatric patients were included in this meta-analysis. Ten RCTs were published from Italy, Russia or Greece, and 19 RCTs were published by Chinese groups. However, appropriate randomization methods were only used in 15 trials. Only one study had explicit allocation concealment. Since only eight RCTs were double-blind and placebo controlled, the evidence was not assessed as high quality. The meta-analysis indicates that treatment with PDT resulted in a significant increase in the proportion of participants who had lower RTIs (RR 1.59; 95% CI 1.45-1.74, p < 0.00001) compared with the conventional treatment. PDT could significantly decrease the duration of cough and fever. The number of patients in using antibiotics was also remarkably decreased in the PDT treatment group. Moreover, PDT administration improved the levels of serum immunoglobulin (IgG, IgA, or IgM) and T-lymphocyte subtypes (CD3+, CD4+). Besides, PDT administration did not increase the risk of adverse events of any cause (RR = 1.05, 95% CI 0.72-1.54, p = 0.80). CONCLUSIONS: PDT showed a good efficacy and safety in treatment of pediatric RRTIs. Further high-quality and large-scale RCTs are still required to provide confirmatory evidence. TRIAL REGISTRATION: The protocol of this study can be found at PROSPERO with the registration number of CRD42018093541.

Novel non-peptidic small molecule inhibitors of secreted aspartic protease 2 (SAP2) for the treatment of resistant fungal infections.

Targeting secreted aspartic protease 2 (SAP2), a kind of virulence factor, represents a new strategy for antifungal drug discovery. In this report, the first-generation of small molecule SAP2 inhibitors was rationally designed and optimized using a structure-based approach. In particular, inhibitor 23h was highly potent and selective and showed good antifungal potency for the treatment of resistant Candida albicans infections.

Immunomodulatory activity of pidotimod administered with standard antibiotic therapy in children hospitalized for community-acquired pneumonia.

BACKGROUND: Several attempts to improve immune function in young children have been made and encouraging results have been collected with pidotimod (PDT), a synthetic dipeptide molecule that seems to have immunomodulatory activity on both innate and adaptive responses. Until now, the effects of PDT on the immune system have only been studied in vivo after long-term administration to evaluate whether its immunomodulatory activity might prevent the development of infections. This study was planned to evaluate the immunomodulatory activity of PDT administered together with standard antibiotic therapy in children hospitalized for community-acquired pneumonia (CAP). METHODS: A total of 20 children hospitalized for community-acquired pneumonia (CAP) were randomized at a 1:1 ratio to receive either standard antibiotics plus pidotimod (PDT) or standard antibiotics alone to evaluate the immunomodulatory activity of PDT. Blood samples for the evaluation of immunological parameters were drawn at the time of recruitment (T0) (i.e., before therapy administration), at T3 and T5 (i.e., 3 and 5 days after the initiation of therapy) as well as at T21 (i.e., 7 days after the therapy ended). RESULTS: Following pneumococcal polysaccharide stimulation, the percentage of dendritic cells (DCs) expressing activation and costimulatory molecules was significantly higher in children receiving PDT plus antibiotics than in the controls. A significant increase in tumor necrosis factor-α and/or interleukin-12 secretion and expression of toll like receptor 2 was observed in PDT-treated children compared with controls; this was followed by an increased release of proinflammatory cytokines by monocytes. In the PDT-treated group, mRNA expression of antimicrobial peptides and genes involved in the inflammatory response were also augmented in comparison with the controls. CONCLUSIONS: These results demonstrate, for the first time, that PDT administered together with standard antibiotics is associated with a favorable persistent immunomodulatory effect in children with CAP.

D-ribose-L-cysteine supplementation enhances wound healing in a rodent model.

