Urinary excretion of n-hexane metabolites

Exposure to n-hexane, a component of many industrial solvent mixtures, is known to cause polyneuropathy in man. The concentration of metabolites in urine following exposure may be useful in biological monitoring. In a comparative study experimental animals (rat, rabbit and monkey) were subjected to single inhalatory treatments of 6, 12 and 24 h with 5,000 ppm of pure n-hexane. At the end of the treatments and at intervals thereafter, urine, and in rats also blood, were collected and analyzed for n-hexane and its metabolites. While the urine of rats contained 2-hexanol, 3-hexanol, methyl n-butyl ketone, 2,5-dimethylfuran, -valerolactone and 2,5-hexanedione, rabbit and monkey urine were found to contain only 2-hexanol, 3-hexanol, methyl n-butyl ketone and 2,5-hexanedione. Within 72 h of the end of exposure, the principal metabolite was 2,5-dimethylfuran in rats and 2-hexanol in rabbits and monkeys. In all three species the excretion rates of methyl n-butyl ketone, 3-hexanol and 2-hexanol peaked several hours earlier than 2,5-hexanedione (and -valerolactone and 2,5-dimethylfuran in rats). In all species 2,5-hexanedione was still detectable in urine 60 h following exposure. n-Hexane metabolites in rat blood were 2-hexanol, methyl-n-butyl ketone, 2,5-dimethylfuran and 2,5-hexanedione. The first two, as well as n-hexane itself, were found in maximum concentration immediately after termination of exposure, while 2,5-dimethylfuran and 2,5-hexanedione, with the longer exposure times, peaked some hours later. The data from urine collected at the end of exposure were compared with those obtained in a parallel study in humans occupationally exposed to a mixture of hexane isomers. Humans chronically exposed to 10–140 ppm n-hexane had 2,5-hexanedione concentrations in urine ranging from 0.4 to 21.7 mg/l, i.e., in the same proportion as rats exposed once for 6 or 12 h to 5,000 ppm.     

Sensitivity to tri-o-cresylphosphate neurotoxicity on n-hexane exposed hens as a model of simultaneous hexacarbon solvent and organophosphorus occupational intoxication

Hens were given a single oral dose (0.235 mg/kg) of tri-o-cresylphosphate (TOCP) during chronic n-hexane treatment (200 mg/kg daily, 5 days/week). They were compared with other animals treated only with n-hexane or only with TOCP. Animals treated with a higher TOCP dose (1 ml/kg) were used as positive controls. The animals treated with both n-hexane and TOCP showed rapid development of severe ataxia. The rate of the ataxia development was similar to that of the positive controls but with earlier onset of the first signs and with less loss of body weight. However, animals treated only with n-hexane, under the same conditions, showed only reversible weakness and sedative effects, and those treated only with TOCP showed slow and slight ataxia development. The n-hexaneand TOCP-treated hens showed axonal swelling with myelin retraction associated with Ranvier's nodes, which is characteristic of long hexacarbon exposure. Some internodal swellings were also observed but less frequently than the paranodal swellings. The time course of the ataxia development was similar to an organophosphorus-induced delayed neuropathy (OPIDN); however, the light microscopy observation more closely resembled hexacarbon neuropathy. The results suggest a potentiation effect of n-hexane and TOCP neurotoxicities which could be related to some human occupational neuropathies.Partial results of this work were previously presented at the XXIVth Congress of the European Society of Toxicology (Rome, March 1983) and at the V Jornadas Toxicológicas Españolas (Madrid, November 1983)Work partly supported by a grant No. 84/1833 from the Fondo de Investigaciones Sanitarias de la Seguridad Social of Spain. M. C. Pellin is a recipient of a followship from the Generalität Valenciana     

