The first clinical trial of an implantable microchip-based drug delivery device is discussed. Human parathyroid hormone fragment (1-34) ] was delivered from the device in vivo. hPTH(1-34) is the only approved anabolic osteoporosis treatment, but requires daily injections, making patient compliance an obstacle to effective treatment. Furthermore, a net increase in bone mineral density requires intermittent or pulsatile hPTH(1-34) delivery, a challenge for implantable drug delivery products. The microchip-based devices, containing discrete doses of lyophilized hPTH(1-34), were implanted in eight osteoporotic postmenopausal women for 4 months and wirelessly programmed to release doses from the device once daily for up to 20 days. A computer-based programmer, operating in the Medical Implant Communications Service band, established a bidirectional wireless communication link with the implant to program the dosing schedule and receive implant status confirming proper operation. Each woman subsequently received hPTH(1-34) injections in escalating doses. The pharmacokinetics, safety, tolerability, and bioequivalence of hPTH(1-34) were assessed. Device dosing produced similar pharmacokinetics to multiple injections and had lower coefficients of variation. Bone marker evaluation indicated that daily release from the device increased bone formation. There were no toxic or adverse events due to the device or drug, and patients stated that the implant did not affect quality of life.

Implanted drug delivery systems are being increasingly used to realize the therapeutic potential of peptides and proteins. Here we describe the controlled pulsatile release of the polypeptide leuprolide from microchip implants over 6 months in dogs. Each microchip contains an array of discrete reservoirs from which dose delivery can be controlled by telemetry.

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Background: Estimates for delays in the interstitial fluid (ISF) glucose response to changes in blood glucose (BG) differ substantially among research groups. We review these findings along with arguments that continuous glucose monitoring (CGM) devices used to measure ISF delay contribute to the variability. We consider the impact of the ISF delay and review approaches to correct for it, including strategies pursued by the manufacturers of these devices. The focus on how the manufacturers have approached the problem is motivated by the observation that clinicians and researchers are often unaware of how the existing CGM devices process the ISF glucose signal. Methods: Numerous models and simulations were used to illustrate problems related to measurement and correction of ISF glucose delay. Results: We find that (1) there is no evidence that the true physiologic ISF glucose delay is longer than 5–10 min and that the values longer than this can be explained by delays in CGM filtering routines; (2) the primary impact of the true ISF delay is on sensor calibration algorithms, making it difficult to estimate calibration factors and offset (OS) currents; (3) inaccurate estimates of the sensor OS current result in overestimation of sensor glucose at low values, making it difficult to detect hypoglycemia; (4) many device companies introduce nonlinear components into their filters, which can be expected to confound attempts by investigators to reconstruct BG using linear deconvolution; and (5) algorithms advocated by academic groups are seldom compared to algorithms pursued by industry, making it difficult to ascertain their value. Conclusions: The absence of any direct comparisons between existing and new algorithms for correcting ISF delay and sensor OS current is, in part, due to the difficulty in extracting relevant details from industry patents and/or extracting unfiltered sensor signals from industry products. The model simulation environment, where all aspects of the signal can be derived, may be more appropriate for developing new filtering and calibration strategies. Nevertheless, clinicians, academic researchers, and the industry would benefit from collaborating when evaluating those strategies.

Infrared spectroscopy has been used to analyse the gas-phase reaction products and the related adsorbed species obtained between room temperature and 400 "C from the dehydrogenation/dehydration reactions of propan-2-01 over a series of differently calcined catalysts of TiO,, ZrO, and HfO,. The ZrO, and HfO, results were independent of the calcination pretreatment, and the surfaces of these oxides, like that from a TiO, sample calcined at 800 "C, were dehydroxylated. Different results were obtained from a TiO, sample calcined at 300 "C which had a hydroxylated surface. The acidic sites and reactivities of the surfaces of Ti0,(300 "C) and Ti0,(800 "C) were explored by pyridine adsorption and infrared spectroscopy. Only Lewis-acid sites were detected by pyridine.On raising the reaction temperature, in all cases the dehydrogenation reaction to give acetone occurred either before or simultaneously to the onset of the dehydration reaction to give propene. Acetone production was most pronounced over ZrO, and HfO, but also occurred more with Ti0,(800 "C) than with Ti0,(300 "C). The dehydrogenation reaction was largely quenched by pre-adsorbed pyridine on both TiO, samples. The TiO, (300 "C) catalyst showed the presence of adsorbed propan-2-01 and 2-propoxide groups at room temperature. The dehydroxylated ZrO,, HfO, and Ti0,(800 "C) samples only showed appreciable amounts of 2-propoxide groups. In each case the 2-propoxide ions occurred in two different forms, presumably formed by adsorption on different types of sites.Both the acetone and propene products appeared as absorptions from 2propoxide surface species decreased in intensity, so the latter are clearly reactive species. Gas-phase acetone production was followed by the chemisorption of acetone at a higher temperature. This subsequently decomposed to give surface acetate species, and finally at 400 "C to give CO, and methane in the gas phase. Propene did not give rise to adsorbed species, or to further products in the gas phase.At the higher temperatures, above 300"C, the reaction was always selective in favour of the dehydration reaction. However, each of the dehydroxylated catalysts showed some selectivity in favour of the dehydrogenation reaction over the earliest temperature range for alcohol decomposition, between 200 and 250 "C.A discussion is given of possible mechanistic pathways for the production of surface 2-propoxide species and the two types of products, based on the infrared-supported assumption that the different adsorbed forms of 2propoxide [and possibly adsorbed propan-2-01 on Ti0,(300 "C)] are reactive intermediates.t On leave from Minia University.