BACKGROUND: Wound healing and chronic wounds are serious public health issues. While wounds heal, cellular stores of antioxidants are depleted. d-ribose-l-cysteine (DRLC) is a precursor to the antioxidant glutathione. The effect of oral supplementation with DRLC on wound healing was studied in rats. METHODS: A rodent model of calibrated wounding was used. Group A rats were given DLRC for 1 week before wounding and for 3, 7, or 14 days after wounding. Group B rats were given DRLC only after wounding. Control animals were given no supplement. Photographic comparisons were made to study wound edema and inflammation. Wound strength was determined by using a laser-vacuum device. RESULTS: During healing, both Group A and B animals showed less edema and inflammation than Control. Group A animals had the weakest wounds at 3 days after surgery, but the strongest wounds after 14 days. Group B animals had similar wound strength to Control animals at 7 days, but stronger wounds after 14 days. CONCLUSIONS: DRLC supplementation appears to reduce wound inflammation early after wounding and enhance wound strength by 14 days. This suggests that increased intracellular glutathione levels may improve and enhance wound healing.

Pidotimod for the prevention of acute respiratory infections in healthy children entering into daycare: A double blind randomized placebo-controlled study.

Acute respiratory tract infections (ARTIs) are very common in pediatric age and reach a peak in the first 4 years of life, especially in children attending daycare. Pidotimod, a synthetic immunostimulant, may reduce the incidence of ARTIs in children with predisposing risk factors. Nevertheless studies on healthy children are presently lacking. We performed a double-blinded randomized placebo-controlled trial study to assess the efficacy of Pidotimod in a population of 3-year-old healthy children who just entered kindergarten. The main outcome was the incidence of respiratory infections in this population and the secondary outcome was the prescription of antibiotics. The study group consisted of healthy 3-year-old children who had not yet attended day-care centers. Patients were enrolled by a convenience sample of 17 family pediatricians (FP). Children were randomized to receive either Pidotimod 400 mg per os or placebo twice daily for the last 10 days of each month from October 2013 to April 2014. Any time a child presented to his/her FP with fever and ARTI was diagnosed, clinical and therapeutic data were collected. A total of 800 children were pre-screened, 733 did not meet the inclusion criteria and 10 refused to participate. Of the 67 eligible subjects, 57 were successfully enrolled within the study recruitment period and randomized to receive Pidotimod (n = 29) or placebo (n = 28). Eight children were lost to follow-up. In the final analysis were thus included 24 children who received Pidotimod and 25 who received placebo. The incidence rate ratio for respiratory infections was 0.78 (95%CI 0.53 to 1.15, p = 0.211) for Pidotimod vs. placebo. The corresponding risk ratio for antibiotic usage was 0.56 (95%CI 0.27 to 1.16, p = 0.120). In our trial, Pidotimod did not prove to be statistically superior to placebo for the prevention of ARTI in a population of healthy children who entered kindergarten. However, Pidotimod showed some potential as a means for reducing antibiotic usage in these children.

[Effectiveness of pidotimod in combination with bacterial lysates in the treatment of the pfapa (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome]. / Efficacia del Pidotimod in associazione a lisato batterico nel trattamento della syndrome PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis).

AIM: PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis) syndrome is the most common autoinflammatory syndrome in pediatrics, accepted as an hyperimmune condition. Pidotimod is a molecule with immunomodulatory activity on both innate and adaptive immune responses; it also has the capacity to modulate the function of the respiratory epithelial cells through the activation of a NK-KB pathway which would involve the host-virus interaction. Moreover, the proven beneficial effect of Pidotimod in enhancing the immune response during vaccination, and its benefits in the prevention of respiratory tract infections, should be noted. METHODS: A joint combination of Pidotimod and bacterial lysates was used to treat 37 children with a clinical diagnosis of PFAPA; within the end of the first year of therapy, the healing rate of PFAPA symptoms was 67.5% (25 children), with a 10.8% (4 cases) still in complete remission within the end of the second year of follow-up. RESULTS: It is important to highlight that 29 children (78.3%) had benefitted from this therapy, in terms of healing, with a marked decrease in the incidence of fever from a total of 360 to 106 episodes, and episodes of periodic fever occurring almost 4 times less frequently. The use of Pidotimod determined a significant reduction of surgical tonsillectomy's treatment. CONCLUSION: This approach had a strong impact on the children's quality of life; a significant decrement in the use of antipyretic drugs, as well as a lower rate of antibiotic prescription, were also noted. It also had a dramatic impact on families' lives, because the treatment lowers the number of absences of family members from work or school/kindergarten.

[Cathepsin K antagonists: preclinical and clinical data]. / Cathepsin K-Inhibitoren: präklinische und klinische Daten.

