Challenges With the Jaw in a Day Technique.

PURPOSE: The Jaw in a Day (JIAD) procedure allows for complete primary reconstruction of bone and teeth during the same operation as tumor resection. We reviewed 12 cases, the largest published case series of the JIAD procedure, and discussed both the prosthodontic and surgical considerations. MATERIALS AND METHODS: A multi-institutional retrospective chart review was completed to identify patients undergoing the JIAD procedure. Patients with a minimum of 6 months' follow-up were included. Variables included skeletal relationship, dental Angle classification changes, postoperative diet, prosthesis complications, flap failure, osseointegration of dental implants, hardware complications, infection, intelligible speech, and patients' subjective satisfaction with facial and dental esthetics. RESULTS: The sample included 12 patients (8 male and 4 female patients) with a mean age of 38 years (range, 15 to 75 years) and an average follow-up period of 19 months (range, 7 to 42 months). Patients underwent the JIAD procedure at the same time as resection of an ameloblastoma (mandibular in 9 and maxillary in 1) or odontogenic myxoma (mandibular in 1 and maxillary in 1). Nine patients' Angle classification remained unchanged after the procedure, with 3 patients showing correction from dental Class III to Class I. On average, 4 implants (range, 2 to 6 implants) were placed. Hybrid or splinted crown prostheses replaced, on average, 8 teeth (range, 3 to 12 teeth) with no prosthetic fractures. All patients had viable fibular flaps, absence of infection, and completely intelligible speech. All but 1 patient had subjective satisfaction with facial and dental esthetics. Complications included plate fracture with fibrous union (1), premature contacts requiring occlusal equilibration (2), implant loss (1), delayed wound healing (1), heterotopic bone formation along the pedicle (1), and dissatisfaction with chin symmetry (1). CONCLUSIONS: The JIAD technique predictably reconstructs bone and teeth in a single operation. The tools and services streamlining this protocol are now widely available. However, there are still several challenges with this protocol that surgeons and patients must overcome. Further study and refinements are necessary to address these.

Burkholdines from Burkholderia ambifaria: antifungal agents and possible virulence factors.

Burkholdines are cyclic lipopeptides with unusual antifungal potency, making them promising leads as a new class of antifungal agents. However, a recent report using knockout mutagenesis indicates that these and related compounds, such as occidiofungins, xylocandins, and cepacidines, may also be synonymous with the long-known hemolytic virulence factors found in diverse Burkholderia isolates. Because of their possible roles in causing Burkholderia infections or curing fungal infections, it is important to fully define their structures and biological activities using pure compounds. Here, we report the structures of three further burkholdines, Bk-1119, Bk-1213, and Bk-1215, which were elucidated using spectroscopic methods. The absolute configuration of this compound class was determined for the first time using a combination of spectroscopy and chemical degradation techniques. Antifungal and hemolytic activities were assessed for five pure burkholdines, representative of the structural diversity of this lipopeptide class. All of the burkholdines were potent antifungal and hemolytic agents, validating their probable role in virulence. However, one of the burkholdines (Bk-1119) exhibited a >30-fold selectivity for fungi versus sheep erythrocytes and was more than 25-fold more potent than amphotericin against some fungal strains. Therefore, burkholdines have potential to selectively target fungal infections.

Convergent synthesis of a helical, prehairpin HR1 trimer from HIV gp41.

A helical, prehairpin trimer covering the majority of the HR1 region of human immunodeficiency virus gp41 was achieved by chemically coupling three identical 51 amino acid peptides. A 1,3,5-tris(aminomethyl)-2,4,6-triethylbenzene pinwheel 'cap' was used to trimerize the peptides by taking advantage of the unique property of triacyl fluoride and orthogonal protection and deprotection. The resulting protein is fully helical, highly thermostable and soluble.

Fibular Reconstruction of the Maxilla and Mandible with Immediate Implant-Supported Prosthetic Rehabilitation: Jaw in a Day.

The fibula free flap is a workhorse flap used to reconstruct ablative, osseous defects in the upper and lower jaws. Traditionally, the fibula free flap is inset into the defect freehand; dental implants are placed secondarily; and final prosthetic rehabilitation often occurs more than 1 year after ablative surgery. Virtual surgical planning and rapid prototyping of cutting guides and guide stents for head and neck reconstruction have facilitated improved accuracy in fibular transfer. This article describes the Jaw in a Day technique, allowing maxillary or mandibular resection, fibular free flap reconstruction, immediate implant placement, and prosthetic rehabilitation in a single operation.

Design and synthesis of human immunodeficiency virus entry inhibitors: sulfonamide as an isostere for the alpha-ketoamide group.

The crystal structures of many tertiary alpha-ketoamides reveal an orthogonal arrangement of the two carbonyl groups. Based on the hypothesis that the alpha-ketoamide HIV attachment inhibitor BMS 806 (formally BMS378806, 26) might bind to its gp120 target via a similar conformation, we designed and synthesized a series of analogs in which the ketoamide group is replaced by an isosteric sulfonamide group. The most potent of these analogs, 14i, demonstrated antiviral potency comparable to 26 in the M33 pseudotyped antiviral assay. Flexible overlay calculations of a ketoamide inhibitor with a sulfonamide inhibitor revealed a single conformation of each that gave significantly better overlap of key pharmacophore features than other conformations and thus suggest a possible binding conformation for each class.

Large-scale manufacture of peptide therapeutics by chemical synthesis.

The large-scale commercial production of a 36-amino-acid peptide by chemical synthesis has been demonstrated in the development of enfuvirtide (T-20 or Fuzeon), a first-in-class membrane fusion inhibitor for the treatment of HIV. The rationale behind route selection and the scale-up of the process used to manufacture enfuvirtide are discussed.

The PICNIC approach to regional care networks.

