Serum tolbutamide and chlorpropamide concentrations in patients with diabetes mellitus

A selective and sensitive gas chromatographic technique was used to measure the steady-state serum concentrations of tolbutamide and chlorpropamide in 97 patients with maturity-onset diabetes mellitus who had been taking these drugs (37 tolbutamide, 60 chlorpropamide) for at least a year. No other antidiabetic agents had been given. The serum tolbutamide concentrations varied widely between the patients (from close to zero to 370 μmol/l (100 μg/ml)), yet the variation in dosage was only sixfold (0·5-3·9 g daily). The serum chlorpropamide concentrations varied even more widely (from close to zero to 882 μmol/l (244 μg/ml)), though the dosage variation was fourfold (125-500 mg daily). There was no systematic relation between dosage and serum concentrations of the drugs.Only 2 (5·4%) of the tolbutamide-treated patients and 10 (16·7%) of the chlorpropamide-treated patients had normal fasting blood glucose concentrations (below 5·5 mmol/l (99 mg/100 ml)), and fewer than half had values below 8·0 mmol/l (144 mg/100 ml). In most cases, therefore, the treatment was insufficient.There was no significant difference in mean fasting blood glucose concentrations between the two treatment groups. The mean steady-state concentration of chlorpropamide, however, was significantly higher than that of tolbutamide. Thus, contrary to common belief, the intrinsic activity of chlorpropamide is apparently not greater than that of tolbutamide. The alleged greater potency of chlorpropamide seems to be related wholly to kinetic differences, such as the less extensive metabolic degradation and slower elimination of the drug.We conclude that treatment with sulphonylureas in conventional dosage is far from optimal and that monitoring the concentrations of these drugs in the blood may help to improve their efficacy.     

Use of β-Blockade and Hemoperfusion for Acute Theophylline Poisoning

Five adults were treated successfully for severe theophylline poisoning due to intentional overdosage. Clinical features included nausea, tremor, delirium, hypotension and cardiac arrhythmias, metabolic acidosis, hyperglycemia, hypokalemia and hypophosphatemia. No seizures or deaths occurred despite very high serum theophylline concentrations (between 96 and 194 μg per ml). Extreme elevations of plasma catecholamines were documented and are implicated in the toxicity. β-Blockade with intravenous administration of propranolol hydrochloride was the most effective therapy for theophylline-induced hypotension. All patients were treated with resin hemoperfusion, which resulted in significant clinical improvement and rapid lowering of the serum theophylline level.     

In Vitro Sensitivity of Torulopsis glabrata to Amphotericin B, 5-Fluorocytosine, and Clotrimazole (Bay 5097)

Thirty-five strains of Torulopsis glabrata were tested by a tube dilution method for their susceptibility to amphotericin B, 5-fluorocytosine, and clotrimazole (Bay 5097). Amphotericin B was the most active in vitro, inhibiting all strains at a concentration of 1 μg/ml and killing all strains at 2 μg/ml. 5-Fluorocytosine inhibited over 80% of strains at 0.24 μg/ml, but three strains required ≥7.8 μg/ml for killing. A concentration of 2 μg of clotrimazole per ml inhibited less than 50% of strains, and 8 μg/ml killed only 10% of strains. Most strains of T. glabrata were killed by therapeutically achievable concentrations of amphotericin B and 5-fluorocytosine, but not clotrimazole.     

Gonococcal Antibiotic Resistance in Los Angeles

One hundred and thirty-five gonococcal isolates collected from Los Angeles in 1972 were studied for antibiotic susceptibility to penicillin, ampicillin, carbenicillin, tetracycline, minocycline, doxycycline and spectinomycin. Only 12 percent of the isolates were sensitive to 0.05 μg per ml of penicillin while 35 percent required at least 0.5 μg per ml for inhibition of growth. The results were slightly better with ampicillin and nearly the same with carbenicillin. Nineteen percent of the isolates required at least 1.0 μg per ml of tetracycline for inhibition of growth and the results were similar with either minocycline or doxycycline. Forty-nine percent were sensitive to 2.0 μg per ml spectinomycin, but 37 percent required at least 8.0 μg per ml for inhibition of growth.In this study nine of eleven isolates resistant to 1.0 μg per ml of tetracycline were also resistant to both penicillin and spectinomycin. Six came from endocervical sites of female patients who contributed only 37 percent of the total number of isolates studied.Correlation between the agar dilution and disc diffusion methods was satisfactory with penicillin but not with ether tetracycline or spectinomycin.     

