Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder.

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-|linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

Oxycodone-related deaths in Sweden 2006-2018.

AIM: To identify and characterize oxycodone related deaths in Sweden from 2006 to 2018 and to compare them to other opioid-related deaths. METHODS: To assess the factors contributing to the deaths, we used multinomial logistic regression to compare oxycodone-related deaths extracted from all forensic autopsy examinations and toxicology cases in the age groups 15-34 (reference group), 35-54 and 55-74 with regard to sex, presence of benzodiazepines and alcohol at the time of death, prescription of oxycodone, benzodiazepines and antidepressants, previous substance use-related (SUD) treatment, and manner of death. The oxycodone related deaths were compared with deaths with presence of other opioids. RESULT: We identified 575 oxycodone-related deaths, and the rate increased during the study period from 0.10 to 1.12 per 100,000 in parallel with an increase of oxycodone prescriptions from 3.17 to 30.33 per 1000. Oxycodone-related deaths amounted to 10.0% of all opioid-related deaths. The deaths occurred mainly in older patients previously being prescribed oxycodone. Benzodiazepines were present at the time of death in 403 (70%) and alcohol in 259 (45%). Prescriptions of any opioid for pain (61%), oxycodone (50%), benzodiazepines (67%) and antidepressants (55%) were common. Only 15% had received treatment for SUD during the last year. CONCLUSION: Oxycodone-related deaths increased in Sweden between 2006 and 2018 in parallel to an increase in oxycodone prescriptions. The increase occurred mainly in older patients being prescribed oxycodone for pain. There might be specific interventions needed to avoid oxycodone-related deaths compared to other opioid-related deaths associated with illicit opioid use.

Factors of Interest in Extended-Release Buprenorphine: Comparisons Between Incarcerated and Non-Incarcerated Patients with Opioid Use Disorder.

PURPOSE: Extended-release buprenorphine (XR-BUP) covers a range of formulations of buprenorphine-based treatments for opioid use disorder (OUD) that release the medication over a period of one week, one month, or six months. OUD is particularly prevalent among incarcerated populations, and previous findings have shown that incarcerated subjects were not less interested in XR-BUP than non-incarcerated subjects. However, no study has ever investigated whether the factors of interest in XR-BUP were similar in incarcerated and non-incarcerated populations. PATIENTS AND METHODS: We carried out post-hoc analyses using data from the "AMBRE" survey, which was conducted among 366 individuals with OUD, that were recruited in 68 French addiction settings, including six prison medical centers. The reasons for interest in XR-BUP were compared between incarcerated and non-incarcerated interviewees, using logistic regressions models, which provided raw and adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). Adjustment variables were gender, age category, level of education, and type of current medication for OUD, respectively. RESULTS: Data from 317 participants (ie, 221 non-incarcerated, and 96 incarcerated individuals) were included in the analyses. Adjusted comparisons found that "no longer taking a daily treatment" (aOR= 2.91; 95% CI= 1.21-6.98) and "having a more discreet medication" (aOR= 1.76; 95% CI= 1.01-3.10) were reasons that appealed more to incarcerated participants than to non-incarcerated ones. On the other hand, the potential reduction of withdrawal symptoms (aOR= 0.54; 95% CI= 0.29-0.99) or the risk of misuse (aOR= 0.56; 95% CI= 0.34-0.94) associated with XR-BUP treatment were considered more important by non-incarcerated individuals than by incarcerated ones. CONCLUSION: Incarcerated interviewees were interested in XR-BUP for different reasons than those outside prison. In particular, incarcerated patients were more interested in practicability and discretion features, and less in improving recovery or reducing misuse than non-incarcerated patients.

Patient-Reported Outcomes of Treatment of Opioid Dependence With Weekly and Monthly Subcutaneous Depot vs Daily Sublingual Buprenorphine: A Randomized Clinical Trial.

