Neurosyphilis and penicillin levels in cerebrospinal fluid

Because neurosyphilis may progress despite therapy with the recommended penicillin regimens, 15 subjects with positive tests for syphilis in the serum and cerebrospinal fluid (CSF) were studied. All of these patients had CSF pleocytosis. Two received penicillin G (5 and 10 million units per day intravenously, respectively) and 13 received benzathine penicillin G, 3.6 million units per week intramuscularly; treatment lasted four weeks. During intravenous and after intramuscular penicillin therapy, a spinal tap was performed on all subjects; later, assays were done. Of two patients who received intravenous penicillin G, one had 0.3 mug/ml and the other had 2.4 mug/ml penicillin in the CSF. Twelve of 13 patients who received benzathine penicillin G had no detectable penicillin in the CSF; one patient had 0.1 mug/ml penicillin in the CSF.     

The morphogenesis of melanotic lesions

A controlled trial of the relative efficacies of procaine penicillin G and pivampicillin for single dose treatment of uncomplicated gonorrhea in female was performed. Confirmation of the disease was obtained by bacteriological isolation of Neisseria gonorrhea from uretral, cervical or rectal exudates inoculated in suitable media. Based upon their previous experience, the authors used probenecid, along with both antibiotics, as a way of increasing the effectiveness of these drugs. Twentynine patients received probenecid 1 g. followed by oral pivampicillin, in a single dose of 1,4 g. Therapeutical results were evaluated in twenty-four, with clinical and bacteriological cure of eighteen. The other group included fifty-two patients treated with probenecid 1 g. followed by a single intramuscular dose of 3.000.000 U. of procaine penicillin G. The therapeutical results in the last group were evaluated in forty patients, with clinical and bacteriological cure of thirty-three. According to the above mentioned results procaine penicillin G seems to offer a slightly superior probability of cure.     

Effect of lyophilization and storage of liver 9,000xg supernatant fraction on the metabolism of imipramine in several species of animals

Six patients with Parkinson's disease and five controls were premedicated with probenecid and the peripheral decarboxylase inhibitor alpha-methyldopathydrazine (Carbidopa) before intravenous administration of 50 muc of 14C-L-dopa in tracer quantity. Seven-and-one-half hours later lumbar CSF was obtained. 14C-homovanillic acid (HVA), a major metabolite of brain dopamine, was isolated by thin-layer chromatography and measured. The statistically significant positive correlation between endogenous HVA and 14C-HVA in the entire patient group and the slightly lower values of endogenous HVA and 14C-HVA in the CSF of the parkinsonians support the assumption that the concentration of HVA in the CSF after probenecid treatment reflects brain dopamine turnover. Measurement of labeled HVA here seems to have little advantage over measurement of endogenous HVA alone.     

Simultaneous therapy of gonorrhea with penicillin and probenecid. Serum penicillin picture

19 patient received penicillin and probenecid. The resulting serum concentrations of penicillin was determined. In regimen I 4 mill. IU depot penicillin was given i.m. simultaneously with 1 g probenecid orally. In regimen II probenecid was given 30 min prior to the administration of penicillin. In both series the average serum concentrations of penicillin were not significantly different (p = 0.01).     

Immunological and trophical effects of Saccharomyces boulardii on the small intestine in healthy human volunteers

