Synthesis, antitumor activity, and antiviral activity of 3-substituted 3-deazacytidines and 3-substituted 3-deazauridines.

Novel 3-substituted analogues of 4-amino-1-beta-D-ribofuranosyl-2(1H)-pyridinone (3-deazacytidine, 3) and 4-hydroxy-1-beta-D-ribofuranosyl-2(1H)-pyridinone (3-deazauridine, 4) have been synthesized and tested for antitumor and antiviral activity. Thus the 3-chloro (9a), 3-bromo (9b), and 3-nitro (9c) analogues of 3 and the 3-chloro (9d), 3-bromo (9e), and 3-nitro (9f) analogues of 4 were prepared by standard glycosylating procedures. Novel requisite heterocycles 4-amino-3-chloro-2(1H)-pyridinone (7a) and 4-amino-3-bromo-2(1H)-pyridinone (7b) were prepared by halogenating 4-amino-2(1H)-pyridinone (5). Requisite heterocycles 4-amino-3-nitro-2(1H)-pyridinone (7c), 3-chloro-4-hydroxy-2(1H)-pyridinone (7d), 3-bromo-4-hydroxy-2(1H)-pyridinone (7e), and 4-hydroxy-3-nitro-2(1H)-pyridinone (7f) were synthesized by known procedures from 4-hydroxy-2(1H)-pyridinone (6). Structure proof of target nucleosides was provided by independent synthesis, 1H NMR, and UV. Compounds 9a-f were devoid of activity against intraperitoneally implanted L1210 leukemia in mice. Compound 9f displayed significant activity against rhinovirus type 34 grown in WISH cells. 4-Amino-3-fluoro-1-beta-D-ribofuranosyl-2(1H)-pyridinone (1) displayed good activity against intraperitoneally implanted P388 leukemia in mice, but it was devoid of activity against M5076 sarcoma, amelanotic (LOX) melanoma xenograft, and subrenal capsule human mammary carcinoma MX-1 xenograft in mice. Compound 1 also displayed significant activity against rhinovirus type 34.

Amelioration of weight gain after heart transplantation by corticosteroid-free maintenance immunosuppression. UTAH Cardiac Transplant Program.

After heart transplantation, recipients frequently become obese. Although the cause is undoubtedly multifactorial, administration of corticosteroids may contribute to posttransplant obesity. To test this hypothesis, we retrospectively reviewed the change in body weight with respect to corticosteroid use after transplantation in all 110 recipients surviving 1 year in the UTAH Cardiac Transplant Program. Fifty-two recipients (47%, group 1) were unable to be withdrawn from maintenance corticosteroids, and 58 recipients (53%, group 2) were successfully withdrawn, the latter group requiring only cyclosporine and azathioprine long-term maintenance immunosuppression. The change in weight from the time of transplantation to 1 year after transplantation in group 1 was 8.7 +/- 1.1 kg; group 2 patients gained only 4.9 +/- 0.9 kg (p = 0.009). In conclusion, successful withdrawal of maintenance corticosteroids after heart transplantation decreased posttransplant weight gain, suggesting that posttransplant obesity is in part related to use of corticosteroids.

A randomized trial of the immunosuppressive efficacy of vincristine in cardiac transplantation.

We evaluated the efficacy of the addition of the lymphoblasticidal agent vincristine to standard immunosuppression in heart transplantation in a prospective randomized study of 92 patients (46 to receive and 46 to not receive vincristine) with a follow-up period of 12 months. Patients received either equine antithymocyte globulin for the first week or OKT3 monoclonal antibody (OKT3) for the first 10 or 14 days after transplantation. Six to eight doses of vincristine were given over 9-12 weeks, beginning 2 days after completion of ATG or OKT3. The number of rejection episodes in the first six months posttransplantation, the percentage of patients corticosteroid maintenance-free at one year, cumulative immunosuppressive drug doses, deaths, infections, and neuropathy were followed. The addition of vincristine resulted in more patients achieving corticosteroid maintenance-free status at one year (vincristine 68%, no vincristine 38%, P = 0.01). In comparing patients at relatively high risk for rejection (those younger than 55 years and all females) with those at relatively low risk (males older than 55 years), only the high-risk vincristine-treated patients showed significantly fewer rejection episodes and a higher corticosteroid maintenance status at one year (66% vs. 32%, P = 0.01). There were no significant differences in survival (vincristine 96%, no vincristine 98%), infection, or amounts of other immunosuppressive agents used. The major side effect was neuropathy, which occurred more frequently in the vincristine-treated group (43% vs. 18%, P less than .001). We conclude that vincristine acts as an immunosuppressive agent in cardiac transplantation, particularly in patients at higher risk for rejection.

