ABSTRACT
A rabbit model of coccidioidal meningitis was used to compare the therapeutic efficacies of terbinafine (TBF) and fluconazole (FCZ). Hydrocortisone acetate-treated New Zealand White male rabbits were infected intracisternally with either 2.2 x 10(4) or 6.4 x 10(4) Coccidioides immitis arthroconidia. Oral treatment with polyethylene glycol 200 (PEG) twice daily (n = 8), TBF twice daily (n = 9; 200 mg/kg of body weight/day), or FCZ once daily (n = 8; 80 mg/kg/day) began on day 5 and continued for 21 days. Mean survival times were 20, 24, and 32 days for rabbits treated with PEG, TBF, and FCZ, respectively. All of the FCZ-treated animals (100%; P = 0.003), 56% of the TBF-treated animals (P = 0.4), and 25% of the PEG-treated animals survived the length of the study. Both FCZ and TBF were effective at reducing the incidence of paresis. Only FCZ was effective at reducing most neurological and systemic signs. FCZ treatments resulted in lower cerebrospinal fluid (CSF) protein concentrations and leukocyte counts and faster clearing of CSF fungal cultures compared with those for PEG-treated controls, but TBF treatments had no significant effect on these parameters. Neither drug affected CSF glucose levels. Mean serum TBF levels by bioassay were within the range of 3.5 to 6.2 microgram/ml at 1, 2, and 4 h postdosing and 0.35 to 7.0 microgram/ml at 14 h postdosing. No TBF was detected in CSF. Mean FCZ levels (24 to 25.5 h postdosing) by bioassay were 16.4 to 19.2 and 13.5 to 19.2 microgram/ml in serum and CSF, respectively. The reduction in the numbers of CFU in the spinal cord and brain was over 100-fold (P = 0.0005) in FCZ-treated animals and 2-fold (P = 0.2) in TBF-treated animals compared with those in PEG-treated animals. Histopathologic severity (semiquantitative scoring system) was significantly attenuated by FCZ treatment (P = 0. 05) and was slightly attenuated by TBF treatment compared with that for the controls. In conclusion, TBF appeared to have a slight effect on survival, histology, and reduction of the numbers of CFU in tissue; however, these effects were not significant. FCZ was effective at controlling coccidioidal meningitis.
Subject(s)
Antifungal Agents/therapeutic use , Coccidioidomycosis/drug therapy , Fluconazole/therapeutic use , Meningitis, Fungal/drug therapy , Naphthalenes/therapeutic use , Animals , Antifungal Agents/blood , Antifungal Agents/cerebrospinal fluid , Cerebrospinal Fluid/cytology , Cerebrospinal Fluid/microbiology , Coccidioides/drug effects , Coccidioidomycosis/pathology , Colony-Forming Units Assay , Disease Models, Animal , Fluconazole/blood , Fluconazole/cerebrospinal fluid , Glucose/cerebrospinal fluid , Leukocytes , Male , Meningitis, Fungal/pathology , Microbial Sensitivity Tests , Naphthalenes/blood , Naphthalenes/cerebrospinal fluid , Rabbits , Terbinafine , Treatment OutcomeABSTRACT
The capability of pravastatin and lovastatin, HMG-CoA reductase inhibitors likely to be taken chronically for hypercholesterolemia, to cross the blood-brain barrier was investigated in normal male volunteers. Lovastatin, which is lipophilic, was detected in cerebrospinal fluid (CSF) at concentrations that may have a pharmacologic effect. Pravastatin, which is hydrophilic, was not detected in CSF. It is concluded that pravastatin may have less potential for causing CNS-related side effects than lovastatin.
Subject(s)
Anticholesteremic Agents/cerebrospinal fluid , Heptanoic Acids/cerebrospinal fluid , Lovastatin/cerebrospinal fluid , Naphthalenes/cerebrospinal fluid , Adult , Anticholesteremic Agents/pharmacokinetics , Blood-Brain Barrier , Heptanoic Acids/pharmacokinetics , Humans , Lovastatin/pharmacokinetics , Male , Naphthalenes/pharmacokinetics , Pravastatin , Reference ValuesSubject(s)
Antidepressive Agents/therapeutic use , Depression/drug therapy , Naphthalenes/therapeutic use , 1-Naphthylamine/analogs & derivatives , Administration, Oral , Adrenergic alpha-Antagonists/therapeutic use , Adrenergic beta-Antagonists/therapeutic use , Antidepressive Agents/adverse effects , Antidepressive Agents/blood , Antidepressive Agents/cerebrospinal fluid , Electrocardiography , Evaluation Studies as Topic , Humans , Methylamines/adverse effects , Methylamines/blood , Methylamines/cerebrospinal fluid , Methylamines/therapeutic use , Naphthalenes/adverse effects , Naphthalenes/blood , Naphthalenes/cerebrospinal fluid , Psychiatric Status Rating ScalesABSTRACT
1. Five new solvent systems are reported for the separation of 1-dimethylaminonaphthalene-5-sulphonylamino acids by thin-layer chromatography on silica gel. After two-dimensional chromatography with a suitable pair of these solvent systems, most of the 1-dimethylaminonaphthalene-5-sulphonyl derivatives were completely separated and could be located by their intense yellow fluorescence when viewed under u.v. light. 2. These techniques have been used to identify 21 amino acids present in superfusates of cat cerebral cortex, plasma and cerebrospinal fluid. 3. A method for the semiquantitative estimation of amino acids in biological fluids is described in which the fluorescent intensity of their separated 1-dimethylaminonaphthalene-5-sulphonyl derivatives was measured.