Recently we investigated the mechanisms mediating the transport of valproic acid (VPA) between blood and brain. In one study efflux of valproic acid (VPA) from rabbit brain was inhibited by probenecid. Efflux of VPA decreased when probenecid was given intravenously but not when probenecid was given by ventriculocisternal (VC) perfusion indicating that the major site of probenecid-sensitive transport was at the brain capillary endothelium and not at the choroid plexus. In another study VPA transport into rat brain was inhibited by para-aminohippurate (PAH). The purpose of the present study were to determine (a) if the efflux of VPA from rabbit brain was also inhibited by PAH, and (b) whether efflux of VPA could occur at the choroid plexus via an PAH-selective transport system. Six control rabbits received VPA by intravenous infusion and tracer concentrations of [3H]VPA and [14C]PAH by VC perfusion. Rabbits in the PAH group (n = 6) received identical treatment with VPA, tracer concentrations of [3H]VPA and [14C]PAH and, in addition, received 20 mM PAH by VC perfusion. PAH had no effect on the VC extraction ratio of [3H]VPA or the steady-state brain concentration of intravenously administered VPA. It is concluded that the efflux of VPA at the rabbit blood-brain barrier is mediated by a transporter different from the PAH-like transporter responsible for the uptake of VPA into rat brain. In addition, the finding that VC perfusion with PAH had no effect on the VC extraction of [3H]VPA provides further evidence that the choroid plexus plays a negligible role in removal of VPA from the CNS.     

Treatment of endometrial carcinoma with high-dose-rate brachytherapy alone in medically inoperable stage I patients

OBJECTIVE: To examine the pharmacokinetics of anticancer drugs in the cerebrospinal fluid (CSF) during chemotherapy by the lumbar-ventricular (LV) and ventricular-lumbar (VL) routes. CASE SUMMARY: A 69-year-old Japanese woman with disseminated glioblastoma received two LV and four VL courses of CSF perfusion chemotherapy with methotrexate, nimustine, and cytarabine hydrochloride. Samples of CSF from the ventricles and lumbar spinal canal were obtained via Ommaya reservoirs during one LV and one VL course. Drug concentrations in the CSF were measured by fluorescence polarization immunoassay or HPLC. RESULTS: During LV CSF perfusion, the highest CSF drug concentrations in both the ventricles and the lumbar spinal canal were observed at the end of perfusion. During treatment, the concentrations of all three drugs in the lumbar spinal canal were higher than those in the ventricles. The CSF AUC of methotrexate in the ventricles was 16.1% of that in the lumbar spinal canal. During VL CSF perfusion, the highest drug concentrations were also observed at the end of perfusion. The drug concentrations in the lumbar spinal canal were initially lower than those in the ventricles. However, the concentrations of methotrexate and cytarabine in the lumbar spinal canal exceeded those in the ventricles 3 hours after perfusion. The AUC of methotrexate in the lumbar spinal canal was 174.9% of that in the ventricles. CONCLUSIONS: The pharmacokinetics of anticancer drugs in ventricular CSF differ from those in lumbar CSF during LV and VL perfusion chemotherapy.     

The influence of CSF calcium and magnesium on the ventilatory response to carbon dioxide during hyperoxia

Respiratory responses to inhaled carbon dioxide were measured in anaesthetized cats during perfusion of the ventriculocisternal system with artificial cerebrospinal fluid. A study was performed to evaluate the effect of changes in the magnesium and/or calcium concentration of the CSF on the CO2 response curve which was described as VE = S (PCSF, CO2 -- B). A decrease of S was observed when the magnesium concentration of the perfusion fluid was increased; the B-value remaining the same. The reverse was true down to magnesium concentrations of 0.6 mmol-1-1. Below this concentration S remained the same or decreased; the B-value was lowered. When both the calcium and magnesium concentrations of the CSF were changed, the relation between S and these concentrations could be described as to be proportional to CCAa-CMgb. The effect of changes in the calcium concentration was much more pronounced than comparable changes of the magnesium concentration as reflected by the magnitude of the exponents a and b which were found to be -2.80 (S.D. 0.11) and -0.60 (S.D. 0.03) respectively.     