Antiviral and cytotoxicity evaluation of 3-nitro-3-deazauridine.

3-Nitro-3-deazauridine (3N-3DU) is a new synthetic nucleoside having activity against members of 5 RNA virus families including: paramyxoviruses (parainfluenza, PIV), picornaviruses (rhino-, RV), rhabdoviruses (vesicular stomatitis, VSV), togaviruses (Semliki Forest, SFV) and bunyaviruses (Punta Toro, PTV). In this report, we evaluate and compare its activity with the parent nucleoside, 3-deazauridine (3DU) and ribavirin as drug standards. Comparison of drug activities utilizes observations of antiviral indices, which are determined by the following formula: maximum tolerated dose (MTD)/minimum inhibitory concentration (MIC). The antiviral index (AI) of 3N-3DU (AI 15.3) was comparable to ribavirin and much higher than 3DU when evaluated against PIV. The 3N-3DU was the most active of the three when tested against RV (AI 24.1), SFV (AI 76.9) or VSV (AI 50). In contrast to the RV activity, 3N-3DU (AI 0.5) and 3DU (AI less than 0.1) were less active than ribavirin (AI 1.3) when evaluated against poliovirus, type 1 (PoV). Ribavirin (AI 10.0) was more active than 3N-3DU (AI 2.4) and 3DU (AI less than 0.1) against PTV. 3N-3DU exhibited comparable toxicity to ribavirin in KB cells, was 4-fold less toxic in WISH cells and 4-fold more toxic in LLC-MK2 cells. Overall, 3N-3DU is markedly less toxic than its parent nucleoside, 3DU. It appears from this study that the structural modification of 3DU resulting from the addition of the nitro group in the 3 position of the base reduces toxicity and enhances the antiviral activity.

Non-osteogenic fibroma of the mandibular condyle.

Non-osteogenic fibroma is a lesion most commonly seen within the metaphyseal region of the tibia or femur presenting during the second decade. Few cases have been reported in the jaws and all occurred in the mandible. This report documents an 18-year-old female with a non-osteogenic fibroma in the condyle.

Rejection prophylaxis with murine monoclonal CD-3 antibody (OKT3): considerations for early hospital discharge.

Murine monoclonal CD-3 antibody (OKT3) is a significant new addition to the immunosuppressant armamentarium for treatment of heart transplant rejection. In the Utah Transplantation Affiliated Hospitals (UTAH) Cardiac Transplant Program, Salt Lake City, a broad experience with OKT3 has been acquired. Fifteen patients were treated for refractory rejection, whereas 68 patients were treated for early rejection prophylaxis therapy utilizing either 10- or 14-day protocols. To facilitate early hospital discharge, 12 patients were able to complete OKT3 therapy as outpatients. A retrospective review of length of initial hospital stay and clinical results revealed that patients who received OKT3 had an average hospital stay (+ standard deviation) of 17.1 days, and their 12-month survival was 96%. Patients who received antithymocyte globulin and/or steroids had an average stay of 27.4 days (p less than 0.05) and a 12-month survival of 93%. In conclusion, the possibility for reduced hospital stay and consequent cost reduction exists with the use of OKT3, especially when completion of therapy can be managed in an outpatient setting.

A simple method of drying virus on inanimate objects for virucidal testing.

A simple method for drying virus on inanimate objects (cover slips) under vacuum in the cold is described. Following this procedure virus maintains high titers (10(6-7)) for periods of 1-3 wk at -70 degrees C depending on the virus. For virucidal assay of disinfectants, cover slips are exposed to medium simulating the disinfectant (virus control) or disinfectant in an upright position in an Ultra-Vu cuvette. Cover slips are readily removed and placed in tissue culture medium for dilution of virus and determination of virus titer. Cytotoxicity of disinfectant is determined by exposing cover slip without virus to disinfectant, then placing it in medium, diluting the medium and incubating with the indicator cells. The use of this technique results in high titers of virus on cover slips, which are inanimate objects requiring minimal manipulation. The titration of virus or cytotoxicity in microplates is cell, medium, serum, and labware economical.

The influence of methylprednisolone on post-operative swelling following oral surgery.

