Folate transport by the choroid plexus in vitro.

Reduced folates are transported from blood into cerebrospinal fluid against a concentration gradient. In vitro, folates were transported into and released by isolated rabbit choroid plexuses. The choroid plexus uptake mechanism was specific for folates, energy dependent, and depressed by cold temperatures. In vivo, the choroid plexus may transport folates from blood to cerebrospinal fluid.

Leukotriene C4 transport by the choroid plexus in vitro.

Nanomolar concentrations of peptidoleukotrienes evoke sustained cerebral edema and arterial constriction. Peptidoleukotrienes are thus considered to play an important role in eliciting cerebral edema after cerebral ischemia and vasospasm after subarachnoid hemorrhage. It was hypothesized that the choroid plexus, the locus of the blood-cerebrospinal fluid barrier, might minimize the vasoactivity of locally generated or systemically derived leukotrienes by transporting leukotrienes from cerebrospinal fluid into the blood. Consistent with this hypothesis, leukotriene C4 in vitro was transported into and released from isolated rabbit choroid plexus by a system that was specific, energy-dependent, probenecid-sensitive, and depressed by cold temperatures. The accumulation of leukotriene C4 in the choroid plexus was not dependent on tissue binding or metabolism of leukotriene C4.

Polonium radiohalos: an alternate interpretation.

A study of the sizes of so-called polonium radiohalos of various types found in biotite from Bancroft, Ontario, has been carried out. The evidence is consistent with the interpretation that these halos are variants of the standard uranium halos. A review of the literature indicates that there is no firm evidence that polonium halos exist, all evidence being equally consistent with the interpretation that these are uranium halos.

High incidence of non-upper aerodigestive primary tumors in patients with esophageal cancer.

Earlier reports have described an association between esophageal cancer (EC) and high incidence of other primary tumors (OPTs) of the upper aerodigestive tract and breast cancer. We evaluated the incidence of non-upper aerodigestive OPTs among Israeli EC patients; 2328 EC patients were retrieved from the Israeli National Cancer Registry between 1980 and 2004. The relative risk of OPTs for EC patients was measured using standardized incidence ratio (SIR). Two cohorts, Israeli National Cancer Registry registered colorectal cancer (CRC) patients and the general Israeli population, were used for reference; 297 EC patients (12.7%) had OPTs, including breast (18.9%), CRC (16.2%), prostate (8.8%), and bladder (8.4%) cancers. Upper aerodigestive OPTs were less common. Most OPTs were identified before (74.4%) or simultaneously with (13.8%) EC diagnosis. The median time interval between OPTs diagnoses and EC development was 6.0 years. The incidence of OPTs was significantly higher among EC patients compared with CRC patients (SIR: 2.05, P < 0.01) or the general Israeli population (SIR: 3.90, 95% CI: 3.46-4.34, P < 0.01) regardless of gender or tumor histology. Patients with EC have high incidence of non-upper aerodigestive malignancies. Unlike previous reports, the distribution of OPTs in EC seems to represent the relative incidences of these cancers in the western populations.

Riboflavin transport in the central nervous system. Characterization and effects of drugs.

The relationship of riboflavin transport to the transport of other substances including drugs in rabbit choroid plexus, the anatomical locus of the blood-cerebrospinal fluid barrier, and brain cells were studied in vivo and in vitro. In vitro, the ability of rabbit choroid plexus to transport riboflavin from the medium (cerebrospinal fluid surface) through the choroid plexus epithelial cells into the extracellular and vascular spaces of the choroid plexus was documented using fluorescence microscopy. These studies provided further evidence that riboflavin is transported from cerebrospinal fluid to blood via the choroid plexus. The transport of [14C]riboflavin by the isolated choroid plexus was inhibited by thiol agents, ouabain, theophylline, various flavins (lumiflavin and lumichrome > sugar containing flavins), and cyclic organic acids including penicillin and fluorescein. Riboflavin inhibited [14C]penicillin transport competitively and the inhibition constant (K1) for riboflavin equaled the concentration of riboflavin at which the saturable transport system for riboflavin is 50% saturated (KT). These and other data suggest that riboflavin, penicillin, and possibly fluorescein are transported by the same transport system in choroid plexus. In vivo, the intra-ventricular injection or riboflavin and [14C]penicillin inhibited [14C]penicillin transport from cerebrospinal fluid. In vitro, various flavins (riboflavin > other sugar-containing flavins > lumiflavin > lumichrome) inhibited [14C]riboflavin accumulation by brain slices. These studies support the notions that: (a) riboflavin accumulation by choroid plexus (active transport) is quite different from that in brain cells (facilitated diffusion and intracellular trapping), and (b) therapeutically important cyclic organic acids (e.g., penicillin) are transported fom cerebrospinal fluid by the riboflavin transport system in choroid plexus.

