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Sr2NiO2Cu2Se2, comprising alternating [Sr2NiO2]2+and [Cu2Se2]2–layers, is reported. Powder neutron diffraction shows that the Ni2+ions, which are in a highly elongated NiO4Se2environment with D4hsymmetry, adopt a high-spin configuration and carry localized magnetic moments which order antiferromagnetically below ∼160 K in a √2a× √2a× 2cexpansion of the nuclear cell with an ordered moment of 1.31(2) μBper Ni2+ion. The adoption of the high-spin configuration for this d8cation in a pseudo-square-planar ligand field is supported by consideration of the experimental bond lengths and the results of density functional theory (DFT) calculations. This is in contrast to the sulfide analogue Sr2NiO2Cu2S2, which, according to both experiment and DFT calculations, has a much more elongated ligand field, more consistent with the low-spin configuration commonly found for square-planar Ni2+, and accordingly, there is no evidence for magnetic moment on the Ni2+ions. Examination of the solid solution Sr2NiO2Cu2(Se1–xSx)2shows direct evidence from the evolution of the crystal structure and the magnetic ordering for the transition from high-spin selenide-rich compounds to low-spin sulfide-rich compounds as a function of composition. Compression of Sr2NiO2Cu2Se2up to 7.2 GPa does not show any structural signature of a change in the spin state. Consideration of the experimental and computed Ni2+coordination environments and their subtle changes as a function of temperature, in addition to transitions evident in the transport properties and magnetic susceptibilities in the end members, Sr2NiO2Cu2Se2and Sr2NiO2Cu2S2, suggest that simple high-spin and low-spin models for Ni2+may not be entirely appropriate and point to further complexities in these compounds.

Biliary excretion of methaqualone metabolites was demonstrated after oral administration of 2-14C-methaqualone to bile-cannulated rats. Over 5- and 24-hr collection periods, 29 and 77% of the 14C-methaqualone dose appeared in the bile, respectively. Enterohepatic recirculation of the bile metabolites was demonstrated after intraduodenal administration of the bile-derived metabolites to bile-cannulated rats; 18 and 52% of the 14C metabolite dose appeared in the bile at the 5- and 24-hr collection periods. After the intraduodenal administration of the bile-derived metabolites to noncannulated rats, 21 and 37% appeared in the urine at the 24- and 72-hr collection periods. Elucidation of the structure of the biliary metabolites showed that 95% appeared as the O-glucuronide conjugate of 2-methyl-3-(2'-hydroxymethylphenyl)-4(3H)-quinazolinone metabolite and the remaining 5% consisted of two unidentified metabolites.

The absorption of methaqualone from the gastro-intestinal tract is a dissolution—and not a permeability-rate limited process. Absorption from solution dosage forms can occur throughout the gastro-intestinal tract with maximum absorption from the intestine. Dissolution of solid dosage forms is favoured in the highly-acidic environment of the stomach and absorption of the in situdissolved drug occurs in both stomach and upper small intestine. Methaqualone is found primarily in the plasma phase of whole blood and is highly bound to plasma proteins. The plasma elimination curve is biexponential with a rapid distributive phase and a slow elimination phase. The principle tissues of distribution are the metabolic and excretory tissues—liver and kidney — and lipid tissue. Metabolism occurs by hydroxylation of the methyl, tolyl and quinazolinone substituents via inducible hepatic microsomal oxidoreductases. Methaqualone is completely bio-transformed and excreted as O-glucuronide conjugates in urine and bile. Enterohepatic recirculation of metabolites occurs and is responsible for the prolonged urinary excretion profile. There is no change in absorption, distribution or elimination kinetics following chronic administration in man.Tablet and capsule formulations with good in vitrodissolution, stability and bioavailability characteristics were developed. Equivalent bioavailability of these tablet formulations was observed in the fasted and post-prandial state. Techniques were developed to correlate dissolution and absorption profiles of these formulations.

