Margin of safety of pentylene glycol derived using measurements of cutaneous absorption and volatility.

The safety assessment of pentylene glycol (PG) has been based on a bioavailability extrapolated from those of other 1,2-glycols or an assumed 100% absorption. To make a better safety assessment and an accurate calculation of the margin of safety (MoS), the skin penetration of PG present in a commercially available sunscreen was measured in pig skin at different exposure durations. The mass balance of PG decreased with increasing exposure durations, from 98% (1 h) to 29% (24 h) and the amount of PG detected in the skin wash decreased over time from 93% to 3%. The decrease in mass balance was attributed to an unexpected volatility of PG, which was confirmed in additional experiments. The maximum bioavailable amount of PG was 123 µg/cm2 after 24 h and was considered to be worst case scenario (10 mg/cm2 i.e. 5-fold the recommended application standard dose, 2 mg/cm2). MoS values for the application of a standard dose of sunscreen after 1-24 h exposure were 140-671 in adults and, if calculated for children ratios, 87-217 Based on the available toxicological data for PG in comparison to the amounts determined to be potentially bioavailable, PG in the test sun protection product SPF 50 + does not show any safety concerns for daily usage at the recommended dosage of 2 mg/cm2 or lower.

An in-vivo study for targeted delivery of copper-organic complex to breast cancer using chitosan polymer nanoparticles.

We have developed a strategy for targeted delivery of metal-diketo complex, "bis(2,4-pentanedionato) copper(II)" to breast cancer cells both in-vitro and in-vivo. This metal-organic complex induced ROS and subsequently DNA damage as well as mitochondrial membrane depolarization was observed. The mitochondria rupture further triggered apoptosis. For in-vitro targeting strategies, two different approaches were employed, folic acid or her-2 specific peptide (KCCYSL) was attached to stearic acid-modified polymeric Chitosan nanoparticles loaded with metal-organic complex "bis(2,4-pentanedionato)copper(II)". This was tested on two pairs of isogenic cells (FR+/FR- MCf-7 and her2+ /her2- MCF-7) and it was observed that cells expressing the receptor were susceptible to the drug whereas non-expressing isogenic cells were almost un-affected. During in-vivo studies, mice receiving targeted delivery of bis(2,4-pentanedionato) copper (II) had increased survivability and reduced tumor volume compared to non-targeted drug delivery. During toxicity studies for liver enzymes it was also found that the mice receiving targeted drug did not show any sign of liver damage as well as other histology changes.

Thermosensitive hexanoyl glycol chitosan-based ocular delivery system for glaucoma therapy.

UNLABELLED: Conventional eye drops quickly move away from the surface of the eye; as a result, ocular bioavailability is very limited. To overcome this issue, we developed a thermosensitive hexanoyl glycol chitosan (HGC) as a carrier for topical drug delivery to the eye. Here, we modulated the degree of N-hexanoylation to control the thermogelling behavior and prepared a new ocular formulation of HGC for glaucoma therapy. The viscosity of the aqueous formulation sharply and significantly increases at body temperature. The results from cytotoxicity evaluation showed that HGC is non-toxic at up to 1.25wt.%. In vivo experiments demonstrated that HGC is maintained on the preocular surface for a comparatively longer period of time due to its enhanced viscosity at body temperature. As a result, when brimonidine was loaded, the formulation exhibited attractive bioavailability properties as well as more prolonged period of lowered intra-ocular pressure (14h) compared with Alphagan P, the marketed medication for brimonidine treatment. STATEMENT OF SIGNIFICANCE: In this manuscript, hexanoyl glycol chitosan (HGC) was synthesized by the N-hexanoylation of glycol chitosan. We have observed that an aqueous solution of HGC exhibited a dramatic increase in viscosity as the temperature increased. The HGC-based formulation showed prolonged retention on the preocular surface and enhanced drug availability and efficacy.

In Vivo Imaging of Glycol Chitosan-Based Nanogel Biodistribution.

