An evaluation of the P450 inhibition and induction potential of daptomycin in primary human hepatocytes.

Two in vitro studies assessed the potential of daptomycin (Cubicin), a newly marketed antibiotic, to affect the cytochrome P450 (CYP450) isoforms in primary cultured human hepatocytes. Both induction and inhibition of isoforms 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 were evaluated. The highest concentrations of daptomycin used in both the induction and inhibition assays were approximately eight-fold higher than the peak total drug concentration (50-60 microg/mL), or the peak free drug concentration (estimated 5-6 microg/mL), in plasma at the clinical dose regimen of 4 mg/kg qd. Results in primary human hepatocytes indicate that daptomycin, at concentrations up to 400 microg total drug/mL, demonstrated no biologically significant induction of any of the CYP450 isoform activities in comparison with the negative control or known inducers. At daptomycin concentrations up to 40 microg free drug/mL, no biologically significant inhibition of the activities of these CYP450 isoforms was observed as compared with known inhibitors. The human hepatocyte results demonstrate that daptomycin has no effects on hepatic CYP450-mediated drug metabolism and, therefore, suggest that daptomycin is unlikely to show potential for pharmacokinetic interactions with concomitantly administered drugs that are metabolized by CYP450 isoforms.

Once-daily dosing in dogs optimizes daptomycin safety.

Daptomycin is a novel lipopeptide antibiotic with potent bactericidal activity against most clinically important gram-positive bacteria, including resistant strains. Daptomycin has been shown to have an effect on skeletal muscle. To guide the clinical dosing regimen with the potential for the least effect on skeletal muscle, two studies were conducted with dogs to compare the effects of repeated intravenous administration every 24 h versus every 8 h for 20 days. The data suggest that skeletal-muscle effects were more closely related to the dosing interval than to either the maximum concentration of the drug in plasma or the area under the concentration-time curve. Both increases in serum creatine phosphokinase activity and the incidence of myopathy observed at 25 mg/kg of body weight every 8 h were greater than those observed at 75 mg/kg every 24 h despite the lower maximum concentration of drug in plasma. Similarly, the effects observed at 25 mg/kg every 8 h were greater than those observed at 75 mg/kg every 24 h at approximately the same area under the concentration-time curve from 0 to 24 h. Once-daily administration appeared to minimize the potential for daptomycin-related skeletal-muscle effects, possibly by allowing for more time between doses for repair of subclinical effects. Thus, these studies with dogs suggest that once-daily dosing of daptomycin in humans should have the potential to minimize skeletal-muscle effects. In fact, interim results of ongoing clinical trials, which have focused on once-daily dosing, appear to be consistent with this conclusion.

Immediate loading of implants in partially and fully edentulous jaws: a series of 27 case reports.

BACKGROUND: The concept of immediate loading of dental implants has been researched in animal and man. High predictability with titanium screw implants can be expected under certain circumstances. Delayed loading, which is empirically based, may offer roadblocks to success in the complex case. Micromotion under a denture, retention of compromised teeth, and the necessity for multiple implant surgeries complicate the situation. The present study was undertaken to demonstrate whether in partial and fully edentulous patients, titanium screw implants may be installed and loaded within 72 hours. METHODS: The study included 27 jaws (23 mandibles and 4 maxillas) in patients who refused to wear a denture or were told of the possibility of immediately loading their implants. Criteria similar to delayed loading was utilized. The patient had to have adequate volume and density for a minimum of 4 (10 mm) implants in the mandible and 6 in the maxilla, in addition to other requirements. After a thorough presurgical evaluation by the restorative dentist, a template and heat-cured/metal-reinforced provisional were fabricated. Following fixture installation, either the fixed provisional was placed or an impression was taken, and the provisional was seated within 72 hours. Once the temporary was placed, it remained until osseointegration was complete. RESULTS: Success rates similar to those in delayed loaded cases may be expected (95%). Fewer sandblasted/acid-etched titanium screws were lost than machined titanium screws. All patients went on to completion of their original prosthetic prescription. CONCLUSIONS: Patients who are partially or fully edentulous may predictably be restored with fixed implant prostheses immediately upon fixture placement if certain parameters are met.

Daptomycin: a novel agent for Gram-positive infections.