Pharmacokinetics of the neurotoxin n-hexane in rat and man

The pharmacokinetics of inhaled n-hexane in rat and man were compared. In the rat metabolism was saturable. Up to 300 ppm, the metabolic rate was directly proportional to the concentration in the atmosphere, reaching 47 mol/(h· kg). Only 17% of n-hexane was exhaled unchanged. Above 300 ppm, the amount of n-hexane in the body rose with increasing atmospheric concentrations from 1.6 up to a limiting value of 9.6, which corresponded to the thermodynamic distribution coefficient of n-hexane between the organism and the atmosphere. Up to 3000 ppm, the rate of metabolism increased to 245 mol/ (h· kg); only a slow further increase was found up to 7000 ppm (285mol/(h· kg)).In man the steady-state concentrations of n-hexane were about 1 ppm. The metabolic clearance was 1321/h, and n-hexane accumulated to a factor of 2.3 in the organism. The thermodynamic distribution coefficient was calculated to be 12. Twenty per cent of n-hexane in the body was exhaled unchanged.At low concentrations the rate of metabolism of n-hexane is limited in both species by transport to the enzyme system. Under these conditions the rate of metabolism of n-hexane should not be influenced by xenobiotics which induce the n-hexane metabolizing enzyme system.Dedicated to Professor Dr. med. Herbert Remmer on the occasion of his 65th birthday     

Plasma levels and β-blocking effect of α-hydroxymetoprolol—Metabolite of metoprolol—in the dog

The plasma levels and the - blocking effect of metoprolol and its active metabolite - hydroxymetoprolol have been studied after i.v. bolus injections of the substances to dogs. For both substances the - blockade increased with the dose, and there was a linear relationship between percent reduction in exercise heart rate and the logarithm of plasma concentration. The dose of the metabolite, however, had to be 5 times higher than that of metoprolol to induce the same degree of - blockade. Because of differences in the volume of distribution, 2.0 liters/kg for - OH-metoprolol and 3.5 liters/kg for metoprolol, the 5 times higher dose of - OH-metoprolol resulted in 10 times higher plasma levels of the metabolite than of metoprolol. - OH-Metoprolol was more slowly eliminated (t_1/27.0 hr, total body clearance 3.5 ml-kg^–1-min^–1) than metoprolol (t_1/22.0 hr, total body clearance 20.0 ml-kg^–1-min^–1). Approximately 5% of an i.v. dose of metoprolol was metabolized to - OH-metoprolol. The half-life of the endogenously formed metabolite was the same as after an i.v. dose of the compound.     

Antifungal Activity of a New Triterpenoid Glycoside from Pithecellobium racemosum (M.)

Purpose. In a continuation of our search for novel antifungal compounds from higher plants, the standard extract of the bark of Pithecellobium racemosum was found to have good activity against important AIDS-related opportunistic yeasts. Methods. The extract was subjected to bioguided fractionation using silica gel column chromatography which led to purification of triterpene glycosides. The structures of these compounds were determined by a combination of spectroscopic (IR, NMR, HRMS) and chemical methods. Results. Compound 1 is a new glycoside, 3-O[-L-arabinopyranosyl (1 -2)][-L arabinopyranosyl (1 -6)]2-acetoamido-2-deoxy--D-gluco-pyranosyl oleanolic acid and Compound 2 was identified as the known compound 3-O-[-L-arabinopyranosyl (l-2)]-L-arabinopyranosyl (1-6)] 2-acetamido-2-deoxy--D-glucopyranosyl echinocystic acid. Conclusions. Compound 1 is a new glycoside, 3-O-[-L-arabinopyranosyl (1-2)]-L-arabinopyranosyl (l-6)]-2-acetoamido-2-deoxy--D-glucopyranosyl oleanolic acid and exhibits moderate antifungal activity against T. mentogrophytes, C. albicans and S. cerevisiae with MIC values of 6.25, 12.5 and 12.5 g/ml respectively.     

Studies on the chemical constituents from the roots of <Emphasis Type="Italic">Platycodon grandiflorum</Emphasis>

Three known monodesmosidic saponins: 3-O--d-glucopyranosyl-2,3,16,23,24-pentahydroxyolean-12-ene-28-oic acid, 3-O--d-glucopyranosyl polygalacic acid, and 3-O--d-glucopyranosyl-(13)--d-glucopyranosyl polygalacic acid; and two known nonsaponin compounds: a mixed compound of n-tetracosanoic acid (lignoceric acid), n-hexacosanoic acid (cerotic acid), and n-octacosanoic acid, and -monopalmitin; were isolated for the first time from the root of Platycodon grandiflorum A. DC. together with another seven known compounds: platycoside G₁ (3-O--d-glucopyranosyl-(16)--d-glucopyranosyl-(16)--d-glucopyranosyl-2,3,16,23,24-pentahydroxyolean-12-ene-28-oic acid 28-O--d-xylopyranosyl-(14)--l-rhamnopyranosyl-(12)--l-arabinopyranoside), deapio-platycodin D, Polygalacin D, deapio-platycodin D₃, platycoside A, -spinasterol, and -spinasteryl-3-O--d-glucopyranoside. Alkaline hydrolysis of platycoside G₁ afforded a new monodesmosidic prosaponin: 3-O--d-glucopyranosyl-(16)--d-glucopyranosyl-(16)--d-glucopyranosyl-2,3,16,23,24-pentahydroxyolean-12-ene-28-oic acid. Their chemical structures were elucidated on the basis of their spectral data and chemical evidence.     