Importance: Patient-reported outcomes in the treatment of opioid dependence may differ between subcutaneously administered depot buprenorphine and daily sublingual buprenorphine. Objective: To compare patient satisfaction between depot buprenorphine and sublingual buprenorphine in adult outpatients with opioid dependence. Design, Setting, and Participants: This open-label, randomized clinical trial was conducted among adult patients with opioid dependence at 6 outpatient clinical sites in Australia from October 2018 to September 2019. Data analysis was conducted from October 2019 to May 2020. Interventions: Participants were randomized to receive treatment with weekly or monthly depot buprenorphine or daily sublingual buprenorphine over 24 weeks. Main Outcomes and Measures: The primary end point was the difference in global treatment satisfaction, assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4 (range, 0-100; higher score indicates greater satisfaction) at week 24. Secondary end points included other patient-reported outcomes, including quality of life, treatment burden, and health-related outcomes, as well as measures of opioid use, retention in treatment, and safety. Results: A total of 119 participants (70 [58.8%] men; mean [SD] age, 44.4 [10.5] years) were enrolled, randomized to, and received either depot buprenorphine (60 participants [50.4%]) or sublingual buprenorphine (59 participants [49.6%]). From the initial sample of 120, a participant (0.8%) in the sublingual buprenorphine group withdrew consent and did not receive study treatment. All participants were receiving sublingual buprenorphine when enrolled. The mean TSQM global satisfaction score was significantly higher for the depot group compared with the sublingual group at week 24 (mean [SE] score, 82.5 [2.3] vs 74.3 [2.3]; difference, 8.2; 95% CI, 1.7 to 14.6; P = .01). Improved outcomes were also observed for several secondary end points after treatment with depot buprenorphine (eg, mean [SE] treatment burden assessed by the Treatment Burden Questionnaire global score, on which lower scores indicate lower burden: 13.2 [2.6] vs 28.6 [2.5]; difference, -15.4; 95% CI, -22.6 to -8.2; P < .001). Thirty-nine participants (65.0%) in the depot buprenorphine group experienced 117 adverse drug reactions, mainly injection site reactions of mild intensity following subcutaneous administration, and 12 participants (20.3%) in the sublingual buprenorphine group experienced 21 adverse drug reactions. No participants withdrew from the trial medication or the trial due to adverse events. Conclusions and Relevance: In this study, participants receiving depot buprenorphine reported improved treatment satisfaction compared with those receiving sublingual buprenorphine. The results highlight the application of patient-reported outcomes as alternative end points to traditional markers of substance use in addiction treatment outcome studies. Trial Registration: anzctr.org.au Identifier: ANZCTR12618001759280.

Determinants of interest in extended-released buprenorphine: A survey among 366 French patients treated with buprenorphine or methadone.

AIM: To explore the factors determining the interest in extended-release buprenorphine (XR-BUP) injections among patients receiving opioid agonist treatment (OAT) in France. METHODS: 366 patients receiving OAT for opioid use disorder, recruited in 66 French centers, were interviewed from 12/2018 to 05/2019. A structured questionnaire assessed their interest in XR-BUP using a [1-10] Likert scale. 'More' vs. 'less' interested groups were defined using the median score of interest, and their characteristics were explored using adjusted odds ratios (aORs) and 95 % confidence interval (95 %CI). Independent variables were as follows: sociodemographic characteristics, OAT-related features (e.g., type of OAT and prescriber, dosing, or duration of treatment), OAT representations, and personal objectives of treatment. RESULTS: The median interest in XR-BUP was 7 (interquartile range: 3-9) out of 10. The participants who were 'more interested' (i.e. those scoring ≥7) showed no substantial difference in sociodemographic characteristics, relative to the 'less interested' participants. However, they more frequently reported forgetting to take their OAT (OR = 1.81; CI95 % = 1.06-3.10) or reported experiencing situations where taking their OAT was impractical (aOR = 1.69; CI95 % = 1.05-2.73). Their treatment objective was more focused on stopping illicit drugs (aOR = 1.67; 95 %CI = 1.02-2.70), reducing health risks (aOR = 3.57; 95 %CI = 1.67-7.69) and craving (aOR = 2.38; 95 %CI = 1.39-4.02) or improving family (aOR = 1.81; 95 %CI = 1.03-3.13) or professional (aOR = 2.22; 95 %CI = 1.43-3.85) recovery. CONCLUSIONS: In France, where the access to OAT is relatively unrestricted, the majority of participants were interested in XR-BUP formulations. Being interested was associated with treatment objectives focused on abstinence and recovery, and with experiencing constraints in taking a daily oral OAT.

Methadone-related deaths among youth and young adults in Sweden 2006-15.

