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Biomedical subjects

F D Goebel

Publications and source records attributed to F D Goebel.

At least 73 records · Page 4Linked to original sources
PubMed1998

Efficacy of the acyclic nucleoside phosphonates (S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine (FPMPA) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) against feline immunodeficiency virus.

The acyclic nucleoside phosphonates (S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine (FPMPA) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) were evaluated for their efficacy and side effects in a double-blind placebo-controlled trial using naturally occurring feline immunodeficiency virus (FIV)-infected cats. This natural retrovirus animal model is considered highly relevant for the pathogenesis and chemotherapy of HIV in humans. Both PMEA and FPMPA proved effective in ameliorating the clinical symptoms of FIV-infected cats, as measured by several clinical parameters including the incidence and severity of stomatitis, Karnofsky's score, immunologic parameters such as relative and absolute CD4+ lymphocyte counts, and virologic parameters including proviral DNA levels in peripheral blood mononuclear cells (PBMC) of drug-treated animals. In contrast with PMEA, FPMPA showed no hematologic side effects at a dose that was 2.5-fold higher than PMEA.

Adenine↗
PubMed1998

Ganciclovir and foscarnet efficacy in AIDS-related CMV polyradiculopathy.

Cytomegalovirus (CMV) polyradiculopathy is a rare complication of AIDS in which ascending motor weakness, sensory loss and urinary retention are associated with polymorphonuclear pleocytosis and positive CMV polymerase chain reaction in the cerebrospinal fluid (CSF). We describe three patients with this syndrome. One patient's paresis improved after ganciclovir therapy. Another patient deteriorated despite foscarnet treatment, but improved after ganciclovir was added. The third patient died from ascending paralysis despite ganciclovir-foscarnet combination. Reviewing the literature, we conclude that antiviral treatment reduced mortality from 100 to 22%. In patients with ascending paralysis treatment, failure may be caused by viral drug resistance, at least in some patients. Risk factors for treatment failure are preceding monotherapy for other CMV diseases or persistent CSF pleocytosis on serial CSF analysis. We suggest that these patients should therefore be treated with the alternative drug or a ganciclovir-foscarnet combination therapy.

AIDS-Related Opportunistic Infections↗
PubMed1998

Lack of protection from HIV infection by the mutant HIV coreceptor CCR5 in intravenously HIV infected hemophilia patients.

The CCR5 chemokine receptor is an important coreceptor for macrophage-tropic HIV strains. Homozygous carriers of the mutated CCR5 receptor with a 32 bp deletion (delta 32-CCR5) are highly protected against HIV infection. A protective effect has also been described for heterozygous individuals carrying both mutated and wildtype CCR5 receptors. We compared the frequency of the mutated delta 32-CCR5 HIV coreceptor in HIV positive patients infected by sexual contact (N = 160) with intravenously HIV infected hemophilic patients (N = 84) and HIV negative individuals (N = 421). We found no protective effect of delta 32-CCR5 HIV coreceptor in hemophilic patients (p = 0.0134). If proteins of plasma concentrates would be responsible for facilitating the entry of HIV macrophages by upregulation of the CCR5 wildtype receptor it would be of therapeutical interest to identify the responsible plasma proteins.

Female↗
PubMed1998

Cytomegalovirus polyradiculopathy in patients with AIDS.

Using the MEDLINE database, we evaluated 103 cases of AIDS-related cytomegalovirus (CMV) polyradiculopathy (PRP). In 13% of cases, PRP was the initial manifestation of AIDS. Hyporeflexia was present in 100% of cases; lower limb weakness, in 100%; urinary retention, in 94%; paresthesia, in 79%; sensory loss, in 80%; and a Babinski's sign, in 16%. Mean cerebrospinal fluid (CSF) parameters +/- SD were as follows: white blood cell count, 651 +/- 1,053 x 10(6)/L; protein level, 2.28 +/- 1.78 g/L; and CSF/serum glucose ratio, 0.48 +/- 0.17. Gadolinium enhancement of meninges on a magnetic resonance image and abnormalities on a myelogram were noted in 31% and 17% of cases, respectively. Mean survival time +/- SD was 5.4 +/- 1.8 weeks for untreated patients and 14.6 +/- 9.4 weeks for patients treated with ganciclovir (P < .0001), but it was only 7.2 +/- 3.0 weeks for patients receiving ganciclovir treatment at the onset of PRP. CMV-related PRP is an uncommon but distinctive complication of AIDS. Early diagnosis is possible, and other causes can be excluded by lumbar magnetic resonance imaging and by the presence of typical CSF changes, as shown by polymerase chain reaction of CMV. Retrospectively, survival time for naive patients was increased by ganciclovir therapy and may even be underestimated in this evaluation of historical reports.