Cathepsin K, a cysteine protease, is an essential enzyme in degradation of collagen type I. Since cathepsin K is relatively specific to osteoclasts, it represents a promising candidate for drug development. In the past decades, efforts have been made in developing highly potent, selective and orally applicable cathepsin K inhibitors. In contrast to balicatib and relacatib, whose drug development programmes were stopped due to cutaneous side-effects related to limited drug specificity, the more specific cathepsin K inhibitors odanacatib (ODN) and ONO-5334 have entered clinical trials. Odanacatib progressively increases bone mineral density (BMD) and decreases bone resorption markers in postmenopausal women with low BMD. Its clinical efficacy and safety was confirmed by several clinical studies but indicates that odanacatib is characterized by a resolution-of-effect with increases in bone resorption and rapid decreases in BMD following treatment discontinuation. A phase III fracture prevention study in postmenopausal women with osteoporosis is currently in the final phase.

Efficacy and safety of pidotimod in the prevention of recurrent respiratory infections in children: a multicentre study.

Acute respiratory infections (ARI) still represent a big challenge for paediatricians, especially in those children defined as "ailed" as they are more susceptible to such kinds of disease. In this paediatric population, the immune system is still under-developed with an evident alteration in cytokine levels. A clinical study was carried out in 5 sites in Russia with the intention to enroll children particularly susceptible to contract respiratory infections (defined as "ailing"), assigning them to a treatment group with pidotimod in comparison with a control group, treating them for 30 days and observing the reduction in the number of ARI episodes throughout the follow-up period (6 months). Moreover, changes in serum immunological markers were evaluated at baseline and 30 days after treatment discontinuation. One hundred and fifty-seven ailing children were enrolled and assigned to two arms: a main pidotimod treatment group or a control group. The percentage of incidence of ARIs in the observation period at three different time points was statistically significant (p < 0.05). At the end of the follow-up period (after 6 months), ARIs had developed in 72 children (92.3%) in the main group and in 79 patients (100%) in the control group. Concerning changes of the immunological markers, the treatment group showed a better profile of normalization compared to the control group. The 30-day pidotimod therapy course led to improvement/reduction in the rate of acute respiratory infection recurrence in ailing children within a 3-month period, with a quick elimination of symptoms and signs of infection and, as a result, a faster recovery. The normalisation of the content of the pro-inflammatory cytokine interleukin-8 confirmed the immune-modulatory effect of the investigational drug, underlying its prophylactic effect.

Pidotimod may prevent recurrent respiratory infections in children.

AIM: Recurrent respiratory infections (RRI) constitute a social problem for both the pharmaco-economic impact and the burden for the family. Pidotimod is a synthetic immunostimulant. The aim of this study was to evaluate the effects of pidotimod on RRI prevention in children. METHODS: Globally, 100 children (49 males, mean age 4.7 ± 1.2 years) with RRI were enrolled in the study. At baseline, children were randomly assigned to the treatment with pidotimod 400 mg/die or not for two months. Children were visited at baseline, after 30 (T1) and 60 (T2) days, and at follow-up (120 days; T3). Number of children with upper and lower airways symptoms, medications use, school attendance, and paediatric visits for RRI were evaluated. RESULTS: Pidotimod treatment was able of significantly reducing the number of children with upper and lower airways symptoms, and medications use, increasing school attendance, and reducing pediatric visits for RRI. CONCLUSION: This study provided the evidence that pidotimod may be able of preventing RRI in children.

Amiloride and SN-6 suppress audiogenic seizure susceptibility in genetically epilepsy-prone rats.

