Nebulization of nanoparticulate amorphous or crystalline tacrolimus - Single-dose pharmacokinetics study in mice.

Developing a pulmonary composition of tacrolimus (TAC) provides direct access to the graft in lung transplant offering the possibility of high drug levels. The objective of this study was to investigate the physicochemical and pharmacokinetic characteristics of the nanostructured aggregates containing amorphous or crystalline nanoparticles of TAC produced by ultra-rapid freezing (URF). TAC and lactose (1:1 ratio; URF-TAC:LAC) and TAC alone (URF-TAC) were investigated for pulmonary delivery and compared to unprocessed TAC. X-ray diffraction (XRD) results indicated that URF-TAC was crystalline, whereas URF-TAC:LAC was amorphous. In vitro results revealed the superior physiochemical characteristics of both URF formulations compared to unprocessed TAC. The surface area of URF processed TAC was higher (25-29m(2)/g) than that of the unprocessed TAC (0.53m(2)/g) and subsequently enhanced dissolution rates. In addition, URF-TAC:LAC displayed the ability to supersaturate in the dissolution media to about 11 times the crystalline equilibrium solubility. Similar aerodynamic particle sizes of 2-3mum, and fine particle fraction between 70% and 75% were found in both formulations. The local and systemic pharmacokinetic studies in mice showed similar AUC((0-24)), higher C(max), and lower T(max) for the URF-TAC:LAC compared to the URF-TAC. Nanostructured aggregates containing amorphous or crystalline nanoparticles of TAC were demonstrated to be effectively delivered via nebulization, with similar in vitro and in vivo performances.     

The current role for femorofemoral bypass

We reviewed our experience with femorofemoral bypass during the past 10 years to define its role relative to other methods in the treatment of aortoiliac occlusive disease. The cumulative patency rate for 82 patients was 80% +/- 5% at 1 year and 67% +/- 7% at 2 and 3 years. The operation was most likely to be successful if the indication was claudication (p less than 0.05) and if the operation was performed as the primary procedure (p less than 0.01). There was no significant difference when patients with or without profundaplasty were compared. It is concluded that femorofemoral bypass is indicated to treat symptomatic unilateral iliac disease when transluminal dilatation is not possible. Femorofemoral bypass is also the procedure of choice for aortofemoral graft occlusion when the thrombosed limb cannot be reopened. Femorofemoral bypass is recommended for both high- and low-risk patients when indicated.     

Overreplication and recombination of DNA in higher eukaryotes: potential consequences and biological implications.

We propose that a fundamental problem in the faithful replication of complex chromosomes of higher eukaryotes is the proper control of both the number and timing of the multiple initiations of replication on single chromosomes. When replication patterns are disrupted by any of a variety of agents, overreplication of DNA can occur. We propose a model that accounts for the generation of a wide variety of chromosomal aberrations-rearrangements, resulting from the various ways in which the overreplicated strands can undergo recombination. We also discuss certain implications of the generation of chromosomal alterations in higher eukaryotes as they may relate to cancer chemotherapy, cancer progression, aging, and rapid speciation-evolution.     

Gastric inhibitory effects of CM57755

Summary The gastric inhibitory effects of CM57755, a new histamine H₂ receptor antagonist, have been compared in ten healthy male volunteers with the actions of an equal dose of cimetidine and with placebo. The inhibitory effect of CM57755 was virtually identical with, and not significantly different from the effects of cimetidine on nocturnal gastric secretion of acid, while neither drug influenced the secretion of pepsin. Neither drug, administered in the evening, influenced the intragastric pH and acidity during the following day, from breakfast onwards. The therapeutic impact of the new drug is likely to resemble that of cimetidine and clinical application will depend on the safety profile.     

Plasmapheresis in children with Guillain-Barré syndrome.

Between 1987 and 1989, we plasmapheresed six children with Guillain-Barré syndrome (GBS). None of the children could walk independently at the start of the treatment, and one was being ventilated. Five patients showed clinical improvement during pheresis, and no significant side effects occurred. The median time from onset of weakness to independent walking for these six children was 17 days. This compares with 43 days for 18 children with GBS in this institution who were given supportive measures only.     

