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Biomedical subjects

P Phillips

Publications and source records attributed to P Phillips.

At least 109 records · Page 6Linked to original sources
PubMed1996

Should we embrace new drugs with open arms? Experience from a community-based, open-arm, randomized clinical trial of combination antiretroviral therapy in advanced HIV disease.

The effect of an open arm in the enrollment to a randomized clinical trial comparing zidovudine (ZDV) plus didanosine (ddI) versus ZDV plus zalcitabine (ddC) was assessed. HIV-infected individuals were eligible to participate in this protocol if they were ddI and ddC naive, had CD4 counts of 50-350/mm3, and were residents of the province of British Columbia. Participating individuals could choose between open-label ZDV/ddI, ZDV/ddC, or randomization to open-label ZDV/ddI or ZDV/ ddC. Study drugs were made available free of charge for all participants through a centralized drug distribution system. There is no other source of these drugs in the province. Primary care physicians were required to renew the patient's prescription every 2 months. Enrollment was initiated in November 1992 and was closed in March 1994 when the randomized arm of the protocol met the predetermined target sample size of 120 evaluable participants. A total of 582 patients received combination therapy in the province through this protocol: 138 (28%) enrolled in the randomized arm and 444 (76%) in the open arm. In the latter group, 320 (72%) were initially prescribed ZDV/ddI and 124 (28%) were prescribed ZDV/ddC. The enrollment rate was strikingly higher in the open arm, with 168 patients enrolled in the first 2 months compared with 138 patients enrolled in the randomized arm over 17 months. Of the 78 study physicians, 69 enrolled patients in the open arm and 23 enrolled patients in the randomized arm of the study. Experienced physicians were more likely to refer patients for randomization (p = 0.025). No statistically significant differences were observed between patients enrolled in either study arm. Our results illustrate the challenge posed to recruitment into clinical trials by the coexistence of an open arm. This is despite the noncoercive, open-label and community-based nature of our randomized protocol and the high priority given to it by a variety of local and national organizations. It is clear that an increased commitment by all interested parties will be required if randomized clinical trials are to be carried out with coexistent open arms.

Adult↗
PubMed1996

Delayed cyclin B1 expression during the G2 arrest following DNA damage.

Exposure of cells to DNA damaging agents results in a G2 arrest. Exposure of HeLa cells to camptothecin, etoposide or nitrogen mustard for 1 h in S phase resulted in delayed expression of cyclin B1 mRNA during the G2 arrest. Initially the levels of cyclin B1 protein were low as well; however, with extended time the cells blocked in G2 regained higher levels of cyclin B1 protein. In the case of cells treated with nitrogen mustard the higher levels coincided with cells exiting the G2 block into G1. However, with camptothecin or etoposide treatment, while the accumulation of cyclin B1 protein was delayed, its levels eventually surpassed peak levels seen in control cells, in spite of the fact that cells were still blocked in G2. These cells did not continue to progress through the cell cycle indicating further complexity to the mechanisms underlying the G2 block. Decreased transcription and stability of cyclin B1 mRNA were shown to occur after treatment with these DNA damaging agents. These results indicate that suppression of cyclin B1 mRNA expression is one consequence of DNA damage in HeLa cells.

Antineoplastic Agents↗
PubMed1996

A comparison of two regimens for the treatment of Mycobacterium avium complex bacteremia in AIDS: rifabutin, ethambutol, and clarithromycin versus rifampin, ethambutol, clofazimine, and ciprofloxacin. Canadian HIV Trials Network Protocol 010 Study Group.

