Famciclovir treatment of hepatitis B virus recurrence after liver transplantation: a pilot study.

Famciclovir treatment of hepatitis B virus recurrence after liver transplantation: a pilot study. Despite hepatitis B immunoprophylaxis hepatitis B virus (HBV) recurrence is a frequent and often fatal complication after orthotopic liver transplantation (OLT). The purine nucleoside analogues penciclovir and its oral form famciclovir (FCV) proved to be well tolerated and effective against herpes simplex and zoster virus infections. In addition, an effective reduction of duck and human HBV replication was observed. Therefore, we conducted an uncontrolled pilot study of famciclovir in patients with HBV recurrence after OLT. Twelve patients have received famciclovir for at least 3 months in an open compassionate-use protocol. FCV was administered orally 500 mg three times a day for all patients (except one patient who was started on 750 mg three times a day for the first 2 weeks). Immediately after starting famciclovir, serum HBV DNA levels declined in 9 of 12 patients (75%) with a mean reduction from baseline levels of 80% after 3 months, 90% after 6 months, and > 95% after 12 months of treatment. With continued treatment, 5 of these 9 patients became negative by conventional hybridization assay, and in one of these HBV DNA became undetectable by polymerase chain reaction (PCR) 28 weeks after the start of treatment. Three patients showed no (sustained) reduction in HBV DNA after at least 3 months of treatment; therefore, FCV was stopped. Latest serum alanine aminotransferase (ALT) levels decreased in 6 of 12 patients (50%) with a median decrease of 80% (range, 40%-95%) in comparison to pretreatment ALT values. ALT levels normalized in 4 patients (33%). One patient died due to sepsis and peritonitis in week 13 of treatment. This event was not related to FCV. No clinically significant side effects were noticed in any patient. The oral nucleoside analog famciclovir reduces HBV replication and transaminase levels in patients with HBV recurrence after liver transplantation. Because long-term FCV treatment is well tolerated, famciclovir appears to be a promising antiviral strategy in the treatment of HBV in immunocompromised patients. Journal ISSN: 1074-3022 Issue: 2-4 (1996) Pages: 253-62

An independent assessment of MEDWatch reporting for abuse/dependence and withdrawal from Ultram (tramadol hydrochloride).
An independent assessment of MEDWatch reporting for abuse/dependence and withdrawal from Ultram (tramadol hydrochloride). OBJECTIVE: Assess the validity of medical products reporting program (MEDWatch) reports of abuse/dependence and withdrawal associated with Ultram (tramadol). METHODS: Reports of possible abuse/dependence or withdrawal associated with Ultram during 13 quarters following launch were spontaneously reported to the manufacturer Ortho-McNeil Pharmaceutical (OMP) and also solicited from 255 NIDA grantees and addiction treatment professionals by an Independent Steering Committee (ISC). Reports were classified by the ISC using DSM-IV criteria, by the Drug Safety and Surveillance (DSS) units of Robert Wood Johnson Pharmaceutical Research Institute (PRI) using World Health Organization Adverse Reaction Terms (WHOART) terms, and reported to the food and drug administration (FDA) via MEDWatch. Rates of abuse/dependence and withdrawal per 100000 persons exposed were calculated separately for classifications made by the PRI and the ISC, and confidence intervals calculated to determine the degree to which they agreed. RESULTS: For 681 reports submitted to PRI, confidence intervals of ISC ratings contained PRI ratings 12 of 13 times for abuse/dependence, and 12 of 13 times for withdrawal. For 242 reports submitted to the ISC, confidence intervals of ISC ratings contained PRI ratings 10 of 13 times for abuse/dependence, and 12 of 13 times for withdrawal. Proactive surveillance increased the total number of cases of abuse/dependence but not withdrawal. Many cases of withdrawal without signs or symptoms of abuse/dependence were identified. CONCLUSIONS: There was good/excellent concordance between MEDWatch and ISC classifications. Proactive surveillance increased cases of abuse/dependence but not withdrawal. Withdrawal with no signs or symptoms of dependence was common. More use of proactive surveillance is likely to improve assessments of public health risks associated with adverse events. Journal ISSN: 0376-8716 Issue: 72-2 (2003) Pages: 163-8

The role of tramadol in cancer pain treatment--a review.
The role of tramadol in cancer pain treatment--a review. In most cancer patients pain can be successfully treated with pharmacological measures using opioid analgesics alone or in combination with adjuvant analgesics (coanalgesics). Weak opioids are usually recommended in the treatment of moderate cancer pain. There is still a debate as to whether the second step of the WHO analgesic ladder comprising opioid analgesics such as tramadol, codeine, dihydrocodeine, and dextropropoxyphene is still needed for the treatment of cancer pain. On the basis of our experience and review of the literature we think that there is definitely a place for weak opioids in the treatment of moderate cancer pain. One of the most interesting and useful weak opioids is tramadol (Adolonta, Contramal, Nobligan, Top-Algic, Tramal, Tramal Long, Tramal Retard, Tramundin, Trodon, Ultram, Zydol). Its unique mechanism of action, analgesic efficacy and profile of adverse reactions have been the reason of performing many experimental and clinical studies with tramadol. In this article we summarize data on pharmacology, mechanisms of action, pharmacokinetics, side effects and clinical experience assessing analgesic efficacy, adverse reactions and safety of tramadol in cancer pain. Journal ISSN: 0941-4355 Issue: 13-1 (2005) Pages: 5-17