The alarming increase in the incidence of Gram-positive infections, including those caused by resistant bacteria, has sparked renewed interest in novel antibiotics. One such agent is daptomycin, a novel lipopeptide antibiotic with proven bactericidal activity in vitro against all clinically relevant Gram-positive bacteria. These include resistant pathogens, such as vancomycin-resistant enterococci (VRE), methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide intermediately susceptible Staphylococcus aureus (GISA), coagulase-negative staphylococci (CNS) and penicillin-resistant Streptococcus pneumoniae (PRSP), for which there are very few therapeutic alternatives. Daptomycin provides rapid, concentration-dependent killing and a relatively prolonged concentration-dependent post-antibiotic effect in vitro. Spontaneous acquisition of resistance to daptomycin occurs rarely. Daptomycin exhibits linear pharmacokinetics, minimal accumulation with once-daily dosing, and low plasma clearance and volume of distribution. Phase II clinical trials indicate that daptomycin at doses of 2 mg/kg q24 h and 3 mg/kg q12 h is efficacious against skin and soft tissue infections and bacteremia, respectively. In addition, results in endocarditis suggested potential efficacy with higher doses. On the basis of clinical trials to date, it appears that daptomycin has an excellent safety profile, with the incidence and nature of serious adverse events comparable to those observed with conventional therapy. Adverse events associated with other classes of antimicrobials (nephrotoxicity, local irritation, ototoxicity, hypersensitivity, and gastrointestinal effects) were uncommon with daptomycin. Minimal skeletal muscle toxicity was seen at only the highest dose tested (4 mg/kg q12 h), predicted by elevations in serum creatinine phosphokinase, and readily reversible upon discontinuation of treatment. There were no signs of toxicity in cardiac or smooth muscle. Phase II and III clinical trials are underway to evaluate daptomycin for the treatment of Gram-positive bacteremia and complicated skin and soft tissue infections, respectively. Daptomycin holds promise as a rapidly acting and highly effective antibiotic for Gram-positive infections.

A paternally derived inverted duplication of 7q with evidence of a telomeric deletion.

We report on a de novo constitutional rearrangement involving the long arm of chromosome 7 in a second trimester fetus with the karyotype of 46,XX, inv dup del (7)(pter-q36::q36-q21.2:) pat. Both a large duplication (q21.2-q36) and a small deletion (within q36) were confirmed by FISH studies. DNA analysis on the family showed that the abnormal chromosome was derived from a single paternal homolog. A mechanism is proposed in light of this finding. The phenotype at autopsy was consistent with reported cases of similar duplications in chromosome 7 in that hydrocephalus, a depressed nasal bridge, low set ears, microretrognathia and a short neck were present.

The excessive loss of Branemark fixtures in type IV bone: a 5-year analysis.

The predictability of branemark implants has been well documented. High success rates in the maxilla and mandible in fully and partially edentulous patients can be expected. A host of factors may be attributed to the etiology of fixture loss. However, the quality of bone stands out as the single greatest determinant in fixture loss. Types I, II, and III bone offer good strength. Type IV bone has a thin cortex and poor medullary strength with low trabecular density. Ninety percent of 1,054 implants placed were in Types I, II, and III bone. Only 3% of these fixtures were lost; of the 10% of the fixtures placed in Type IV bone, 35% failed. Presurgical determination of Type IV bone may be one method to decrease implant failure.

Osseointegration. Complications. Prevention, recognition, treatment.

Practitioners often have delayed responses to the problems involved with complications. This was especially true in the first years of endosseous implantology. Eventually, hindsight becomes insight. This maturation is a necessary and normal process. It can be enhanced by careful documentation of the procedures and process of care such as numerous clinical photographs during treatment, and treating patients with several members of the team present (example: the prosthodontist scrubbing with the surgeon on very early or complex cases.) It is possible to improve the quality of care. Postsurgical case management conferences are invaluable. It is also important that each team member not only see his or her own role, but also the responsibility to see that the entire treatment is adequately done. Each individual must have a sense of responsibility for the management of the entire case. It is important that the practitioner not take a defensive posture regarding his or her own treatment. Reformatted computerized tomography (CT) including radiographic bone density measurement (Houncefield units) can be very valuable in determining bone quality and anatomy and will provide insight into where and where not to place fixtures. In the event of a complication, it is important that it be recognized early that it not be "covered up" and that the damage be contained and prevented from causing a secondary complication and further morbidity to the patient.

A platelet alpha granule membrane protein that is associated with the plasma membrane after activation. Characterization and subcellular localization of platelet activation-dependent granule-external membrane protein.

