Studies on the effect of short-term oral dihydroergotamine and troxerutin in patients with varicose veins

OBJECTIVE: To evaluate the clinical efficacy and pharmacologic effects of dihydroergotamine and troxerutin on varicose veins. METHODS: A double-blind, randomized, placebo-controlled parallel-group study was conducted in 53 patients with primary varicose veins. Patients received either a fixed combination of 3 mg dihydroergotamine and 300 mg troxerutin three times a day or placebo for 3 weeks. Symptomatic improvement was assessed by a self-assessment score, venocontracting effects on a varicose vein were quantified by the venous compliance technique (VCT), and changes in venous dysfunction were measured by digital photoplethysmography (DPPG). RESULTS: A significant reduction (p < 0.01) of subjective symptoms was observed in both groups. Results from VCT and DPPG after the therapy with dihydroergotamine and troxerutin or placebo were not significantly different (p > 0.05) from pretreatment values. Furthermore, no significant intergroup difference was observed when the before- and after-therapy differences of values of the self-assessment scores (VCT and DPPG) were compared. CONCLUSION: In our study, 3 weeks of treatment with a fixed drug combination of 3 mg dihydroergotamine plus 300 mg troxerutin three times a day had no measurable effect compared with placebo on any of the evaluated end points.     

Interstitial methotrexate kinetics in primary breast cancer lesions

The transfer of cytotoxic agents across the tumor endothelium into the interstitial tumor space is considered a critical step in clinical resistance of solid tumors to antineoplastic chemotherapy. However, experimental data on drug transfer from the blood into the interstitium of solid tumors are scarce. Therefore, in this study, we used an innovative technique, in vivo microdialysis, for measuring interstitial tumor pharmacokinetics and plasma-to-tumor transfer rates of methotrexate (MTX) in breast cancer patients. Microdialysis probes were inserted into the primary tumor and the periumbilical s.c. adipose layer of nine previously chemotherapy-naive breast cancer patients to monitor interstitial concentrations following i.v. administration of MTX (40 mg/m2) during a three-drug treatment regimen. Mean interstitial MTX load in breast tumors, expressed as area under curve (AUC), was 60 +/- 20% (mean +/- SE; coefficient of variation = 100%) of mean plasma MTX load. There was no correlation between plasma AUC and the AUC in the interstitial space of tumor tissue (P = 0.93). Not one of the parameters plasma, interstitial tumor load, and transfer rate of MTX to the interstitial space was associated with favorable clinical response. In conclusion, plasma levels of MTX are not predictive of intratumor levels. There is a high interindividual variability in transendothelial MTX transfer. Under the present conditions, access of MTX to the interstitial space is not a rate-limiting step for clinical response to chemotherapy.     

Acute skin GVHD following syngeneic BMT for CLL

A 41-year-old woman received a syngeneic BMT for CLL and subsequently developed acute skin GVHD. Transfusion-related allogeneic GVHD was excluded on the basis of an unchanged HLA type in circulating lymphocytes. Short tandem repeat PCR was used to confirm syngeneicity between donor and recipient. The patient had a personal and family history of autoimmune disease which may have made her particularly susceptible to development of syngeneic GVHD. The distinction between allogeneic and syngeneic or autologous GVHD is important because of therapeutic implications.     

The sequential occurrence of viral mutations in a liver transplant recipient re-infected with hepatitis B: hepatitis B immune globulin escape, famciclovir non-response, followed by lamivudine resistance resulting in graft loss

BACKGROUND/AIMS: The purpose of this study was to characterize the clinical, histological and virological events in an orthotopic liver transplant (OLT) recipient with recurrent hepatitis B infection who was initially managed with hepatitis B immune globulin (HBIg) and when viral recurrence occurred, with nucleoside analogue salvage therapy. The aims were to document the mutations occurring in the hepatitis B virus (HBV) polymerase gene as a consequence of HBIg escape, famciclovir non-response and subsequent lamivudine resistance. METHODS: Throughout the follow-up of 796 days, the patient was seen at least at 4-week intervals. Clinical, biochemical and virological data were registered according to protocol. HBV DNA was quantified throughout the treatment period. The viral polymerase gene was sequenced from serum samples collected at representative time intervals. Consecutive liver biopsies were scored according to the modified Knodell classification. RESULTS: Clinically, the patient was in excellent condition until the development of acute hepatitis during the lamivudine therapy period, 765 days post-OLT. Until this terminal event, serum transaminase activity was only 1-2 times the upper limit of normal with serum bilirubin and prothrombin time within the normal range. Subsequent liver biopsies showed chronic active hepatitis with no signs of fibrosis. The post-mortem biopsy showed severe acute hepatitis B with massive necrosis. The HBV polymerase gene was sequenced during HBIg, famciclovir and lamivudine treatment. One mutation I533L was detected during HBIg treatment. No amino acid changes were selected during famciclovir treatment. Three amino acid changes were selected while the patient was on lamivudine treatment, which include L533I, S559T and M550I. CONCLUSIONS: We have documented HBV recurrence in a liver transplant recipient with the emergence of a multidrug resistant HBV which caused graft loss. The primary resistance to famciclovir in spite of therapeutic penciclovir levels may be as a result of a combination of the mutations found in the polymerase region. After 300 days of lamivudine treatment, a drug-resistant population emerged which was associated with a greater than three log increase in HBV DNA and contributed to loss of graft function. This is the first report of such an adverse clinical outcome due to the emergence of a mutant virus as a consequence of immunoprophylactic and antiviral therapy in a liver transplant recipient.     