Effects of chronic n-hexane exposure on nervous system-specific and muscle-specific proteins

Two kinds of nervous system-specific and muscle-specific proteins, enolase and S-100 protein, were quantitatively determined in peripheral nerves and skeletal muscles of rats chronically exposed to a neurotoxic solvent — n-hexane. Three groups of animals were exposed to n-hexane vapor at three different solvent concentrations (500 ppm, 1200 ppm, 3000 ppm) for 12 h/day, 7 days/ week for 16 weeks. The body weight gain and motor nerve conduction velocity (MCV) in exposure groups show progressively concentration-dependent decreases compared to control values. Histopathological examination also demonstrates the degeneration of peripheral nerves in 3000 ppm- and 1200 ppm-exposed rats. The significant decrease in the amount of S-100 protein in peripheral nerves was observed not only in the high level exposure groups (3000 ppm and 1200 ppm), but also in the lowest level group (500 ppm), although the MCV and morphological examination remained unchanged at this level. In addition, the muscle-specific S-100 protein in 3000 ppm exposed rats' soleus also displayed a significant reduction. In contrast to this, however, enolase isozymes were not significantly changed by either dosage level in both nervous tissue and skeletal muscle. The experiment suggests that -and -S-100 proteins which are specifically localized in nervous system and muscles, respectively, are more vulnerable than enolase isozymes under treatment with n-hexane, and may possibly serve as a specific indicator to evaluate the neurotoxic effects. Further research would be worthwhile to elucidate the role of the specific S-100 protein in evaluating the neurologic damage induced by various industrial chemicals.     

Vasopressin stimulates release of β-lipotropin and β-endorphin in conscious rats as measured by radioimmunoassay of unextracted plasma

Summary Using a newly developed radioimmunoassay to determine the -endorphin-like immunoreactivity (-EI) in unextracted plasma, the effect of vasopressin injections on plasma -EI was investigated in conscious rats. Arginine vasopressin caused a dose-dependent increase of plasma -EI from 34.5±7.8 fmol ml^–1 (n=6) in vehicle-treated animals to 205.0±36.1 fmol ml^–1 (n=7) after injection of the highest vasopressin dose employed (486 ng/100 g b.w.). In view of the appreciable cross-reactivity of -lipotropin (-LPH) in the radioimmunoassay used, plasma was extracted and subjected to gel chromatography on a Sephadex G-50 column. On average, about 70% of the -EI co-eluted with human -LPH and about 30% with human -endorphin in plasma extracts obtained from both control and vasopressin-treated rats. No peripheral conversion of human -LPH occurred under the experimental conditions, since after i.v. bolus injection of human -LPH 97% of the -EI comigrated with human -LPH during gel filtration. A similar blood pressure increase to that induced by the vasopressin injections, when elicited by noradrenaline or angiotensin II i.v., was not followed by an elevation of plasma -EI.These data indicate that vasopressin stimulates -lipotropin and -endorphin release into the systemic circulation in vivo.     

β 1- andβ 2-adrenoceptor binding and functional response in right and left atria of rat heart

