Sesame Oil Solution Research Articles

A Prodrug Strategy to Reposition Atovaquone as a Long-Acting Injectable for Malaria Chemoprotection.

Recent malaria drug discovery approaches have been extensively focused on the development of oral, smallmolecule inhibitors for disease treatment whereas parenteral routes of administration have been avoided due to limitations in deploying a shelf-stable injectable even though it could be dosed less frequently. However, an updated target candidate profile from Medicines for Malaria Venture (MMV) and stakeholders have advocated for long-acting injectable chemopreventive agents as an important interventive tool to improve malaria prevention. Here, we present strategies for the development of a long-acting, intramuscular, injectable atovaquone prophylactic therapy. We have generated three prodrug approaches that are contrasted by their differential physiochemical properties and pharmacokinetic profiles: mCBK068, a docosahexaenoic acid ester of atovaquone formulated in sesame oil, mCKX352, a heptanoic acid ester of atovaquone formulated as a solution in sesame oil, and mCBE161, an acetic acid ester of atovaquone formulated as an aqueous suspension. As a result, from a single 20 mg/kg intramuscular injection, mCKX352 and mCBE161 maintain blood plasma exposure of atovaquone above the minimal efficacious concentration for >70 days and >30 days, respectively, in cynomolgus monkeys. The differences in plasma exposure are reflective of the prodrug strategy, which imparts altered chemical properties that ultimately influence aqueous solubility and depot release kinetics. On the strength of the pharmacokinetic and safety profiles, mCBE161 is being advanced as a first-in-class clinical candidate for first-in-human trials.

Short-Term Cannabidiol with Δ-9-Tetrahydrocannabinol in Parkinson's Disease: A Randomized Trial.

Cannabis use is frequent in Parkinson's disease (PD), despite inadequate evidence of benefits and risks. The aim is to study short-term efficacy and tolerability of relatively high cannabidiol (CBD)/low Δ-9-tetrahydrocannabinol (THC) to provide preliminary data for a longer trial. Persons with PD with ≥20 on motor Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) who had negative cannabis testing took cannabis extract (National Institute of Drug Abuse) oral sesame oil solution for 2 weeks, increasing to final dose of 2.5 mg/kg/day. Primary outcome was change in motor MDS-UPDRS from baseline to final dose. Participants were randomized to CBD/THC (n = 31) or placebo (n = 30). Mean final dose (CBD/THC group) was 191.8 ± 48.9 mg CBD and 6.4 ± 1.6 mg THC daily. Motor MDS-UPDRS was reduced by 4.57 (95% CI, -8.11 to -1.03; P = 0.013) in CBD/THC group, and 2.77 (-4.92 to -0.61; P = 0.014) in placebo; the difference between groups was non-significant: -1.80 (-5.88 to 2.27; P = 0.379). Several assessments had a strong placebo response. Sleep, cognition, and activities of daily living showed a treatment effect, favoring placebo. Overall adverse events were mild and reported more in CBD/THC than placebo group. On 2.5 mg/kg/day CBD plasma level was 54.0 ± 33.8 ng/mL; THC 1.06 ± 0.91 ng/mL. The brief duration and strong placebo response limits interpretation of effects, but there was no benefit, perhaps worsened cognition and sleep, and there was many mild adverse events. Longer duration high quality trials that monitor cannabinoid concentrations are essential and would require improved availability of research cannabinoid products in the United States. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Pure Sesame Oil vs Isotonic Sodium Chloride Solution as Treatment for Dry Nasal Mucosa

Pure Sesame Oil vs Isotonic Sodium Chloride Solution as Treatment for Dry Nasal Mucosa