In Vitro Susceptibility of Neisseria gonorrhoeae to Nine Antimicrobial Agents

The in vitro action of nine antibiotics was tested by the agar streak method against 45 gonococcal strains isolated from penicillin-therapy failures. The penicillin susceptibility range of these strains was 0.003 to 1.32 μg/ml, and the tetracycline susceptibility range was 0.125 to 2.0 μg/ml. Minimal inhibitory concentrations of minocycline and doxycycline paralleled the activity of tetracycline and ranged from 0.125 to 1.0 μg/ml and 0.125 to 2.0 μg/ml, respectively. Rifampicin, with a narrow range of 0.5 to 1.0 μg/ml, inhibited 75% of the strains at 0.5 μg/ml. The range for cephaloridine and cephaloglycine was 0.5 to 20.0 μg/ml, but another cephalosporium derivative, cephalexin, exhibited greater activity in its range of 0.25 to 20.0 μg/ml. A semisynthetic penicillin, carbenicillin, with a range of 0.025 to 0.75 μg/ml, displayed more activity against the lower susceptible penicillin G gonococcal strains.     

Nicotine Content of Tobacco Roots and Toxicity to Meloidogyne incognita

The motility of Meloidogyne incognita second-stage juveniles (J2) and their ability to induce root galls in tomato were progressively decreased upon exposure to nicotine at concentrations of 1-100 μg/ml. EC₅₀ values ranged from 14.5 to 22.3 μg/ml, but J2 motility and root-gall induction were not eliminated at 100 μg/ml nicotine. Nicotine in both resistant NC 89 and susceptible NC 2326 tobacco roots was increased significantly 4 days after exposure to M. incognita. The increase was greater in resistant than in susceptible tobacco. Root nicotine concentrations were estimated to be 661.1-979.1 μg/g fresh weight. More M. incognita were detected in roots of susceptible than in roots of resistant tobacco. Numbers of nematodes within resistant roots decreased as duration of exposure to M. incognita was increased from 4 to 16 days. Concentrations of nicotine were apparently sufficient to affect M. incognita in both susceptible and resistant tobacco roots. Localization of nicotine at infection sites must be determined to ascertain its association with resistance.     

Supplemental Substrate Enhancement of 2,4-Dinitrophenol Mineralization by a Bacterial Consortium

A Janthinobacterium sp. and an actinomycete, both capable of mineralizing 2,4-dinitrophenol (DNP), were used to construct a consortium to mineralize DNP in nonaxenic bench-scale sequencing batch reactors (SBRs). Average K_m values for DNP mineralization by pure cultures of the Janthinobacterium sp. and the actinomycete were 0.01 and 0.13 μg/ml, respectively, and the average maximum specific growth rate (μ_max) values for them were 0.06 and 0.23/h, respectively. In the presence of NH₄Cl, nitrite accumulation in pure culture experiments and in the SBRs was stoichiometric to initial DNP concentration and the addition of nitrogen enhanced DNP mineralization in the SBRs. Mineralization of 10 μg of DNP per ml was further enhanced in SBRs by the addition of glucose at concentrations of 100 and 500 μg/ml but not at 10 μg/ml. Possible mechanisms for this enhanced DNP mineralization in SBRs were suggested by kinetic analyses and biomass measurements. Average μ_max values for DNP mineralization in the presence of 0, 10, 100, and 500 μg of glucose per ml were 0.33, 0.13, 0.42, and 0.59/h, respectively. In addition, there was greater standing biomass in reactors amended with glucose. At steady-state operation, all SBRs contained heterogeneous microbial communities but only one organism, an actinomycete, that was capable of mineralizing DNP. This research demonstrates the usefulness of supplemental substrates for enhancing the degradation of toxic chemicals in bioreactors that contain heterogeneous microbial communities.     

