Influence of foscarnet on HIV-associated Kaposi's sarcoma derived cell lines.

Recent reports showed a positive therapeutic effect of foscarnet on Kaposi's sarcoma (KS) in HIV-positive patients. We investigated the therapeutic effect of foscarnet on KS-derived cell lines. Three KS spindle cell cultures of HIV-positive patients as well three fibroblast cell cultures of HIV-positive as HIV-negative patients were established. The influence of different foscarnet concentrations (50, 100, 200, 400, 600, 1000 microg/ml) on these cell lines were analysed. There was no significant change in fibroblast cell numbers suggesting that there is neither a proliferative nor an antiproliferative effect of foscarnet on these cell lines. Furthermore, incubation of the three KS-derived cell lines of HIV-positive patients with different foscarnet concentrations did not change KS-cell number significantly.

Cytokine profile of HIV-positive Kaposi's sarcoma derived cells in vitro.

Kaposi's sarcoma (KS) is the most frequent neoplastic complication observed in HIV-infected patients. Cutaneous KS is the most common manifestation but visceral and lymph node involvement may occur. HIV-infection does not only lead to a decrease of certain cell types (CD4 T-lymphocytes), but also modifies the function of non-infected cells such as B-lymphocytes and NK-cells by upregulating cytokine release of IL-1, IL-6, GM-CSF, IFN-gamma and TNF-alpha. These multifunctional mediators show both autocrine and paracrine proliferative effects on normal endothelial cells and AIDS-related KS-cells. Using ELISA-, RIA- and IRMA-techniques we analysed the influence of seven cytokines (IL-1beta, IL-6, TNF-alpha, GM-CSF, IFN-alpha, IFN-beta, IFN-gamma) and the soluble IL-2 receptor (sIL-2R) on the growth of eight different KS-derived cell lines compared with eight fibroblast cell lines, established from skin biopsies of HIV-positive individuals. Furthermore, we analysed the dose-dependent effect of the above mentioned cytokines on KS-derived cells in vitro. The KS-derived cell culture medium demonstrated significantly higher concentrations than the fibroblast cell lines in view of the following cytokines: sIL-2R, IL-1beta, IL-6, TNF-alpha, GM-CSF, IFN-gamma (p<0.05). The most pronounced differences between KS-cells and fibroblasts were observed for IL-1beta and IFN-gamma. The antiproliferative effect of IFN-beta and IFN-gamma began at a concentration of 20 and 50 IU/ml, respectively, whereas for IFN-alpha an antiproliferative effect was observed at a concentration of 100 U/ml. Furthermore we observed a proliferative effect in low concentrations (2-5 IU/ml) of IFN-gamma in our in vitro model

Effects of antipsoriatic therapies on hepatic microsomal enzyme activity in patients with psoriasis.

OBJECTIVE: The influence of several antipsoriatic therapies on microsomal enzyme activity was assessed by comparing measurements of antipyrine kinetics prior to and two weeks after initiation of therapy. METHODS: Serum and urine analysis was carried out by means of high performance liquid chromatography (HPLC). Each form of therapy was examined separately. 10 patients were treated with etretinate. The groups treated with 8-methoxypsoralene (8-MOP) in combination with UVA irradiation (PUVA), etretinate in combination with PUVA (RePUVA), anthralin, or combined UVA and UVB irradiation (SUP) consisted of 7 patients each. RESULTS: Neither anthralin nor SUP therapy led to any significant changes in antipyrine kinetics. Antipyrine clearance under the other regimens was, however, reduced. It was 23% lower in PUVA-treated patients, 20% lower in those receiving retinoids and 28% lower in those under RePUVA (p<0.05 - 0. 01). CONCLUSIONS: PUVA, etretinate and RePUVA inhibit microsomal enzyme activity in the liver. Possible drug interactions with other P subset450 inducing or inhibiting agents should be considered in the therapy of psoriatic patients.

Changes of antipyrine pharmacokinetics during influenza and after administration of interferon-alpha and -beta.