Lipophilic nalmefene prodrugs to achieve a one-month sustained release

Nalmefene is an opioid antagonist which as a once-a-day tablet formulation has recently been approved for reducing ethanol intake in alcoholic subjects. In order to address the compliance issue in this patient population, a number of potential nalmefene prodrugs were synthesized with the aim of providing a formulation that could provide plasma drug concentrations in the region of 0.5–1.0ng/mL for a one-month period when dosed intramuscular to dogs or minipigs. In an initial series of studies, three different lipophilic nalmefene derivatives were evaluated: the palmitate (C16), the octadecyl glutarate diester (C18-C5) and the decyl carbamate (CB10). They were administered intramuscularly to dogs in a sesame oil solution at a dose of 1mg-eq. nalmefene/kg. The decyl carbamate was released relatively quickly from the oil depot and its carbamate bond was too stable to be used as a prodrug. The other two derivatives delivered a fairly constant level of 0.2–0.3ng nalmefene/mL plasma for one month and since there was no significant difference between these two, the less complex palmitate monoester was chosen to demonstrate that dog plasma nalmefene concentrations were dose-dependent at 1, 5 and 20mg-eq. nalmefene/kg. In a second set of experiments, the effect of the chain length of the fatty acid monoester promoieties was examined. The increasingly lipophilic octanoate (C8), decanoate (C10) and dodecanoate (C12) derivatives were evaluated in dogs and in minipigs, at a dose of 5mg-eq. nalmefene/kg and plasma nalmefene concentrations were measured over a four-week period. The pharmacokinetic profiles were very similar in both species with Cmax decreasing and Tmax increasing with increasing fatty acid chain length and the target plasma concentrations (0.5–1.0ng/mL over a month-long period) were achieved with the dodecanoate (C12) prodrug. These data therefore demonstrate that sustained plasma nalmefene concentrations can be achieved in both dog and minipig using nalmefene prodrugs and that the pharmacokinetic profile of nalmefene can be tuned by varying the length of the alkyl group.

Estradiol and striatal dopamine receptor antagonism influence memory system bias in the female rat

Estradiol (E2) has been shown to influence learning and memory systems used by female rats to find a reward. Rats with high levels of E2 tend to use allocentric, or place, memory while rats with low levels of E2 use egocentric, or response, memory. It has been shown that systemic dopamine receptor antagonism interacts with E2 to affect which memory system is used. Here, dopamine antagonists were administered directly into either the dorsal striatum or nucleus accumbens to determine where in the brain this interaction takes place. Seventy-four young adult, female, Sprague-Dawley rats were trained and tested in a modified plus-maze. All rats were ovariectomized, received a subcutaneous low E2 implant, and were implanted with bilateral cannulae into either the dorsal striatum or the nucleus accumbens. Additionally, high E2 rats received daily injections of E2 in a sesame oil solution while low E2 rats received daily injections of vehicle. After reaching criterion levels of performance in a plus-maze task, rats were administered microinjections of either a dopamine D1 receptor (SCH 23390; 0.1μg/ml and 0.01μg/ml) or D2 receptor (raclopride; 2μg/ml and 0.5μg/ml) antagonist or a vehicle control (saline) in a counterbalanced manner. High E2 rats exhibited a trend towards a place memory bias while low E2 rats showed a response memory bias. Dorsal striatal administration of a D1, but not D2, dopamine receptor antagonist caused a switch in the memory system used by both high and low E rats. There was no significant effect of dopamine receptor antagonism in the nucleus accumbens group. Thus, E2 determined which memory system controlled behavior in a plus-maze task. Moreover, this effect was modulated by dopamine D1R antagonism in the dorsal but not ventral striatum suggesting that memory systems are, in part, mediated by E2 and dopamine in this region.

The Effects of Cysteamine On the Mice with the 3-Methylcholanthrene and Induced Fibrosarcoma: Investigation of the Genotoxicity