PICNIC is a pioneering project to develop an architecture for next generation regional healthcare networks. This paper gives an overview of the project and some of the reasoning behind the interrelated technical and business choices.

Pharmacokinetics and tolerability of the new second-generation nonnucleoside reverse- transcriptase inhibitor KM-023 in healthy subjects.

BACKGROUND: KM-023 is a new second-generation nonnucleoside reverse-transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus (HIV) type 1 infection. OBJECTIVE: This study determined KM-023 tolerability and pharmacokinetic characteristics in healthy subjects. MATERIALS AND METHODS: A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 80 healthy South Korean male volunteers. The subjects were allocated to single- or multiple-dose (once daily for 7 days) groups that received 75, 150, 300, or 600 mg drug or placebo in a 4:1 ratio. Safety and pharmacokinetic assessments were performed during the study. Plasma and urine concentrations were quantified using liquid chromatography-tandem mass spectrometry. RESULTS: The average maximum concentration (Cmax) and area under the concentration-time curve from time 0 to infinity (AUC∞) values of KM-023 for the 75-600 mg doses in the single-dose study ranged from 440.2 ng/mL to 1,245.4 ng/mL and 11,142.4 ng · h/mL to 33,705.6 ng · h/mL, respectively. Values of the mean Cmax at a steady state and AUC within the dosing interval ranged from 385.1 ng/mL to 1,096.7 ng/mL and 3,698.9 ng · h/mL to 10,232.6 ng · h/mL, respectively, following 75-600 mg doses in the multiple-dose study. Dose proportionality was not observed for KM-023. KM-023 showed a 0.6-fold accumulation after multiple doses in the 600 mg dose group. The mean half-life values ranged between 20.7 and 31.2 hours. KM-023 was generally well tolerated without serious adverse events. CONCLUSION: KM-023 demonstrated dose- and time-dependent nonlinear pharmacokinetic characteristics after single or multiple doses over a dose range (75-600 mg) in healthy subjects. KM-023 showed favorable tolerability in this study. This Phase I clinical trial information can be used to design further clinical studies appropriately to evaluate KM-023 in patients with HIV-1 infection.

Burkholdines 1097 and 1229, potent antifungal peptides from Burkholderia ambifaria 2.2N.

Potent antifungal cyclic lipopeptides, burkholdines (Bk), were isolated from a culture of Burkholderia ambifaria 2.2N. Bk-1229 (1) and Bk-1097 (2) are octapeptides comprised of nonproteinogenic amino acids, including beta-hydroxytyrosine, beta-hydroxyasparagine, and a new fatty acyl amino acid. 1 and 2 are fungicidal against a panel of fungi with potencies 2-60-fold better than amphotericin B control.

Heterobiaryl human immunodeficiency virus entry inhibitors.

Previously disclosed HIV (human immunodeficiency virus) attachment inhibitors, exemplified by BMS 806 (formally BMS378806, 1), are characterized by a substituted indole or azaindole ring linked to a benzoylpiperazine via a ketoamide or sulfonamide group. In the present report, we describe the discovery of a novel series of potent HIV entry inhibitors in which the indole or azaindole ring of previous inhibitors is replaced by a heterobiaryl group. Several of these analogues exhibited IC(50) values of less than 5 nM in a pseudotyped antiviral assay, and compound 13k was demonstrated to exhibit potency and selectivity similar to those of 1 against a panel of clinical viral isolates. Moreover, current structure-activity relationship studies of these novel biaryl gp120 inhibitors revealed that around the biaryl, a fine crevice might exist in the gp120 binding site. Taken in sum, these data reveal a hitherto unsuspected flexibility in the structure-activity relationships for these inhibitors and suggest new avenues for exploration and gp120 inhibitor design.

Second virial coefficient determination of a therapeutic peptide by self-interaction chromatography.

Self-interaction of macromolecules has been shown to play an important role in a number of physical processes, including crystallization, solubility, viscosity, and aggregation. Peptide self-interaction is not as well studied as for larger proteins, but should play an equally important role. The osmotic second virial coefficient, B, can be used to quantify peptide and protein self-interaction. B values are typically measured using static light scattering (SLS). Peptides, however, do not scatter enough light to allow such measurements. This study describes the first use of self-interaction chromatography (SIC) for the measurement of peptide B values because SIC does not have the molecular size limitations of SLS. In the present work, SIC was used to measure B for enfuvirtide, a 36-amino acid therapeutic peptide, as a function of salt concentration, salt type, and pH. B was found to correlate strongly with solubility and apparent molecular weight. In general, the solubility of enfuvirtide increases with pH from 6 to 10 and decreases as the salt concentration increases from 0 to 0.5M for three different salts. The effect of peptide concentration on B was also investigated and shown to have a significant effect, but only at high concentrations (>80 mg/mL).

Development of HIV fusion inhibitors.

In the past 25 years, the worldwide AIDS epidemic has grown such that roughly 38 million people were estimated to be living with the disease worldwide at the end of 2003. The introduction of antiretroviral-based therapies, beginning in 1987, has enabled many to live with HIV as a chronic, rather than terminal, disease. However, the emergence and spread of drug-resistant strains highlights the continued need for new therapies with novel modes of action. In 2003, the FDA and EMEA approved enfuvirtide (Fuzeon), a 36 amino acid peptide derived from the natural gp41 HR2 sequence, as the first HIV fusion inhibitor. T-1249, a 39 amino acid fusion inhibitor, is active against viruses that develop resistance to enfuvirtide. The development of FIs and the processes to manufacture enfuvirtide and T-1249 on an unprecedented scale for peptide therapeutics are presented. Synthetic routes based on a combination of solid phase peptide synthesis and solution phase fragment condensation as well as the analytical controls necessary to insure a robust process are discussed.