OBJECTIVE: During viral infections serum levels of interferons are elevated. In this study we wanted to observe the effects of endogenous interferon (IFN) during an acute viral infection (influenza) and after external application of interferons on the pharmacokinetics of antipyrine which is a parameter of hepatic cytochrome P450 enzyme activity. METHODS: Endogenous plasma levels of interferons and the antipyrine pharmacokinetics in 10 otherwise healthy volunteers were investigated before outbreak and in the symptomatic interval of an acute viral respiratory infection. The serum interferon levels were determined by RIA. In another trial 2 groups of 9 HIV patients each in stage CDC/WHO B2/3 received low-dose interferon therapy with 0,75 Mio. I.U. interferon-alpha or -beta s.c./die. The concentrations of antipyrine in serum were measured by HPLC. The antipyrine kinetics were determined before the infection or the interferon therapy, respectively, and during viral infection or during interferon or after interferon therapy, respectively. RESULTS: The plasma levels of IFNalpha and IFNgamma were significantly elevated from 4.7 U/ml to 12.6 U/ml and 0.3 U/ml to 3.4 U/ml, respectively, whereas the antipyrine clearance showed a decrease from 57.9 ml/min to 45 ml/min in the symptomatic interval of an acute viral infection. During therapy with low-dose interferons we observed a significant difference after 12 week treatment with IFNalpha or IFNbeta, respectively. In the first group we observed a decreased antipyrine clearance from 49.0 ml/min to 41.7 ml/min; in the second group the antipyrine clearance decreased from 49.0 ml/min to 41.7 ml/min. CONCLUSION: Viral infections (influenza) are able to inhibit the hepatic monooxygenase system due to elevated serum interferon levels. Low doses of exogenous interferons inhibit the cytochrome P450 monooxygenase system.

Effect of zidovudine therapy in patients with HIV infection on endogenous interferon plasma levels and the hepatic cytochrome P450 enzyme system.

In this study, we wanted to investigate if there are differences in endogenous interferon (IFN) plasma levels in patients with different stages of HIV infections before and after therapy with zidovudine (ZDV) and determined the influence of ZDV therapy on the hepatic monooxygenase system by measuring the antipyrine pharmacokinetics. Therefore we investigated the endogenous IFN plasma levels in patients with asymptomatic HIV infection (CDC/WHO A1, n = 10) and patients with AIDS (CDC/WHO C3, n = 10). In AIDS plasma IFN-alpha and IFN-gamma levels are elevated (15.6 +/- 5.8 U/ml; 2.1 +/- 0.7 U/ml) compared to patients with an asymptomatic HIV infection (6.1 +/- 3.3 U/ml; 0.6 +/- 0.3 U/ml). The antipyrine clearance was significantly reduced in the group of AIDS patients (43.1 +/- 7.2 ml/min compared to 56.4 +/- 8.7 ml/min). In a second study with 11 patients in stage CDC/WHO A1/2 and CDC/ WHO B/C3 each, we studied the effect of a 14-day administration of ZDV on the endogenous plasma IFN levels and the CYP450 enzyme activity using the antipyrine pharmacokinetics as a parameter. We investigated the antipyrine clearance, clearance to metabolite and half-life by using HPLC. IFNs were measured by RIA or ELISA, respectively. In the first group no significant alterations of antipyrine kinetics or plasma IFN levels were observed after treatment with ZDV. In contrast to these results, we found a significant decrease in IFN-alpha and IFN-gamma (19.8 +/- 3.6 U/ml, 4.6 +/- 1.5 U/ml before; 7.9 +/- 2.6 U/ml, 1.9 +/- 1.3 U/ml after administration of ZDV), a decrease in antipyrine half-life, an elevation of the antipyrine clearance (49.8 +/- 15.7 ml/min, 57.3 +/- 13.7 ml/min) and an elevation of the clearances to metabolite.

Pharmacokinetic interaction of fluconazole and zidovudine in HIV-positive patients.

To investigate the interaction of fluconazole and zidovudine in HIV-positive non-smoking male patients with AIDS categorized as CDC group IV we studied two groups, each consisting of 10 male, non-smoking, HIV-positive patients with CDC group IV disease, with the patients in the first group additionally suffering from candida esophagitis. In the first group, the pharmacokinetics of 500 mg oral zidovudine were determined both before and after 7 days of treatment with fluconazole 400 mg/d. In the second group, the pharmacokinetics of 200 mg oral fluconazole were determined before and after 14 days of treatment with zidovudine 4 x 250 mg/d. In order to determine the microsomal enzyme activity, the 6-beta-hydroxycortisol/17-hydroxycorticosteroid ratio and antipyrine pharmacokinetic parameters were determined. 6-beta-hydroxycortisol was quantitated by RIA. The 17-hydroxycorticosteroids were determined by a colorimetric method. Zidovudine (ZDV) and zidovudine glucuronide (GZDV), and the fluconazole and antipyrine plasma and urine concentrations were measured by HPLC. Administration of fluconazole resulted in a significant increase in the half-life of zidovudine and antipyrine (0.97 +/- 0.17 h prior to vs. 1.11 +/- 0. 14 h after fluconazole administration and 11.9 +/- 1.9 h prior to vs. 13.7 +/- 3.0 h after fluconazole, respectively) while the 6-beta-hydroxycortisol excretion decreased significantly (472.3 +/- 80.6 microg/24 h before and 340.6 +/- 82.1 microg/24 h after administration of fluconazole). No changes were found in the GZDV plasma kinetics and the ZDV and GZDV urinary excretion. Treatment with ZDV did not have any impact on the half-life of fluconazole. Administration of zidovudine did, however, result in a significant reduction in antipyrine half-life (11.7 +/- 2.0 h before vs. 9.9 +/- 2.3h after ZDV) and a significant increase in 6-beta-hydroxycortisol excretion (438,7 +/- 138.2 microg/24 h before and 684.6 +/- 157.3 microg/24 h after ZDV). Since the antipyrine clearance is altered after administration of ZDV, it is assumed that zidovudine induces cytochrome P450 enzymes. This effect, however, does not alter the pharmacokinetics of fluconazole. High doses of fluconazole can inhibit the plasma elimination of both antipyrine and zidovudine, but the extent of this inhibitory effect is so small that no clinically relevant accumulation is to be expected.