Bu calismada, fare kemik iligi hucrelerinde 3-Metilkolantrenin genotoksisitesine karsi sisteaminin etkisi arastirildi. Deneyde beyaz erkek fareler (Mus musculus albino) kullanildi. Fareler her grupta 15 adet olacak sekilde bes gruba ayrildi. Birinci grup negatif kontrol grubu olarak tutuldu. Ikinci gruba susam yagi (0.2 ml, deri alti), ucuncu gruba sisteamin (%0.1 suda oral ad libitum), dorduncu gruba 3-Metilkolantren (1 mg 3-Metilkolantren/0.2 ml susam yagi cozeltisinden 0.2 ml deri alti yolla), besinci gruba 3-Metilkolantren (1 mg 3-Metilkolantren/0.2 ml susam yagi cozeltisinden 0.2 ml deri alti yolla) ve sisteamin (%0.1 oraninda suda hazirlanmis sisteamin cozeltisinden oral yolla ad libitum olarak verildi. Butun gruplardaki hayvanlar 4 ay sonra eter anestezisi esliginde servikal dislokasyonla otanazi edildi. Her gruptan 8 adet farenin femur kemik iligi hucrelerinde mitotik aktivite ile mikronukleus testi kullanilarak genotoksik ve sitotoksik etkiler belirlendi. 3-Metilkolantren'in mikronukleuslu polikromatik eritrositlerin sayilarinda cogalma ve kemik iligi hucrelerinde sitotoksik etki meydana getirdigi tespit edildi. Ayrica mitotik aktiviteyi dusurdugu gozlendi. Bu etkiler istatistiksel acidan onemli bulundu (P<0.01). Sisteaminin ise genotoksik ve sitotoksik etki yapmadigi belirlendi. 3-Metilkolantren ile birlikte uygulanan sisteaminin yalniz basina verilen 3-Metilkolantrene gore mikronukleuslu polikromatik eritrosit sayilarinda onemli derecede dusus, mitotik aktivitede ise artis yaptigi gozlendi. Arastirma sonucunda sisteaminin farelerde 3-Metilkolantren ile induklenen genotoksisiteye karsi koruyucu etki gosterdigi belirlendi. Summary In this study, the effect of cysteamine against the genotoxicity of 3 Methylcholanthrene's in the cell of mouse bone marrow was examined. In the experiment total of 75 white male mice were used. They were split into 5 groups. First group was kept as negative control group. Sesame oil to the second group (0.2 ml, subcutaneous), cysteamine to the third group (oral ad libitum 0.1% in water), 3-Methylcholanthrene to the forth group (1 mg 3- Methylcholanthrene /0.2 ml from the sesame oil solution 0.2 ml, subcutaneously) and cysteamine (ad libitum via oral route from the solution of cysteamine that was prepared in water at the rate of 0.1%) was given. Four months later animals in all groups were euthanasied with cervical dislocation (with ether anesthesia). Genotoxic and cytotoxic effects were defined by using mitotic activty and micronucleus in the cells of femur bone marrow of 8 mice from each group. It was determined that 3- Methylcholanthrene has brought about reproduction in the numbers of micronucleus polychromatic erythrocytes and cytotoxic effects in the cells of bone marrow. Furthermore, it was observed that it has slow down the mitotic activity. These effects were statistically considered as significant (P<0.01). On the other hand it was determined that the cysteamine did not has an genotoxic and cytotoxic effect. It was observed that when cysteamine used with 3- Methylcholanthrene caused to fall in the numbers of micronucleus polychromatic erythrocytes and upregulation in mitotic activity in comparison with 3- Methylcholanthrene that was given by itself. In the end of the study, it was observed that cysteamine had protective effect against the genotoxicity induced with 3- Methylcholanthrene on the mice.

Stability Studies on Aqueous and Oily Ophthalmic Solutions of Diclofenac

Various aqueous and oily diclofenac ophthalmic formulations were subjected to accelerated and long term stability studies. Degradation of diclofenac was found to follow first-order kinetics. Among the aqueous formulations containing preservative, formulation with PMA, PMN, SA, MP/PP and SMS showed diclofenac content above 90% after 6 months of accelerated and 12 months of room temperature storage. Diclofenac 0.1%, w/v aqueous formulation (pH 7.4), with 5-10% overages, containing SMS, MP/PP or PMN look promising taking both stability and corneal permeability in view. However, for use in cataract surgery formulation without preservative appears ideal. Oily ophthalmic formulations except those in olive and mustard oil, had more than 90% drug content after 6 months of accelerated and 12 months of room temperature storage. Diclofenac (0.2%, w/v) ophthalmic solution in sesame oil with 3% overage and containing benzyl alcohol (0.5%, v/v) as preservative, appears ideal, taking both stability and corneal permeability in view.