AIDS-Related Opportunistic Infections↗
PubMed1998

Presence of matrix metalloproteinase-9 activity in the cerebrospinal fluid of human immunodeficiency virus-infected patients.

To determine whether matrix metalloproteinase (MMP)-9 is a potential mediator involved in the frequently detected blood-brain barrier leakage in human immunodeficiency virus (HIV)-infected patients, zymography was used to detect MMP-9 activity in cerebrospinal fluid (CSF) samples of 80 HIV-infected patients and of 10 control patients. CSF MMP-9 activity was detected in 40% of HIV-infected patients (but not in controls) and was significantly more frequent in HIV-infected patients than in those without neurologic deficits (50% vs. 13.6%). The frequency of CSF MMP-9 activity did not significantly differ between neurologically symptomatic HIV-infected patients with or without opportunistic central nervous system disease (51.6% vs. 48.1%). Additionally, the presence of CSF MMP-9 activity in HIV-infected patients was associated with an increased CSF white blood cell count and an elevated CSF-to-serum albumin ratio, suggesting that it may play a role in blood-brain/CSF barrier leakage in HIV-infected patients.

CD4 Lymphocyte Count↗
PubMed1998

Randomized comparative trial of pegylated liposomal doxorubicin versus bleomycin and vincristine in the treatment of AIDS-related Kaposi's sarcoma. International Pegylated Liposomal Doxorubicin Study Group.

PURPOSE: Cytotoxic chemotherapy is frequently required for the more severe manifestations of human immunodeficiency virus (HIV)-related Kaposi's sarcoma. Combinations of bleomycin and vincristine (BV) or BV with the addition of doxorubicin (ABV) are the most commonly used regimens against which new treatments may be compared. We report a multicenter phase III study that compared pegylated liposomal doxorubicin (PLD) to the BV combination. PATIENTS AND METHODS: We conducted a randomized study that compared PLD 20 mg/m2 with a combination of bleomycin 15 IU/m2 and vincristine 2 mg in 241 patients with HIV-related Kaposi's sarcoma. Both regimens were administered by intravenous infusion every 3 weeks for six cycles. RESULTS: A total of 121 patients received PLD and 120 patients the BV combination. The response to PLD was superior to BV: 58.7% versus 23.3% (P < .001). Patients who were randomized to receive BV, however, were more likely to terminate treatment early because of an adverse event (26.7% v 10.7%), and fewer completed the full six cycles of treatment (30.8% v 55.4%). Treatment with BV was associated with a significantly higher incidence of peripheral neuropathy (P < .001), whereas PLD treatment was more commonly associated with neutropenia and delays in receiving treatment (P < or = .001). CONCLUSION: Pegylated liposomal doxorubicin is an effective treatment for HIV-related Kaposi's sarcoma with a higher response rate than the BV combination. It is well tolerated but more myelosuppressive.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Absorption and elimination kinetics of zidovudine in the cerebrospinal fluid in HIV-1-infected patients.