Combination of chemotherapy and antiviral therapy for Epstein-Barr virus-associated non-Hodgkin's lymphoma of high grade malignancy in cases of HIV infection.

Two HIV patients with Epstein-Barr virus (EBV)-associated B cell lymphoma of high grade malignancy enjoyed prolonged remission after therapy with COPBLAM and the antiviral agent Acyclovir. After 3, respectively 5 cycles of treatment, the patients (stage C3 according to CDC) responded to the administered drugs by achieving complete remission. Under maintenance therapy with Acyclovir for 32, respectively 31 months, both patients still remain free of lymphoma as of today.

Oligosymptomatic neurosyphilis with false negative CSF-VDRL in HIV-infected individuals?

The true prevalence of neurosyphilis in HIV-infection is unknown, since a sufficiently sensitive and specific test is lacking. In a prospective study we found reactive serum TPHA and FTA-ABS IgG tests in 95 (31%) of 307 HIV-infected patients. Three of 11 patients with latent syphilis revealed reactive CSF-VDRL tests, six others only demonstrated CSF abnormalities. Resolution of CSF abnormalities during a six month follow up after high dose antibiotic therapy led to the diagnosis of oligosymptomatic or asymptomatic neurosyphilis in all nine patients. Thus, the specificity of the CSF-VDRL was 100%, but the sensitivity was only 33%. The overall prevalence of neurosyphilis was 2.9%, increasing to 9.5% in patients with a reactive serum TPHA. Our study emphasizes the importance of antibiotic therapy for presumptive neurosyphilis in HIV-infected patients with latent syphilis and CSF abnormalities but nonreactive CSF-VDRL tests, even if they are neurologically asymptomatic or present with complaints inconclusive of neurosyphilis.

Nerve conduction changes in asymptomatic HIV-1 seropositive individuals in the absence of other risk factors for neuropathy.

The major problem in determining the role of HIV-1 infection in the pathogenesis of peripheral neuropathy is the difficulty in separating possible effects of confounding factors such as other infections, malnutrition, neurotoxic medication, drug abuse and antiretroviral treatment. We therefore selected 28 neurologically asymptomatic HIV-seropositive homosexual men (category A, CDC 1993) without other recognized reasons for peripheral nerve disease and 20 age, sex and height matched healthy controls for a prospective nerve conduction study. Nine (32%) HIV-seropositive patients had single nerve conduction abnormalities and 2 (7%) had at least two abnormalities considered to be indicative of subclinical neuropathy. Even patients with normal CD4 cell counts showed significantly lower mean sural nerve conduction velocities and higher tibial distal motor latencies compared to controls (ANOVA; p < 0.05). There was an overall trend toward more frequent nerve conduction changes in subgroups with abnormal CD4 cell counts, lymphocyte responsiveness or beta 2-microglobulin levels. Using strict selection criteria subclinical nerve conduction changes can be found even in the absence of symptomatic HIV-disease or potential confounding factors suggesting that HIV-1 plays a direct role in the pathogenesis of associated peripheral nervous system disease.

Foscarnet treatment in various cytomegalovirus infections.

