Hansen solubility parameter as a tool to predict cocrystal formation

The objective of this study was to investigate whether the miscibility of a drug and coformer, as predicted by Hansen solubility parameters (HSPs), can indicate cocrystal formation and guide cocrystal screening. It was also our aim to evaluate various HSPs-based approaches in miscibility prediction. HSPs for indomethacin (the model drug) and over thirty coformers were calculated according to the group contribution method. Differences in the HSPs between indomethacin and each coformer were then calculated using three established approaches, and the miscibility was predicted. Subsequently, differential scanning calorimetry was used to investigate the experimental miscibility and cocrystal formation. The formation of cocrystals was also verified using liquid-assisted grinding. All except one of the drug-coformers that were predicted to be miscible were confirmed experimentally as miscible. All tested theoretical approaches were in agreement in predicting miscibility. All systems that formed cocrystals were miscible. Remarkably, two new cocrystals of indomethacin were discovered in this study. Though it may be necessary to test this approach in a wide range of different coformer and drug compound types for accurate generalizations, the trends with tested systems were clear and suggest that the drug and coformer should be miscible for cocrystal formation. Thus, predicting the miscibility of cocrystal components using solubility parameters can guide the selection of potential coformers prior to exhaustive cocrystal screening work.     

Prenatal TCDD in mice increases adult autoimmunity

Two immunologically different mouse strains, C57BL/6 and SNF₁, were exposed to a mid-gestation dose of TCDD. The C57BL/6 mouse has a high-affinity aryl hydrocarbon receptor (AhR) and is sensitive to TCDD. The SNF₁ mouse has a low-affinity AhR but spontaneously develops autoimmune nephritis. Autoreactive Vβ⁺CD4⁺17a and Vβ⁺CD3⁺ T cells were increased at 24-weeks-of-age in offspring of C57BL/6 mice, more so in females than males. The cytokine IFN-γ was elevated in the females, while IL-10 was elevated in males. Phenotypic changes in B-lineage cells were present in bone marrow and spleen, and circulating autoantibodies were increased after prenatal TCDD. Kidneys of males showed significant anti-IgG and anti-C3 deposition, suggesting early-stage autoimmune disease. The SNF₁ offspring similarly showed increased peripheral Vβ⁺ cells in the females, increased autoantibody production in both sexes, and increased IFN-γ production in females. Male SNF₁ mice had increased anti-IgG and anti-C3 deposition in kidneys. Both mouse models therefore showed clear signatures of enhanced autoimmunity after prenatal TCDD.     

Hepatitis C infection, Cognition, and inflammation in an Egyptian sample

Chronic hepatitis C (HCV) infection is associated with cognitive impairments which might be mediated through a secondary inflammatory cascade. Egypt has an unusually high prevalence of HCV monoinfections and is an ideal site for the study of the isolated effects of HCV infection. Therefore, in a hospital‐based cross‐sectional study based in Egypt, this study compared cognitive functioning and serum markers of inflammation in 11 HCV positive cases and 14 HCV negative controls. The Wisconsin Card Sorting Test was used to assess cognitive flexibility and the Brief Visuospatial Memory Test‐Revised was used to assess learning and memory. Circulating levels of soluble tumor necrosis factor receptor II (sTNFR‐II), monocyte chemotactic protein‐1 (MCP‐1/CCL2), and soluble CD14 (sCD14) were determined as indices of inflammation. HCV positive cases had higher levels of sTNFR‐II (t = ?3.5, P = 0.002). HCV positive cases also had significantly worse cognitive flexibility with higher number of total errors (t = ?2.18, P = 0.04), and preservative responses (t = ?2.12, P = 0.05), and lower number of conceptual level responses (t = 1.32, P = 0.04) on the Wisconsin Card Sorting test. In conclusion, results from this pilot study indicate that HCV+ patients have worse cognitive performance and somewhat greater inflammatory activity as compared to controls. The increased inflammation may be associated with the cognitive impairments observed in these HCV+ patients. J. Med. Virol. 83:261–266, 2011. © 2010 Wiley‐Liss, Inc.     