The preclinical development of nanomedicines raises several challenges and requires a comprehensive characterization. Among them is the evaluation of the biodistribution following systemic administration. In previous work, the biocompatibility and in vitro targeting ability of a glycol chitosan (GC) based nanogel have been validated. In the present study, its biodistribution in the mice is assessed, using near-infrared (NIR) fluorescence imaging as a tool to track the nanogel over time, after intravenous administration. Rapid whole body biodistribution of both Cy5.5 labeled GC nanogel and free polymer is found at early times. It remains widespreadly distributed in the body at least up to 6 h postinjection and its concentration then decreases drastically after 24 h. Nanogel blood circulation half-life lies around 2 h with the free linear GC polymer presenting lower blood clearance rate. After 24 h, the blood NIR fluorescence intensity associated with both samples decreases to insignificant values. NIR imaging of the organs shows that the nanogel had a body clearance time of ≈48 h, because at this time point a weak signal of NIR fluorescence is observed only in the kidneys. Hereupon it can be concluded that the engineered GC nanogel has a fairly long blood circulation time, suitable for biomedical applications, namely, drug delivery, simultaneously allowing efficient and quick body clearance.

Safety assessment of 1,2-glycols as used in cosmetics.

Caprylyl glycol and related 1,2-glycols are used mostly as skin and hair conditioning agents and viscosity agents in cosmetic products, and caprylyl glycol and pentylene glycol also function as cosmetic preservatives. The Cosmetic Ingredient Review (CIR) Expert Panel noted that, while these ingredients are dermally absorbed, modeling data predicted decreased skin penetration of longer chain 1,2-glycols. Because the negative oral toxicity data on shorter chain 1,2-glycols and genotoxicity data support the safety of the 1,2-glycols reviewed in this safety assessment, the Panel concluded that these ingredients are safe in the present practices of use and concentration described in this safety assessment.

Potential of the octanol-water partition coefficient (logP) to predict the dermal penetration behaviour of amphiphilic compounds in aqueous solutions.

Aqueous amphiphilic compounds may exhibit enhanced skin penetration compared with neat compounds. Conventional models do not predict this percutaneous penetration behaviour. We investigated the potential of the octanol-water partition coefficient (logP) to predict dermal fluxes for eight compounds applied neat and as 50% aqueous solutions in diffusion cell experiments using human skin. Data for seven other compounds were accessed from literature. In total, seven glycol ethers, three alcohols, two glycols, and three other chemicals were considered. Of these 15 compounds, 10 penetrated faster through the skin as aqueous solutions than as neat compounds. The other five compounds exhibited larger fluxes as neat applications. For 13 of the 15 compounds, a consistent relationship was identified between the percutaneous penetration behaviour and the logP. Compared with the neat applications, positive logP were associated with larger fluxes for eight of the diluted compounds, and negative logP were associated with smaller fluxes for five of the diluted compounds. Our study demonstrates that decreases or enhancements in dermal penetration upon aqueous dilution can be predicted for many compounds from the sign of logP (i.e., positive or negative). This approach may be suitable as a first approximation in risk assessments of dermal exposure.

Kinetics of monomer biodegradation in soil.

In modern intensive agriculture, plastics are used in several applications (i.e. mulch films, drip irrigation tubes, string, clips, pots, etc.). Interest towards applying biodegradable plastics to replace the conventional plastics is promising. Ten monomers, which can be applied in the synthesis of potentially biodegradable polyesters, were tested according to ASTM 5988-96 (standard respirometric test to evaluate aerobic biodegradation in soil by measuring the carbon dioxide evolution): adipic acid, azelaic acid, 1,4-butanediol, 1,2-ethanediol, 1,6-hexanediol, lactic acid, glucose, sebacic acid, succinic acid and terephthalic acid. Eight replicates were carried out for each monomer for 27-45 days. The numerical code AQUASIM was applied to process the CO2 experimental data in order to estimate values for the parameters describing the different mechanisms occurring to the monomers in soil: i) the first order solubilization kinetic constant, K(sol) (d⁻¹); ii) the first order biodegradation kinetic constant, K(b) (d⁻¹); iii) the lag time in biodegradation, t(lag) (d); and iv) the carbon fraction biodegraded but not transformed into CO2, Y (-). The following range of values were obtained: [0.006 d⁻¹, 6.9 d⁻¹] for K(sol), [0.1 d⁻¹, 1.2 d⁻¹] for K(b), and [0.32-0.58] for Y; t(lag) was observed for azelaic acid, 1,2-ethanediol, and terephthalic acid, with estimated values between 3.0 e 4.9 d.

