Hepatic arterial and intravenous administration of 1,25-dihydroxyvitamin D3--evidence of a clinically significant hepatic first-pass effect.

PURPOSE: We have previously shown that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] inhibits the proliferation of a number of human cancers, including colorectal and hepatocellular carcinoma, both of which affect the liver and are major causes of cancer death. However, the clinical use of 1,25(OH)2D3 and analogues has been restricted by the development of hypercalcaemia upon systemic administration. We hypothesized that a clinically significant hepatic first-pass effect may exist upon the administration of 1,25(OH)2D3 as a hepatic arterial infusion, and that such an effect may allow high levels of 1,25(OH)2D3 to be delivered to the liver whilst avoiding high systemic levels. METHODS: To examine this hypothesis, two groups of Landrace pigs were given identical doses of 1,25(OH)2D3 as continuous infusions, one group systemically, the other as a hepatic arterial infusion. Serum levels of 1,25(OH)2D3, calcium, phosphate and a number of liver and kidney function tests were performed regularly. RESULTS: Concentrations of 1,25(OH)2D3 and calcium remained normal in the hepatic arterial infusion animals, in contrast to the intravenous infusion animals which developed elevated levels of 1,25(OH)2D3 and hypercalcaemia. Hepatic arterial infusion of 1,25(OH)2D3 did not produce any adverse effects upon renal or hepatic function. CONCLUSION: The present findings support the existence of a clinically significant hepatic first-pass effect when 1,25(OH)2D3 is administered as a continuous hepatic arterial infusion. Hepatic arterial infusion of 1,25(OH)2D3 has great potential in the treatment of hepatic cancers.

A prospective multicenter clinical study of the Osseotite implant: four-year interim report.

This article reports the 4-year interim results of a multicenter study evaluating the clinical performance of the Osseotite dental implant. At 4 study centers, 485 Osseotite implants were consecutively placed in 181 patients (219 were placed in the mandible and 266 in the maxilla). A total of 355 implants were placed in posterior regions. Short implants (10 mm or less) represented 31.5% (n = 153) of all implants placed in this study. Patients were restored with 210 restorations, distributed as 123 short-span prostheses, 58 single-tooth replacements, 28 long-span prostheses, and 1 maxillary overdenture. At this 4-year interim evaluation, the mean time from implant placement to the most recent evaluation was 52.6 +/- 3.0 months, with a mean loading time of 43.3 +/- 3.8 months. Of the 485 implants placed, there have been 6 failures. All implant failures occurred prior to loading and were categorized as early implant failures. Five of the 6 failures occurred in the maxilla. Only one of the 153 short implants failed to integrate. Baseline radiographs were obtained at prosthesis connection. Radiographic analysis 1 year post-restoration showed a mean bone loss of 0.09 +/- 0.7 mm. From baseline to the end of the second year of function, an overall mean bone loss of 0.13 +/- 0.8 mm was recorded, indicating no additional bone was lost after the first year of implant function. At 4 years, the cumulative implant success rate for all implants placed in this study was 98.7%, with a 99.4% success rate in the posterior mandible and 98.4% success rate in the posterior maxilla. Results of this 4-year interim analysis indicate that this implant achieved a high success rate in posterior regions and that all failures with this implant in this patient population occurred prior to implant loading. When the clinical success of implants 10 mm or shorter was compared to that of implants greater than 10 mm in length, the shorter implants in this study performed similarly to longer implants.

Relationship of ascorbic acid levels of blood and gingival tissue with response to periodontal therapy.

The effect of ascorbic acid megadoses on gingival clinical parameters and vitamin content of blood and gingival tissue was studied. 10 nondeficient individuals, carefully matched according to age, periodontal status, and oral hygiene level, were divided into 2 groups: one received 250 mg q.i.d. of ascorbic acid and the other a placebo. After 1 week on the tablet all patients were scaled and root planed and received oral hygiene instructions. Blood samples and clinical parameters were obtained at baseline and 2, 6, and 7 weeks after. A gingival biopsy was taken at week 6. Correlations between the clinical parameters and the ascorbic acid levels at the different time periods revealed no significant differences between the vitamin and the placebo groups, therefore suggesting that the use of megadoses of vitamin C in normal human subjects does not have a predictable or strong effect on the gingival response to initial therapy.