Summary The properties of ₁- and ₂-adrenoceptors in right and left atria of rat heart, and their roles in mediating chronotropic and inotropic responses to-adrenoceptor agonists were examined. [¹²⁵I](-)-pindolol (¹²⁵IPIN) bound saturably and specifically to a single class of high affinity sites in homogenates of both right and left atria. Thek ₁'s for association in right and left atria were 6.5×10⁹ l/mol-min and 2.3×10⁹ l/mol-min respectively, while thek _–1's for dissociation were 0.20 min^–1 and 0.17 min^–1. The kinetically determinedK _D's were 75 pmol/l in right and 30 pmol/l in left atria and were similar to the equilibriumK _D's determined from Scatchard analysis of saturation isotherms of specific¹²⁵IPIN binding. Inhibition of¹²⁵IPIN binding by-adrenoceptor antagonists was stereoselective and the order of potency was timolol > 1-propranolol > d-propranolol > sotalol. Inhibition by ₁- and ₂-adrenoceptor subtype selective antagonists yielded flat displacement curves with low Hill coefficients. Nonlinear regression analysis of displacement by ₁-selective (practolol, atenolol and metoprolol) and ₂-selective (ICI 118,551) antagonists gave estimates of the proportion of ₁- and ₂-adrenoceptors present in rat atria. Right atria contained 67±4.2% ₂-adrenoceptors and 33±4.2% ₂-adrenoceptor, while left atria contained 67±2.8% ₁- and 33±2.8% ₂-adrenoceptors. Increases in the rate of spontaneously beating right atria and the force of electrically driven left atria caused by-adrenoceptor agonists were also measured. pA₂ values for non-subtype selective-adrenoceptor antagonists in inhibiting isoprenaline-induced increases in rate and force were highly correlated withK _D values determined for specific¹²⁵IPIN binding. pA₂ values for ₁- and ₂-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the pK _D values of these drugs in binding to ₁-adrenoceptors, but not with the pK _D values in binding to ₂-adrenoceptors. Dose-response curves for stimulation of both rate and force by the ₂-selective agonists procaterol and zinterol were shifted to a much greater extent by selective blockade of ₁-adrenoceptors with metoprolol than by selective blockade of ₂-adrenoceptors with ICI 118,551, suggesting that these compounds caused their effects by activating ₁-adrenoceptors. These results suggest that ₁- and ₂-adrenoceptors coexist in both left and right atria of rat heart in approximately a 21 ratio, however only ₁-adrenoceptors mediate the chronotropic and inotropic effects of-adrenoceptor agonists.Supported by a grant from the American Heart Association — Georgia Affiliate     

Influence of flupenthixol and flupenthixol-decanoate on methylphenidate and apomorphine-induced compulsive gnawing in mice

-Flupenthixol and -flupenthixol decanoate were tested in mice against methylphenidate-induced stereotyped gnaw-compulsions. The effect of both -flupenthixol, and -flupenthixol decanoate disappeared 2 days after administration.In addition, the influence of -flupenthixol and -flupenthixol decanoate on the apomorphine-induced behaviour in mice was followed over a period of 12 days. Under these conditions apomorphine-induced compulsive gnawing was seen on the days on which the methylphenidate antagonistic effect had subsided.The apomorphine-induced compulsive gnawing seen in -flupenthixol and -flupenthixol decanoate pretreated animals could be antagonized by additional small doses of -flupenthixol given 2 h before apomorphine. The interference of the neuroleptic drugs with dopaminergic receptors is discussed.     

Liposomes Containing Interferon-Gamma as Adjuvant in Tumor Cell Vaccines

Purpose. Liposomal systems may be useful as a cytokine supplementin tumor cell vaccines by providing a cytokine reservoir at the antigenpresentation site. Here, we examined the effect of liposomeincorporation of mIFN on its potency as adjuvant in an established tumor cellvaccination protocol in the murine B16 melanoma model. Adjuvanticityof the mIFN-liposomes was compared to that achieved bymIFN-gene transfection of the B16 tumor cells. Furthermore, we studiedwhether liposomal incorporation of mIFN indeed increases theresidence time of the cytokine at the vaccination site. Methods. C57B1/6 mice were immunized with i) irradiated IFN-genetransfected B16 melanoma cells or ii) irradiated wild type B16 cellssupplemented with (liposomal) mIFN, followed by a challenge withviable B16 cells. The residence time of the (liposomal) cytokine at thesubcutaneous (s.c.) vaccination site was monitored using radiolabeledmIFN and liposomes. Results. Immunization with irradiated tumor cells admixed withliposomal mIFN generated comparable protection against B16 challenge asimmunization with mIFN-gene modified tumor cells. Irradiated tumorcells admixed with soluble mIFN did not generate any protectiveresponses. Radiolabeling studies indicated that free mIFN rapidlycleared from the s.c. injection site. Association of [¹²⁵I]-mIFNwith liposomes increased the local residence time substantially: liposomalassociation of mIFN resulted in a prolonged local residence time ofthe cytokine as reflected by a 4-fold increase of the area under thecurve. The amount of released cytokine in the optimal dose rangecorresponds to the amount released by the gene-transfected cells. Moderate but significant CTL-activity against B16 cells was found for miceimmunized with irradiated cells supplemented with mIFN-liposomescompared to untreated control animals. Conclusions. Prolonged presence of mIFN at the site of antigenpresentation is crucial for the generation of systemic immune responsesin the B16 melanoma model. These studies show that liposomalencapsulation of cytokines is an attractive strategy for paracrine cytokinedelivery in tumor vaccine development.     