Low and conventional dose cyclopenthiazide on glucose and lipid metabolism in mild hypertension.

In a double-blind, placebo controlled, randomised parallel study we investigated the antihypertensive activity and metabolic adverse effects of three doses of cyclopenthiazide in 53 patients with mild hypertension. After a 4 week placebo washout period, patients with diastolic blood pressures between 90-110 mm Hg were randomly assigned to receive 50 micrograms, 125 micrograms and 500 micrograms of cyclopenthiazide or matching placebo, over an 8 week active treatment period. Blood pressure was recorded at 2 weekly intervals during the trial. Venous samples were taken for evaluation of drug effect on indices of carbohydrate and lipid metabolism just prior to, and on completion of, the active treatment period. Systolic and diastolic blood pressure decreased significantly (P less than 0.05) with the 125 micrograms and 500 micrograms doses of cyclopenthiazide. No change was apparent in any index of glucose and lipid metabolism over time. Low and conventional doses of cyclopenthiazide lower blood pressure without alteration to the metabolic profile in the short term.     

Comparison of convection heat sterilization units for the orthodontic office

Convection heat has become a popular means of sterilization for orthodontic practices. Several commercial brands are currently being marketed. This investigation compares the Cox sterilizer, the Dentronix DDS 5000, and a Farberware convection oven by means of thermal and bacteriologic testing. Thermal testing was conducted with a thermocouple in well-defined areas of each oven, while bacterologic evaluation involved Bacillus subtilis spore strips placed in specific sectors. The results showed that specific areas of the Cox sterilizer dropped below 375 degrees F during the sterilization cycle, while the DDS 5000 maintained temperatures above 375 degrees F. The Farberware oven reached a mean temperature (including 1 standard deviation) above 375 degrees F when set at 400 degrees F after the oven was allowed to warm up for 13 minutes. Spore growth was detected in several sectors of both the Cox sterilizer and the DDS 5000. No growth was seen in the Farberware oven.     

A double-blind, randomized, sham-controlled trial of the gastric bubble for obesity

We investigated the effect of an endoscopically placed gastric balloon, the Garren-Edwards gastric bubble (GEGB), on weight loss in obese patients. Fifty-nine obese patients were entered into a prospective double-blind study and randomized into two groups. In one group (34 patients) the GEGB was inserted, and in the other group (25 patients) a sham insertion was done. All patients participated in a standard weight loss program consisting of dietary therapy, behavior modification, and physical exercise. The bubble was removed endoscopically after 3 months from both groups. Patients were followed for an additional 9 months after bubble removal and weight loss was monitored. Weight loss was the same in both groups at 3 months (18.7 lb vs. 17.2 lb). This was true whether determined by change in pounds, percentage of body weight, or body mass index. We concluded that the GEGB was of no added benefit as compared with sham insertion, when combined with a standard weight loss program. Because of the lack of proven efficacy and the relatively high cost, we recommend that such devices be restricted to controlled studies until significant benefits are proven.     

Histocompatibility Antigens in Primary Biliary Cirrhosis

HLA-A, -B, and -DR antigens were examined in 71 patients with primary biliary cirrhosis (PBC) enrolled in a randomized, double-blind trial of colchicine versus placebo. All patients had typical laboratory and histological features of PBC, except that six had a negative test for antimitochondrial antibody. Frequencies of these antigens were compared with the international Caucasian panel of the Eighth International Workshop and with a local Caucasian panel. Antigen frequencies were compared using the chi 2 test, with a correction for the number of antigens tested. The PBC patients had a significant excess of DR4 (29 of 70 typed, or 41.1%) compared to the international (804 of 3811, or 21.1%, corrected p value less than 0.05) but not the local panel (47 or 129, or 36.4%). Of PBC patients, 52.9% had only one DR antigen identified, compared to 67.5% for the international panel and 49.6% for the local panel. In past studies, the HLA antigen most strongly correlated with PBC was DR8, but this was not included in our panel of antisera. However, no significant relationship between HLA and PBC was found among the antigens screened.