Accumulation of Trehalose and Sucrose in Cyanobacteria Exposed to Matric Water Stress

The drought-resistant cyanobacteria Phormidium autumnale, strain LPP₄, and a Chroococcidiopsis sp. accumulated trehalose, sucrose, and both trehalose and sucrose, respectively, in response to matric water stress. Accumulated sugar concentrations reached values of up to 6.2 μg of trehalose per μg of chlorophyll in P. autumnale, 6.9 μg of sucrose per μg of chlorophyll in LPP₄, and 4.1 μg of sucrose and 3.2 μg of trehalose per μg of chlorophyll in the Chroococcidiopsis sp. The same sugars were accumulated by these cyanobacteria in similar concentrations under osmotic water stress. Cyanobacteria that did not show drought resistance (Plectonema boryanum and Synechococcus strain PCC 7942) did not accumulate significant amounts of sugars when matric water stress was applied.     

Experience in Monitoring Gentamicin Therapy during Treatment of Serious Gram-Negative Sepsis

This paper reports our experience in monitoring gentamicin therapy during the treatment of 68 episodes of serious Gram-negative sepsis in 65 hospital patients. Most of the patients had major underlying disease. Of those who were adequately treated (peak serum concentrations of 5 μg/ml or more in 72 hours for septicaemia, urinary tract infection, and wound infection; and 8 μg/ml or more at some time during the course of treatment for pneumonia) 84% (46 out of 55) were cured. These serum concentrations could be achieved only by starting with a regimen of 5 mg/kg/day in three divided doses in all adult patients, subsequent dosage being determined by the results of rapid serum assay. The incidence of nephrotoxicity and symptomatic ototoxicity was no greater than in previous series. The main reason for assaying serum gentamicin is to ensure that an adequate dosage is achieved as soon as possible. In patients with impaired renal function or receiving prolonged high dosage assays also serve to guard against an excessive accumulation of gentamicin and an increased risk of toxicity.     

In Vitro Hatch and Survival of Heterodera glycines as Affected by Alachlor and Phenamiphos

Heterodera glycines (race 1) eggs were exposed to aqueous solutions o f selected concentrations o f the herbicide alachlor and the organophosphate nematicide phenamiphos alone and in herbicide-nematicide combinations. Phenamiphos (0.5 μg/ml) + alachlor (0.063, 0.125, or 1.0 μg/ ml) treatments increased the incidence o f juvenile hatch over that of untreated controls at 18 days. At 18 and 25 days, phenamiphos (0.5 μg/ml) treatments contained more juveniles than did phenamiphos at 1.0 μg/ml. Phenamiphos (1.0 μg/ml) alone and in combination with alachlor (1.0 μg/ ml) suppressed hatch for 21 days and juvenile survival for more than 21 days. Alachlor treatments enhanced juvenile survival compared to the untreated control at 14 and 21 days. Technical alachlor gave results similar to those of the formulated product.     

Isolation and Characterization of Coumaphos-Metabolizing Bacteria from Cattle Dip