The perinatal distribution of butorphanol was determined in relation to maternal-neonatal transfer and colostrum/milk excretion in obstetric patients. Parenteral butorphanol passed the placental barrier and was found in neonatal cord serum. The mean neonatal serum concentration of butorphanol was not different from the mean maternal serum concentration of butorphanol, following a 1 or 2mg intramuscular dose. Butorphanol was detected in the milk of lactating women following oral and intramuscular administration. Serum and milk concentrations appeared to be parallel with time. This observation was confirmed by the constancy of the mean milk-to-serum concentration ratio (0.7 intramuscular, 1.9 oral). We calculated that 4 μg would be the maximum amount of butorphanol, which would be expected to be present in the full daily milk output (1 L) following administration four times a day of 2mg intramuscular or of 8mg oral doses. An oral dose of 4 μg to an infant weighing 4kg corresponds to the negligible oral dose of 0.07mg to a 70kg adult. The demonstrated safety and efficacy of butorphanol as an obstetric analgesic and the characteristics of the maternal-neonatal transfer and milk excretion are indicative of the potential excellence of this agent for obstetric use.

Ceforanide (BL-S786R) is a new, broad-spectrum, parenteral cephalosporin. Pharmacokinetic properties were determined in rats (100 mg/kg), rabbits (30 mg/kg), dogs (25 mg/kg), and humans (2 g or 30 mg/kg) and compared with equivalent single doses of cefazolin. Plasma half-lives for ceforanide and cefazolin were 1.1 and 0.5 h in the rat, 5 and 0.3 h in the rabbit, 1 and 0.8 h in the dog, and 2.6 and 2 h in humans, respectively. The slower elimination of ceforanide, as reflected by longer plasma half-life, larger area under the curve, and peak plasma concentrations, was due to slower body and renal clearances. The apparent volumes of distribution of ceforanide and cefazolin were comparable. Rats, dogs, and humans excreted 80 to 100% of the ceforanide dose in the 0- to 24-h urine; rabbits excreted only 50%. Tubular secretion constituted 50% of ceforanide renal excretion in rabbits, dogs, and humans and 90% in rats; the remainder was excreted by glomerular filtration. There was no apparent correlation between the extent of tubular secretion and degree of plasma protein binding in different species. There was no significant pharmacokinetic interaction between ceforanide and amikacin in the rat. The slower elimination kinetics of ceforanide are indicative of the potential for a longer dosing interval and more effective antibiotic therapy as compared with available cephalosporins.

A single oral solution dose (40 mg/m2) of 14C-prednimustine was administered to each of four cancer patients. Plasma, urine, and feces were collected at appropriate times and analyzed for total radioactivity. Plasma samples were analyzed for prednimustine. Peak plasma levels of radioactivity (1–3 µg 14C-prednimustine equivalents) occurred at 1.5–3 h in three patients and at 5–6 h in one patient. No intact prednimustine was detected in the plasma; this means that if present, it would be at a concentration of 0.02 µg/ml or less and would account for less than 1% of the total drug-related material at the time of peak plasma levels. Solvent-extractable metabolites had a plasma half-life of about 8 h or less. By 24 h essentially all the plasma radioactivity appeared to be covalently bound, and it was eliminated slowly with an estimated terminal elimination half-life of about 10 days. Rapid urinary excretion occurred in the first 24 h, and 40%–60% of the dose was recovered in the urine in 72 h. Although prednimustine was well absorbed, the ester was subject to extensive presystemic metabolism and was not present in the systemic circulation after oral administration.

The pharmacokinetics and safety of ceforanide and cefazolin were compared in normal subjects after 30-min intravenous infusions of 2-, 3-, and 4-g single doses and 4-g twice-daily doses for 10 days. No significant differences were observed in plasma-renal pharmacokinetic parameters between single and multiple doses of ceforanide. Half-life (t½, 2.8 h), plasma clearance (Clp, 48 ml/min per 1.73 m2), and renal clearance (Cl0−12hr, 47 ml/min per 1.73 m2; tubular secretion, 44%, and glomerular filtration, 56%) did not change with increased dose or on multiple dosing. No significant change was observed in t½(1.9 h), area under the plasma concentration-time curve, Clr(60 ml/min per 1.73 m2; tubular secretion, 80%, and glomerular filtration, 20%), or Clp(75 ml/min per 1.73 m2) for 4-g single doses compared with twice-daily administration of cefazolin. A small increase in cefazolin clearance was observed when plasma concentrations were greater than 100 μg/ml, when the single dose was increased from 2 to 4 g; this was a result of the decrease in percentage of plasma protein binding and increased renal clearance due to increased glomerular filtration. The increase in renal clearance resulted in a lack of linear proportionality of the plasma area under the curve with dose over a range of 2 to 4 for both cephalosporins, although this effect was much less marked with ceforanide. Both compounds were well tolerated both locally and systemically. There was no evidence of any change in renal function based on clearances of drug, p-aminohippuric acid, or creatinine, and other standard clinical parameters.