A comparison of pentane-1,5-diol to other diols for use in dermatology.

BACKGROUND: The use of pentane-1,5-diol in topical pharmaceutical products is relatively new compared with, e.g., propane-1,2-diol (propylene glycol), also an aliphatic diol, which has been used for many years. Yet, what are the differences between diols in clinical efficacy, safety and other characteristics? OBJECTIVE: The objective of this overview was to compare the efficacy, safety, chemical and pharmaceutical characteristics of pentane-1,5-diol with other aliphatic diols used in pharmaceutical formulations in dermatology. METHODS: A survey of the literature was carried out based on searches limited to aliphatic diols. RESULTS/CONCLUSION: Pentane-1,5-diol was found to be safe and more effective than several other diols with respect to drug delivery-enhancing potency, pharmaceutical and cosmetic properties, antimicrobial spectrum and toxicity. Results from formal clinical trials with pentane-1,5-diol verify its efficacy and safety. These characteristics together with its low cost make pentane-1,5-diol an attractive substance for use in pharmaceutical formulations for topical administration.

Toxic alcohol ingestions: clinical features, diagnosis, and management.

Alcohol-related intoxications, including methanol, ethylene glycol, diethylene glycol, and propylene glycol, and alcoholic ketoacidosis can present with a high anion gap metabolic acidosis and increased serum osmolal gap, whereas isopropanol intoxication presents with hyperosmolality alone. The effects of these substances, except for isopropanol and possibly alcoholic ketoacidosis, are due to their metabolites, which can cause metabolic acidosis and cellular dysfunction. Accumulation of the alcohols in the blood can cause an increment in the osmolality, and accumulation of their metabolites can cause an increase in the anion gap and a decrease in serum bicarbonate concentration. The presence of both laboratory abnormalities concurrently is an important diagnostic clue, although either can be absent, depending on the time after exposure when blood is sampled. In addition to metabolic acidosis, acute renal failure and neurologic disease can occur in some of the intoxications. Dialysis to remove the unmetabolized alcohol and possibly the organic acid anion can be helpful in treatment of several of the alcohol-related intoxications. Administration of fomepizole or ethanol to inhibit alcohol dehydrogenase, a critical enzyme in metabolism of the alcohols, is beneficial in treatment of ethylene glycol and methanol intoxication and possibly diethylene glycol and propylene glycol intoxication. Given the potentially high morbidity and mortality of these intoxications, it is important for the clinician to have a high degree of suspicion for these disorders in cases of high anion gap metabolic acidosis, acute renal failure, or unexplained neurologic disease so that treatment can be initiated early.

Effect of n-hexane on the disposition and toxicity of the 1,3-butadiene metabolite 3-butene-1,2-diol.

3-Butene-1,2-diol (butenediol), a major metabolite of 1,3-butadiene (butadiene), can undergo either detoxification or biotransformation to potentially toxic metabolites, including 3,4-epoxy-1,2-butanediol and hydroxymethylvinyl ketone (HMVK). Butadiene exposure can occur concomitantly with hexanes, which share common biotransformation pathways with butadiene. To determine the potential influence of hexane co-exposure on butadiene toxicity, the present study examined the effect of n-hexane on butenediol disposition [as measured by urinary excretion of (N-acetyl-S-(3,4-dihydroxybutyl)-L-cysteine) (MI level)] and genotoxicity (as measured by the frequency of bone marrow micronucleated erythrocytes) and acute toxicity (as measured by body weight changes) in the rat. The results show that butenediol was not genotoxic to adult or immature rats but was acutely toxic to adult but not immature rats. The results also suggest that n-hexane co-exposure may attenuate the acute toxicity by butenediol in adult rats and that immature rats may be less sensitive than adults to the acute toxicity.

Modelling the effects of alcohol ethoxylates on diffusion of pesticides in the cuticular wax of Chenopodium album leaves.