Coumaphos, an organophosphate insecticide, is used for tick control in cattle dipping vats along the U.S.-Mexican border. Recently, several vats (problem vats) have experienced a loss of efficacy because of microbial degradation. Three morphologically distinct bacteria (designated B-1, B-2, and B-3) that metabolized coumaphos were isolated from enrichment cultures that were initiated from problem vat dip material. In general, amino acids, pyrimidines, and acetate supported growth; carbohydrates were not utilized. Only B-2 required growth factors. In resting cell experiments, coumaphos was hydrolyzed to diethylthiophosphoric acid and chlorferon by all three isolates. Chlorferon was subsequently metabolized by B-1 and B-2 to α-chloro-β-methyl-2,3,4-trihydroxy-trans-cinnamic acid. Only B-1 produced additional metabolites. Experiments with [benzo ring-labeled U-¹⁴C]coumaphos or chlorferon demonstrated that B-1 was capable of both mineralizing and incorporating into biomass the aromatic portion of the molecule. The majority of label, however, was recovered in the form of soluble products, including α-chloro-β-methyl-2,3,4-trihydroxy-trans-cinnamic acid. Although B-1 had the capacity to use chlorferon as a carbon source at low concentrations (100 μg/ml), visible growth at higher concentrations (1,000 μg/ml) was not observed. The addition of 400 μg of chlorferon per ml to B-1 cells in the mid-log phase of growth resulted in complete inhibition of growth, while the addition of 100 to 200 μg of chlorferon per ml resulted in partial inhibition. The growth of B-2 and B-3 was inhibited by 100 μg of chlorferon per ml. These data suggest that, although B-1 and, to a lesser extent, B-2 and B-3 are responsible for the primary degradation of coumaphos, other organisms in the enrichment culture may play a secondary role in coumaphos degradation by removing inhibitory products of coumaphos metabolism.     

Evaluation of Chemicals for Restricting Colony Spreading by a Xerophilic Mold, Eurotium amstelodami, on Dichloran-18% Glycerol Agar

Twenty chemicals were screened for their effectiveness in restricting colony spreading by four strains of a xerophilic mold, Eurotium amstelodami, on dichloran-18% glycerol agar. Triton X-100, Triton X-301, Tergitol NP-7, and Tergitol 15-S-3 (each at 200 μg/ml) and 1,000 μg of sodium deoxycholate, 1 μg of iprodione, 0.1 μg of propiconazole, and 0.01 μg of Maxim per ml were judged to be most effective for restricting the rate of colony spreading.     

Lead Intoxication in Children in Birmingham

Of 38 children investigated between 1966 and 1971 who had a blood lead concentration greater than 37 μg/100 ml eight had encephalopathy and one died; all these eight had a blood lead concentration of 99 μg/100 ml or above. Blood lead levels are related to haemoglobin concentrations and anaemia is common in children with blood lead concentrations of 37-60 μg/100 ml, levels previously accepted as harmless.Children with blood lead concentrations greater than 60 μg/100 ml show radiological evidence of lead intoxication, and treatment for this should be considered when blood lead concentration exceeds 37 μg/100 ml. Children presenting with unexplained encephalopathy should be radiographed for evidence of lead intoxication.     

Effect of Sulfide on Nitrogen Fixation in a Stream Sediment-Water System

Nitrogen fixation (C₂H₂ reduction) in a sediment-water system was studied under anaerobic incubation conditions. Sodium sulfide at low concentrations stimulated activity, with a twofold increase in C₂H₄ production occurring in the presence of 8 μmol of S²⁻ per ml of stream water. Sodium sulfide at concentrations of 16 μmol of S²⁻ per ml or greater inhibited nitrogen fixation, with 64 μmol of S²⁻ per ml being completely inhibitory. Sulfide at levels of 16 μmol/ml or above inhibited CO₂ production, and the degree of inhibition increased with increasing concentration of sulfide. Titanium (III) citrate (used to modify Eh levels) stimulated both nitrogen fixation and CO₂ production, but could not duplicate, at any concentration tested, the twofold increase in nitrogen fixation caused by 8 μmol of S²⁻ per ml. Sulfide additions caused pH changes in the sediment, and when the sediment was adjusted and maintained at pH 7.0 all concentrations of sulfide inhibited nitrogen fixation activity. From considerations of the redox equilibria of H₂, H₂S, and other sulfur species at various pH values, it appeared that H₂S was the toxic entity and that HS⁻ was less toxic. The observed stimulation of activity was apparently due to a pH change coupled with the concurrent production of HS⁻ from H₂S.     