The Liposome Partitioning System for Correlating Biological Activities of Imidazolidine Derivatives

The partitioning of 10 imidazolidines in various liposome/buffer systems (log K _m) has been determined and compared to partitioning in the n-octanol/buffer system (log P). The log K _m, which was generally greater than the log P, increased or decreased upon the addition of dicetylphosphate (DCP) or stearylamine (STA), respectively, to dimyristoylphosphatidylcholine (DMPC) liposomes. Quantitative correlations of ₂-adrenergic potencies of imidazolidines have been made by regression analyses with log P, log K _m, binding affinity, and intrinsic activity. Both central and peripheral potencies correlated with log K _m but not with log P Multiple regressions yielded improved predictable quantification of these potencies. Thus, the liposomal membrane system shows certain advantages over the n-octanol/buffer system for the prediction of biological activities of the imidazolidines.     

Effects of MEK on kinetics ofn-hexane metabolites in serum

The neurotoxicity ofn-hexane is thought to be caused ultimately by 2,5-hexanedione (2,5-HD), one of then-hexane metabolites. The potentiation ofn-hexane neurotoxicity by co-exposure with MEK, therefore, is suspected to be related to kinetics of 2,5-HD in blood. To clarify the kinetics ofn-hexane metabolites in the mixed exposure ofn-hexane and MEK, rats were exposed to 2000 ppmn-hexane or a mixture of 2000 ppmn-hexane and 2000 ppm MEK, and the time courses of serumn-hexane metabolites were determined. 2,5-HD in serum increased until 2 h after the end of exposure, when serum 2,5-HD concentration reached a peak of 16.35 g/ml in then-hexane-alone group. In contrast, 2,5-HD in the mixed exposure group increased much more slowly during and after exposure than in then-hexane-alone group. It reached a peak of 2.12 g/ml at 8 h after the end of exposure. Serum MBK, a precursor of 2,5-HD in the co-exposure group, was about half in then-hexane-alone group during exposure. However, MBK decreased more slowly in the co-exposure group than in then-hexane-alone group after the end of the exposure. The results suggest that co-exposed MEK might inhibit oxidation ofn-hexane and decrease clearance ofn-hexane metabolites. Co-exposed MEK did not increase serum 2,5-HD, which was considered a main neurotoxic metabolite. Therefore the enhancement of neurotoxicity could not be attributed to increased serum 2,5-HD in the co-exposed group. The mechanism of enhancement of neurotoxicity ofn-hexane by MEK should be studied further.     

In Vitro Evaluation of Dexamethasone-β-D-Glucuronide for Colon-Specific Drug Delivery

Dexamethasone--D-glucuronide is a potential prodrug for colonic delivery of the antiinflammatory corticosteroid dexamethasone. Previous studies [T. R. Tozer et al., Pharm. Res. 8:445–454 (1991)] indicated that a glucoside prodrug of dexamethasone was susceptible to hydrolysis in the upper gastrointestinal tract. Resistance of dexamethasone--D-glucuronide to hydrolysis in the upper gastrointestinal tract was therefore assessed. Conventional, germfree, and colitic rats were used to examine enzyme levels along the gastrointestinal tract to compare the stability of two model substrates (p-nitrophenyl--D-glucoside and --D-glucuronide) and to evaluate the prodrug dexamethasone--D-glucuronide. Hydrolytic activity was examined in the luminal contents, mucosa, and underlying muscle/connective tissues in all three types of rats. Enzymatic activity (-D-glucosidase and -D-glucuronidase) was greatest in the lumen of cecum and colon of conventional rats. In contrast, germ-free rats exhibited relatively high levels of -D-glucosidase activity (about 80% of total activity in the conventional rats) in the proximal small intestine (PSI) and the distal small intestine (DSI). Rats with induced colitis (acetic acid) showed reduced levels of luminal -D-glucuronidase activity in the large intestine; however, -D-glucosidase activity was relatively unchanged relative to that of the conventional rat. Mucosal -D-glucuronidase activity was significantly lower in the colitic rats compared with that in the conventional animals. Despite reduced luminal levels of -D-glucuronidase activity in the colitic rats, there was still a sharp gradient of activity between the small and the large intestines. Permeability of the glucoside and glucuronide prodrugs of dexamethasone through a monolayer of Caco-2 cells was relatively low compared to that of dexamethasone. The results indicate that dexamethasone--D-glucuronide should be relatively stable and poorly absorbed in the upper gastrointestinal tract. Once the compound reaches the large intestine, it should be hydrolyzed to dexamethasone and glucuronic acid. Specificity of colonic delivery in humans should be even greater due to lower levels of -D-glucuronidase activity in the small intestine compared with that in the laboratory rat.     