BACKGROUND: Bacteremia with the Mycobacterium avium complex is common in patients with the acquired immunodeficiency syndrome (AIDS), but the most effective treatment for this infection remains unclear. METHODS: We randomly assigned 229 patients with AIDS and M. avium complex bacteremia to receive either rifampin (600 mg daily), ethambutol (approximately 15 mg per kilogram of body weight daily), clofazimine (100 mg daily), and ciprofloxacin (750 mg twice daily) (the four-drug group) or rifabutin (600 mg daily), ethambutol (as above), and clarithromycin (1000 mg twice daily) (the three-drug group). In the three-drug group the dose of rifabutin was reduced by half after 125 patients were randomized, because 24 of 63 patients had uveitis. RESULTS: Among 187 patients who could be evaluated, blood cultures became negative more often in the three-drug group than in the four-drug group (69 percent vs. 29 percent, P<0.001). Among patients treated for at least four weeks, the bacteremia resolved more frequently in the three-drug group (78 percent vs. 40 percent, P<0.001). In the three-drug group, bacteremia resolved more often with the 600-mg dose of rifabutin than with the 300-mg dose (P=0.025), but the latter regimen was more effective than the four-drug regimen (P<0.05). The median survival was 8.6 months in the three-drug group and 5.2 months in the four-drug group (P = 0.001). The median Karnofsky performance score was higher in the three-drug group than in the four-drug group from week 2 to week 16 (P<0.05). Mild uveitis developed in 3 of the 53 patients receiving the 300-mg dose of rifabutin, an incidence about one quarter that observed with the 600-mg dose (P<0.001). CONCLUSIONS: In patients with AIDS and M. avium complex bacteremia, treatment with the three-drug regimen of rifabutin, ethambutol, and clarithromycin leads to resolution of the bacteremia more frequently and more rapidly than treatment with rifampin, ethambutol, clofazimine, and ciprofloxacin, and survival rates are better.

AIDS-Related Opportunistic Infections↗
PubMed1996

Treatment of children with newly diagnosed brain stem gliomas with intravenous recombinant beta-interferon and hyperfractionated radiation therapy: a childrens cancer group phase I/II study.

BACKGROUND: Prognosis for the majority of children with brain stem gliomas is dismal. In previous studies, recombinant beta-interferon (r beta IF) has been shown to be effective for children with recurrent brain stem gliomas and may also act synergistically with radiotherapy (RT). METHODS: Thirty-two children with diffuse intrinsic brain stem gliomas were treated with (r beta IF) and 7200 centigray (cGy) of hyperfractionated RT (100 cGy twice-daily fractions) to determine the toxicity of treatment and the tolerance of the brain stem to this regimen, as well as to assess survival. Patients were treated with r beta IF 3 times per week during RT and then for 8 weeks following RT. Initially, a dose escalation trial was performed. RESULTS: Interferon was initially begun at 12.5 x 10(6) IU/m2 and escalated up to 400 x 10(6) IU/m2. The safe starting dose was determined to be 100 x 10 (6) IU/m2. Due to unacceptable toxicity, the maintenance dose was reduced to 200 x 10 (6) IU/m2. Therapy was relatively well tolerated, although 13 of the patients required dose modifications due to hepatic or hematologic toxicity. Four of the patients had to discontinue treatment due to this toxicity. One patient died while receiving maintenance IF of encephalopathy, seizures, and brain stem dysfunction; believed possibly due to the r beta IF. Thirty of the 32 patients have developed progressive disease. The median time to progression from study entry was five months and the median time to death was 9 months. CONCLUSIONS: We conclude that r beta IF plus hyperfractionated therapy can be tolerated by children with newly diagnosed brain stem gliomas, although there is occasional dose-limiting hepatic, blood, and central nervous system toxicity. This therapy did not result in a higher rate of disease control.

Adolescent↗
PubMed1996

Report on the third EDNAP collaborative STR exercise. European DNA Profiling Group.

This report describes an inter-laboratory exercise completed on behalf of the European DNA Profiling (EDNAP) group. The exercise is one in a series designated to identify STR loci which could be used for harmonisation between participating European forensic science laboratories. Participants were asked to identify the alleles present in five bloodstains at the STR loci HUMTHO1 and HUMVWFA31/A. Two of the stains were prepared from mixtures of two different blood samples. There were no special instructions and each laboratory was requested to use the methodology normally employed for crime case investigations. All participating laboratories achieved the same results for both loci. In addition, the laboratories were also requested to report the results obtained from any other loci which would normally be used in crime case investigations. A comparison of these results showed some inter-laboratory variation.

Alleles↗
PubMed1996

The use of oral ganciclovir in the treatment of cytomegalovirus retinitis in patients with AIDS.