Concentrations of morphine and morphine metabolites in CSF and plasma during continuous subcutaneous morphine administration in cancer pain patients

Plasma and cerebrospinal fluid (CSF) steady-state concentrations (Css) of morphine (M) and the main metabolites morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), were determined by high performance liquid chromatography (HPLC) in 21 cancer patients treated with chronic subcutaneous morphine infusion. There was a moderate, but statistically significant correlation between the daily dose of morphine and the concentrations of morphine, M3G and M6G in CSF. A poorer correlation to concentrations were seen in plasma. The mean +/- SEM CSF/plasma morphine concentration ratio was 0.36 +/- 0.07. In plasma and CSF, the mean steady state concentration of M3G but not M6G substantially exceeded that of morphine where the mean CSF M/M3G/M6G ratio was 1:15:0.5 (molar basis), and the mean plasma ratio was M/M3G/M6G 1:31:3 (molar basis). The mean M3G and M6G concentrations in CSF were approximately 8 and 10% of those found in plasma, but there was a wide interindividual variation. Plasma concentrations of both morphine glucuronides were positively correlated to serum creatinine. Neither pain intensity, evaluated by visual analogue scale (VAS), nor side effects showed any relationship to the CSF M3G concentrations, M3G/M or the M3G/M6G ratios. We conclude that during steady state subcutaneous administration of morphine, there is a large interindividual variation in plasma morphine with poor relationship to the daily administered dose. In CSF this correlation was more evident. Plasma and CSF concentrations of M3G and CSF concentrations of M6G correlated with administered morphine dose. There was an accumulation of both morphine glucuronides in patients with elevated serum creatinine. Measurements of morphine, M3G and M6G in CSF did not show any overt relationship to analgesia or side effects.     

Analysis of penicillin G in milk by liquid chromatography

A liquid chromatographic (LC) method that was previously developed for penicillin G residues in animal tissues has been adapted to milk and milk products. After protein precipitation with sodium tungstate, samples are applied to a C18 solid-phase extraction cartridge, from which penicillin is eluted, derivatized with 1,2,4-triazole-mercuric chloride solution, and analyzed by isocratic liquid chromatography (LC) on a C18 column with UV detection at 325 nm. Quantitation is done with reference to penicillin V as an internal standard. Penicillin G recoveries were determined to be > 70% on standards fortified at 3-60 ppb. Accuracy approached 100% using the penicillin V internal standard. The detection limit for penicillin G residues was 3 ppb in fluid milk. Samples may be confirmed by thermospray/LC at concentrations approaching the detection limit of the UV method.     

Transport of 2,4,5-trichlorophenoxyacetic acid across the blood-cerebrospinal fluid barrier of the rabbit

Transport of the anionic herbicide, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) across the blood-cerebrospinal fluid barrier was investigated using the isolated choroid plexus of the adult rabbit in vitro and ventriculocisternal perfusion in vivo. In vitro, 2,4,5-T transport was effective, with tissue concentrations 20 times those in the medium after only 5 min of incubation with 1 microM 2,4,5-T. The tissue to medium ratios reached steady state by 20 min at approximately 45-fold. Uptake was energy dependent and inhibited by ouabain, phloridzin and several organic anions (probenecid, 2,4-dichlorophenoxyacetic acid and octanoate). Neither tyrosine (transported by a separate system) nor the neurotoxin, quinolinic acid, inhibited 2,4,5-T transport. Kinetic analysis yielded an apparent Km of 58 microM and Vmax of 111 nmol g-1 min-1 in the lateral ventricular choroid plexus with similar values (57 microM and 87 nmol g-1 min-1) in the fourth ventricular plexus. In vivo, the steady-state clearance of 2,4,5-T from the cerebrospinal fluid exceeded that of inulin and was reduced in a dose-dependent fashion by 2,4-dichlorophenoxyacetic acid and probenecid. Together, these data indicate that 2,4,5-T is cleared from the brain and cerebrospinal fluid by the organic anion transport system and that alterations in such transport may have a significant impact on the toxicity of this agent in the central nervous system.     