Current knowledge of zidovudine (ZDV) levels in human cerebrospinal fluid (CSF) is limited to single sample determination and extrapolation to time after administration. Longitudinal studies have not been performed. Pharmacokinetic parameters of ZDV in CSF were determined in six HIV-1-infected patients. CSF samples were collected by an intraspinal catheter over a period of 6 hours after a single intravenous (IV) dose of ZDV (2.5 mg/kg). ZDV concentrations were measured by high-performance liquid chromatography (HPLC). ZDV was cleared rapidly from plasma, with a mean terminal elimination half-life (t 1/2) of 75.5 +/- 4.9 minutes. ZDV penetrated slowly into the CSF, reaching maximal concentration (Cmax) 2 hours after the start of the infusion in all patients. ZDV was cleared from the CSF with a mean t 1/2 of 187.6 +/- 69.3 minutes. Mean Cmax in the CSF was 1.3 +/- 1.2 micromol/l (17% of that of plasma), and mean area under the concentration time curve (AUC) was 358 +/- 200 micromol x minutes/l (75% of that of plasma). There was a significant correlation between plasma and CSF for Cmax (r = 0.88, p = .009) and AUC (r = 0.89, p = .014). Calculated trough levels in CSF for a 12-hour dosing interval were 0.090 +/- 0.065 micromol/l and thus about twice the 50% inhibitory concentration (IC50) of susceptible HIV strains. The CSF-plasma ratio of ZDV increased in a nearly linear fashion with time after drug administration. Thus, ZDV has a distinct pharmacokinetic profile in CSF compared with other compartments of the body.

Absorption↗
PubMed1997

Mild rhabdomyolysis after high-dose trimethoprim-sulfamethoxazole in a patient with HIV infection.

Adverse drug reactions to trimethoprim-sulfamethoxazole (TMP/SMX) are common in HIV-positive patients. However, only one case of TMP/SMX-related rhabdomyolysis has been reported, so far. We report a 55-year old-man with asymptomatic rhabdomyolysis after oral high-dose TMP/SMX for suspected PCP. Laboratory changes settled after discontinuation of the drug.

AIDS-Related Opportunistic Infections↗
PubMed1997

Survival of European patients with Kaposi's sarcoma as AIDS-defining condition during the first decade of AIDS. AIDS in Europe Study Group.

OBJECTIVES: To determine whether the survival of patients with Kaposi's sarcoma as first manifestation of AIDS has changed between 1979 and 1989; and to define whether prognosis factors could be identified. PATIENTS AND METHODS: This is a multicentric retrospective cohort study from 52 centers in 17 European countries involving adults AIDS patients diagnosed between 1979 and 1989. Variables such as age, sex, geographical regions, transmission groups, date of Kaposi's sarcoma diagnosis, zidovudine use, CD4+ cell count and concomitant opportunistic infections or AIDS-related malignancies were evaluated by using uni- and multivariable proportional hazard models. Log-rank tests were used to determine which variables were associated with survival. RESULTS: From the 6,546 AIDS patients recruited in the database of the AIDS in Europe Study Group, 1,394 were diagnosed with Kaposi's sarcoma at the time of AIDS diagnosis, from 1979 and 1989. A total of 1,047 Kaposi's sarcoma patients died during the follow-up period. By Kaplan-Meier analyses, the median and mean survival for these Kaposi's sarcoma patients were 17 and 25 months, respectively, with no change over time. However, age, sex (female), geographic region, low CD4+ cell count (< 150 x 10(6)/l) and some opportunistic infections and non-Hodgkin's lymphoma were associated with a poorer prognosis. Zidovudine use, year of diagnosis and risk factor for HIV-1 infection brought no additional information as predictor of mortality. CONCLUSIONS: This study suggests that the survival of patients with Kaposi's sarcoma as first manifestation of AIDS has remained poor during the last decade in contrast with the overall AIDS survival which had significantly improved from a median of 13-18 months during the same period of observation. There is a need for further prospective information to explain the worse prognosis in women and the geographical variations.

AIDS-Related Opportunistic Infections↗
PubMed1997

Kaposi's sarcoma: is the hunt for the culprit over now?

Patients suffering from the acquired immune deficiency syndrome (AIDS) have a 20000-fold increased risk of developing a severe form of Kaposi's sarcoma (KS), a previously rare malignancy involving sharply defined nodular lesions of the skin and/or oral mucosa. Epidemiological evidence has long suggested that an infectious agent is the probable cause of KS. Recently sequences from a putative new herpesvirus have been found to be associated with KS in virtually 100% of the cases analyzed. The suspected etiological agent, a new human herpesvirus termed Kaposi's sarcoma associated herpes virus (human herpes virus 8) has now been propagated in cell culture. This significant advance should form the basis for a detailed analysis of the pathogenetic mechanisms involved in the development of KS.