AIMS: To identify methadone-related deaths and determine the prevalence among youth and young adults in Sweden 2006-15. DESIGN, SETTING AND PARTICIPANTS: National retrospective registry study comparing data from all forensic autopsy examinations and toxicology cases involving methadone during 2006-15 in individuals aged 15-29 years with police records, previous pharmaceutical prescriptions and health-care episodes. MEASUREMENTS: Multinomial logistic regression. To assess the factors contributing to the deaths, we compared individuals with and without previous substance use treatment and opioid use-related diagnoses with regard to previous opioid agonist treatment (OAT), psychiatric care and previous pain medication. To assess the circumstances of deaths, we analyzed the presence of other drugs and other factors at time of death. FINDINGS: We identified 269 methadone-related deaths, and the rate increased during the study period. Seventy-two (27%) cases had not previously received substance use treatment, 112 (42%) had received treatment but had no opioid use-related diagnosis and 85 (32%) had received treatment and had an opioid use-related diagnosis. In total, only 10 individuals had been prescribed methadone during the year before death. Prescriptions of benzodiazepines (60%), antidepressants (62%) and opioids for pain (22%) the year before death were common. Most deaths occurred during sleep with a time lag from ingestion of methadone. CONCLUSION: Prescription opioid- and methadone-related deaths increased in the group aged 15-29 years in Sweden between 2006 and 2015. Exposure to non-prescribed methadone and prescribed benzodiazepines, antidepressants and opioids for pain appears to be common in drug-related deaths in youth and young adults in Sweden.

Optimal dose of buprenorphine in opioid use disorder treatment: a review of pharmacodynamic and efficacy data.

Context: There is currently no consensus regarding optimal dose or dose-range of buprenorphine (BUP) for treatment of opioid use disorder (OUD).Objective: To elucidate the relationship between BUP dose and opioid receptor blockade, retention in treatment and illicit opioid drug use.Methods: Systematic review of the scientific literature through searches in the databases MEDLINE and PubMed.Results: The review of the opioid receptor blockade studies did not find evidence that a daily sublingual (SL) BUP tablet dose higher than 16 mg confers added blockade benefit, while doses under 8 mg are insufficient to produce opioid receptor blockade. The data are inconclusive regarding the relative effectiveness of an 8 mg SL BUP tablet dose versus a 16 mg SL BUP tablet dose in terms of opioid receptor blockade. The review did not establish any clear relationship between BUP dose and treatment retention or illicit opioid use.Conclusions: The BUP dose in treatment of OUD should be individualized based on a continuous clinical benefit-risk assessment. Further research is needed to better understand the relationship between dose and efficacy over time in patients with this complex disorder.

What place for prolonged-release buprenorphine depot-formulation Buvidal® in the treatment arsenal of opioid dependence? Insights from the French experience on buprenorphine.

Introduction: Since the 1990s, opioid maintenance treatments (OMTs), i.e. mostly methadone and buprenorphine, have represented the therapeutic cornerstone of opioid dependence. In France, the public health strategy on opioid dependence, identified here as the 'French model', has consisted of offering a facilitated access to buprenorphine, to reach a large treatment coverage and reduce opioid-related mortality. Areas covered: Recently, a new formulation of subcutaneous buprenorphine depot (Buvidal®) has been approved in Europe for treatment of opioid dependence. The place of Buvidal® among the pre-existing arsenal of OMTs is discussed in the light of the pharmacological specificities of this new formulation, and with the particular standpoint of the French model on opioid dependence. Expert opinion: Buvidal® could constitute a promising treatment option mainly in case of: 1) OMT initiation, including in non-specialized addiction medicine care; 2) Discharge from prison or hospital; Diversion/misuse of 3) buprenorphine or 4) methadone; 5) Clinically stabilized patients wishing to avoid daily oral taking of the medication. As such, this new formulation should be highly accessible, which will require specific pathways through care as the product is intended to be administered by a healthcare professional.

Efficacy and safety of a sublingual buprenorphine/naloxone rapidly dissolving tablet for the treatment of adults with opioid dependence: A randomized trial.

