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A Rohlfs

Publications and source records attributed to A Rohlfs.

7 recordsLinked to original sources
PubMed2004

Cyclosporin A pharmacokinetics and efficacy in the treatment of atopic dermatitis in dogs.

A series of experiments was conducted to study cyclosporin A (CsA) pharmacokinetics in dogs and the factors influencing variability of blood concentrations. In a first study, influence of feeding on drug absorption and blood profile was evaluated. Administration of CsA as micro-emulsion (ME) formulation with food decreased the bioavailability by 22% and increased the individual variability of drug absorption. In a second study, pharmacokinetic profiles from laboratory fasted beagle dogs receiving orally CsA ME formulation were analyzed. CsA was measured in blood samples by high-performance liquid chromatography (HPLC, 34 profiles) and fluorescent polarization immunoassay (FPIA, 16 profiles). A two-compartment model with first-order absorption was used to calculate the pharmacokinetic parameters. Using FPIA, blood concentrations were 1.5 to 1.7 times higher than when using HPLC, but elimination half-life and MRT were similar. The coefficient of variation of key pharmacokinetic parameters ranged from 27 to 34% following HPLC assay. The same range of variation was obtained after FPIA assay. In a third study, in a clinical trial evaluating CsA for the treatment of canine atopic dermatitis, a single blood sample was collected in dogs which had received CsA for 28 days. No significant correlation was found between clinical improvement and CsA blood concentrations. Considering the large margin of safety of CsA in dogs, the limited inter-individual variability and the lack of correlation between blood concentrations and clinical response, routine monitoring of blood CsA does not appear necessary in dogs with atopic dermatitis.

Administration, Oral↗
PubMed1997

Hemispheric asymmetries in spontaneous firing characteristics of substantia nigra pars reticulata neurons following a unilateral 6-hydroxydopamine lesion of the rat nigrostriatal pathway.

Single unit activity of substantia nigra pars reticulata (SNR) neurons was recorded bilaterally in rats subjected to unilateral 6-hydroxydopamine lesions of the ascending mesostriatal dopaminergic pathway, resulting in an almost complete loss of dopaminergic neurons in the ipsilateral SN pars compacta. Firing rate and firing pattern of SNR neurons in lesioned rats were compared with respective data from sham-lesioned rats and naive controls. In lesioned rats, the mean firing rate of SNR neurons at the lesioned side was significantly reduced and there was an increase in the occurrence of bursting activity. In contrast, firing rate in the contralateral SNR was significantly increased without change in the frequency of bursting neurons. This asymmetrical change in spontaneous firing characteristics of SNR neurons following the lesion could be involved in the complex behavioral changes seen in this model of Parkinson's disease.

Animals↗
PubMed1996

A comparison of the effects of valproate and its major active metabolite E-2-en-valproate on single unit activity of substantia nigra pars reticulata neurons in rats.

Numerous findings suggest that the substantia nigra pars reticulata (SNR) acts as a seizure-gating mechanism and constitutes a site where protection against a broad spectrum of seizures can be obtained by inhibiting the activity of GABAergic output neurons to SNR target regions, particularly the superior colliculus. Most pharmacological studies on SNR neurons have been conducted with local microinjection of drugs, whereas studies with systemic administration of anticonvulsant drugs, e.g., the antiepileptic drug valproic acid (VPA), have yielded inconsistent data. In the present study, we examined the dose response and time course of the effects of anticonvulsant doses of VPA and its major active metabolite E-2-en-VPA on extracellularly recorded spontaneous single unit activity of nondopaminergic SNR neurons in a large group of chloral hydrate-anesthetized rats. The activity of each neuron was recorded over a period of at least 30 min after intravenous drug or vehicle administration. Both drugs rapidly decreased the firing rate of SNR neurons. Compared with predrug base-line values of neuronal firing of SNR neurons, the average peak inhibition of neuronal activity was approximately 16% at the lowest dose (50 mg/kg), approximately 20% (VPA) or 30% (E-2-en-VPA) at 100 mg/kg and approximately 50% (VPA) or 60% (E-2-en-VPA) at the highest dose (200 mg/kg) tested. ED50 values calculated from these data were 240 mg/kg for VPA and 159 mg/kg for E-2-en-VPA, respectively. Determination of drug levels in SN at time of peak effect after administration of 100 mg/kg VPA or E-2-en-VPA indicated that E-2-en-VPA exhibited its inhibitory effect on SNR firing at significantly lower concentration than VPA, suggesting that E-2-en-VPA is more potent than VPA in this regard. Except one SNR neuron, all neurons recorded in 52 rats reacted with a reduction in firing rate to administration of VPA or E-2-en-VPA, demonstrating a rather homogeneous susceptibility of SNR neurons to these drugs. The inhibition of SNR neurons by these drugs could be a result of increased GABA turnover, which has previously been reported to be induced in this region by systemic administration of VPA. We conclude that the ability of VPA and E-2-en-VPA to reduce firing of SNR neurons could be critically involved in their effectiveness in inhibiting seizures in various experimental models.