The usefulness of cerebrospinal fluid tests for neurosyphilis

To determine the usefulness of cerebrospinal fluid (CSF) tests for syphilis at a large academic hospital, clinical and laboratory data on 644 patients in whom such testing was requested over a 12-month period were analysed. In 198 cases (31%) the Treponema pallidum haemagglutination (TPHA) screening test could not be performed because of insufficient fluid. Thirty-eight of the remaining patients were diagnosed as having active neurosyphilis. Examination of 22 files of patients who had a positive TPHA and fluorescent treponemal antibody absorption (FTA-Abs) test together with a negative CSF Venereal Disease Research Laboratory (VDRL) test revealed that other CSF measures indicating disease activity (CSF protein, cells or IgG index) were not utilised optimally. In 10 (45%) of these patients neurosyphilis was not diagnosed despite either abnormal or incomplete CSF biochemical analysis, indicating that if the CSF VDRL is used as the sole marker for disease activity, some cases of neurosyphilis are likely to be missed.     

Load distribution in osseointegrated implant supporting extended and non extended dentures

There is a controversy among prosthodontists concerning the most favourable superstructure design of a prosthesis supported by implants. Some investigators used the fully extended denture, others used a non extended. This study evaluated the load distribution pattern occurring in implants with the two designs. A real clinical situation which includes 4 osseointegrated implants that are connected to each other with a superstructure bar and support an acrylic dentures was transferred into a 3-D geometric model. With the 3-D FEM it was possible to compare between the two types of acrylic dentures.     

Intrauterine cortisol, aldosterone, and corticosteroid binding globulin-like activity during early porcine pregnancy and the estrous cycle

Studies were conducted to determine whether the corticosteroids cortisol and aldosterone, and corticosteroid-binding globulin (CBG) were present in the porcine early-embryonic environment. Cortisol was measured in uterine flushings from white crossbred gilts at Days 7, 10, 13, and 16 of the estrous cycle and pregnancy. Total content of cortisol increased (p < 0.01) between Days 13 and 16, and immunoreactive CBG (ir-CBG) increased (p < 0.01) between Days 10 and 13, in both cyclic and pregnant gilts. In a separate study with Chinese Meishan gilts, total cortisol and aldosterone content of uterine flushings increased (p < 0.02) between Days 10 and 15 of the estrous cycle and pregnancy. In another study with white crossbred gilts, CBG-like binding activity in uterine flushings was low at Day 10, then increased over 100-fold at Day 15 (p < 0.01). However, levels of CBG-like binding activity on Day 15 were 100-fold lower than those of ir-CBG measured in the previous study and could bind less than 4% of the uterine luminal cortisol. Differences between ir-CBG and CBG binding might be due to the ability of the CBG antibody to recognize either biologically inactive CBG or structurally similar molecules. CBG-like binding activity, which appeared unrelated to glucocorticoid receptors, was also present in the endometrial cytosol of white crossbred gilts. Concentrations (fmol/mg protein) of endometrial CBG-like activity decreased (p = 0.03) between Days 10 and 15 of the estrous cycle and pregnancy, did not differ with reproductive status, and on Day 15 were comparable to concentrations in uterine flushings but threefold lower (p < 0.01) than those in the serum. Equilibrium dissociation constants for CBG-like binding activities were comparable among the three locations. These studies indicate that corticosteroids are present-primarily in the free form-within the porcine uterine lumen and could influence early porcine conceptus development. Endometrial CBG-like binding activity could mediate actions of cortisol or progesterone on uterine function.     

In vitro and in vivo effect of glucocorticoids on IgE and IgG subclass secretion

Hydrocortisone (HC) as well as its synthetic derivatives have been shown to strongly enhance interleukin-4 (IL-4)-induced in vitro IgE synthesis. To investigate possible effects on IgG subclasses, peripheral blood mononuclear cells (PBMC) were incubated with different glucocorticosteroids in the absence or presence of IL-4. The glucocorticoids alone led to a strongly enhanced secretion of IgG1, IgG2 and IgG3, but not IgG4. The addition of IL-4 induced marked increases in IgG1 and IgG4, no changes in IgG3, but a consistent decrease in IgG2 synthesis. In order to find out whether these profound in vitro effects of corticosteroids are also reflected by changes in antibody serum levels during steroid treatment, 10 healthy volunteers took 25 mg prednisone for 7 consecutive days. We could not observe any significant changes of IgE or IgG subclass serum levels during or after this period. However, cell cultures performed after the glucocorticoid treatment revealed a marked decrease in the ability to produce IgG4 and a significantly lower potential to produce IgE in response to IL-4 alone or IL-4 and HC. We conclude that, although strongly implicated by the in vitro results, glucocorticosteroid treatment does not result in an increased allergy risk.