&lt;i&gt;In Vitro&lt;/i&gt; Corneal Permeation of Diclofenac from Oil Drops

In vitro transcorneal permeation of diclofenac from oil drops was studied using freshly excised goat cornea. The maximum apparent corneal permeability coefficient (Papp) was obtained with 0.2% (w/v) diclofenac drops in sesame oil followed by safflower oil, while formulation in castor oil provided minimal Papp. The addition of benzyl alcohol, a preservative, in oil drops, increased the Papp value of diclofenac. Partition experiments indicated increased partitioning of diclofenac in the aqueous phase in the presence of benzyl alcohol, and the same could be responsible for the benzyl alcohol-induced increase in Papp. The solubility of diclofenac was higher in castor, arachis, and sunflower oil. But drug permeation from 0.5-1.0% (w/v) diclofenac drops in castor oil or 0.5% (w/v) drops in arachis /sunflower oil was less than that observed with 0.2% (w/v) drops in sesame oil. Thus diclofenac 0.2% (w/v) drops in sesame oil containing 0.5% (v/v) benzyl alcohol provides maximum Papp. The formulation increased corneal hydration indicating corneal damage. Since corneal hydration is less than 83% the damage appears to be reversible. The saturation solubility of diclofenac in sesame oil at 4 degrees C is 0.33% (w/v). Hence diclofenac 0.2% (w/v) solution in sesame oil will not precipitate at 4 degrees C and therefore the chances of crystallization of diclofenac from the formulation due to climatic change leading to physical instability appear to be remote.

Evaluation of tripalmitin crystallization in sesame oil through a modified avrami equation

AbstractTripalmitin (TP) crystallization in sesame oil solutions (0.98, 1.80, and 2.62%, wt/vol) was investigated by utilizing a modification of the Avrami equation. The modified equation retains the original correspondence to the nucleation process (i.e., n) and crystal growth and simply corrects the value of the crystallization rate constant (z) by eliminating the influence of n. The energy of activation (Ea) values for TP crystallization in sesame oil solution, calculated with the modified z, were quite similar to those calculated with the reciprocal of time required to achieve 50% of TP crystallization (tF=0.50−1). However, Eavalues calculated with z from Avrami’s original equation were quite different from those obtained with tF=0.50−1. Thus, z and Eavalues calculated through the Avrami equation yield erroneous results, especially when comparing crystallization processes having different magnitudes of n, as in this study. Additional analysis that considered the viscosity of the TP oil solutions concluded that, at equal supercooling conditions (e.g., 22.0–22.5), the magnitude of z and Eabecame more dependent upon the crystal growth process as oil viscosity decreased. In contrast, as viscosity of the oil phase increased, the main crystallization process, evaluated through z and Ea′was nucleation. Furthermore, within the supercooling interval achieved at the temperatures utilized, the increase in supercooling at constant viscosity conditions (e.g., 5.25–5.5 dynes/cm2) would produce a higher degree of nucleation without an appreciable effect on TP crystal size. The results obtained indicate that investigating the effects of supercooling, molecular diffusion (i.e., viscosity) and TP concentration on the magnitude of z and Eaduring TP crystallization in sesame oil requires a multiple variable statistical approach.

Enhanced selective lymphatic delivery of cyclosporin a by solubilizers and intensified immunosuppressive activity against mice skin allograft.

The absorption and lymphatic delivery of a new immunosuppressive drug, cyclosporin A (CsA), were studied in rats by administering CsA orally after solubilization with HCO-60 (polyoxyethylated hydrogenated castor oil), sugar ester, and oils. After the administration of solubilized CsA (7 mg/kg) to rats with thoracic lymph duct cannulas, both plasma and lymph CsA levels were measured over 6 hr. The lymph CsA levels were strongly affected by the solubilizers. The rank order of the solubilizers in enhancing lymph absorption was HCO-60 (57 µg/ml) > sugar ester (46 µg/ml) > sesame oil (3.5 µg/ml) > linoleic acid (0.4 µg/ml), where the parentheses show the maximum lymph CsA levels. Plasma CsA levels were below 2 µg/ml in each group of animals and were barely altered by the solubilizers. These results support the selective lymphatic delivery of CsA with solubilizers such as HCO-60 and sugar ester. The immunosuppressive activity of CsA (1 mg/kg) solubilized with HCO-60 was nearly equivalent to the sesame oil solution with 7 to 15 mg/kg CsA in the skin-allograft mice model.

Dosage form characteristics of microsphere-in-oil emulsion. II: Examination of some factors affecting lymphotropicity.