This study compares the influence of methylprednisolone with that of a placebo on post-operative pain and swelling, and on healing. Twenty patients undergoing the removal of symmetrically placed bilateral lower third molar teeth under local analgesia by the same operator one side at a time were used. In each individual patient, for one side 40 mg methylprednisolone (Solumedrone Upjohn Limited) was given intravenously immediately preoperatively and for the other side a placebo was given on a double-blind random basis. The results showed that the mean post-operative swelling at 24 hours was reduced by 56% (p = .0003) when methylprednisolone was used compared with the opposite side of the same patient when the placebo was used. The severity of pain also was reduced over the first day but healing was similar for each side. Sixteen patients indicated a preference for the overall post-operative course when methylprednisolone was used.

Combined heart failure transplant program: advantages in assessing medical compliance.

Compliance, motivation, and strong family support have been identified as important factors to the success of heart transplantation. Approaches to psychosocial evaluations determining suitability of candidates vary among transplant centers. Although testing, interviewing, and retrospective analyses of patient profiles are valuable, they do not allow for longitudinal evaluation of patients who have been denied transplantation under these standard methods of assessment. The Utah Cardiac Transplant Program (UCTP) combines heart failure and transplant services to provide maximum conventional and experimental therapy to patients with end-stage cardiac dysfunction. A single medical team provides care to all patients. From March 8, 1985 to November 1, 1986, UCTP evaluated 170 patients, assigning 57 to conventional medication therapy, 72 to experimental medication therapy, and 41 directly to heart transplantation. Of the 72 patients assigned to experimental therapy, 21 were subsequently assigned to heart transplantation. In the initial evaluation of four patients, it was determined that they did not have adequate family support or emotional stability to undergo transplantation. After monitoring these four patients through a drug study, it was found that the initial evaluation was incorrect, as the patients demonstrated the ability to adhere to a complex regimen involving multiple diagnostic tests, clinic visits, and medication therapy. Three of these patients subsequently underwent successful transplantations and are alive with a mean follow-up time of 212 days. In conclusion, combining all modalities of treatment for end-stage heart disease into one unified program has definite advantages that include longitudinal evaluation of patients previously denied transplantation.

The influence of closure or dressing of third molar sockets on post-operative swelling and pain.

This study compares the influence of complete closure as opposed to partial closure and dressing of lower third molar sockets on post-operative pain and swelling, and on healing. These closure techniques were used on opposite sides of the mouths of each of 70 patients undergoing bilateral third molar surgery. The comparison of the two techniques within each individual patient showed that complete closure resulted in more pain and swelling post-operatively in a significant number of patients, but that the use of a dressing delayed satisfactory healing in a few patients.

Dermoid cyst of the mandible.

A mid-line cyst of the mandible is described which possessed the histological features of a dermoid cyst. This appears to be the first fully documented example of a totally intra-osseous dermoid cyst in the mandible. The pathogenesis of the present lesion is discussed in relation to both the odontogenic and the non-odontogenic cysts that may occur in the mandibular mid-line.

The development of a method of assessing swelling following third molar surgery.

A method of measuring post-operative facial swelling following third molar surgery should satisfy the following criteria. Firstly, the accuracy should be assessed, secondly the measurement should be in volume units, and thirdly the method should be both practical and ethical in the clinical situation and not limited by static apparatus. No published method satisfies all of these criteria. In an attempt to develop a satisfactory method, direct physical measurements using a face bow, ultrasound and portable stereophotogrammetry were investigated. None of these three methods was limited by static apparatus. Portable stereophotogrammetry could not be used because of variations in posing for which a correction could not be applied. Repeated measurements on non-operated subjects showed that the face bow was more accurate than the ultrasound method at a single measurement site. Therefore, the face bow method was developed to give volume measurements in cubic centrimetres by using nine measurement sites at the intersections of a square grid located over the swelling. The mean difference between two readings taken on separate occasions on non-operated subjects was -0.94 cc (s.d. +/- 1.90). The mean swelling measured at twenty third molar operation sites was 23.19 cc. It is concluded that this face bow method satisfies the criteria laid down.

The management of Ludwig's angina.

A severe case of Ludwig's Angina which was treated along the historical lines of surgical decompression is presented. The problem resulting from this approach are discussed together with alternative methods of management. The conclusion is made that surgical decompression as a means of avoiding respiratory obstruction should be abandoned and that tracheotomy should be used.