We examined the effect of foscarnet (Foscavir) in 15 AIDS patients with cytomegalovirus infection. Cytomegalovirus infection was presented as retinits (n = 8), colitis (n = 3), oral (n = 1) and perianal ulcers (n = 3) and pneumonitis (n = 1). Induction therapy with foscarnet showed a complete response in 9 and a partial response in 6 patients after a medium therapy of 3.5 weeks. Three patients showed progressive disease under ganciclovir and were treated subsequently with foscarnet. Main side effects were ulcers of the glans penis (n = 6) and a rise of creatinine (> 1.5 mg/dl; n = 4). Therapy was changed to ganciclovir because of renal toxicity in 1 patient receiving induction therapy with foscarnet. Within a period of foscarnet therapy between 5 and 9 months (median: 7 months) no clinical progression occurred. Medium survival after diagnosis of cytomegalovirus infection was 7.4 months. We describe our experience with foscarnet and compare treatment results of cytomegalovirus infection at certain locations.

Endogenous interferon plasma levels and antipyrine pharmacokinetics in patients with viral infections.

We investigated the pharmacokinetics of antipyrine and the endogenous plasma levels of interferon alpha (IFN alpha), interferon beta (IFN beta) and interferon gamma (IFN gamma) in 10 otherwise healthy volunteers before outbreak (baseline) and in the symptomatic interval of an acute viral respiratory infection, and also in HIV-1 infected homosexual patients in stadium WR 2-3 (n = 11) and WR 5-6 (n = 11) before and one day after application of the antiretroviral agent zidovudine 800 mg day-1 for 14 days. Interferons were measured by RIA or ELISA, respectively. The concentrations of antipyrine and its metabolites in serum and urine were measured by HPLC. Antipyrine is a pharmacokinetic model substance to estimate the cytochrome P 450 enzyme activity. The plasma levels of IFN alpha and IFN gamma in the symptomatic interval of an acute viral respiratory infection were elevated from 4.7 U ml-1 to 12.6 U ml-1 and from 0.3 U ml-1 to 3.4 U ml-1, respectively. The antipyrine clearance showed a significant decrease from 57.9 ml min-1 to 45.0 ml min-1. In the HIV-1 infected patients in stadium WR 2-3 no alterations in plasma levels of interferons or in the pharmacokinetics of antipyrine were observed after treatment with zidovudine. In contrast to these results, in patients in stadium WR 5-6 we found a significant decrease of IFN alpha and an elevation of the clearance and the clearances to metabolite of antipyrine by about 20 percent.

[Electroencephalography and cranial computed tomography in a posterior infarct]. / Elektroenzephalographie und kranielle Computertomographie beim Posteriorinfarkt.

In this study we interpreted the electroencephalograms of 50 patients, all suffering from a cerebral infarction occurred in the circulation area of A. cerebri posterior with or without involvement of thalamic structures. The diagnosis was established by clinical findings and via CT-examinations. Besides the EEG-findings which always occurred in the occipital region we found alterations which exceeded the above mentioned posterior disorder of the brain function. In most cases these have been bilateral paroxysmal disorders projected into the temporal regions but lateralized to the region of the existing posterior infarction. If we had CT-examinations of cerebral infarctions in the circulation area of A. cerebri posterior without an involvement of thalamic structures, there was no projected activity which exceeded the posterior disorder in EEG. In all cases with the additional affection of thalamic structures in CT the bilateral paroxysmal EEG disorders into the temporal region were found.

Pharmacokinetic interaction of antimicrobial agents with levomethadon in drug-addicted AIDS patients.

Morphine and its derivatives are metabolized by the liver microsomal enzyme system with a high first-pass effect after oral application. In four of 44 HIV-infected i.v. drug abusers who participated in a levomethadon maintenance program, we observed sustained symptoms of under-dosage and loss of effect of there to fore well-tolerated substitution therapy during rifampin treatment or therapy with zidovudine or fucidic acid. As a pharmacological model substance for cytochrome p 450 enzymes, measurement of antipyrine in serum by high pressure liquid chromatography revealed induction of cytochrome p 450 isoenzymes. The half-life of antipyrine decreased (patient 1 from 11.3 to 8.4 h and patient 2 from 10.7 to 7.6 h after rifampin, patient 3 from 12.2 to 8.6 h after fucidic acid, and patient 4 from 10.6 to 8.6 h after zidovudine). In i.v. drug abusers on levomethadon maintenance programs, adjustment of the levomethadon dosage may be necessary when specific therapy for HIV infection and associated diseases requires the use of drugs known to be potent inducers of the liver microsomal enzyme system.

Comparative effects of rifampin and/or probenecid on the pharmacokinetics of temazepam and nitrazepam.