Inhibition of penicillin transport from the cerebrospinal fluid after intracisternal inoculation of bacteria.

The effect of intracisternal inoculation of bacteria on the choroid plexus system, which transports penicillin from cerebrospinal fluid (CSF) to blood, was studied in vitro and in vivo. Meningeal and choroid plexus inflammations as well as CSF pleocytosis were induced in rabbits with intracisternal inoculations of Hemophilus influenzae or Staphylococcus aureus. At various times after bacterial inoculation, the choroid plexuses of the inoculated rabbits were removed and incubated in artificial CSF containing [(14)C]penicillin. The ability of the choroid plexuses to accumulate pencillin in vitro was measured and was found to be depressed as compared with controls. This depression of choroid plexus uptake reversed with resolution of the inflammatory process. In vivo on the day after intracisternal inoculation of Hemophilus influenzae, a decrease in the disappearance of penicillin relative to inulin in the inoculated rabbits (as compared to the controls) was observed when [(14)C]penicillin and [(3)H]inulin were injected intraventricularly and cisternal CSF was sampled 2 h later. This decrease could not be explained by penicillin binding to the CSF exudate. However, the choroid plexus transport system for penicillin was only partially depressed in those inoculated rabbits with bacterially induced inflammation, since in vitro the choroid plexuses could still accumulate penicillin and in vivo CSF penicillin levels could be further increased with probenecid pretreatment. These results suggest that CSF penicillin levels are increased in this model due to three factors: a depression of active efflux of penicillin from the CSF, an increase in permeability to penicillin of inflamed meninges, and, less significantly, by CSF binding of penicillin.

Should tonometry screening be done by technicians instead of physicians?

A random sample of 768 clinic patients 40 years or older were screened by a technician utilizing Schlotz tonometry. All patients with an intraocular pressure of 20 mm Hg or more were referred for ophthalmological evaluation. The prevalence of frank glaucoma and suspected glaucoma in this infirm population was 1.8% and 2.5%, respectively. The cost of detecting frank or suspected glaucoma decreased in the second half of the study due to a decrease in the number of false-positive tests. These findings suggest that all clinic patients 40 years or older should be screened for glaucoma. Because many internists are reluctant to screen for glaucoma and because there are large number of false-positive tests by those who do tonometry episodically, we suggest that technicians do glaucoma screening.

Does intervention by a nurse improve medication compliance?

A random sample of patients taking two or more drugs, at least one of which was digoxin or methyldopa, was drawn from a medical clinic population. After giving informed consent, the patients were randomized into control and experimental groups. The experimental group was seen by a specially prepared nurse interventionist who attempted to improve medication compliance. The levels of the drugs in the blood were taken as indicators of medication compliance. Our results document that patients exposed to nurse intervention were more compliant than the general clinic population, but were not more compliant than a nonintervention control group. Problems encountered in the collection and interpretation of compliance study data were identified and discussed.

Serious adverse reactions associated with sulindac.

Sulindac is a nonsteroidal anti-inflammatory agent that has been associated with serious adverse reactions. We saw four patients with reactions associated with sulindac. Our patients, one of whom died, had high temperatures and involvement of one or more organs, including the skin, liver, CNS, lymph nodes, bone marrow, and lungs. Eight similar previously reported cases also are summarized. In view of these cases of sulindac-induced toxicity, six of which were proved unequivocally by drug rechallenge, we suggest that physicians be cautious in prescribing this agent.