We have identified and purified a platelet integral membrane protein (140,000 mol wt), using the KC4 monoclonal antibody specific for activated platelets, that is internal in resting platelets but exposed on activated platelets (Hsu-Lin S.-C., C.L. Berman, B.C. Furie, D. August, and B. Furie, 1984, J. Biol. Chem. 259: 9121-9126.). The expression of the protein on the platelet surface is secretion-dependent. This protein has been named platelet activation-dependent granule-external membrane (PADGEM) protein. PADGEM protein is distinct from the surface glycoproteins of resting platelets, but identical to the S12 antigen, GMP-140. Using immunofluorescent staining, resting platelets failed to stain for PADGEM protein with the KC4 antibody, but after permeabilization showed a punctate staining of the cell interior. Thrombin-stimulated intact platelets stained with a peripheral rim pattern thus demonstrating the translocation of PADGEM protein from an internal location to the cell surface. PADGEM protein expression on the platelet surface at varying thrombin concentrations correlated with alpha granule release, as measured by the secretion of platelet factor 4. Further evidence for an alpha granule localization of PADGEM protein was provided by nitrogen cavitation of resting platelets followed by metrizamide density gradient centrifugation; PADGEM protein codistributed with platelet factor 4. Using immunoelectron microscopy, the protein was localized to the alpha granule in frozen ultrathin sections of resting platelets labeled using rabbit anti-PADGEM protein antibodies, whereas in thrombin-activated platelets, the plasma membrane was labeled. These studies indicate that PADGEM protein is a component of the alpha granule membrane of resting platelets and is incorporated into the plasma membrane upon activation and secretion.

Repair of anterior gingival deformity with durapatite. A case report.

After the extraction of a maxillary anterior tooth, a gingival deformity may occur due to the loss of the labial plate of bone. This often creates an esthetic problem in the construction of a fixed partial denture. In the past, various surgical techniques have been devised to eliminate this gingival defect. A technique using durapatite is discussed.

A platelet membrane protein expressed during platelet activation and secretion. Studies using a monoclonal antibody specific for thrombin-activated platelets.

To identify structures on the platelet surface which become expressed after platelet activation, we have prepared murine monoclonal antibodies specific for thrombin-activated platelets. Hybridomas were screened for clones producing antibodies which bound to thrombin-activated platelets but not to resting platelets. Clone KC4 was identified. The binding of purified I-labeled KC4 antibody, an IgG1k, to thrombin-activated platelets was saturable. Minimal binding was observed to resting platelets. The interaction of antibody with thrombin-activated platelets was characterized by a binding constant, KD, of 7.2 +/- 0.4 nM and revealed 13,400 +/- 3,000 binding sites per platelet. The presence of Ca2+ or EDTA, a pH ranging from 4 to 10, or high ionic strength had no influence on antigen-antibody interaction. The KC4 antigen was expressed on the platelet surface after activation with ADP, collagen, epinephrine, or thrombin. The extent of [14C] serotonin release during activation was directly proportional to the availability of antigen on the platelet surface regardless of agonist or platelet aggregation. The antibody is directed against a single protein which migrated between GPIIb and GPIIa after sodium dodecyl sulfate gel electrophoresis. This protein was purified from platelet membranes by immunoaffinity chromatography using KC4 antibody-agarose and demonstrated an apparent molecular weight of 140,000 in sodium dodecyl sulfate-polyacrylamide gel electrophoresis under both nonreducing and reducing conditions. Of the cells examined, only platelets contained this protein. These results indicate that platelet secretion is associated with the expression of an Mr = 140,000 integral membrane protein composed of a single polypeptide chain. This protein may be component of the internal granule membrane which is fused with the plasma membrane during activation.

Treatment of juvenile periodontitis patients by control of infection and inflammation. Four case reports.

Four patients, ages 14-17, who demonstrated characteristics of juvenile periodontitis, underwent antibiotic and surgical therapy to control microbial etiologic factors. No occlusal equilibration or bone grafting techniques were employed. Subsequent to treatment, all four patients demonstrated decreased pocket depths and mobility on teeth associated with vertical osseous defects. Osseous repair was evident on postoperative radiographs. Reentry procedures, on one patient, confirmed that osseous repair had occurred in 2- to 3-wall, 3-wall, hemi-circumferential and furcal defects. If infection and inflammation are controlled, it appears that the potential for osseous repair in juvenile periodontitis patients is greater than has been thought.