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N H Brockmeyer

Publications and source records attributed to N H Brockmeyer.

At least 73 records · Page 4Linked to original sources
PubMed1993

Foscarnet penetrates the blood-brain barrier: rationale for therapy of cytomegalovirus encephalitis.

Foscarnet (phosphonoformate) is a potent virustatic drug against herpes-like viruses and is widely used in the therapy of cytomegalovirus infections in immunosuppressed patients. To obtain data on its penetration across the blood-brain barrier, we determined concentrations of foscarnet in cerebrospinal fluid and in plasma specimens from 26 patients with human immunodeficiency virus (stages 2 to 6 by Walter Reed Army Institute of Research classification) after a single infusion of 90 mg of foscarnet per kg of body weight and at steady state by electrochemical detection by high-pressure liquid chromatography. Penetration coefficients were correlated with the integrity of the blood-brain barrier. After a single infusion of foscarnet, levels in plasma ranged from 297 to 1,775 micrograms/ml (990 to 5,920 mumol/liter), with a mean of 766 +/- 400 micrograms/ml. Corresponding levels in cerebrospinal fluid were 57 to 225 micrograms/ml (190 to 750 mumol/liter), with a mean of 131 +/- 52 micrograms/ml. The penetration coefficient was 0.05 to 0.72 (mean, 0.23 +/- 0.16). At steady state, mean foscarnet levels in plasma were 464 +/- 219 micrograms/ml (1,553 mumol/liter) and mean levels in cerebrospinal fluid were 308 +/- 155 micrograms/ml (1,023 mumol/liter). The penetration coefficient was 0.66 +/- 0.11. Although penetration coefficients were highly variable after a single administration and at steady state, the concentrations of foscarnet attained in cerebrospinal fluid are sufficient for complete inhibition of cytomegalovirus replication in vitro. In conclusion, we show that foscarnet seems to be the drug of choice for the treatment of cytomegalovirus encephalitis, because it penetrates the blood-brain barrier and is found in the cerebrospinal fluid in virustatic concentrations. Foscarnet might be considered for additive therapy for human immunodeficiency virus encephalitis in combination with zidovudine or dideoxyinosine.

AIDS-Related Opportunistic Infections↗
PubMed1993

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.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Expression of platelet-derived growth factor and its receptor in AIDS-related Kaposi sarcoma in vivo suggests paracrine and autocrine mechanisms of tumor maintenance.

As previously described, proliferation of Kaposi sarcoma (KS)-derived cells in vitro is dependent on the presence of platelet-derived growth factor (PDGF). To test the hypothesis that PDGF may also be a major growth factor for KS cells in vivo, we performed in situ hybridization and immunohistochemical staining for PDGF and PDGF receptors in tissue sections of AIDS-related KS. The data suggest that KS consists of two types of tumor cells. (i) The main population are spindle-shaped cells with elongated nuclei (KS-s cells). They reveal a strong expression of PDGF beta receptors but do not express the PDGF-A and PDGF-B isoforms. (ii) A minor population of KS cells express PDGF beta receptor as well as PDGF-A and PDGF-B (KS-p cells). These cells are often grouped in whorls and surrounding vascular slits. They reveal spherical nuclei with evenly distributed chromatin and inconspicuous nucleoli. PDGF alpha receptor is not expressed in either form of KS cells. The results suggest that the isoforms of PDGF and the PDGF beta receptor are differentially expressed in two different cell types in KS and that PDGF isoforms may contribute to the pathogenesis of KS.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Granulocyte colony-stimulating factor treatment in AIDS patients.

Frequent complications of human immunodeficiency virus infection are hematopoietic failure and poor tolerance of myelosuppressive drugs. Reasons for neutropenia resulting from hematopoietic failure are infection of the bone marrow and hematotoxicity of treatment with zidovudine, ganciclovir, sulfonamides, and interferons. Moreover, tumor necrosis factor-alpha, transforming growth factor-beta and interferon-gamma have been shown to suppress proliferation of bone marrow cells. Both granulocyte (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) increase neutrophil counts and ameliorate phagocytic and bactericidic function of neutrophils. We report eight cases of AIDS patients with serious infections and neutropenia (< 750 cells/microliters), who were treated concomitantly with recombinant human G-CSF (3-4 micrograms subcutaneously per kilogram body weight daily). G-CSF treatment was well tolerated in all patients and showed no side effects or disturbances of other lineages than neutrophils. Life-threatening bacterial infections were treated successfully by stimulating the neutrophil immune system. This therapy shortened the duration of subsequent treatment with antibiotics. Since human immunodeficiency virus infects CD4-positive monocytes and macrophages, which are stimulated by GM-CSF, G-CSF seems to be the cytokine of choice, if stimulation of the neutrophil lineage is warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1992

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.

Acquired Immunodeficiency Syndrome↗
PubMed1991

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.

Acquired Immunodeficiency Syndrome↗
PubMed1991

[Comparative study of the therapy of Candida esophagitis in HIV-1-infected patients with fluconazole or amphotericin B and flucytosine].