Cuticular waxes represent the first and, in most cases, the limiting barrier for foliar uptake of pesticides from solution. Sorption of pesticides in reconstituted cuticular wax (wax/water partition coefficients) of Chenopodium album L. and in isolated cuticular membranes (cuticle/water partition coefficients) of Prunus laurocerasus L. was determined. Diffusion coefficients of pesticides in reconstituted cuticular wax of C. album leaves were size-dependent, increasing with increasing molar volume. In the presence of alcohol ethoxylates, diffusion coefficients were enhanced by up to two orders of magnitude, and size selectivity was significantly decreased. The accelerating effect and the decrease in size selectivity were attributed to plasticisation of the cuticular wax by the alcohol ethoxylates increasing the fluidity in the wax. A free volume model adopted from polymer science was successfully applied to predict diffusion coefficients of pesticides on the basis of the transport properties of the wax (size selectivity and crystallinity), the molar volume of the diffusing compound and the accelerator concentration in the wax.

Species and tissue differences in the toxicity of 3-butene-1,2-diol in male Sprague-Dawley rats and B6C3F1 mice.

3-Butene-1,2-diol (BDD) is a major metabolite of 1,3-butadiene (BD), but the role of BDD in BD toxicity and carcinogenicity remains unclear. In this study, the acute toxicity of BDD was investigated in male Sprague-Dawley rats and B6C3F1 mice. Of the rats given 250 mg/kg BDD, 2 out of 4 died within 24 h; rats experienced hypoglycemia, significant alterations of liver integrity tests, and had lesions in the liver 4 h after treatment, but no lesions were detected in extrahepatic tissues. Rat hepatic GSH and GSSG levels were significantly depleted at both 1 and 4 h after the BDD treatment. Rats administered 200 mg/kg BDD also had liver lesions but no death or hypoglycemia was observed four or 24 h after treatment; these rats had depleted hepatic GSH and GSSG levels at 1 h but not at 4 or 24 h after treatment. Mice administered 250 mg/kg BDD exhibited modest alterations of liver integrity tests, but no death, hypoglycemia, or lesions in any tissue, and hepatic GSH and GSSG levels were depleted at 1 h but not at 4 h. The plasma half-life of BDD was four times longer in rats than in mice. Additional studies in rats showed the depletion of hepatic GSH and GSSG preceded the BDD-induced hypoglycemia and hepatotoxicity. Thus, the long half-life of BDD in rat plasma and the sustained depletion of hepatic GSH and GSSG may in part explain the higher sensitivity of the rat to BDD-induced hepatotoxicity. Furthermore, the results indicate that BDD may play a role in BD-induced toxicity.

Erythrocyte membrane permeability for a series of diols.

Erythrocyte membrane permeability coefficients for a series of diols have been defined by the method developed. The method is based on the physical and mathematical modeling of hypotonic hemolysis process. There have been also determined membrane permeability coefficients for erythrocytes treated with p-chloromercuribenzenesulfonic acid monosodium salt (pCMBS), which is known to block aqueous protein channels. Permeating process is shown to be conditioned both by hydrophilic/hydrophobic properties of the molecules and their geometrical parameters. The obtained results propose that, when exceeding the molecules diameter over a value of 4 A, the permeability coefficient reduces due to decreasing of flow through the aqueous protein pores of a constant size. Permeability coefficients for comparatively hydrophobic molecules are almost directly proportional to the coefficients of partition between hydrophobic and hydrophilic phases, by pointing to a lipid way of permeation of these molecules through erythrocyte membranes.

Metabolism of 3-butene-1,2-diol in B6C3F1 mice. Evidence for involvement of alcohol dehydrogenase and cytochrome p450.

3-Butene-1,2-diol (BDD), a metabolite of 1,3-butadiene, is rapidly metabolized by B6C3F1 mice at doses ranging from 10 to 250 mg/kg. Calculation of plasma clearance suggested that the kinetics of BDD metabolism were dose-dependent. Clearance varied 5-fold in this dose range. Urinary excretion of BDD was also dose-dependent but did not exceed 5% of the administered dose. A small fraction of the dose (<1%) was excreted as glucuronide or sulfate conjugates. Benzylimidazole, a cytochrome P450 inhibitor, decreased the clearance of BDD (25 mg/kg) by 44%, whereas 4-methylpyrazole, an alcohol dehydrogenase and cytochrome P450 inhibitor, decreased BDD clearance by 82%. BDD administration (250 mg/kg) resulted in depletion of hepatic and renal nonprotein thiols, by 48 and 22%, respectively. Pretreatment of mice with 4-methylpyrazole provided partial protection against depletion of nonprotein thiols, whereas pretreatment with benzylimidazole was ineffective. Incubation of BDD with NADPH and mouse liver microsomes resulted in time-dependent inactivation of p-nitrophenol hydroxylase (PNPH) activity, a marker for cytochrome P450. Inclusion of glutathione, with or without glutathione peroxidase, did not attenuate the inactivation of PNPH, whereas deferoxamine, superoxide dismutase, catalase, and mannitol provided modest protection. These results are consistent with suicide inhibition of PNPH by BDD, with a minor role for reactive oxygen species in the loss of PNPH. Treatment of mice with BDD (250 mg/kg) inactivated hepatic microsomal PNPH activity by 50% after 60 min. These results suggest that BDD is extensively and rapidly metabolized in mice, and they provide evidence for the formation of reactive intermediates that could play a role in the toxicity of 1, 3-butadiene.