Effect of conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium on maximum tolerated dose and gastrointestinal symptoms following kidney transplantation

Despite the potential tolerability advantage of enteric-coated mycophenolate sodium (EC-MPS), no prospective, randomized trial has evaluated whether conversion from mycophenolate mofetil (MMF) to EC-MPS permits mycophenolic acid dose to be increased or gastrointestinal side-effects to be ameliorated. In a randomized, multicenter, open-label trial, kidney transplant recipients experiencing gastrointestinal side-effects either remained on MMF or switched to an equimolar dose of EC-MPS, adjusted 2 weeks subsequently to target the highest tolerated dose up to 1440 mg/day (EC-MPS) or 2000 mg/day (MMF). Patients were followed up to 12 weeks postrandomization. One hundred and thirty-four patients were randomized. The primary efficacy endpoint, the proportion of patients receiving a higher mycophenolic acid (MPA) dose at week 12 than at randomization, was significantly greater in the EC-MPS arm (32/68, 47.1%) than the MMF arm (10/61, 16.4%; P  < 0.001). At the final visit, 50.0% (34/68) of EC-MPS patients were receiving the maximum recommended dose versus 26.2% (16/61) of MMF patients ( P  = 0.007). Kidney transplant patients receiving reduced-dose MMF because of gastrointestinal side-effects can tolerate a significant increase in MPA dose after conversion to EC-MPS. Patient-reported gastrointestinal outcomes with higher doses of EC-MPS remained at least as good as in MMF-treated controls.     

Methicillin-resistant <Emphasis Type="Italic">Staphylococcus aureus</Emphasis> (MRSA) in hospitalized children: correlation of molecular analysis with clinical presentation and antibiotic susceptibility testing (ABST) results

The molecular analysis of methicillin-resistant Staphylococcus aureus (MRSA) from 98 children admitted to the Children’s Hospital of Michigan, Detroit, MI, with serious MRSA infections during 2006–2007 was correlated with risk factors, clinical features, and antibiotic susceptibility testing (ABST) results. Isolates were characterized by staphylococcal cassette chromosome (SCC) mec type, the presence of Panton-Valentine leukocidin (PVL) genes, repetitive sequence (rep) polymerase chain reaction (PCR) and pulsed-field gel electrophoresis (PFGE), requirement for surgical intervention, antibiograms, and response to therapy. rep-PCR was more rapid than PFGE typing and correlated well. SCCmec type IV-containing isolates caused 92.8% of all infections, but the demographics and diseases associated with subtypes IVa and IVd differed. Subtype IVa (all PFGE type USA300 and PVL-positive) was identified in 81/93 (87.1%) of patients with community-onset (CO) MRSA, including 21/35 of those with risk factors for health care-associated (HA) infection. All other clones were PVL-negative. Subtype IVd (10 isolates; 9 USA800 and 1 eMRSA15) caused mainly HA-MRSA and no skin and soft tissue infections (SSTI). Seven classic HA-MRSA strains (SCCmec types II [6; 3 USA100 and 3 USA600] and III [1; USA200]) caused HA and hospital-onset (HO) infections. Surgical intervention was required in 68/81 patients infected with USA300 and 8/17 of the others. Most USA300 were susceptible (S) to clindamycin (CD) and patients were treated with CD alone or in combination. The other isolates were generally treated with vancomycin (VA) alone or in combination. This work was presented in part at the Infectious Diseases Society of America Annual Meeting, San Diego, CA, USA, 4–7 October 2007.     

A foreign body in the floor of the mouth

A case of unusual presentation of foreign body in the floor of mouth is reported. The patient presented with a history and clinical findings of sublingual ranula. Marsupialisation and sublingual sialadenectomy was planned. After marsupialisation, a foreign body (spray cover) was found between the lumen of the submandibular duct and the ranula.