OBJECTIVE: To recommend the appropriate use of oral ganciclovir as an alternative to intravenous (i.v.) maintenance therapy for cytomegalovirus (CMV) retinitis in patients with AIDS. OPTIONS: i.v. infusion of ganciclovir and foscarnet have been the only approved choices for maintenance therapy until the introduction of oral ganciclovir. OUTCOMES: Ease of administering maintenance therapy and improved quality of life for patients with AIDS. VALUES: The medical advisory group comprised physicians treating patients with AIDS therapy. Ease of administration of maintenance therapy and quality of patients' lives were considered important. BENEFITS, HARMS AND COSTS: Oral ganciclovir is a safe and convenient alternative to i.v. maintenance therapy for patients with CMV retinitis. However, its low bio-availability precludes its use for induction therapy and necessitates careful monitoring for compliance. Compared with i.v. administration of ganciclovir, oral maintenance therapy is cost effective. EVIDENCE: Evidence for the guidelines was gathered from data presented at a symposium on CMV retinitis and oral ganciclovir, clinical trials of oral ganciclovir and input from a visiting expert. It was presented at a meeting of the advisory board whose members are involved in the care of patients with AIDS and the management of CMV retinitis. The guidelines were approved by each member of the advisory board. RECOMMENDATIONS: Diagnosis, treatment and follow-up of CMV retinitis should always be in consultation with an ophthalmologist who is experienced in treating this disease. The patient should be fully informed about the limitations of the oral form of ganciclovir; he or she should be involved in decision making and carefully monitored. Oral ganciclovir should not be used for induction therapy or for maintenance therapy in high-risk patients. VALIDATION: Similar guidelines have been produced in England where the drug has been available since January 1995. SPONSOR: The deliberations of the advisory board and the preparation of this report were funded through an educational grant from Hoffmann-La Roche (Canada).

AIDS-Related Opportunistic Infections↗
PubMed1996

Pattern of utilization of rifabutin for prophylaxis of Mycobacterium avium complex among patients with advanced human immunodeficiency virus disease in a community setting.

OBJECTIVE: To characterize the pattern of utilization, effectiveness, and safety profile of rifabutin for Mycobacterium avium complex (MAC) prophylaxis among individuals with advanced human immunodeficiency virus disease in a community setting. METHODS: Individuals who, while registered in the provincial drug distribution program, had at least one CD4 count below 100 cells/mm3 for the period 1 May 1993 to 31 March 1994 were included. MAC diagnoses were identified through a record linkage with the mycobacterial reference laboratory of the Provincial Centre for Disease Control. In order to determine the occurrence of adverse events, a survey was sent in March 1994 to the 98 primary care physicians prescribing rifabutin prophylaxis in the province. We achieved 100% response rate to the survey. RESULTS: During the study period 515 patients in our drug treatment program were eligible to receive MAC prophylaxis. Of these, 340 (66%) were being prescribed rifabutin as recommended by current guidelines. Rifabutin prophylaxis use was significantly associated with use of antiretroviral therapy. The product limit estimate of the cumulative incidence of MAC at 10 months was 13.0% among those receiving rifabutin prophylaxis. Diagnosis of MAC was significantly associated with a lower baseline CD4 count (cumulative incidence 7.1% and 18.1% for CD4 > or = 50 and < 50 cells/mm3, respectively, P = 0.01). A total of four cases of uveitis, eight cases of pseudo-jaundice, and five cases of arthralgia in 16 patients were identified by our survey. CONCLUSION: Our data demonstrates that rifabutin prophylaxis of MAC is being used by approximately 66% of eligible individuals. Rifabutin use was associated with antiretroviral use, which may reflect individuals' attitudes towards medications. Our intention-to-treat analysis, with a 10 month cumulative MAC incidence of 13.0% among those receiving rifabutin prophylaxis, is in keeping with break-through rates previously reported in the context of clinical trials. Our results also support previous observations that the risk of MAC infection greatly increases at CD4 counts < 50 cells/mm3. Rifabutin prophylaxis was generally well-tolerated in our program.

AIDS-Related Opportunistic Infections↗
PubMed1996

Species distribution in human immunodeficiency virus-related mycobacterial infections: implications for selection of initial treatment.

Management of mycobacterial infection is species specific; however, treatment is prompted by positive smears or cultures, often several weeks before species identification. The objective of this study was to determine the species distribution of mycobacterial isolates from various body sites in patients infected with human immunodeficiency virus (HIV). All mycobacterial isolates recovered at St. Paul's Hospital (Vancouver, British Columbia, Canada) from April 1989 to March 1993 were reviewed. Among 357 HIV-positive patients with mycobacterial infections, 64% (96) of the sputum isolates were Mycobacterium avium complex (MAC), 18% were Mycobacterium tuberculosis, and 17% were Mycobacterium kansasii. Lymph node involvement (25 patients) was due to either MAC (72%) or M. tuberculosis (24%). Two hundred ninety-eight episodes of mycobacteremia were due to MAC (98%), M. tuberculosis (1%), and M. kansasii (1%). Similarly, cultures of 84 bone marrow biopsy specimens (99%), 19 intestinal biopsy specimens (100%), and 30 stool specimens (97%) yielded predominantly MAC. These results have implications for initial therapy, particularly in areas where rapid methods for species identification are not readily available. Because of considerable geographic variation, development of guidelines for selection of initial therapy depends on regional determination of species distribution in HIV-related mycobacterial infections.