Bacterioplankton in Antarctic Ocean Waters During Late Austral Winter: Abundance, Frequency of Dividing Cells, and Estimates of Production

Bacterioplankton productivity in Antarctic waters of the eastern South Pacific Ocean and Drake Passage was estimated by direct counts and frequency of dividing cells (FDC). Total bacterioplankton assemblages were enumerated by epifluorescent microscopy. The experimentally determined relationship between in situ FDC and the potential instantaneous growth rate constant (μ) is best described by the regression equation ln μ = 0.081 FDC − 3.73. In the eastern South Pacific Ocean, bacterioplankton abundance (2 × 10⁵ to 3.5 × 10⁵ cells per ml) and FDC (11%) were highest at the Polar Front (Antarctic Convergence). North of the Subantarctic Front, abundance and FDC were between 1 × 10⁵ to 2 × 10⁵ cells per ml and 3 to 5%, respectively, and were vertically homogeneous to a depth of 600 m. In Drake Passage, abundance (10 × 10⁵ cells per ml) and FDC (16%) were highest in waters south of the Polar Front and near the sea ice. Subantarctic waters in Drake Passage contained 4 × 10⁵ cells per ml with 4 to 5% FDC. Instantaneous growth rate constants ranged between 0.029 and 0.088 h⁻¹. Using estimates of potential μ and measured standing stocks, we estimated productivity to range from 0.62 μg of C per liter · day in the eastern South Pacific Ocean to 17.1 μg of C per liter · day in the Drake Passage near the sea ice.     

Root Cortical Cell Spherical Bodies Associated with an Induced Resistance Reaction in Monoxenic Cultures of Meloidogyne incognita

The root-knot nematode Meloidogyne incognita was monoxenically cultured on excised roots of soybean cv. Pickett and tomato cv. Rutgers in agar media containing either 0 to 1,600 μg/ml ammonium nitrate or 0 to 100 μg/ml urea. Observations with scanning and transmission electron microscopy indicated that an elevated concentration of ammonium nitrate or urea inhibited giant cell formation and suppressed nematode development in the infected soybean roots. In the tomato roots, concentrations of ammonium nitrate above 400 μg/ml or urea above 25 μg/ml inhibited giant cell formation and nematode development. Coincident with the nitrogen concentrations that suppressed giant cell formation was the appearance of electron-dense spherical bodies in the cortical parenchyma cells of both the soybean and tomato roots. These bodies, which were 1-4 μm in diameter, appeared to form in the cytoplasm and migrate to the cell vacuole.     

Effects of Aldicarb and Its Sulfoxide and Sulfone on the Biology of Tylenchulus semipenetrans

In laboratory testing, egg hatch of Tylenchulus semipenetrans was stimulated at concentrations of 1 and 10 μg/ml aldicarb solution and inhibited at 50 and 100 μg/ml. Aldicarb was more inhibitory to egg hatch than the aldicarb sulfoxide and the aldicarb sulfone. Inhibition of hatch at the high concentration was associated with delays in the molting processes, lack of larval movement within the egg, and delays in embryonic development. Nematode motility was reduced at 10, 50, and 100 μg/ml of aldicarb and aldicarb sulfoxide solution, and at 50 and 100 μg/ml aldicarb sulfone. Male development was retarded at 10 μg/nrl and almost completely inhibited at 50 and 100 μg/ml of the three chemicals. In greenhouse tests, female development antl reproduction on roots of citrus seedlings were suppressed by aldicarb at rates of 2.6 μg/ml and completely inhibited at 10.6 μg/ml of soil solution during a 50-day experimental period. Under field conditions, there was little systemic movement of aldicarb into roots located outside treated areas. Aldicarb reduced the nematode larvae and the female adult population in the second year after the second treatment. There were no differences in egg hatch and sex ratio of citrus nematodes between treated and nontreated roots.     