This prospective, randomized, active-controlled, non-inferiority study evaluated the efficacy and safety of a sublingual buprenorphine/naloxone rapidly dissolving tablet (Zubsolv®; buprenorphine/naloxone rapidly dissolving tablet) versus generic buprenorphine for induction of opioid maintenance among dependent adults. The study, conducted at 13 sites from June 2013 to January 2014, included a 2-day blinded induction phase and a 27-day open-label stabilization/maintenance phase. During the blinded induction, patients received fixed doses of buprenorphine/naloxone rapidly dissolving tablets or generic buprenorphine. During open-label stabilization/early maintenance, all patients received buprenorphine/naloxone rapidly dissolving tablets. The primary efficacy assessment was treatment retention at day 3; buprenorphine/naloxone rapidly dissolving tablets were considered non-inferior to generic buprenorphine if the lower limit of the 95% confidence interval for the difference between the treatments was ≥-10% in patients retained on day 3. Secondary assessments included opioid withdrawal symptoms and cravings as measured using the Clinical Opiate Withdrawal Scale, the Subjective Opiate Withdrawal Scale, and the opioid cravings visual analogue scale. Safety was also assessed. A total of 313 patients were randomly assigned to induction with generic buprenorphine or buprenorphine/naloxone rapidly dissolving tablets. The mean age was 38.4 years, and the mean duration of opioid dependence was 12.4 years. For the primary efficacy assessment, 235 of 256 patients (91.8%) were retained at day 3 and continued to the maintenance phase. The lower limit of the 95% confidence interval was -13.7; thus, buprenorphine/naloxone rapidly dissolving tablets did not demonstrate non-inferiority to generic buprenorphine, and significantly more patients who received induction with generic buprenorphine (122/128 [95.3%]) were retained at day 3 compared with those who received induction with buprenorphine/naloxone rapidly dissolving tablets (113/128 [88.3%]; 95% confidence interval: -13.7, -0.4; p = 0.040). The rates of clinical response, as measured by the Clinical Opiate Withdrawal Scale, the Subjective Opiate Withdrawal Scale, and the visual analogue scale, were comparable among patients regardless of the induction medication. Treatment with buprenorphine/naloxone rapidly dissolving tablets was generally safe and reduced the severity of withdrawal symptoms and cravings.

Effects of a higher-bioavailability buprenorphine/naloxone sublingual tablet versus buprenorphine/naloxone film for the treatment of opioid dependence during induction and stabilization: a multicenter, randomized trial.

PURPOSE: Sublingual buprenorphine and combination buprenorphine/naloxone (BNX) are effective options for the treatment of opioid dependence. A BNX sublingual tablet approved by the US Food and Drug Administration for the induction and maintenance treatment of opioid-dependence in adults was developed as a higher-bioavailability formulation, allowing for a 30% lesser dose of buprenorphine with bioequivalent systemic exposure compared with another BNX sublingual tablet formulation. No data were previously available comparing the higher-bioavailability BNX sublingual tablet to generic buprenorphine or BNX sublingual film; we therefore evaluated treatment retention during induction and stabilization with the higher-bioavailability BNX sublingual tablet versus generic buprenorphine or BNX sublingual film. METHODS: This multicenter, prospective, randomized, parallel-group noninferiority trial was conducted at 43 centers in the United States. Eligible patients were adults aged 18 to 65 years who met the criteria for opioid dependence and had at least mild withdrawal symptoms. On days 1 and 2, patients received blinded, fixed-dose induction with the higher-bioavailability BNX sublingual tablet or generic buprenorphine. On days 3 to 14, patients induced with BNX received open-label, titrated doses of the BNX tablet for stabilization; patients induced with buprenorphine received sublingual BNX film. Co-primary end points were treatment retention on days 3 and 15; noninferiority was concluded if the lower limit of the 95% CI of the between-group difference in treatment retention was ≥-10%. Tolerability was assessed throughout the study period. FINDINGS: A total of 758 opioid-dependent patients were included in the study (BNX sublingual tablet, 383 patients; generic buprenorphine, 375). Day-3 retention rates were 93.9% (309/329) and 92.6% (302/326) with the BNX tablet and buprenorphine, respectively (between-group difference 95% CI, -2.6 to 5.1). Day-15 retention rates were 83.0% (273/329) and 82.5% (269/326) with the BNX tablet and BNX film, respectively (between-group difference 95% CI, -5.3 to 6.3). No unexpected tolerability issues were identified; the safety profile of the BNX sublingual tablet was similar to those of generic buprenorphine and BNX film. IMPLICATIONS: Based on the findings from this study in patients with opioid dependence, the higher-bioavailability BNX sublingual tablet formulation was noninferior to both generic buprenorphine (induction) and BNX film (stabilization). These findings suggest that BNX sublingual tablets are an efficacious and well-tolerated option for induction and early stabilization treatment of opioid dependence. ClinicalTrials.gov identifier: NCT01908842.

