Hyperthermia delivered by scanned focused ultrasound was combined with external beam radiation to treat 15 patients with primary malignant tumors of the brain. A preliminary craniectomy was performed to avoid attenuation of the ultrasound beam by the skull, and multiple thermal sensors were employed to ascertain intratumoral temperatures. The target temperature was 42.5 degrees C at the tumor boundary. This was attained at more than one point during every complete treatment, while a mean temperature in excess of 42 degrees C was achieved within the scanned tumor volume during at least 1 treatment in 11 patients. Technical problems and toxicities are described.

Loperamide (LOP) is a peripherally acting opioid receptor agonist used for the management of chronic diarrhea through the reduction of gut motility. The lack of central opioid effects is partly due to the efflux activity of the multidrug resistance transporter P-glycoprotein (P-gp) at the blood-brain barrier. The protease inhibitors are substrates for P-gp and have the potential to cause increased LOP levels in the brain. Because protease inhibitors, including tipranavir (TPV), are often associated with diarrhea, they are commonly used in combination with LOP. The level of respiratory depression, the level of pupil constriction, the pharmacokinetics, and the safety of LOP alone compared with those of LOP-ritonavir (RTV), LOP-TPV, and LOP-TPV-RTV were evaluated in a randomized, open-label, parallel-group study with 24 healthy human immunodeficiency virus type 1-negative adults. Respiratory depression was assessed by determination of the ventilatory response to carbon dioxide. Tipranavir-containing regimens (LOP-TPV and LOP-TPV-RTV) caused decreases in the area under the concentration-time curve from time zero to infinity for LOP (51% and 63% decreases, respectively) and its metabolite (72% and 77% decreases, respectively), whereas RTV caused increases in the levels of exposure of LOP (121% increase) and its metabolite (44% increase). In vitro and in vivo data suggest that TPV is a substrate for and an inducer of P-gp activity. The respiratory response to LOP in combination with TPV and/or RTV was not different from that to LOP alone. There was no evidence that LOP had opioid effects in the central nervous system, as measured indirectly by CO 2 response curves and pupillary response in the presence of TPV and/or RTV.Loperamide (LOP; Imodium, McNeil-PPC, Inc.) is a peripherally acting opioid receptor agonist that reduces gut motility and that is used for the management of chronic diarrhea (8,25). The principal metabolic fate of loperamide in humans involves oxidative N-dealkylation to N-demethyl-loperamide as the principal metabolite. In human liver microsomes, cytochrome P450 3A4 (CYP3A4) appears to be the major isozyme responsible for loperamide metabolism, with minor contributions from CYP2B6 (9). At the doses used to control diarrhea, LOP has very poor penetration of the blood-brain barrier and produces no central opioid effects, such as respiratory depression, pupillary constrictions, analgesia, or changes in alertness (26). The poor central nervous system (CNS) penetration is attributed both to LOP active cellular efflux via the multidrug resistance transporter P-glycoprotein (P-gp) in the blood-brain barrier and to low systemic oral bioavailability (24). When P-gp is inhibited, LOP and its metabolites may potentially enter the brain and cause opioid-induced central neurological adverse events (AEs) (23, 24).Current treatment for human immunodeficiency virus type 1 (HIV-1) infection consists of a combination of antiretroviral agents of different classes. Tipranavir (TPV) is a potent nonpeptidic HIV-1 and HIV-...

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Patients with diabetes have difficulty controlling their blood sugar and suffer from acute effects of hypoglycemia and long-term effects of hyperglycemia, which include disease of the eyes, kidneys and nerves/feet. In this paper, we describe a new system that is used to automatically control blood sugar in people with diabetes through the fully automated measurement of blood glucose levels and the delivery of insulin and glucagon via the subcutaneous route. When a patient's blood sugar goes too high, insulin is given to the patient to bring his/her blood sugar back to a normal level. To prevent a patient's blood sugar from going too low, the patient is given a hormone called glucagon which raises the patient's blood sugar. While other groups have described methods for automatically delivering insulin and glucagon, many of these systems still require human interaction to enter the venous blood sugar levels into the control system. This paper describes the development of a fully automated closed-loop dual sensor bi-hormonal artificial pancreas system that does not require human interaction. The system described in this paper is comprised of two sensors for measuring glucose, two pumps for independent delivery of insulin and glucagon, and a laptop computer running a custom software application that controls the sensor acquisition and insulin and glucagon delivery based on the glucose values recorded. Two control algorithms are designed into the software: (1) an algorithm that delivers insulin and glucagon according to their proportional and derivative errors and proportional and derivative gains and (2) an adaptive algorithm that adjusts the gain factors based on the patient's current insulin sensitivity as determined using a mathematical model. Results from this work may ultimately lead to development of a portable, easy to use, artificial pancreas device that can enable far better glycemic control in patients with diabetes.