Influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid

Summary— The aim of this quantitative structure-activity relationship (QSAR) study was to investigate the influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid (CSF). The lipophilicity was expressed as the chromatographic capacity factor (log k'_w) determined by high-performance liquid chromatography in a reversed-phase system. The penetration of eight cephalosporins into CSF was studied in male Wistar rats receiving the drugs intramuscularly (1.5 mg/kg). One hour after administration, CSF and blood samples were collected, and concentrations of free drug were measured in CSF (C_CSF) and in plasma (C_P). A significant parabolic relationship was sought between lipophilicity (log k'_w) and the capacity of diffusion across the blood-brain barrier expressed as log (C_CSF/C_P). The cephalosporins exhibiting a moderate lipophilicity diffused well into CSF. A pharmacokinetic study was performed at 1, 2 and 4 h after administration of three cephalosporins: cefazolin, ceftriaxone and cefsulodin. These compounds were choosen according to their lipophilicities (low, moderate and high values, respectively). The AUC_0–4h for both free plasma (AUC_P) and cerebrospinal fluid (AUC_CSF) concentrations were determined. The AUC_CSF/AUC_P ratio presented a maximum value for a strongly albumin bound cephalosporin, ceftriaxone. In our experimental conditions, the ideal lipophilicity (log k'_w) range for diffusion of cephalosporins from plasma into CSF was between 1.6 and 1.8.     

Osteoporosis: radiographic detection of fluoride-induced extra-axial bone formation

New bone formation in the peripheral skeleton was detected radiographically in 67% (22/33) of patients studied for new periarticular pain among 72 patients with osteoporosis being treated with fluoride, 66-88 mg/d, for 6 or more months. Changes included periosteal and endosteal new bone formation as well as trabecular thickening and were localized in areas of high mechanical stress. Sufficient mineral deposition for radiographic detection required 6 or more months of fluoride treatment. Radiologists must differentiate fluoride-induced new bone formation from other-processes, such as fractures and tumor, and elicit information on fluoride intake in suspicious cases.     

Clinical indicators of mycobacteraemia in adults admitted to hospital in Blantyre

The aims of the study were to measure the prevalence and outcome of mycobacteraemia in febrile hospitalised adults; to determine what proportion could be identified using routine methods; to assess clinical indicators of mycobacteraemia and the usefulness of a diagnostic trial of anti-TB treatment. We prospectively examined adults with fever or a history of fever admitted to adult medical wards of QECH, Blantyre. All had blood cultured for bacteria and mycobacteria, chest x-ray and sputum smears. M. tuberculosis was the commonest blood isolate, affecting 57 of 344 patients (17%). In 44 (77%) patients with mycobacteraemia, TB was identified using routine investigations; in only 6 (11%) it was not suspected. Strong clinical indicators of mycobacteraemia were anaemia, HIV seropositivity, cough, chronic fever, and a clinical diagnosis of AIDS on the day of admission. Of nine patients selected for a therapeutic trial of TB treatment, six had mycobacteraemia, of whom five died during the trial. Mortality on short course chemotherapy on the TB ward after one month, was similar whether patients had mycobacteramia (21%) or not (32%). TB can be identified with routine methods in most patients with mycobacteraemia. If treated, mycobacteraemia has as good an early outcome as TB without mycobacteraemia. Strengthening of basic facilities is likely to improve detection and treatment of mycobacterial disease.     

Vertebral bone density in children: effect of puberty

To determine changes in bone density during growth, trabecular vertebral density and an index of spinal cortical bone were measured with quantitative computed tomography in 101 children. The children were divided by age into three groups: prepubertal, indeterminate, and pubertal. Compared with prepubertal children, pubertal adolescents had significantly higher trabecular bone density and more compact bone in the spine (P less than .001). After controlling for puberty, vertebral bone density failed to correlate significantly with age, sex, weight, height, surface area, and body mass index. The results indicate that bone density increases markedly during puberty.     

Esophageal anastomotic leaks: preliminary results of treatment with balloon dilation

Disruption of a cervical esophagogastric or esophagocolonic anastomosis shortly after surgery is a common complication, and fistula drainage from the leaking anastomosis may be prolonged. Narrowing of the anastomosis apparently contributes to the development and maintenance of the fistula. Fluoroscopically guided balloon dilation of anastomotic strictures was performed in three patients with anastomotic leaks. Preliminary results suggest that the procedure is safe and promotes healing of the fistula.     

Effect of platelet-activating factor (PAF) on human platelets

The effect of pure synthetic PAF (1-0-alkyl-2-acetyl-sn-glycero-3- phosphorylcholine) was studied in human platelets. PAF (0.2--2.0 micrograms/ml) produced a dose-dependent aggregation in human platelet- rich plasma (PRP) or platelet suspension obtained by gel-filtration (GFP). In addition, PAF (0.8 microgram/ml) induced secretion of 14C- serotonin (45% +/- 10%; mean +/- SD, n = 9) and platelet factor 4 (PF4) (12.89 +/- 3.81 micrograms/10(9) platelets; n = 9) in PRP. Similar results were obtained in GFP. Aggregation and release of 14C-serotonin and PF4 were inhibited by the metabolic inhibitors 2-deoxyglucose (16.7 mM) and antimycin-A (8.3 micrograms/ml), by the membrane-active drugs mepacrine (10 microM) and chlorpromazine (0.025 mM), by PGI2 (5.34 nM), which elevates intracellular c-AMP, by indomethacin (10 microM) or aspirin (100 microM). The ADP scavengers, creatine phosphate and creatine phosphokinase (CP/CPK), inhibited the second wave of aggregation but not secretion. These data suggest that the major effect of PAF on human platelets is mediated through the cyclo-oxygenase pathway and not through a third pathway.