Pharmacokinetics of 2-ethyl-1,3-hexanediol. III. In vitro skin penetration comparisons using the excised skin of humans, rats, and rabbits.

Excised skin from Fischer 344 rats, New Zealand White rabbits, and human females (obtained from mammoplasty patients) were compared for their in vitro skin penetration potential with 2-[14C]-ethyl-1,3-hexanediol (EHD). EHD was applied as both an undiluted dose and a 3% v/v aqueous dose using a flowthrough skin penetration chamber design and was analyzed over 0-6 hr. The undiluted dose was equivalent to a 150 mg/kg dose used in vivo with rats (Frantz et al., Drug Metab. Dispos. 20(1), 6-18, 1992), but normalized on a per cm2 surface area basis, and applied under occluded conditions (covered as for in vivo studies). Undiluted applications of EHD did not substantially penetrate skin, with effluent recoveries of approximately 0.9% of the applied dose for human skin, 2-4% for rat skin, and 3-6% for rabbit skin. By comparison, nonoccluded human skin showed lower effluent radioactivity (0.6%), which was attributed to EHD evaporation from skin. With undiluted EHD, approximately 97% of the recovered 14C was an unabsorbed dose for human skin, with 94% for rat skin and 85% for rabbit skin (expressed as a percentage of the recovered dose). Based on HPLC analysis of effluent samples, 99-100% of the undiluted [14C]EHD penetrated rat, rabbit, and human skin in the unmetabolized form. In contrast, approximately 5% of the applied aqueous dose was recovered in the effluents for human skin, while 6-9% appeared in effluents for rat skin; rabbit skin was not evaluated for aqueous doses. The fraction of unabsorbed aqueous EHD dose totaled 53% of the applied dose for human skin and 63% for rat skin. Evaporative loss of undiluted [14C]EHD was also measured (captured on activated charcoal) in separate experiments and compared with a known standard chemical, N,N[14C]diethyl-m-toluamide (DEET). Evaporation of EHD was clearly a competing factor with penetration, particularly for human skin preparations, and evaporative losses were similar to those seen in previous studies. Penetration of skin was also greater for both EHD and DEET when evaporation was not permitted (stopped chamber). Permeability constant (kp) values were calculated using the pseudo steady-state slopes from plots for cumulative mg/cm2 penetration vs time. For undiluted EHD, human skin had the slowest penetration rate, while rabbit skin kp values were the largest. The kp values for water solutions of EHD on rat and human skin demonstrated a slightly higher penetration, with values of the same order of magnitude as that observed for a concurrently run [14C]ethanol control. The minimal skin penetration observed in vitro in this study, taken together with in vivo percutaneous pharmacokinetic studies (Frantz et al., 1992) and the known percutaneous toxicology of EHD, suggests that penetration through human skin and systemic adverse effects should be minimal.

[Metabolic impact and complications of intra-uterine resection]. / Incidents et accidents métaboliques des résections endo-utérines.

Hysteroscopic surgery with the use of a resectoscope are currently going through major developments. They are often aimed at healthy women who consider having relatively minor surgery. Many complications can affect endometrial resection. Some metabolic complications due to the irrigating liquid have been identified recently in gynaecological surgery, and can be defined as the whole group of clinical symptoms linked to the passage of the irrigation liquid into systemic circulation. Neurological and cardiovascular disorders are due to an acute dilutional hyponatremia and to the very toxicity of glycol and/or of its metabolites. The way the irrigating liquid is resorbed has an effect on the order in which these accidents happen. The duration of the resection, its depth, as well as the intrauterine pressure are the three factors which make it easier for a clinical syndrome to appear. Whatever the mechanism responsible, the clinical and biological consequences are the same and can be more or less serious, depending on how much liquid has been resorbed: they are non-existent up to one liter, and appear between 1.5 and 2 liters. Recent studies have shown that natremia and glycinemia are closely and inversely related. By taking a number of precautions, accidents--which are relatively rare but can be very serious--could be prevented.