Expanded role of charcoal therapy in the poisoned and overdosed patient.

Activated charcoal is widely used as an adsorbent for the management of patients with drug overdoses and poisonings. Activated charcoal can be used orally to prevent drug and poison absorption in cases of overdose and poisoning. Multiple oral doses of charcoal increase the elimination of several, but not all, drugs and poisons. The effectiveness of multiple oral doses of charcoal in accelerating drug clearance is dependent primarily on the endogenous clearance of the drug or poison and its volume of distribution. Multiple doses of charcoal are used to shorten the period of supportive care in certain patients or to more rapidly remove drugs or poisons that may cause tissue damage, eg, theophylline. Charcoal is a safe, effective, and inexpensive alternative to more invasive treatments for some cases of drug overdose and poisoning.

An approach to the management of the poisoned patient.

Our systematic approach to the evaluation and treatment of the acutely poisoned patient involves establishing an accurate diagnosis and prognosis that often may be based on quantitation of the blood concentration of the toxic substance. The major feature of this approach is the proper selection of treatment(s) for the poisoned patient, ie, decontamination and supportive care and, in some cases, antidotal therapy and/or active removal of the toxic substance. Invasive, expensive methods of active removal (eg, hemodialysis or hemoperfusion) are generally recommended only if specific criteria are satisfied. Noninvasive, inexpensive methods of active removal (eg, manipulation of urinary pH or the oral administration of multiple doses of activated charcoal) may have significant utility in the treatment of poisoned patients not requiring invasive methods. This systematic approach to the poisoned patient should lead to an effective use of treatment modalities with minimal risks and optimal clinical results.

Search for DNA alterations in Alzheimer's disease.

The DNA of brain cortex obtained from autopsy specimens of eight patients with Alzheimer's disease and eight controls was examined for content of normal and abnormal bases. DNA, purified by hydroxyapatite chromatography, was hydrolyzed under mild conditions and the deoxynucleosides were measured by high performance liquid chromatography (HPLC). No differences in the mole percentages of deoxynucleosides in DNA were detected in patients with Alzheimer's disease compared to controls, nor were abnormal deoxynucleosides found. Restriction-nuclease digests examined by agarose gel electrophoresis also showed no changes. Thus, diffuse and persistent damage to the DNA in brain in Alzheimer's disease was not detected by these methods.

Kinetics of single doses of fenbufen in patients with renal insufficiency.

Fenbufen (gamma-oxo[1,1'-biphenyl]-4-butanoic acid) is a nonsteroidal anti-inflammatory analgesic that is metabolized to four major metabolites: gamma-hydroxy [1,1'-biphenyl]-4-butanoic acid (II), [1,1'-biphenyl]-4-acetic acid (III), 4'hydroxy [1,1'-biphenyl]-4-acetic acid (IV), and gamma, 4'-dihydroxy [1, 1'-biphenyl]-4-butanoic acid (V). Fenbufen and metabolites II and III circulate to plasma and are pharmacologically active; metabolites IV and V are normally excreted in urine. Single 800-mg doses of fenbufen were safely administered to 10 healthy subjects and to 16 patients with varying degrees of renal insufficiency. Drug and metabolite concentrations in serum and urine were determined at intervals for 3 days. It was found that renal impairment altered the metabolic pattern of fenbufen. Although t1/2 beta was the same for fenbufen and II, their plasma levels fell. No change was found in the plasma levels of III. There was evidence of moderate cumulation in plasma of the two more polar urinary metabolites (IV, V) corresponding to the degree of renal insufficiency. The total of all five compounds excreted into the urine was diminished. To account for this, either biliary and gastrointestinal excretion increased or there may have been further hepatic biotransformation of the metabolites.

The effect of dietary protein-calorie restriction on the renal elimination of cimetidine.