AIMS: We have recently reported that amiloride, a potent and nonselective blocker of acid-sensing ion channels, prevents the development of pilocarpine-induced seizures and status epilepticus. Amiloride is also known to suppress the activity of Na(+) /Ca(2+) and Na(+) /H(+) exchangers that have been implicated in the pathophysiology of seizures. Here, we evaluated the effects of amiloride, SN-6 (a potent blocker of Na(+) /Ca(2+) exchangers) and zoniporide (a potent blocker of Na(+) /H(+) exchangers) on acoustically evoked seizures (audiogenic seizures, AGS) in genetically epilepsy-prone rats (GEPR-3s), a model of inherited generalized epilepsy. METHODS: Male, six-week-old GEPR-3s were used. The GEPR-3s were tested for AGS susceptibility before and after treatment with various doses of amiloride, SN-6, and zoniporide (1, 3, 10, and 30 mg/kg; per os). RESULTS: We found that pretreatment with amiloride and SN-6 markedly reduced the incidence and severity of AGS in the GEPR-3s. In contrast, administration of zoniporide only minimally reduced the incidence and severity of AGS in the GEPR-3s. A combination of noneffective doses of SN-6 and zoniporide also suppressed AGS susceptibility in the GEPR-3s. CONCLUSIONS: These findings suggest acid-sensing ion channels and the Na(+) /Ca(2+) exchanger may play an important role in the pathophysiology of inherited AGS susceptibility in the GEPR-3s.

Pidotimod: the past and the present.

At the end of 1990s, acute respiratory tract infections (ARTIs) were called the 'forgotten pandemic', with a clear dichotomy between developing and industrialised countries in mortality and morbidity, the main outcomes associated with ARTIs. This definition still applies 20 years later, when the introduction of new and safe antibiotics and vaccines has certainly contributed to controlling the most life-threatening ARTIs, but has not had a major impact on viral ARTIs in paediatric age. One functional approach to preventing and treating ARTIs is non-specifically increasing the immune response or enhancing the children's innate defence mechanisms. Different kinds of biologically active substances--called immunostimulants--of natural and synthetic origins and with different mechanisms of action have been introduced in some countries for the prevention of ARTIs in children. Recently, research focused on one of these compounds, Pidotimod, has attempted to better clarify and define its mechanisms of action both in vitro and in vivo. In this paper, we critically examine the most recent findings on Pidotimod. Certainly the improvement of research methodology in the last 20 years and the acquired knowledge in various fields of clinical immunology should be the starting point for research on Pidotimod. Preclinical research will be essential to better understand the mechanisms of action of this compound. However, in vivo studies, especially randomised control trials, will be necessary to establish the real efficacy of Pidotimod in the prevention of ARTIs in paediatric age.

Anti-diabetic and anti-inflammatory effect of a novel selective 11ß-HSD1 inhibitor in the diet-induced obese mice.

It has been reported that the selective inhibitors of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) have considerable potential for treating type 2 diabetes mellitus, metabolic syndrome and inflammation. In the present study, we investigated the anti-diabetic and anti-inflammatory effects of N-(5-carbamoyladamantan-2-yl)-3-((2-fluorophenyl) sulfonyl)thiazolidine-2-carboxamide (KR-67105), a novel 11ß-HSD1 inhibitor, in diabetic mice model and preadipocyte model. KR-67105 concentration dependently inhibited 11ß-HSD1 activity in human and mouse 11ß-HSD1 overexpressing cells and mouse 3T3-L1 adipocytes. Furthermore, KR-67105 concentration-dependently inhibited 11ß-HSD1 activity in the ex vivo assay of C57BL/6 mice. In the study with diet-induced obese (DIO) mice, the administration of KR-67105 (100mg/kg/day, orally for 28 days) improved the glucose tolerance and insulin sensitivity as determined by the oral glucose tolerance test and the insulin tolerance test. Anti-diabetic effect by KR-67105 was associated with the suppression of diabetic related genes expression in liver and fat. Furthermore, KR-67105 suppressed 11ß-HSD1 activity in liver and fat of diabetic mice, but showed no effect on adrenal grand weight/body weight ratio and plasma corticosterone concentration in diabetic mice. In 3T3-L1 preadipocytes, cortisone induced the mRNA of inflammatory cytokines and 11ß-HSD1 and reactive oxygen species formation. This effect was abolished by co-incubation with KR-67105 in a concentration-dependent manner. Moreover, KR-67105 attenuated cortisone induced iNOS expression and phosphorylation of NF-κB p65, p38 MAPK, and ERK1/2 in preadipocytes. Taken together, it is concluded that a selective 11ß-HSD1 inhibitor, KR-67105, may provide a new therapeutic window in the prevention and treatment of type 2 diabetes with chronic inflammation without toxicity.