Differential effects of verapamil and flunarizine on cardiac L-type and T-type Ca channels

Summary Whole cell experiments were used to study whether the L-type and the T-type Ca channel in guinea-pig ventricular myocytes are blocked similarly by verapamil and flunarizine. The L-type current is blocked by 5 ol/l verapamil and 5 ol/l flunarizine in a use-dependent way, and block can be relieved by hyperpolarizing pulses in a potential-dependent way. The T-type current is not affected by 10 mol/l verapamil while it is blocked by 10 ol/l flunarizine in a use-dependent way. Verapamil selectively blocks the L-type channel in contrast to flunarizine. Send offprint requests to J. Tytgat at the above address     

Behavioural and anticonvulsant effects of Ca2+ channel toxins in DBA/2 mice

This study investigated the behavioural and anticonvulsant effects of voltage-sensitive calcium channel blockers in DBA/2 mice.-Conotoxin MVIIC (0.1, 0.3 g ICV/mouse) and-agatoxin IVA (0.1, 0.3, 1 g ICV), which act predominantly at P- and/or Q-type calcium channels, prevented clonic and tonic sound-induced seizures in this animal model of reflex epilepsy (ED₅₀ values with 95% confidence limits for protection against clonic sound-induced seizures were 0.09 (0.04–0.36) g ICV and 0.09 (0.05–0.15) g ICV, respectively and against tonic seizures 0.07 (0.03–0.16) g ICV and 0.08 (0.04–0.13) g ICV, respectively). The N-type calcium channel antagonists-conotoxin GVIA and-conotoxin MVIIA were also tested in this model.-Conotoxin GVIA was anticonvulsant in DBA/2 mice, but only at high doses (3 g ICV prevented tonic seizures in 60% of the animals; 10 g ICV prevented clonic seizures in 60% and tonic seizures in 90% of the animals), whereas-conotoxin MVIIA did not inhibit sound-induced seizures in doses up to 10 g ICV. Both-conotoxin GVIA and-conotoxin MVIIA induced an intense shaking syndrome in doses as low as 0.1 g ICV, whereas-conotoxin MVIIC and-agatoxin IVA did not produce shaking at any of the doses examined. Finally,-conotoxin GI (0.01–1 g ICV) and-conotoxin SI (0.3–30 g ICV), which both act at acetylcholine nicotinic receptors, were not anticonvulsant and did not induce shaking in DBA/2 mice. These results confirm that blockers of N- and P-/Q-type calcium channels produce different behavioural responses in animals. The anticonvulsant effects of-conotoxin MVIIC and-agatoxin IVA in DBA/2 mice are consistent with reports that P- and/or Q-type calcium channel blockers inhibit the release of excitatory amino acids and are worthy of further exploration.     

A Population Growth Model of Dissolution

Purpose. To develop a new approach for describing drug dissolution which does not require the presuppositions of time continuity and Fick's law of diffusion and which can be applied to both homogeneous and heterogeneous media. Methods. The mass dissolved is considered to be a function of a discrete time index specifying successive 'generations' (n). The recurrence equation: _n+1 = _n + r(l – _n)(1 – _n X ₀/) was derived for the fractions of dose dissolved _n and _{n +1}, between generations n and n + 1, where r is a dimensionless proportionality constant, X ₀ is the dose and is the amount of drug corresponding to the drug's solubility in the dissolution medium. Results. The equation has two steady state solutions, _ss = 1 when (X ₀/) 1 and _ss = /X ₀ when (X ₀/) > 1 and the usual behavior encountered in dissolution studies, i.e, a monotonic exponential increase of _n reaching asymptotically the steady state when either r < /X ₀ < 1 or r < 1 < /X ₀. Good fits were obtained when the model equation was applied to danazol data after appropriate transformation of the time scale to 'generations'. The dissolution process is controlled by the two dimensionless parameters /X ₀ and r, which were found to be analogous to the fundamental parameters dose anddissolution number, respectively. The model was also used for the prediction of fraction of dose absorbed for highly permeable drugs. Conclusions. The model does not rely on diffusion principles and therefore it can be applied under both homogeneous and non-homogeneous conditions. This feature will facilitate the correlation of in vitro dissolution data obtained under homogeneous conditions and in vivo observations adhering to the heterogeneous milieu of the GI tract.     