The renal elimination of the weak-base cimetidine was studied in five healthy male subjects during normal and restricted (low-protein, low-calorie) diets in a randomized crossover fashion. An intravenous dose of cimetidine, 7 mg/kg, was administered on day 7 of the normal (100 gm/70 kg protein/day) and the restricted (19 gm/70 kg protein/day) diets. The renal clearance of cimetidine was unchanged by the dietary restriction; however, the fractional excretion of cimetidine increased from 3.06 to 3.94 (P less than 0.05), indicating an apparent increase in net tubular secretion of cimetidine during the restricted diet. We conclude that cimetidine dosage adjustments are apparently not necessary for patients with acutely restricted nutrient intake, although other weakly acidic and basic drugs may require dosage changes.

Model for theophylline overdose treatment with oral activated charcoal.

The effect of repeated oral doses of activated charcoal on theophylline kinetics was studied in six subjects with hepatic cirrhosis and five patients with moderate theophylline poisoning to determine whether an activated charcoal regimen would be a useful strategy in patients with theophylline poisoning who did not require hemoperfusion. Six subjects with cirrhosis were injected IV with 6 mg/kg aminophylline followed by either water or water with activated charcoal (140 gm) in divided doses over 12 hr. In these subjects, treatment with activated charcoal decreased the mean (+/- SE) serum theophylline t1/2 from 12.7 +/- 4.0 hr to 4.0 +/- 0.7 hr. Subjects with the longest control t1/2s demonstrated the greatest charcoal effect. We developed a mathematical model that predicts that treatment with repeated oral doses of activated charcoal would result in an average serum theophylline t1/2 of 7.1 hr or less even if the subject's endogenous theophylline t1/2 is very long. In a pilot study of five patients with moderate theophylline poisoning, treatment with repeated oral doses of activated charcoal was well tolerated and led to a mean (+/- SE) t1/2 that was shorter than expected (4.9 +/- 0.8 hr, range 3.1 to 7.1 hr). We conclude that repeated oral doses of activated charcoal are relatively more effective in decreasing the serum theophylline t1/2 in persons with long endogenous t1/2s and that this may be useful for certain patients with mild or moderate theophylline poisoning.

Renal clearances of oxypurinol and inulin on an isocaloric, low-protein diet.

In previous studies a low-calorie, low-protein diet caused a sustained reduction in both oxypurinol and uric acid renal clearances (CLR). With the hypothesis that the decrease in CLR was due to the low-protein and not the low-caloric content of the diet, we studied the CLR of oxypurinol, uric acid, creatinine, and inulin in normal subjects during isocaloric (2600 calories per 70 kg per day), normal-protein (150 gm per day), and low-protein (19 gm per day) diets. There were three major findings: (1) the CLR of oxypurinol declined from 26.6 +/- 1.8 ml/min on the normal-protein diet to 13.5 +/- 1.4 ml/min on the isocaloric low-protein diet (p less than 0.05); (2) the CLR of inulin and creatinine fell 14% and 20%, respectively, on the low-protein diet compared with the normal-protein diet (both p less than 0.05); and (3) there was a diurnal variation in the CLR of oxypurinol. We conclude that the decreased CLR of oxypurinol was the result of the reduced protein content of the diet and the CLR of both inulin and creatinine were decreased on the low-protein diet.

Diphenhydramine in Orientals and Caucasians.

The kinetics and psychomotor effects of diphenhydramine were investigated in Orientals and Caucasians. Each of 5 Oriental and 5 Caucasian young adults received on 1 of 3 occasions diphenhydramine 50 mg/70 kg body weight either intravenously or orally, or placebo. Plasma levels of diphenhydramine were measured hourly for 8 hr at each session. Tests of subjective sedation and psychomotor performance were performed at hourly intervals. The results showed that after both intravenous and oral diphenhydramine, at all times Orientals had plasma levels approximately half those of Caucasians. With the assumption of linear kinetics and a 1-compartment open model, analysis of the data showed that the volume of distribution (VD) and plasma clearance (Cl) but not plasma half-life (t 1/2) were higher in Orientals than Caucasians: [VD = 480 +/- 24 (SEM) and 292 +/- 36 1/70 kg; Cl = 79 +/- 7 and 51 +/- 7 1/70 kg/hr; t 1/2 = 4.1 +/- 0.4 and 4.3 +/- 0.4 hr]. Unbound diphenhydramine in fresh plasma was higher in Orientals than Caucasians [24.0 +/- 1.9% (SEM) and 14.8 +/- 1.5%] and probably explains the increased VD in Orientals. Orientals had significantly less sedation and deterioration in psychomotor performance.