Antibiotic susceptibility profile of group B streptococcus acquired vertically

OBJECTIVE: To determine the contemporary antibiotic susceptibility profile of vertically acquired group B streptococcal isolates. METHODS: Susceptibility to ampicillin, penicillin G, erythromycin, clindamycin, cefazolin, and gentamicin was assessed by two methods, minimal inhibitory concentration and disc diffusion. RESULTS: The susceptibility profiles of 119 colonizing and eight invasive strains of group B streptococcus isolated from January 1996 to September 1997 at two hospitals in Birmingham, Alabama-University of Alabama at Birmingham and Cooper Green-were studied. Minimal inhibitory concentration determinations indicated that all colonizing strains were susceptible or moderately susceptible to ampicillin and penicillin G. Resistance was noted by at least one strain to each of the other antibiotics; all were resistant to gentamicin, whereas 27 (21%) were resistant to erythromycin, five (4%) to clindamycin, and one (1%) to cefazolin. All of the eight invasive strains were susceptible or moderately susceptible to ampicillin, penicillin G, clindamycin, and cefazolin; one (13%) was resistant to erythromycin, and all were resistant to gentamicin. Disc diffusion results generally were concordant with minimal inhibitory concentration results, although by disc diffusion fewer isolates were classified as susceptible, and more as moderately susceptible, to ampicillin and penicillin G than by minimal inhibitory concentration. CONCLUSION: Universal susceptibility of group B streptococcus to members of the penicillin family supports the continued use of penicillin G or ampicillin for early onset neonatal group B streptococcal disease prevention. For patients allergic to beta-lactam agents, clindamycin (4% resistance) may be a better alternative than erythromycin (21% resistance).     

Mechanism of valproic acid uptake by isolated rat brain microvessels

In an effort to characterize putative transport systems of valproic acid (VPA) at the blood-brain barrier, the effects of various substrates and inhibitors of known anion transporters on the equilibrium vessel-to-medium concentration (vessel/medium) ratio of VPA were investigated using isolated rat brain microvessels. The equilibrium vessel/medium ratio of VPA was decreased by the presence of high millimolar concentration of unlabeled VPA, indicating that a saturable transport system was involved in VPA transport from medium to microvessels. Short-chain monocarboxylates such as propionic acid, pyruvic acid, and L-lactic acid did not alter the vessel/medium ratio, whereas medium-chain fatty acids and unsaturated metabolites of VPA significantly inhibited the net transport of VPA. Dicarboxylates, tricarboxylate, and p-aminohippuric acid did not affect VPA accumulation in the brain microvessels. Several anionic drugs including salicylic acid, penicillin G, cefazolin, and probenecid significantly reduced the vessel/medium ratio of VPA. In addition, disulfonate inhibitors of inorganic anion exchangers, SH-group modifying reagent, and metabolic inhibitor showed remarkable inhibitory effects on the net transport of VPA between brain microvessels and medium. These results suggest that VPA may be actively transported through the antiluminal membrane via a carrier-mediated system shared by other anionic drugs.     

Immobilization of whole-cell penicillin G acylase by entrapping within polymethacrylamide beads

Escherichia coli ATCC 11105 containing the periplasmic penicillin G acylase was entrapped within a copolymer of methacrylamide and N,N'-methylenebisacrylamide. A solution of monomer that was made up from methacrylamide and N,N'-methylenebisacrylamide dissolved in buffer was mixed with lyophilized cells and ammonium persulfate. This suspension was then pumped drop by drop into in soybean oil supplemented with 0.06% (v/v) 3-(dimethylamino)-propionitril. During submerging in the oil phase, the droplets were hardened and induced to polymerize within the droplets. Particles with a volume ranging from 0.013-0.017 mL per bead containing a biomass concentration up to 38.0 g/L were prepared. The optimal condition for the deacylation of penicillin G to 6-aminopencillanic acid (6-APA) catalyzed by the immobilized whole-cell penicillin G acylase was found to be 45 degrees C and pH 8.0. Product inhibition of this enzyme by 6-APA could be eliminated by controlling pH value at 8 during the course of penicillin G hydrolysis using a pH-stat. Conversion determined by the pH-stat method were 0.3% higher than that by p-dimethylaminobenzaldehyde method. Cell concentration in the matrix was found to be an important factor influencing the maximum velocity and the specific activity retained in the matrix. A kinetic model, in which the mass transfer resistances as a result of external film mass transfer and pore diffusion were assumed to be negligible, could properly describe the hydrolysis of penicillin G by the cells entrapped within the polymethacylamide beads.     