Adult↗
PubMed1997

Pharmacokinetics of zidovudine after rectal administration in human immunodeficiency virus-infected patients.

We evaluated the pharmacokinetics of rectally administered zidovudine (ZDV) in 10 human immunodeficiency virus-infected adults. After rectal administration of an aqueous ZDV solution (250 mg of ZDV), mean peak ZDV levels were 1.3 +/- 0.7 micromol/liter (mean +/- standard deviation) versus 5.0 +/- 2.2 micromol/liter (P < 0.0001) after oral intake of a 250-mg ZDV capsule. The half-life at beta phase was 87.8 +/- 39.6 min for rectally administered ZDV versus 55.8 +/- 20.1 min (P = 0.035) for orally administered ZDV. The mean area under the concentration-time curve from 0 min to infinity was 232 +/- 181 micromol/liter x min after rectal administration versus 362 +/- 110 micromol/liter x min after oral intake. Although the two routes were not bioequivalent, ZDV was absorbed considerably after rectal administration, with a pharmacokinetic profile resembling that of a sustained-release device.

Administration, Oral↗
PubMed1997

Single dose, dose-escalating trial with fozivudine tidoxil (BM 21.1290).

BACKGROUND AND OBJECTIVES: In vitro and in vivo experimental data for fozivudine tidoxil [BM21.1290 (FZD) an ether-lipid conjugate of zidovudine] have shown better efficacy, no myelotoxicity and better tolerability compared with zidovudine. Therefore, the objectives of our study were to evaluate the safety of FZD in patients with human immunodeficiency virus (HIV) infection and to establish basic pharmacokinetic data. PATIENTS AND METHODS: In a Phase I dose-escalating trial, seven different single dose applications were studied in 39 patients: 50, 100, 300, 600, 900, 1200 and 1800 mg in capsule and tablet formulations. Inclusion criteria were HIV infection, CD4 count > 100 cells/mm3 and informed consent. Exclusion criteria were active opportunistic manifestations, concomitant zidovudine therapy and neutropenia (< 750 neutrophils/mm3). Safety parameters, 24 h plasma levels and urinary excretion were determined. RESULTS: The tolerance of FZD was excellent up to single doses of 1800 mg. In only one case, a single episode of loose stool was reproducible in a second treatment period and was therefore considered to be a probable drug-related event. In an amendment to the trial, a tablet formulation of FZD did not induce diarrhoea in this patient. FZD was available in measurable concentrations after 2 to 4 h. Maximum concentrations were reached after 4 to 8 h. After normalization for a dose of 100 mg/patient, the mean AUC was 8.6 mg x h/l and the mean Cmax was 1.13 mg/l; t1/2 was 3.78 h. Interestingly, plasma concentrations of zidovudine and zidovudine glucuronide were much lower than with equimolar zidovudine doses. CONCLUSIONS: The zidovudine conjugate FZD is safe and well tolerated at the seven doses tested. Phase II trials are warranted.

Adult↗
PubMed1997

Phase I/II trial with fozivudine tidoxil (BM 21.1290): a 7 day randomized, placebo-controlled dose-escalating trial.

BACKGROUND AND OBJECTIVES: A Phase I dose-escalating trial with single doses of fozivudine tidoxil (BM21.1290; FZD), in vitro, and experimental in vivo data indicated that further investigations with this compound were warranted. Advantages of fozivudine tidoxil are the direct delivery of zidovudine monophosphate intracellularly and high concentrations in lymphatic tissues. Our objectives were to evaluate safety, tolerability and efficacy of fozivudine tidoxil in human immunodeficiency virus (HIV)-infected patients. PATIENTS AND METHODS: In a Phase I/II dose-escalating trial, three doses of fozivudine tidoxil (400, 800 or 1200 mg/day) were administered for 1 week. The study was randomized and placebo controlled. Inclusion criteria were HIV infection, CD4 count > 100 cells/mm3 and informed consent. The exclusion criteria were active opportunistic infection and prior antiretroviral treatment. RESULTS: The tolerability of fozivudine tidoxil was excellent in all dose groups. No treatment discontinuations were necessary. Steady-state pharmacokinetics did show slightly higher concentrations as compared with levels after the first dose (20%). Viral load reduction was most pronounced in the 1200 mg/day dose group (-0.64 log). No viral load reduction was seen in the placebo group. CONCLUSIONS: The zidovudine conjugate fozivudine tidoxil is safe and well tolerated at the three doses tested. Based on the differences in molecular weights, the 1200 mg dose is roughly equivalent to 400 mg zidovudine.

