Experimental demonstration of the immunogenicity of silicone-protein complexes

Although silicones, as a class, are nontoxic in animal and tissue studies, implanted silicone prostheses and medical devices are associated with various local and systemic host inflammatory reactions. They also have been associated with a form of autoimmune disease. To test the hypothesis that silicones may evoke an immunologically mediated inflammatory reaction, 10 guinea pigs were stimulated for 1 month with intraperitoneal injections of sterile medical-grade silicone oil admixed with homologous serum and complete Freund's adjuvant. Ten controls were stimulated with saline. Four additional animals were passively sensitized with splenic homogenates from four sensitized animals. Intradermal antigenic challenges consisted of silicone-homologous serum, pure silicone, saline-homologous serum, and purified protein derivative. Cutaneous reaction patterns were graded grossly and microscopically. Silicone-serum and purified protein derivative antigens evoked three to four times greater palpable lesions in all 10 actively and all 4 passively sensitized animals at approximately 24 h compared to controls. Biopsies showed a moderate to marked lymphocytic infiltrate. Control sites and naive animals showed only edema at the challenge sites. The data suggest that silicone-protein complexes are potentially immunogenic.     

Effect of goldenseal (Hydrastis canadensis) and kava kava (Piper methysticum) supplementation on digoxin pharmacokinetics in humans.

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.     

Probing insulin's secondary structure after entrapment into alginate/chitosan nanoparticles.

The aim of the present study was to probe the structural integrity of insulin after being entrapped into chitosan/alginate nanoparticles produced by ionotropic polyelectrolyte pre-gelation. By manipulating the alginate:chitosan mass ratio and the pH during nanoparticle production, desired nanoparticles with a mean size of 850 (+/-88)nm and insulin association efficiency of 81 (+/-2)% were obtained. Insulin secondary structure was assessed by Fourier transform infrared (FTIR) and circular dichroism (CD) after entrapment into nanoparticles and after release from the particles under gastrointestinal simulated conditions. FTIR second-derivative spectra and area-overlap compared to an insulin standard confirmed that no significant conformational changes of insulin occurred in terms of alpha-helix and beta-sheet content. Far-UV-CD spectra corroborated the preservation of insulin structure during the nanoparticle production procedure. The presented nanoparticulate system is a promising carrier for insulin oral delivery since it preserves insulin structure and therefore also, potentially, its bioactivity.     

Reduced prevalence of early preterm delivery in women with Type 1 diabetes and microalbuminuria--possible effect of early antihypertensive treatment during pregnancy.

AIMS: In normotensive women with Type 1 diabetes and microalbuminuria we previously found preterm delivery (< 34 weeks) in 23% of the pregnancies. Antihypertensive treatment was initiated in late pregnancy when preeclampsia was diagnosed and diastolic blood pressure > 90 mmHg. From April 2000 our routine was changed and early antihypertensive treatment with methyldopa was initiated if antihypertensive treatment was given prior to pregnancy, if urinary albumin excretion (UAE) was > 2 g/24 h, or blood pressure > 140/90 mmHg. The present study describes the impact of this more aggressive antiypertensive treatment in the prevalence of preterm delivery. METHODS: The old cohort (1995-1999) consisted of 26 and the new cohort (2000-2003) of 20 pregnant women with Type 1 diabetes and microalbuminuria. All were referred before gestational week 17. RESULTS: The cohorts were comparable with regard to age, diabetes duration, prepregnancy body mass index, HbA1c, blood pressure 121 (13)/71 (8) vs. 121 (14)/73 (8) mmHg [mean (sd)] and early UAE 69 (16-278) vs. 74 (30-287) mg/24 h (geometric mean and range). Antihypertensive treatment was initiated in the old cohort at 29 (20-33) weeks, n = 9, and in the new at 13 (0-34) weeks, n = 10. The prevalence of preterm delivery before 34 weeks was reduced from 23% to zero (P = 0.02), preterm delivery before 37 weeks from 62% to 40% (P = 0.15) and preeclampsia from 42% to 20% (P = 0.11). Perinatal mortality occurred in 4% vs. 0%. Birth weight was 3124 (767) g vs. 3279 (663) g. CONCLUSION: Introduction of early antihypertensive treatment with methyldopa in normotensive pregnant women with Type 1 diabetes and microalbuminuria resulted in a significant reduction in preterm delivery before gestational week 34.     

Probing the importance of N-glycosylation for [3H] clobenpropit binding to human H3 receptors expressed in HEK 293 cells

Inflammation Research - .     

Central metabotropic glutamate receptors differentially participate in interleukin-1beta-induced mechanical allodynia in the orofacial area of conscious rats.

The present study investigated the role of central metabotropic glutamate receptors (mGluRs) in interleukin-1beta (IL-1beta)-induced mechanical allodynia and mirror-image mechanical allodynia in the orofacial area. Experiments were carried out on male Sprague-Dawley rats weighing 230 to 280 g. After administration of 0.01, 0.1, 1, or 10 pg of IL-1beta into a subcutaneous area of the vibrissa pad, we examined the withdrawal behavioral responses produced by 10 successive trials of an air-puff ramp pressure applied ipsilaterally or contralaterally to the IL-1beta injection site. Subcutaneous injection of IL-1beta produced mechanical allodynia and mirror-image mechanical allodynia in the orofacial area. Intracisternal administration of CPCCOEt, a mGluR1 antagonist, or MPEP, a mGluR5 antagonist, reduced IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia. Intracisternal administration of APDC, a group II mGluR agonist, or L-AP4, a group III mGluR agonist, reduced both IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia. The antiallodynic effect, induced by APDC or L-AP4, was blocked by intracisternal pretreatment with LY341495, a group II mGluR antagonist, or CPPG, a group III mGluR antagonist. These results suggest that groups I, II, and III mGluRs differentially modulated IL-1beta-induced mechanical allodynia, as well as mirror-image mechanical allodynia, in the orofacial area. PERSPECTIVE: Central group I mGluR antagonists and groups II and III mGluR agonists modulate IL-1beta-induced mechanical allodynia and mirror-image mechanical allodynia in the orofacial area. Therefore, the central application of group I mGluR antagonists or groups II and III mGluR agonists might be of therapeutic value in treating pain disorder.