Pharmaceutical and pharmacokinetic characterization of a novel sublingual buprenorphine/naloxone tablet formulation in healthy volunteers.

CONTEXT: Bitter taste, as well as dissolve time, presents a significant challenge for the acceptability of formulations for oral transmucosal drug delivery. OBJECTIVE: To characterize a novel sublingual tablet formulation of buprenorphine/naloxone with regards to pharmacokinetics, dissolve time and formulation acceptability. METHODS: Dry mixing techniques were employed to produce a small and fast dissolving buprenorphine/naloxone sublingual tablet formulation, OX219 (Zubsolv®), using sucralose and menthol as sweetener and flavor to mask the bitter taste of the active ingredients. Two cross-over studies were performed in healthy volunteers to evaluate pharmacokinetics, dissolve time and acceptability of OX219 5.7/1.4 mg tablets compared to the commercially available buprenorphine/naloxone formulations Suboxone® tablets and films (8/2 mg). RESULTS: Buprenorphine exposure was equivalent in OX219 and Suboxone tablets. Sublingual dissolve times were significantly shorter for OX219 than for Suboxone tablets and were similar to Suboxone films. The OX219 formulation received significantly higher subjective ratings for taste and overall acceptability than both Suboxone formulations. OX219 was preferred over Suboxone tablet and film formulations by 77.4% and 88.9% of subjects, respectively. CONCLUSIONS: A sublingual tablet formulation with an improved acceptability has been successfully developed.

Increased CD8+ central memory T cells in patients with multiple sclerosis.

A T-cell-mediated autoimmune process against central nervous system myelin is believed to underlie the pathogenesis of multiple sclerosis (MS). Formation of immunological memory is based on the differentiation of naïve T cells to memory T cells after exposure to antigens and specific cytokines. The aim of this study was to analyse peripheral blood mononuclear cells in patients with MS for different T-cell subsets including naïve and memory T cells. Flow cytometry and enzyme-linked immunosorbent assay were used to analyse memory T-cell subsets and plasma concentration of interleukin-15 (IL-15) in peripheral blood of MS patients, patients with other neurological disorders and healthy controls. MS patients had a skewed distribution of T cells with an increased level of CD8+/CCR7+/CD45RA - central memory T cells (TCM) compared to healthy controls. In addition, MS patients showed significantly higher levels of plasma IL-15 than healthy controls did. Upregulated CD8+ TCM in MS patients may reflect a persistent chronic inflammatory response that may have been induced during early stages of the disease. This derangement may be important for maintaining chronic inflammation in MS.

Increased central memory T cells in patients with chronic pancreatitis.

BACKGROUND/AIMS: A dysregulated immune response has been suggested to be important for the pathogenesis of chronic pancreatitis (CP). Formation of immunological memory is based on the differentiation of naive T lymphocytes to memory T lymphocytes after exposure to antigens and specific cytokines. The aim of this study was to analyze peripheral blood mononuclear cells (PBMCs) in patients with CP for different T lymphocyte subsets including naive and memory T cells. METHODS: PBMCs from 9 patients who had undergone pancreatic resection due to CP, 9 CP patients who had not been resected and 9 healthy controls were analyzed by flow cytometry. RESULTS: Patients with CP had a skewed distribution of T lymphocytes, with an increased level of CCR7+/CD45RA- central memory T lymphocytes compared to healthy controls. Nonresected CP patients and subjects who had undergone pancreatic resection due to CP had similar levels of central memory T lymphocytes. CONCLUSION: Our results indicate that the dysregulation of the immune system in chronic pancreatitis seems to persist even after removal of large parts of the local inflammatory site. We suggest that the increase of central memory T lymphocytes may be important for maintaining the inflammatory process in chronic pancreatitis.

Expression of B-cell-activating factor of the TNF family (BAFF) and its receptors in multiple sclerosis.

The role of B cells and antibodies in the pathogenesis of multiple sclerosis (MS) is controversial. We investigated the expression of B-cell-activating factor of the tumor necrosis factor family (BAFF), a protein indispensable for B-cell survival, and of its three receptors in MS patients and controls. BAFF mRNA levels in monocytes, and BAFF-receptor mRNA in B and T cells, were higher in patients than in healthy controls; yet, BAFF protein levels in cerebrospinal fluid and plasma were similar in patients and headache controls. In addition, each MS disease course was associated with a unique expression pattern for all four molecules.

Cellular basis of ectopic germinal center formation and autoantibody production in the target organ of patients with Sjögren's syndrome.