The pharmacokinetics of nitrazepam and temazepam were investigated in 16 healthy volunteers before and after seven days of the administration of rifampin 600 mg/d and/or probenecid 500 mg/d. In order to determine the endoplasmatic reticulum enzyme function, 6-beta-hydroxycortisol excretion and antipyrine pharmacokinetic parameters were evaluated. After the administration of rifampin, the total body clearance of antipyrine and nitrazepam increased by 87% and 83%, respectively. After the combined treatment with rifampin and probenecid, the elimination of the two drugs was also increased, even though to a lesser extent (33%, 31%). After the administration of probenecid only, the total clearances of antipyrine and nitrazepam were decreased by 22% and 25%, respectively. The urinary clearance of the antipyrine metabolites also decreased. In norantipyrine and 4-OH-antipyrine, this was due to a significant reduction of glucuronide fraction (211 +/- 32 to 159 +/- 26 mg, and 259 +/- 39 to 191 +/- 25 mg). The sulphate fraction of norantipyrine increased by 18% and that of 4-OH-antipyrine by 21%. Apart from a reduced excretion of the glucuronide fraction, the pharmacokinetics of temazepam were neither altered significantly by probenecid nor by rifampin. According to the outcome of this investigation, probenecid seems to bring about not merely an inhibition of phase II but also an inhibition of phase I metabolization.

Cimetidine and the immuno-response in healthy volunteers.

We compared the immunologic measurements from treatment of 12 healthy volunteers (six male, six female) with 800 and 1,600 mg cimetidine. In the first trial 800 mg cimetidine was administered daily to the volunteers over a period of 7 d; after an interruption of 2 months, 1,600 mg of cimetidine was applied daily for 21 d. The most striking result of our study was an increased mitogen-induced lymphocyte proliferation. This conclusion can be drawn from the fact that phytohaemagglutinin (PHA) (0.4 microgram/well) and pokeweed mitogen (PWM) (0.4 microgram/well) induced lymphocyte proliferation were found to be significantly increased in comparison to pretreatment values on day 7 in both cimetidine regimens (800 mg; PHA: mean proliferation 66,500 before treatment to 166,00 cpm, PWM: mean proliferation 8,800 before treatment to 34,000 cpm; 1,600 mg; PHA; mean proliferation 48,700 before treatment to 81,600 cpm; PWM: mean proliferation 6,300 before treatment to 16,200 cpm). Increased mitogen-induced proliferation following cimetidine intake is of special interest because the mechanisms of this activation process are incompletely known. Lymphocyte proliferation response is dependent on the availability of extracellular calcium. The function of the other bivalent cations is unknown. We found that the extent of mitogen-induced lymphocyte proliferation correlates with cellular intralymphocytic zinc and magnesium amounts (coefficients of correlation [r]) (800 mg: PHA/Mg r = 0.84; PHA/Zn r = 0.86; PWM/Mg r = 0.88; PWM/Zn r = 0.87). Though the application of both cimetidine doses causes enhanced mitogen-induced lymphocyte proliferation on day 7, T lymphocytes with different phenotypic properties appear to be influenced by cimetidine. In the first dose regimen (800 mg) the number of the CD8 lymphocytes decreased significantly from 16.1% (365 cell/microliters blood) to 12.7% (264 cells/microliters blood) after 7 d of cimetidine intake. After the period of high-dose (1,600 mg) cimetidine administration (at day 21) numbers of CD4 lymphocytes were significantly increased from 41.5% (860 cells/microliters blood) to 56.3% (1,210 cells/microliters blood). Our results show that although different cimetidine doses obviously influence different cell types of healthy volunteers, the cellular mechanisms are the same, namely, a proliferation and an increased incorporation of magnesium and zinc in lymphocytes.

Effect of aminophylline on cisplatin nephrotoxicity in the rat.

1. The effect of the methylxanthine aminophylline on cisplatin (5 mg kg-1 i.v.)-induced acute renal failure was investigated in the rat. Renal function was measured 5 days after cisplatin administration. 2. Cisplatin caused a polyuric acute renal failure. The creatinine clearance was significantly reduced. 3. Aminophylline (24 mg kg-1 12h-1) ameliorated the cisplatin nephrotoxicity when administered during the maintenance phase of acute tubular necrosis. However, it had no effect when only administered prophylactically before the cisplatin application. 4. Enprofylline (20 mg kg-1 4h-1 with dose adjustment), a methylxanthine lacking adenosine receptor antagonism in comparison to aminophylline, had no protective effect on cisplatin nephrotoxicity. 5. Adenosine is a renal vasoconstrictor and decreases glomerular filtration rate. Endogenous adenosine in the kidney is formed by degradation of ATP and is thought to be involved in various forms of acute renal failure. The results suggest that adenosine may be involved in the haemodynamic changes in the kidney induced by cisplatin.