Pharmacokinetics of 2-ethyl-1,3-hexanediol. II. Nonsystemic disposition following single percutaneous or peroral doses in Fischer 344 rats.

The pharmacokinetics of [1,3-14C]-2-ethyl-1,3-hexanediol (EHD) were investigated following single percutaneous doses of 150 mg/kg, applied to male and female Fischer 344 rats, or single peroral doses of 1.5 or 150 mg EHD/kg given by gavage to male Fischer 344 rats. EHD-derived radioactivity was slowly absorbed through skin and relatively rapidly excreted through the urine in a first-order manner over 48 hr postdosing. Skin penetration of 14C was sufficiently slow that the terminal rate constant for the plasma concentration data had to be derived from the absorption phase of this curve, based on the terminal rate constant for a comparable intravenous dose plasma curve [Frantz et al.: Drug Metab. Dispos. 19, 881 (1991)]. Plasma data from perorally doses rats exhibited dose-linearity over a 1.5-150 mg/kg range, with plasma 14C concentration vs. time plots for oral doses of EHD resembling the iv time-course data. This resulted from a very rapid absorption phase (5.5 min t1/2), with plasma 14C levels for both dose levels decreasing in a biexponential manner. The major route of excretion after peroral doses was in urine, making this mode of excretion consistent for both routes of administration evaluated in this study and including the doses given in previous iv work. Kinetic analysis confirmed that this route of excretion was first-order. HPLC analysis of urine from both routes demonstrated that EHD was metabolized and excreted as at least two major, water-soluble urinary metabolites; these metabolites were not identified in this investigation. No unmetabolized EHD was detected in urine, indicating that EHD may be completely metabolized in the rat. Overall, EHD was absorbed, distributed, metabolized, and eliminated from the Fischer rat in a first-order manner following either cutaneous or peroral doses. The results of this study indicate that the kinetic patterns observed experimentally will be dose-proportional for doses administered in the range of 1.5-150 mg/kg.

Pharmacokinetics of 2-ethyl-1,3-hexanediol. I. Systemic disposition following single intravenous doses in male Fischer 344 rats.

A determination of the systemic pharmacokinetics of [1,3-14C]-2-ethyl-1,3-hexanediol (EHD) was conducted following i.v. dosing of male Fischer 344 rats. Pharmacokinetic analyses of the plasma data indicated that there is dose linearity in the 1.5 to 150 mg/kg range, and that EHD is cleared from plasma in a biexponential manner according to first order transfer and elimination processes. The data show that EHD-derived radioactivity is very rapidly distributed and then is slowly eliminated (probably as EHD metabolites) over a 48-hr period after a single i.v. injection. EHD is not found in the urine as unchanged test material by HPLC analysis following these i.v. doses, indicating that this chemical is probably completely metabolized in the rat. The appearance of EHD-derived radioactivity in the urine also follows a first order behavior, as evidenced by calculations of rate constants which are similar to the terminal rate constants from plasma radioactivity data. Both U infinity-Ut and dU/dt analyses of urine radioactivity data demonstrated that first order rate constants can be derived from urinary excretion data and supported the overall conclusion that the elimination of EHD from the rat follows first order processes in this range of i.v. doses.

Azido glycols: potent, low molecular weight renin inhibitors containing an unusual post scissile site residue.

Azidomethyl-substituted 1,2- and 1,3-diols were prepared from Boc-cyclohexylalanal and evaluated as transition state analogue renin inhibitors, leading to the development of a small (MW less than 600), nanomolar inhibitor. Remarkable aqueous solubility enhancement followed the incorporation of an N-terminal urea functionality. Evaluation of selected compounds both in vivo and in vitro demonstrated that while transport across the intestine occurred upon id administration, extensive liver extraction resulted in low systemic levels.