Therapeutics and delivery vehicles for local treatment of osteomyelitis

Osteomyelitis, or the infection of the bone, presents a major complication in orthopedics and may lead to prolonged hospital visits, implant failure, and in more extreme cases, amputation of affected limbs. Typical treatment for this disease involves surgical debridement followed by long-term, systemic antibiotic administration, which contributes to the development of antibiotic-resistant bacteria and has limited ability to eradicate challenging biofilm-forming pathogens including Staphylococcus aureus—the most common cause of osteomyelitis. Local delivery of high doses of antibiotics via traditional bone cement can reduce systemic side effects of an antibiotic. Nonetheless, growing concerns over burst release (then subtherapeutic dose) of antibiotics, along with microbial colonization of the nondegradable cement biomaterial, further exacerbate antibiotic resistance and highlight the need to engineer alternative antimicrobial therapeutics and local delivery vehicles with increased efficacy against, in particular, biofilm-forming, antibiotic-resistant bacteria. Furthermore, limited guidance exists regarding both standardized formulation protocols and validated assays to predict efficacy of a therapeutic against multiple strains of bacteria. Ideally, antimicrobial strategies would be highly specific while exhibiting a broad spectrum of bactericidal activity. With a focus on S. aureus infection, this review addresses the efficacy of novel therapeutics and local delivery vehicles, as alternatives to the traditional antibiotic regimens. The aim of this review is to discuss these components with regards to long bone osteomyelitis and to encourage positive directions for future research efforts.     

Practical management of patients with non-small-cell lung cancer treated with gefitinib.

PURPOSE: The use of gefitinib, the first drug approved to inhibit the epidermal growth factor receptor tyrosine kinase, is indicated in patients with non-small-cell lung cancer with tumors progressive after chemotherapy. The unique mechanism of action of this agent leads to distinctive patterns of response and toxicity in persons with lung cancer. Many of the principles of management relevant to gefitinib are distinct from those with conventional cytotoxic drugs. To meet this need, we present practical guidelines on the use of gefitinib in patients with non-small-cell lung cancer. METHODS: This article reviews gefitinib's indications, dosing, response phenomena, and patterns of relapse in individuals with radiographic response. RESULTS: We present our recommendations for the management of rash and diarrhea caused by this agent. CONCLUSION: This information can guide practitioners and help them inform their patients about what to expect when they receive gefitinib.     

Wilson's disease in children: 37-year experience and revised King's score for liver transplantation.

Wilson's disease (WD) is a rare liver-based disorder of copper metabolism. Prognostic criteria described by our group in 1986 to predict death without transplantation have not been universally validated. The clinical features of 88 children were reviewed, retrospectively in 74 and prospectively in 14. Data from the retrospectively recruited patients that died or survived on long-term chelation were used to evaluate the validity of our old scoring system and to devise a new prognostic index, then assessed in the 14 prospectively recruited patients. Using the old scoring system, 5 children scoring > or = 7, the cutoff value for death without transplantation, survived, whereas 4 scoring < or = 7 died (sensitivity 87% and specificity 90%). A new index based on serum bilirubin, international normalized ratio, aspartate aminotransferase (AST), and white cell count (WCC) at presentation identified a cutoff score of 11 for death and proved to be 93% sensitive and 98% specific, with a positive predictive value of 88%. When the new index was evaluated prospectively in 14 patients, it predicted the need for transplantation in only the 4 who required it, although 1 child with a score of 11 survived on medical treatment. In conclusion, the new Wilson Index is more sensitive and specific in predicting mortality without transplantation than the old scoring system, but needs to be validated in a larger number of patients.     

Metabolic, molecular genetic and toxicological aspects of the acetylation polymorphism in inbred mice.

Over the past 10 years, much fascinating information has been obtained concerning the biochemistry, genetics, toxicological implications and molecular genetics of the N-acetylation polymorphism in mice. Using C57BL/6J (B6) mice as representative of rapid acetylation and A/J (A) mice as representing slow acetylation, it has been shown that the polymorphism observed in N-acetyltransferase (NAT) activity in liver also occurs in kidney, bladder, blood, and other tissues. The development of congenic acetylator mouse lines derived from B6 and A, have provided the necessary tools to study the role of the acetylation polymorphism, on either the B6 or A genetic background, free of nearly all other genetic differences between these strains. Eliminating genes which modify and complicate the differences due to the acetylator genes make the congenic lines very useful in toxicology studies, particularly those involving carcinogenesis. The molecular genetic basis of the acetylator polymorphism in B6 and A mice involves two Nat genes. Nat-1 encodes a protein termed NAT1 which is identical in rapid and slow acetylator strains. Nat-2, however, differs between rapid and slow strains by a single nucleotide change in the coding region. The corresponding NAT2 proteins differ by a single change at amino acid 99: an hydrophilic asparagine in rapid acetylator NAT2 to an hydrophobic isoleucine in NAT2 from slow acetylators. The mechanistic basis for the differences between rapid and slow acetylation in mice appears to be that NAT2 from the rapid B6 strain is 15-fold more stable at 37 degrees C and is transcribed/translated with a maximal efficiency twice that of the enzyme from slow acetylator A mice. Results discussed in this review indicate that mice provide an excellent system for studying the N-acetyltransferase polymorphism and also are useful for modelling several aspects of the human N-acetyltransferase polymorphism.