OBJECTIVE: To investigate functional properties of the germinal center (GC)-like structures observed in salivary glands of patients with Sjögren's syndrome (SS) and to determine the frequency with which such structures develop. METHODS: Hematoxylin and eosin-stained sections from 165 minor salivary gland biopsy samples were screened for GC-like structures. Expression of markers for GCs (CD3, CD20, Ki-67, CD35, CD31), adhesion molecules (intercellular adhesion molecule 1, lymphocyte function-associated antigen 1, vascular cell adhesion molecule 1, very late activation antigen 4), chemokines (CXCL13, CCL21, CXCL12), and production of autoantibodies (anti-Ro/SSA and anti-La/SSB) was investigated by immunohistochemistry. Apoptosis was investigated by TUNEL staining. RESULTS: GC-like structures were observed in 28 of 165 patients (17%). When GCs were defined as T and B cell aggregates with proliferating cells with a network of follicular dendritic cells and activated endothelial cells, such microenvironments were found in all patients in whom structures with GC-like morphology were observed. The defined microenvironments were not found in patients without apparent GC-like structures. The GCs formed within the target tissue showed functional features with production of autoantibodies (anti-Ro/SSA and anti-La/SSB) and apoptotic events (by TUNEL staining), and the local production of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly increased (P = 0.04) in patients with GC development. CONCLUSION: Lymphoid neogenesis and functional ectopic GC formation take place in salivary glands of a subset of patients with SS. Our data suggest that the ectopic secondary lymphoid follicles contain all elements needed for driving the autoimmune response. Our findings underscore a key role for the target organ in recruitment of inflammatory cells and propagation of the disease process.

Genotypes of CCR2 and CCR5 chemokine receptors in human myasthenia gravis.

The aim of this study was to examine the association of human autoimmune myasthenia gravis (MG) with two DNA polymorphisms of the chemokine receptors CCR5-Delta 32 and CCR2-64I. CCR2 and CCR5 interact primarily with the human CC family ligands CCL2 (formerly called monocyte chemoattractant protein; MCP-1), CCL3 and CCL4 (macrophage inflammatory protein-1 alpha and -1 beta; MIP-1 alpha/beta), and their main function is to recruit leukocytes from circulation into the tissues, thus playing an important role in human inflammatory disorders. A PCR-based genotyping method was used to determine the genetic variation at the CCR5 gene and an automated real-time Pyrosequencing technology was employed for the analysis of G right curved arrow A point mutation at the CCR2 gene. Results obtained from 158 patients and 272 healthy controls demonstrate no evidence of association between genetic variants of CCR2 and CCR5 with MG and its clinical manifestations. CCR2-64I and CCR5-Delta 32 genotypes are thus unlikely to be involved in protection or predisposition to MG.

Lack of association of CCR2-64I and CCR5-Delta 32 with type 1 diabetes and latent autoimmune diabetes in adults.

It is well known that type 1 diabetes mellitus (T1DM) is a complex genetic disease resulting from the autoimmune destruction of pancreatic beta cells. Several genes have been associated with susceptibility and/or protection for T1DM, but the disease risk is mostly influenced by genes located in the class II region of the major histocompatibility complex. The attraction of leukocytes to tissues is essential for inflammation and the beginning of autoimmune reaction. The process is controlled by chemokines, which are chemotactic cytolines. Some studies have shown that CCR2-64I and CCR5-Delta 32 might be important for protection of susceptibility to some immunologically-mediated disorders. In the present study, we demonstrate the lack of association between CCR2-64I and CCR5-Delta 32 gene polymorphism and TIDM and we describe a new method for a simple and more precise genotyping of the CCR2 gene.

[Chemokines a hope of specific anti-inflammatory treatment]. / Kemokiner ger hopp om specifik antiinflammatorisk behandling.

Inflammation is a serious medical problem that causes suffering in many common diseases such as rheumatoid arthritis and asthma. Despite the fact that the clinical signs of inflammation--rubor, tumor, calor and dolor--have been known for almost two thousand years, our knowledge of the molecular pathways that mediate inflammation is still limited. Today's anti-inflammatory drugs are non-specific and have many undesirable side effects. The discovery of chemokines as small specific regulatory proteins of the immune system has increased our understanding of the inflammatory process. We have reason to believe that chemokines and their receptors are going to be targets for a new kind of anti-inflammatory therapy.