Amnesia following infarction in the right retrosplenial region

An animal model of subarachnoid cavity drugs perfusion and its prelimilary clinical application in treatment of acute spinal cord injury (SCI) were reported. Analysis of the heart rate (HR), ECG blood pressure (CVP, CAP) cerebrospinal fluid (CSF) pressuer and CSF gas and pH values of 10 healthy adult goats during subarachnoid daxamethasone verapamil perfusion showed that this model was safe anti reliable. 26 patients with acute SCI were selected for a clinical obseration. Good results were obtained in 7 cases who received this treatment of subarachnoid cavity perfusion with dexamethasone and verapamil.     

Meningitis caused by Streptococcus bovis

Streptococcus bovis was isolated from the CSF of a 66-year-old man with meningitis. His clinical appearance was unusual in that he lacked typical signs and symptoms of pyogenic meningitis. Streptococcus bovis was also recovered from his blood, which suggested that bacterial endocarditis was the source of his CNS infection. He was cured after four weeks of therapy with intravenous penicillin G potassium. This is the fourth reported case of meningitis caused by S bovis. The previous three patients also had endocarditis caused by S bovis. Because of the reported propensity of S bovis to infect heart valves and the frequent association of S bovis bacteremia with malignant gastrointestinal (GI) tract tumors, recovery of this organism form CSF should prompt a search for bacterial endocarditis and occult GI cancer.     

Public health activity for the prevention of nutritional anemia of women in a Japanese rural population

Changes in the concentration of the main noradrenaline metabolite in rat brain, 4-hydroxy-3-methoxy-phenylethyleneglycol sulphate (MOPEG-SO4) have been studied during and after injury by limb ischaemia. In the hypothalamus the MOPEG-SO4 concentration rose in about 30 min to a new plateau level which was maintained during a 4 h period of bilateral hind-limb ischaemia and then rose further when the circulation to the limbs was restored. After about 2 h hind-limb ischaemia the concentration in the hind-brain, particularly in the caudal half, rose progressively and this rise continued when the tourniquets were removed after 4 h. Limb ischaemia did not affect the MOPEG-SO4 concentration in the cerebellum but the concentration rose in the cerebrospinal fluid. Attempts to study the production of MOPEG-SO4 in more detail by inhibiting its transport from the brain with probenecid were not helpful and reasons are given for thinking that probenecid is not a useful tool for this type of investigation. The results are considered to provide further evidence that trauma activates ascending and descending pathways which arise from the noradrenergic nerve cells in the hind-brain.     

Elucidation of conditions allowing conversion of penicillin G and other penicillins to deacetoxycephalosporins by resting cells and extracts of Streptomyces clavuligerus NP1

Using resting cells and extracts of Streptomyces clavuligerus NP1, we have been able to convert penicillin G (benzylpenicillin) to deacetoxycephalosporin G. Conversion was achieved by increasing by 45x the concentration of FeSO4 (1.8 mM) and doubling the concentration of alpha-ketoglutarate (1.28 mM) as compared with standard conditions used for the normal cell-free conversion of penicillin N to deacetoxycephalosporin C. ATP, MgSO4, KCl, and DTT, important in cell-free expansion of penicillin N, did not play a significant role in the ring expansion of penicillin G by resting cells or cell-free extracts. When these conditions were used with 14 other penicillins, ring expansion was achieved in all cases.     