Retransplantation for precore mutant-related chronic hepatitis B infection: prolonged survival in a patient receiving sequential ganciclovir/famciclovir therapy.
Retransplantation for precore mutant-related chronic hepatitis B infection: prolonged survival in a patient receiving sequential ganciclovir/famciclovir therapy. Retransplantation for hepatitis B-related liver allograft failure is rarely successful. Recurrence of infection is almost universal, and the second allograft is invariably lost more rapidly than the first. In a recent multicenter study, only 1 of 20 hepatitis B virus (HBV)-positive patients who underwent liver retransplantation survived beyond 6 months. This report describes the long-term effect of antiviral therapy in a 56-year-old man who was retransplanted for HBV-related allograft loss 14 months after his initial liver transplant. He was treated after the second transplant with intravenous daily ganciclovir. After 10 months of this therapy HBV recurrence was detected. After a change to oral famciclovir therapy, there was a decrease in serum HBV DNA and amino-transferase levels and an improvement in the patient's clinical condition. Famiciclovir therapy has now been continued for 26 months, and the patient remains well 3 years after his second transplant, despite persistent HBV infection and progression to cirrhosis. These observations indicate that the use of long-term antiviral therapy offers promise for improving outcomes in patients who undergo retransplantation after HBV-related liver allograft failure. Journal ISSN: 1074-3022 Issue: 2-6 (1996) Pages: 472-4

NSAID alternatives.
NSAID alternatives. Patients taking celecoxib (Celebrex) because they cannot tolerate the GI effects of nonspecific NSAIDs could continue to do so, but should not exceed recommended dosage. For analgesia and osteoarthritis, acetaminophen (Tylenol, and others) or tramadol (Ultram, and others) are reasonable alternatives to NSAIDS. For rheumatoid arthritis, disease-modifying drugs (DMARDs) can be used. Journal ISSN: 0025-732X Issue: 47-1200 (2005) Pages: 8

Therapy for genital herpes in immunocompromised patients: a national survey. The Herpes Simplex Advisory Panel.
Therapy for genital herpes in immunocompromised patients: a national survey. The Herpes Simplex Advisory Panel. OBJECTIVES: To estimate the extent of aciclovir refractory herpes simplex virus (HSV) infection in HIV coinfected patients in the United Kingdom and survey clinicians on their approaches to its management. DESIGN: Questionnaire survey of representative sample of one third of United Kingdom HIV physicians. MAIN OUTCOME MEASURES: Use of antiviral therapies for genital HSV infections in HIV positive patients, reported frequency of aciclovir refractory HSV infection, its therapy, and access to antiviral susceptibility testing facilities. RESULTS: 53 responses were obtained (response rate 61%), representing a sample size of 23% of United Kingdom HIV physicians. Use of non-standard antiviral regimens for HSV infections in HIV coinfected patients was widely practised, irrespective of the clinical characteristics of the HSV infection. Aciclovir refractory HSV infection has been observed by 37 (70%) respondents. Although foscarnet was the most frequently used therapy, used by 27/37 (73%) respondents, in only seven of these 27 (19%) was it a first line treatment for aciclovir refractory cases, frequently being used at a late stage in the clinical course. Antiviral susceptibility testing facilities were available to 46 (87%) clinicians. No respondents reported any evidence of transmission of aciclovir resistant strains. CONCLUSIONS: HIV coinfection has a stronger influence on therapeutic choice than clinical immunosuppression or severity of herpetic infection. Aciclovir treatment failure is commoner than hitherto recognised. There is a need for wider awareness of use of foscarnet at an earlier stage in management of refractory HSV infection. Journal ISSN: 0266-4348 Issue: 73-5 (1997) Pages: 391-3

Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective.
Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective. Hepatitis B virus (HBV) variant strains may develop during therapy for chronic infection with the nucleoside analog 2',3'-dideoxy-3'-thiacytidine (3TC). HBV mutants result from isoleucine (I) or valine (V) substitutions in the methionine (M) of the YMDD motif in the viral reverse-transcriptase catalytic domain. In addition, other mutations in the reverse-transcriptase "B domain" involving either a phenylalanine (F)-to-leucine (L) at amino acid 501 (F501L) or an L-to-M substitution at amino acid 515 (L515M) have been observed during 3TC and Famciclovir therapy as well. To determine the biologic consequences of these mutations on viral replication, variant viral genomes were constructed and transiently transfected into hepatocellular carcinoma (HCC) and HEK 293 human embryo kidney-derived cell lines. In transiently transfected HCC cells, the viruses bearing the YI/VDD or F501L mutations had greatly impaired replication as compared to wild-type virus, whereas the virus carrying the L515M substitution showed the least defect. Double mutants with the L515M substitution showed intermediate defect between the YI/VDD or F501L and the L515M single-mutant strains. In contrast, when transfected into HEK 293 cells, the viruses bearing the YI/VDD or L515M mutation replicated as wild-type. However, under conditions of deoxynucleotide depletion produced by hydroxyurea treatment of HEK 293 cells, all mutants but not the wild-type virus exhibited a reduced replication phenotype similar to that observed in HCC cells. In both HCC and HEK 293 cells, the mutant viruses carrying the F501L substitution showed a decreased pregenomic RNA encapsidation level, suggesting that the defect in HBV DNA synthesis occurs at the RNA packaging level. These findings show that 3TC and Famciclovir selected mutations alter the properties of the HBV reverse transcriptase, resulting in impaired viral replication within the cell. Journal ISSN: 0270-9139 Issue: 27-2 (1998) Pages: 628-33

Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons. A double-blind, placebo-controlled trial.
Famciclovir for the suppression of symptomatic and asymptomatic herpes simplex virus reactivation in HIV-infected persons. A double-blind, placebo-controlled trial. BACKGROUND: Herpes simplex virus (HSV) infection is one of the most common opportunistic infections in HIV-infected persons. However, most documentation of the effectiveness of antiviral therapy in reducing HSV reactivation is anecdotal. OBJECTIVE: To evaluate the quantitative effect of antiviral therapy on the frequency of HSV reactivation in HIV-infected persons. DESIGN: Double-blind, placebo-controlled, crossover trial. SETTING: Research clinic at a university hospital. PATIENTS: 48 persons (45 men and 3 women) who were HIV positive and HSV seropositive. INTERVENTION: Patients were randomly assigned to receive famciclovir, 500 mg orally twice daily, or placebo for 8 weeks. They then crossed over to receive the other regimen after a 1-week washout period. MEASUREMENTS: Patients obtained daily cultures of their perirectal, urethral, oral, and genital areas and kept dairy records of signs and symptoms of genital and oral-labial herpes. RESULTS: The median CD4 cell count at study entry was 384 cells/mm3. In the intention-to-treat analysis of the first study period, HSV was isolated on 122 of 1114 (11%) placebo days compared with 9 of 1071 (1%) famciclovir days (relative risk, 0.15; P < 0.001). For patients who completed the crossover, the median difference in days with symptoms between placebo and famciclovir was 13.8% of days and the median difference in days on which HSV was isolated was 5.4% of days (P < 0.001 for both). Percentage of days with HSV-2 shedding was reduced from 9.7% to 1.3%. Breakthrough reactivations that occurred while patients were receiving famciclovir were infrequent, short, and often asymptomatic, HSV-2 isolates from these reactivations were susceptible to penciclovir in vitro. CONCLUSIONS: Antiviral chemotherapy with famciclovir results in clinically and statistically significant reductions in the symptoms associated with HSV infection and the symptomatic and asymptomatic shedding of HSV among HIV-positive persons. Journal ISSN: 0003-4819 Issue: 128-1 (1998) Pages: 21-8

Tramadol (Ultram) concentrations in death investigation and impaired driving cases and their significance.
Tramadol (Ultram) concentrations in death investigation and impaired driving cases and their significance. We reviewed a series of 66 deaths in Washington State between 1995-2000 in which tramadol (Ultram and Ultracet, Ortho-McNeil) was detected in the decedent's blood, in order to assess the role tramadol was determined to have played. Additionally, we reviewed a series of 83 impaired driving cases in which tramadol was detected in order to establish a non-lethal blood tramadol concentration reference range. In both populations, tramadol was consistently found together with other analgesic, muscle relaxant, and CNS depressant drugs. Death was rarely attributable to tramadol alone. However, tramadol may be a significant contributor to lethal intoxication when taken in excess with other drugs, via the potential interaction with serotonergic antidepressant medications, as well as the potential for increased CNS depression. Although the incidence of tramadol detection has increased consistently over the last eight years, there is no evidence of a corresponding increase in the number of cases in which death was attributed solely to tramadol. Blood drug concentrations in many deaths exceeded the therapeutic serum range of 0.28-0.61 mg/L; however, the concentrations overlapped almost completely with the range identified in living subjects arrested for impaired driving. These findings suggest caution in the interpretation of blood tramadol concentrations outside of the recognized therapeutic range. It also suggests that the drug, even when used in moderate excess, is not a principle cause of death in suicidal or accidental deaths. Journal ISSN: 0022-1198 Issue: 49-5 (2004) Pages: 1101-5