Animals↗
PubMed1995

Reduction in firing rate of substantia nigra pars reticulata neurons by valproate: influence of different types of anesthesia in rats.

Nondopaminergic, presumably GABAergic neurons in the substantia nigra pars reticulata (SNR) are thought to function as a gating mechanism for seizure propagation. Systemic administration of anticonvulsant doses of the antiepileptic drug valproate (VPA) has previously been reported to inhibit the firing of nondopaminergic SNR neurons in anesthetized but not in awake, paralyzed and locally anesthetized rats, suggesting that the findings in anesthetized rats were due to an interaction between VPA and the general anesthetic used. In the present study, we determined the influence of different anesthetic measures on the effect of an anticonvulsant dose of VPA (100 mg/kg) on extracellularly recorded spontaneous single unit activity of nondopaminergic SNR neurons in rats. Rats were anesthetized by continuous infusion of the general anesthetic chloral hydrate, the dissociative anesthetic ketamine or the narcotic opioid fentanyl, or were only locally anesthetized and paralyzed. VPA significantly reduced SNR firing in all groups with a time course that matched its anticonvulsant time course in rodents. However, VPA's inhibitory effect on SNR firing was significantly less marked under anesthesia with chloral hydrate than in any of the other groups, indicating that this anesthetic suppresses the action of VPA, which may be related to an interaction with GABA-related processes in the SNR. The closest approximation to the effect of VPA in awake rats was obtained under anesthesia with ketamine, while VPA's inhibitory action on SNR neuronal firing seemed to be enhanced in the fentanyl group, which exhibited the highest baseline firing rates of all groups. Determination of VPA in the SN showed that the difference in VPA's inhibitory effect on SNR neurons was not secondary to differences in local drug concentrations. The data demonstrate that VPA is capable of significantly slowing the spontaneous activity of nondopaminergic SNR neurons, but that the magnitude of this effect depends on the anesthetic measures used. In view of the presumed role of SNR neurons in seizure propagation and the finding that VPA consistently inhibits these neurons at an anticonvulsant dose, the present data suggest that suppression of spontaneous SNR neuronal firing may be an important mechanism through which VPA exerts its anticonvulsant properties.

Anesthetics↗
PubMed1993

Actin and cell movement.

The primary locomotory organelle of non-muscle, eukaryotic cells is the lamellipodium, a thin layer of cytoplasm that exhibits active protrusive activity. Earlier studies have implicated actin polymerization in the formation of lamellipodia, whereby actin monomers insert at the front and dissociate at the rear, in a treadmilling fashion. However, other models based on gel swelling and a breakdown of actin networks at the site of protrusion of the lamellipodium have also been proposed. By employing videomicroscopy and electron microscopy of the same cells, in this case mouse macrophages, it could be shown that lamellipodial protrusion is directly linked with the growth of dense actin meshworks. The gel swelling and cortical breakdown models are not supported by this data. Using rapidly locomoting fish keratocytes, Theriot and Mitchison (Nature 352, 126-131, 1991) recently obtained results that they interpreted as supporting a form of actin filament dynamics different from treadmilling. In their new "nucleation release model" the actin filaments in the lamellipodium are predicted as being very short (less than 0.5 micron) and randomly organized. We have now investigated the ultrastructure of the keratocyte cytoskeleton. Our results show that the actin filaments in these cells are very long and organized in dense and regular, more or less orthogonal networks. A gradient of filament density across the rear part of the lamellipodium suggests that the filaments are graded in length. These data support a treadmilling type model for the eratocyte.

Actins↗
PubMedDate not supplied

The influence of solvent stress on MMS-induced genetic change in Saccharomyces cerevisiae.

MMS induced mitotic recombination but not mitotic chromosome loss when tested in pure form in strain D61.M of Saccharomyces cerevisiae, confirming previous results of Albertini (1991), whereas in Aspergillus nidulans it also induced chromosomal malsegregation in addition to mitotic recombination (Käfer, 1988). However, induction of mitotic chromosome loss was observed in combination with strong inducers of chromosome loss such as the aprotic polar solvents ethyl acetate and to a lesser extent methyl ethyl ketone but not with gamma-valerolactone and propionitrile. In addition to this, 4 solvents, dimethyl formamide, dimethyl sulfoxide, dioxane and pyridine, enhanced the MMS-induced mitotic recombination in strain D61.M. An enhancement of MMS-induced mitotic recombination and reverse mutation could be demonstrated for ethyl acetate and gamma-valerolactone in yeast strain D7.

Acetates↗