Effect of Cadmium on Fungi and on Interactions Between Fungi and Bacteria in Soil: Influence of Clay Minerals and pH

Fungi (Rhizopus stolonifer, Trichoderma viride, Fusarium oxysporum f. sp. conglutinans, Cunninghamella echinulata, and several species of Aspergillus and Penicillium) tolerated higher concentrations of cadmium (Cd) when grown in soil than when grown on laboratory media, indicating that soil mitigated the toxic effects of Cd. In soil amended with clay minerals, montmorillonite provided partial or total protection against fungistatic effects of Cd, whereas additions of kaolinite provided little or no protection. Growth rates of Aspergillus niger were inhibited to a greater extent by 100 or 250 μg of Cd per g in soil adjusted to pH 7.2 than in the same soil at its natural pH of 5.1. However, there were no differences in the growth rates of Aspergillus fischeri with 100 or 250 μg of Cd per g in the same soil, whether at pH 5.1 or adjusted to pH 7.2. Growth of A. niger and A. fischeri in a soil contaminated with a low concentration of Cd (i.e., 28 μg/g), obtained from a site near a Japanese smelter, did not differ significantly from growth in a soil collected some distance away and containing 4 μg of Cd per g. Growth of A. niger in sterile soil amended with 100 μg of Cd per g and inoculated with Bacillus cereus or Agrobacterium tumefaciens was reduced to a greater extent than in the same soil containing 100 μg of Cd per g but no bacteria. The inhibitory effects of Agrobacterium radiobacter to A. niger were slightly reduced in the presence of 100 μg of Cd per g, whereas the inhibitory effects of Serratia marcescens were enhanced.     

Comparative In Vitro Activities of Lysostaphin and Other Antistaphylococcal Antibiotics on Clinical Isolates of Staphylococcus aureus

The in vitro activity of lysostaphin against clinical isolates of Staphylococcus aureus was determined by conventional tube-dilution methods. For comparison, minimal inhibitory concentration (MIC) values were also determined for penicillin G, ampicillin, methicillin, ristocetin, vancomycin, and erythromycin. Phage type and penicillinase and coagulase production were determined for each isolate. The MIC values for lysostaphin ranged from <0.047 to 12.5 μg/ml; 96% of the penicillinase-positive strains were inhibited by 1.56 μg/ml of lysostaphin, whereas 3.12 μg/ml of vancomycin and methicillin were required to attain the same degree of inhibition.     

In Vitro Antimicrobial Activity and Human Pharmacology of Cephalexin, a New Orally Absorbed Cephalosporin C Antibiotic

Concentrations of cephalexin (an orally absorbed derivative of cephalosporin C) in serum and urine were determined in normal volunteers and patients. The in vitro antibacterial activity was also studied. All strains of group A β-hemolytic streptococci and Diplococcus pneumoniae were inhibited by 3.1 μg/ml. Of the Staphylococcus aureus strains, 88% were inhibited by 6.3 μg/ml, and 12.5 μg/ml was inhibitory for all S. aureus, 80% of Escherichia coli, 72% of Klebsiella-Aerobacter, and 56% of Proteus mirabilis strains. About 90 to 96% of E. coli, Klebsiella Aerobacter, and P. mirabilis strains were inhibited by 25 μg of cephalexin per ml. Pseudomonas and indole-positive Proteus strains proved to be quite resistant to cephalexin. Cephalexin was well absorbed after oral administration. A peak serum concentration of cephalexin of at least 5 μg/ml was achieved in each volunteer with 250 and 500-mg doses. A mean peak serum concentration of 7.7 μg/ml was achieved with 250-mg doses; 12.3μg/ml was achieved with 500-mg doses of antibiotic. Food did not interfere with absorption. Probenecid enhanced both the peak serum concentration and the duration of antibiotic activity in the serum. Over 90% of the administered dose was excreted in the urine within 6 hr. The mean peak serum concentration of cephalexin after an oral dose of 500 mg was adequate to inhibit all group A streptococci, D. pneumoniae, and S. aureus, 85% of E. coli, and about 40 to 75% of Klebsiella-Aerobacter and P. mirabilis strains. Levels of cephalexin in urine were adequate to inhibit over 90% of E. coli, and P. mirabilis and 80 to 96% of Klebsiella-Aerobacter strains.