The in vitro effects of alkanes,alcohols, and ketones on rat lung cytochrome P450-dependent alkoxyphenoxazone dealkylase activities

The sensitivities of cytochrome P450 (EC 1.14.14.1)-dependent benzyloxy- and ethoxyphenoxazone dealkylase (BzOPh'ase and EtOPh'ase, respectively) activities towards a series of aliphatic hydrocarbons were measured in the microsomal fraction of lung obtained from -naphthoflavone-treated rats. The unsubstituted hydrocarbons were straight-chain (n-hexane through n-undecane) and branch-chain (eight carbons). The substituted compounds were alcohols and ketones of hexane and octane. The data are expressed as I₅₀ values, i.e. the hydrocarbon concentration required to cause 50% decrease in the rate of enzymecatalyzed product (resorufin) formation. The unsubstituted aliphatic hydrocarbons exhibited I₅₀ values towards BzOPh'ase from 0.76 M (2,5-dimethylhexane) to 8.8 M (n-hexane). The lung EtOPh'ase activity was insensitive to-wards the tested unsubstituted aliphatic hydrocarbons. When the alcohols and ketones of hexane and octane were tested against lung BzOPh'ase activity, I₅₀ values ranged from 16 M (1-octanol) to 4.8 mM (2,5-hexanedione). Lung EtOPh'ase activity exhibited some sensitivity towards the alcohols and ketones, and I₅₀ values ranged from 0.52 mM (4-octanol) to 40.5 mM (2-hexanol). The data show rat lung BzOPh'ase and EtOPh'ase activites are differentially sensitive towards the selected unsubstituted aliphatic hydrocarbons and corresponding alcohols and ketones. The difference in sensitivities may reflect different requirements for an adventitious interaction between a hydrocarbon and enzyme active site.     

Preparation of Heptakis(2,6-di-O-ethyl)-β-cyclodextrin and Its Nuclear Magnetic Resonance Spectroscopic Characterization

Heptakis(2,6-di-O-ethyl)--cyclodextrin (DE--CyD) was prepared and its ¹H and ¹³C nuclear magnetic resonance (NMR) signals in DMSO-d₆ were unequivocally assigned by two-dimensional COSY and ROESY. The results on ¹H coupling constants indicated that all ethylated glucose units are in a ⁴C₁ chair conformation. The average spin-lattice relaxation times (T ₁) of ring carbons of DE--CyD were only slightly shorter, and their standard deviations from the mean T _l value were larger, than those of -cyclodextrin (-CyD) and heptakis(2,6-di-O-methyl)--cyclodextrin (DM--CyD), suggesting the presence of slightly irregular internal motion in the ethylated glucose units. The temperature dependence of chemical shift of DE--CyD in DMSO-d₆ suggested that the C3 hydroxyl protons may participate as proton donor in the intramolecular hydrogen bond to the C2 ethoxyl groups of neighboring glucose, and the intramolecular hydrogen bond of DE- and DM--CyDs is much stronger than that of -CyD, suggesting the stable macrocyclic ring structure of DE--CyD.     

Studies on the constituents of Scutellaria species (XXI): constituents of the leaves of Scutellaria strigillosa Hemsley

From the leaves of Scutellaria strigillosa, 14 compounds, chrysin, apigenin, 5,7,2-trihydroxyflavone, norwogonin, ursolic acid, 6-hydroxy-4-stigmasten-3-one, 6-hydroxy-4,22-stigmastadien-3-one, 2 R,4 R,8 R--tocopherol, (S)-5,5 -bi--tocopheryl, (R)-5,5 -bi--tocopheryl, solanachromene, tocopherylquinone, jodrellin T, and 14,15-dihydrojodrellin T were isolated. The structures were determined on the basis of chemical and spectral data.