Lack of effect of oral activated charcoal on imipramine clearance.

The effect of oral activated charcoal on the pharmacokinetics of intravenous imipramine was studied in a randomized, crossover trial. Four normal men received intravenous imipramine (12.5 mg/70 kg) on two separate occasions, followed by either water or water plus high-surface-area activated charcoal (180 gm) in divided doses over 24 hours. Serum imipramine concentrations were measured from 0 to 24 hours after the imipramine infusion. There was no difference in the mean (+/- SE) t1/2 (9.0 +/- 0.8 vs. 10.9 +/- 1.6 hours), apparent volume of distribution (11.2 +/- 2.1 vs. 12.4 +/- 2.1 L/kg), or systemic clearance (992.2 +/- 138.3 vs. 930.3 +/- 101.9 ml/min/70 kg) of imipramine after dosing without and with oral activated charcoal, respectively (P greater than 0.05; paired t test). These results suggest that multiple oral doses of activated charcoal do not increase the clearance of imipramine in man.

Effects of size and frequency of oral doses of charcoal on theophylline clearance.

The effect of size and frequency of oral doses of activated charcoal on theophylline kinetics was studied. Six fasting, healthy men received intravenous infusions of aminophylline (6 mg/kg) over 1 hr, followed by either no activated charcoal as a control, 5 gm activated charcoal every 2 hr for 6 doses, 10 gm every 2 hr for 6 doses, 10 gm every hr for 12 doses, 20 gm every 2 hr for 6 doses, or 40 gm every 4 hr for 3 doses. Five grams every 2 hr decreased serum theophylline t 1/2 from the control of 9.1 +/- 0.7 to 5.6 +/- 0.4 (SE) hr and decreased the AUC from the control of 123 +/- 11 to 79 +/- 6 mg X hr/l. The regimen of 20 gm every 2 hr further decreased theophylline t 1/2 to 4.3 +/- 0.4 hr and decreased AUC to 62 +/- 6 mg X hr/l. When a 120-gm dose of activated charcoal was given as a regimen of 40 gm every 4 hr or as a regimen of 10 gm every hr, there were small differences in serum theophylline t 1/2 (5.4 +/- 0.3 and 4.3 +/- 0.2 hr) and in AUC (73 +/- 5 and 60 +/- 4 mg X hr/l). Repeated small doses of oral activated charcoal enhanced the total body clearance of theophylline, and larger doses induced a relatively small further increase. There was little difference between the effects of the same total dose every 4 hr vs every hour.

Diphenhydramine: kinetics and psychomotor effects in elderly women.

Kinetics and sedative and psychomotor effects of diphenhydramine were investigated in elderly Caucasian women (greater than 64 yr. old). In a double-blind trial, each of 12 healthy subjects received on one of three occasions 50 mg/70 kg IV or oral diphenhydramine HCl or oral placebo. Plasma levels of diphenhydramine were measured in six subjects and tests of sedation and psychomotor performance were performed hourly for 8 hr in all subjects. Kinetic analysis showed that the volume of distribution (295 +/- 50 [SEM] l/70 kg), clearance (42 +/- 5 l/70 kg/hr), and plasma t1/2 (4.9 +/- 0.7 hr) were of the same order as in young adults. As in young adults, there was minimal psychomotor impairment after oral and after intravenous diphenhydramine. In contrast to young adults, however, elderly women did not report significant sedation after diphenhydramine. These results suggest that diphenhydramine may not be an effective sedative/hypnotic in elderly women.