Aldosterone secretion during high sodium cerebrospinal fluid perfusion of the brain ventricles

Conscious sheep with permanent indwelling cannulae in the lateral ventricles and the cisterna magna were Na depleted and then perfused for 9 h with an artificial CSF solution. There were 3 experimental groups: Group I (n=5) received perfusion with aritifical CSF containing NA 170 MEq./1, Group II (n=7) received perfusion with artificial CSF containing Na 145 mEq./1, Group III (n=7) received no perfusion. In Group I the blood aldosterone level fell from 26.4 +/- 7.4 to 8.6 +/- 2.3 ng/100 ml by 9 h after perfusion. There was no significant change in plasma [Na] or [K], blood angiotensin II or plasma renin concentration. Blood cortisol and corticosterone levels rose. There was also a fall in post-perfusion. Group III showed no significant change in blood aldosterone concentration. Multivariate statistical analysis showed that the fall in aldosterone levels during 170 mEq./l Na perfusion could not be accounted for by changes, either alone or together, of ACTH as evidenced by alteration in blood cortisol or corticosterone, or by change of plasma [Na], [K] or renin concentrations. This data supports the hypothesis of an additional factor which may be of CNS origin being involved in the control of aldosterone secretion.     

Penicillin-resistant mechanisms in Pseudomonas aeruginosa: binding of penicillin to Pseudomonas aeruginosa KM 338

A comparison of the binding of radioactive penicillin G to whole cells and the membrane fraction derived from Pseudomonas aeruginosa KM 338 was made. This organism has intrinsic resistance to penicillin. The binding to the membrane fraction which catalyzed peptidoglycan synthesis followed saturation type kinetics and saturation was achieved at approximately 2 nmol of penicillin G per ml, whereas binding to the whole cells was entirely of the nonsaturation type. The binding of carbenicillin to the membrane fraction was determined by competition between radioactive penicillin G and unlabeled carbenicillin for the binding sites. It was bound at the same sites in almost the same manner. When whole cells were pretreated with high concentration of unlabeled penicillin G or carbenicillin, the subsequent binding of radioactive penicillin G to the membrane fraction from carbenicillin-treated cells was entirely nonspecific, but with penicillin G-pretreated cells it was still specific. There was apparently specific binding of radioactive penicillin G to ethylenediaminetetraacetate-treated cells. P. aeruginosa KM 338 had an extremely low activity of beta-lactamase compared with other enzyme-producing organisms. This enzyme from P. aeruginosa KM 338 was of the cephalosporinase type. These data indicate that penicillin resistance of P. aeruginosa KM 338 may be a consequence of the development of a permeability barrier which prevents the antibiotic from reaching its sites of action in the cytoplasmic membrane.     

1998 Labat Lecture: the role of the neurolytic celiac plexus block in pancreatic cancer pain management: do we have the answers?

Adrenomedullin (AM), a potent vasodilator peptide, has been shown to act within the central nervous system to modulate fluid and electrolyte balance. AM-immunoreactive cells have been found in the anterior pituitary gland and the choroid plexus of humans. In addition, AM activity has been implicated in the regulation of maternal circulation during pregnancy. To determine the relationship between AM concentration in the cerebrospinal fluid (CSF) and plasma, we measured AM levels in CSF and plasma of pregnant (group P, n = 12) and non-pregnant (group NP, n = 10) women scheduled to undergo gynecologic or obstetric surgery. In both groups, the concentration of AM in the plasma exceeded that in the CSF. Plasma AM concentration was significantly higher in pregnant than non-pregnant women (17.3+/-5.8 vs 5.1+/-1.4 pmol/l, mean +/- S.D.; P<0.01), whereas CSF AM concentration did not differ between the two groups (1.3+/-0.9 and 0.9+/-0.4 pmol/l in groups P and NP respectively). No significant correlation was found between AM concentrations in the CSF and plasma. The present findings suggest that AM is present in the CSF and that its concentration in the CSF is regulated independently from that in the plasma.