A simple and sensitive radioimmunoassay (RIA) procedure was developed and validated for the analysis of tallysomycin S10b in human plasma and urine. The assay utilized antisera developed in rabbits, 125I-tallysomycin as the radioligand, and dextran-coated charcoal to separate free and bound antigen. The antibody was specific in that it did not cross-react with either tallysomycin A or bleomycin. The lower limit of quantification was 5 ng per ml plasma or urine, and the linear range of the assay was 5–320 ng tallysomycin S10b base per ml plasma or urine. The within-day assay variability (%RSD) for plasma and urine was 11% at a concentration of 50 ng per ml, and 3% and 7% for plasma and urine, respectively at 200 ng per ml. Within-day accuracy ranged from 100% to 108% of the theoretical value. Tallysomycin S10b was stable in human plasma and urine at concentrations of 20 and 160 ng per ml for at least 7 months when stored at-20°C. The method was applied to the analysis of plasma and urine samples from a patient given tallysomycin S10b as part of a phase I study.

Phosphanilic acid is an antibacterial agent with a mode of action and antibacterial spectrum similar to those of sulfamethoxazole, with the exception that it has potent antipseudomonal activity. Bioavailability studies in rats (50, 300, and 600 mg/kg, oral and subcutaneous), dogs (50, 150, and 450 mg/kg, oral and intravenous infusion), and humans (400 and 800 mg, oral) showed that the extent of oral absorption of potassium phosphanilate was low. The bioavailability, calculated by comparing the oral values for area under the plasma concentration curve with those for the respective parenteral doses, was 10% for rats and 45 (50 and 150 mg/kg) and 19% (450 mg/kg) for dogs. The 24-h urinary recovery also confirmed the low oral bioavailability, i.e., rat, 13 (oral) and 75% (subcutaneous); dog, 15 to 29 (oral) and 87% (intravenous) of the dose. Plasma levels and urinary recovery (4%, oral) were low and variable in humans. The poor absorption of oral doses may be due to drug precipitation in the stomach, low permeability of the soluble species due to extensive in situ ionization (pKa, 1.8 to 2) in the intestine, or first-pass metabolism to N-acetylphosphanilic acid. The plasma t½values after parenteral administration were 0.3 h in rats and 1.3 h in dogs. Although the lack of adequate blood levels of phosphanilic acid after oral administration in humans precludes the use of this compound for treatment of systemic infections, the sustained urinary concentration at levels severalfold higher than the minimal inhibitory concentration (1 μg/ml) for at least 10 h postdose was indicative of the therapeutic usefulness in urinary tract infections.

A radioimmunoassay was developed for the analysis of butorphanol in human serum. The procedure involves extraction of serum with hexane containing 2% isoamyl alcohol, followed by evaporative solvent removal and radioimmunoassay of the reconstituted residue. The antibody significantly cross-reacts with unidentified butorphanol metabolites but not with two known metabolites, hydroxybutorphanol and norbutorphanol. Extraction eliminated interference from the butorphanol metabolites normally present in serum. The antibody also cross-reacts with pentazocine and cyclazocine but not with morphine, hydromorphone, oxymorphine, codeine, methadone, and meperidine. Butorphanol tartrate was administered intravenously (2mg) to normal male volunteers. Serum butorphanol levels declined biexponentially with an average terminal half-life of 2.7hr. Enzymatic serum hydrolysis prior to extraction yielded additional butorphanol, indicating the presence of butorphanol conjugates. The specificity of the assay for butorphanol was confirmed by GLC-mass fragmentography.

Linkage relationships were determined for six genes in Chlamydomonas reinhardtii: pyr, act, can-la, ey, y-1, and nic-7. Four of these were combined with five other genes to form linkage test strains.