AIDS-Related Opportunistic Infections↗
PubMed1996

Itraconazole cyclodextrin solution for fluconazole-refractory oropharyngeal candidiasis in AIDS: correlation of clinical response with in vitro susceptibility.

OBJECTIVE: To evaluate the efficacy of itraconazole cyclodextrin solution in fluconazole-refractory oropharyngeal candidiasis (OPC), and to correlate clinical outcome with in vitro susceptibility and serum azole levels. DESIGN: A prospective, open-label, intervention study. SETTING: A university hospital, which serves as the provincial HIV referral center. PATIENTS AND INTERVENTIONS: Thirty six HIV-infected individuals referred for fluconazole-refractory OPC were evaluated prospectively between May 1993 and March 1995, including clinical assessment, serum azole levels, and susceptibility testing of Candida spp, isolates. Itraconazole solution was administered orally at a daily dose of 200 mg for 14 days, followed by suppressive therapy. Thirty-four patients were evaluable. MAIN OUTCOME MEASURE: Resolution of oral pseudomembranous lesions. RESULTS: Initial isolates were Candida albicans (n = 33), C. glabrata (n = 1), C. krusei (n = 1), and mixed infection with C. albicans and C. krusei (n = 1). Fluconazole serum levels obtained at the time of failed therapy ranged from 4.7 to 40 mg/l (median, 12.9 mg/l). Itraconazole was generally well tolerated. Clinical responses were observed in 65% (22 out of 34) of evaluable cases. Among the responders, relapse had occurred within 2 months for four (36%) out of 11 cases who continued with follow-up. The median fluconazole minimal inhibitory concentration (MIC) was 64 mg/l for isolates from fluconazole-refractory cases, compared with a median of 0.5 mg/l for control isolates (P = 0.002). The median itraconazole MIC for isolates from fluconazole-refractory cases was 1.25 mg/l, compared with a median of 0.078 mg/l for controls (P = 0.011). CONCLUSION: A correlation between clinical response and in vitro susceptibility was clearly demonstrated for fluconazole, but not for itraconazole. Itraconazole cyclodextrin solution may be effective for fluconazole-refractory OPC and should be considered prior to salvage therapy with intravenous amphotericin B.

AIDS-Related Opportunistic Infections↗
PubMed1996

AIDS-related extrapulmonary Pneumocystis carinii infection presenting as a solitary rectal ulcer.

Extrapulmonary infection with Pneumocystis carinii, although uncommon, is increasingly recognized. Use of aerosolized pentamidine versus a systemic medication is thought to be a contributing factor due to the low concentrations of drug that are incapable of suppressing systemic infection. Infection with P carinii has been reported in every organ system including the gastrointestinal system. A 28-year-old acquired immunodeficiency syndrome patient receiving prophylaxis with aerosolized pentamidine who presented with a solitary rectal ulcer is reported. Initial biopsy was characteristic of extrapulmonary P carinii infection, with numerous organisms present. Occasional cytomegalovirus inclusion bodies were noted which may have been a copathogen but which were not treated. Treatment with intravenous pentamidine resulted in documented eradication of P carinii and complete resolution of the ulcer. Although lower gastrointestinal pneumocystosis has been described without ulceration, this is the first description of rectal ulceration presenting as the initial manifestation of extrapulmonary pneumocystosis.

AIDS-Related Opportunistic Infections↗
PubMed1996

Transmission of Mycobacterium tuberculosis to recipients of single lung transplants from the same donor.

Recipients of organ transplants are at increased risk for infection both because of immunosuppression and because of the transfer of microbes through the donor organs. We report two cases of M. tuberculosis disease in recipients of single lung transplants who shared a common donor. Both recipients developed pulmonary tuberculosis, one having fever and pulmonary infiltrates and the other having subclinical disease with M. tuberculosis organisms being recovered from bronchoalveolar lavage. Restriction fragment length polymorphism analysis on both isolates of M. tuberculosis revealed a common source. The donor of both lungs had a normal chest radiograph and no known prior history of M. tuberculosis infection of disease. These cases are the first report of two single lung recipients developing pulmonary tuberculosis from a common donor.

Adult↗