In 20 HIV-patients (17 male homosexuals, 1 male and 1 female i.v. drug abuser and 1 female patient with M. Willebrand-Jürgens) Candida esophagitis was diagnosed by esophagogastroduodenoscopy. Clinically they presented retrosternal pain or an exacerbation of oral candidosis under local antimycotics. The diagnosis of Candida esophagitis was based on histopathologic examination and culture studies of biopsy specimen from macroscopically suspect lesions. Candida antigen was found in the serum of 30% of the patients, immunofluorescence was positive for Candida antibodies in 25%. A CMV- or HSV-esophagitis could be ruled out by direct immunofluorescence, in situ hybridoma experiments and by virus culture assays. In 11/20 patients the Candida esophagitis was the first manifestation of full blown AIDS. 10 patients were treated daily with a combination of amphotericin B 0.4 mg/kg KG and flucytosine 150 mg/kg/KG and 10 patients by oral administration of fluconazole 400 mg/d each for 8 days. Secondary prophylaxis was carried out with 2.4 g/d (24 ml) amphotericin B as oral suspension in the amphotericin group and with 50 mg/d fluconazole p.o. in the fluconazole group. Both therapy regimens showed a complete remission in a control esophagogastroduodenoscopy after 10 days. Side effects were only moderate. After an observation period between 7-24 months there were three relapses in the amphotericin group and four in the fluconazole group. After 24 months 10 patients had died, a rate comparable to that after Pneumocystis carinii pneumonia. In total, there is no difference between both therapy regimens, the oral administration of fluconazole once a day allowed treatment as an outpatient and was appreciated by the patients.

Amphotericin B↗
PubMed1990

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.

17-Hydroxycorticosteroids↗
PubMed1989

Immunomodulation of cimetidine in healthy volunteers.

The effect of cimetidine, a histamine H2-receptor antagonist, on the immune system in man was investigated in 11 healthy volunteers. Cimetidine was administered orally in daily doses of 800 mg for a period of 7 days. At the end of the administration period the number of peripheral CD8+ (cytotoxic/suppressor) cells had diminished significantly (P less than 0.05) along with a corresponding increase in the CD4+ (helper/inducer): CD8+ (cytotoxic/suppressor) cell ratio (P less than 0.01). Compared with pretreatment values, a significant in vitro blastogenic response to mitogen stimulation with concanavalin A (P less than 0.005), phytohemagglutinin (P less than 0.01), and pokeweed mitogen (P less than 0.05) was observed in lymphocytes of volunteers after cimetidine intake. The cell-mediated hypersensitivity as assessed by skin testing of seven recall antigens was also enhanced significantly (P less than 0.001). Using Spearman's coefficient of correlation to compare mitogen-stimulation tests and skin tests of delayed hypersensitivity to the CD4+:CD8+ ratio, yielded a positive correlation (r = 0.89; r = 0.85, respectively). These effects were reversible 96 h after the last cimetidine dose. In contrast, leukocytes, total T lymphocytes (CD2+, CD3+), CD4+ (helper/inducer) cells, natural killer cells (Leu7+), immunoglobulins, and total complement, C3, C4 were unaffected by cimetidine administration.

Adult↗
PubMed1989

Kinetics of oral and intravenous mexiletine: lack of effect of cimetidine and ranitidine.

The pharmacokinetics of mexiletine, a Class I antiarrhythmic drug, was investigated in 6 healthy volunteers after single oral doses and 15 min intravenous infusions of 3 mg/kg. Cimetidine and ranitidine are commonly used H2-receptor antagonists, which interact adversely with many drugs, e.g. inhibition of the metabolism of Class I antiarrhythmics such as lidocaine and quinidine by cimetidine. To investigate the effects of the two drugs on the kinetics of mexiletine, cimetidine 800 mg.day-1 or ranitidine 600 mg.day-1 were administered orally for one week. Neither H2-receptor antagonist altered the distribution and elimination of mexiletine, nor did they affect its overall kinetics, or excretion of the metabolites para- and 4-OH-methylmexiletine after oral and intravenous administration of mexiletine.

Administration, Oral↗
PubMed1989

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.

Adult↗
PubMed1989

The immunomodulatory potency of cimetidine in healthy volunteers.

The effect of cimetidine, a histamine H2 receptor antagonist, was investigated in 12 healthy volunteers over a period of six weeks. Cimetidine was administered orally in a daily doses of 1,600 mg during the first three weeks of evaluation. Significant alterations in values of immunoglobulins (IgG, IgA), complement (C3), B-lymphocytes and T-helper cell counts were found after cimetidine intake. The in vitro lymphocyte proliferation response to plant mitogens was increased. In contrast to results obtained from a previous study with healthy volunteers who were given 800 mg cimetidine, we found no significant increase in the CD4/CD8 ratio and no decrease in the CD8 but a significant increase in the CD4 cell count. Whereas the peripheral blood immune system showed signs of immune system activation following 800 and 1,600 mg cimetidine intake, reactivity patterns of skin immune system, however, differed in both studies. The data suggests that cimetidine has a dose and time dependent effect on the immune system.

Adjuvants, Immunologic↗
PubMed1988

Intrathecal production of HIV antibodies in suspected AIDS encephalopathy.

Thirty-one serum and CSF samples from 21 HIV-antibody-positive patients with neurological deficits were examined to prove or exclude intrathecal production of HIV antibodies. By dilution, sera were adjusted to the IgG concentration of the corresponding CSF samples. Both samples were then serially diluted in log2 steps down to the detection limit and were tested in an anti-HIV ELISA. From the dilution obtained at the cut-off level, a quotient QHIV was derived as an indicator of intrathecal production of HIV antibodies. Six of a total of eight samples with a QHIV value of greater than or equal to 2 were correlated which the clinical diagnosis of AIDS-related dementia complex (ARDC). However, a QHIV less than 1 did not exclude the development of ARDC, as was shown during follow-up in one case. Different methods are compared for the determination of intrathecal production of IgG and anti-HIV. A quotient QHIV greater than or equal to 2 is suggested to be highly indicative of intrathecal production of anti-HIV as well as of the development of ARDC.

Acquired Immunodeficiency Syndrome↗