Adult↗
PubMed1997

Gastrointestinal lymphomas in patients with AIDS.

Non-Hodgkin-lymphoma (NHL)-most frequently high grade B-cell lymphoma-occurs in 5-10% of individuals with HIV-infection. The gastrointestinal tract (GIT) is the most frequent extranodal site of the disease. The optimal therapy for HIV-related lymphoma remains a matter of controversy. In a retrospective analysis we found gastrointestinal lymphoma in ten of 306 HIV-infected patients (3.3%) with a median CD4-count of 92/microliter at time of diagnosis. Median survival for the chemotherapy treatment group was 15 months. The high incidence of gastrointestinal NHL prompted us to commence a prospective survey on diagnostic procedures, therapy and outcome of patients with HIV-infection and gastrointestinal symptoms. 93 of 341 HIV-infected patients with gastrointestinal symptoms were examined by endoscopy. In selected patients we used in addition endoscopic ultrasound (EUS) for visualization and staging before and after chemotherapy. NHL of the GIT was detected in seven of 93 endoscopically examined patients (7.5%). All patients were treated with CHOP initially. Mean survival time was ten months, mean CD4-count at diagnosis 193/microliter (range 0-417). Our results indicate that the diagnosis of gastrointestinal lymphoma should be considered in any HIV-infected patient presenting with unexplained gastrointestinal symptoms. In this group of patients NHL was detected in 7.5% of cases. The use of EUS improves the staging procedure before therapy. Treatment with CHOP resulted in relatively high remission rates and was associated with a low rate of treatment-induced myelosuppression.

Adult↗
PubMed1996

Epidemiology of AIDS dementia complex in Europe. AIDS in Europe Study Group.

The aim of the study was to describe the epidemiology of AIDS dementia complex (ADC) in Europe and to assess the possible role of zidovudine therapy in preventing or delaying its occurrence. We used an inception cohort, with data collected retrospectively from patients' clinical records from 52 clinical centers in 17 countries across Europe. The subjects were 6,548 adult people with AIDS consecutively diagnosed from 1979 to 1989. The main outcome measures were codiagnosis of ADC at the time of AIDS diagnosis and ADC-free time after AIDS diagnosis. ADC was reported in 295 patients (4.5%) at the time of AIDS diagnosis and during follow-up in a further 402 of the 5,160 patients (7.8%) who were diagnosed with AIDS based on diseases other than ADC. Whether at the time of AIDS diagnosis or later, the occurrence of ADC was significantly associated with age, transmission category, and CD4+ cell counts. The risk was greater in older patients (14 and 19% greater, at AIDS diagnosis and after, respectively, for a 5-year difference in age), in i.v. drug users than in homosexual and bisexual men (89 and 60% greater, at AIDS diagnosis and after, respectively), and for people with lower CD4+ cell counts (14 and 30% greater for a reduction of 1 on the natural log scale). Risk was almost double for women than for men. A significant reduction, of approximately 40%, was found in the risk of developing ADC after AIDS diagnosis for patients receiving zidovudine therapy, but this effect was present only during the first 18 months of treatment, irrespective of whether treatment began before or after AIDS diagnosis. In conclusion, an increase in the risk of developing ADC either at the time of AIDS diagnosis or thereafter is associated with increasing age, i.v. drug use, and decreased CD4+ cell count. Women tend to have a higher risk of ADC at the time of AIDS diagnosis. Zidovudine therapy appears to have a definite, but time-limited, effect of protecting patients against ADC development after AIDS diagnosis.

AIDS Dementia Complex↗