The relation between the physico-chemical properties and lymphotropicity of microsphere-in-oil (S/O) emulsion was investigated in comparison with water-in-oil (W/O) emulsion and sesame oil without any pharmaceutical modification. S/O emulsion gave the best lymph node accumulation of tripalmitin (14C), used as an oil tracer, after intramuscular injection. W/O emulsion was next most effective. Increase of injection volume and massage of the injection site accelerated the lymphatic transport of S/O emulsion, suggesting that hydrostatic tissue pressure plays a role in lymphatic delivery. Sesame oil solution of tripalmitin (14C) injected without any pharmaceutical modification was not effectively transferred to the lymph nodes, but addition of surfactants to the oil resulted in an increased accumulation of tripalmitin (14C) in the lymph nodes. Measurements of surface and interfacial tension of various formulations revealed that addition of surfactants caused a marked decrease of interfacial tension against water, which would promote dispersion of the formulations into smaller oil droplets. Microscopic observations of the thigh muscle after intramuscular injection of various oil formulations revealed a correlation between their extent of dispersion and their lymphotropicity. These results suggst that S/O emulsions have physico-chemical properties suitable for effective lymphotropic transport.

II. MANIFESTATION OF THE ANTI-ANDROGENIC ACTION OF A STEROID ESTER TSAA-330 (16β-ETHYL-17β-HYDROXY-4-OESTREN-3-ONE CAPROATE) AND ELUCIDATION OF ITS LONG-LASTING MECHANISM USING A SIMPLE STEROID DETERMINATION TECHNIQUE

Using a simple steroid determination technique, in situ steroid absorption from a subcutaneously injected sesame oil solution in rats was pursued following the time-course changes in the steroid concentration. Based on the knowledge thus obtained, the anti-androgenic effect of a steroidal compound, TSAA-330, could be manifested in the subcutaneous route. (1) Anti-androgenic steroid TSAA-291 and its esters in the subcutaneously injected sesame oil solution were selectively absorbed into the general circulation at different rates according to their chemical nature and structures, while the oil itself remained at the injected site for a considerably long period. At the injected site where subcutaneous doses of steroids molar equivalent to 50 mg of TSAA-291 were administered in 5 ml/rat of sesame oil, TSAA-291 decreased to the level of 10% of the initial concentration on the 4th day. TSAA-328 decreased slowly to the 50% and 20% levels on the 7th and 21st day, respectively. TSAA-335 decreased more slowly to the 50% level on the 14th day. TSAA-330 decreased most slowly only to the 70% level on the 49th day. (2) A single subcutaneous administration of 200 mg of TSAA-330 suppressed the weight increase of the accessory sex organs caused by a single subcutaneous injection of testosterone caproate (10 mg) in the immature orchiectomized rat. The suppressive effect was obvious from 2 weeks after the administration, and seemed to last for more than two weeks. The levator ani weight was not affected by the administration of TSAA-330. (3) Dose-dependent inhibitions of the accessory sex organs were obtained three weeks after a single subcutaneous administration of 50 to 400 mg of TSAA-330 in the adult male rat. (4) Daily oral administrations of 50 mg of TSAA-291 or TSAA-330 to the adult male rat for 8 days resulted in depression of the accessory sex organs to almost the same extent obtained with either agent. One week after the last administration, however, the weight of the accessory sex organs of the TSAA-291-administered animals recovered to almost the comparable level with the control, whereas a significant after-effect of the inhibition was still evident in the TSAA-330-administered animals.

Effects of oral 2,6- cis-diphenylhexamethylcyclotetrasiloxane on the reproductive system of the male rat

In a previous study, it was found that treatment with a series of low molecular weight linear and cyclic phenylmethylpolysiloxanes results in suppression of the male endocrine system. A structure-activity relationship in the rat demonstrated that the most active member is 2,6- cis-diphenylhexamethylcyclotetrasiloxane, referred to as cyclic 2,6- cis-[(PhMeSiO) 2(Me 2SiO) 2]. This organosiloxane has been shown to have estrogenlike antigonadotropic activity in the mature male rat as shown by a decrease in accessory tissue weight, decrease in plasma testosterone, pituitary enlargement, alterations in pituitary content of follicle-stimulating hormone, luteinizing hormone, and prolactin, and the effects of replacement therapy with androgen and gonadotropins. In the rat, accessory tissue depression requires up to 7 days of po dosing in a sesame oil solution whereas pituitary gonadotropin content is altered within 24 hr of a single po dose. Cyclic 2,6- cis-[(PhMeSiO) 2(Me 2SiO) 2] also depresses plasma cholesterol. Drug-metabolizing enzymes are induced as determined indirectly by shortening of hexobarbital sleep time and decreased antipyrine toxicity.

Separation of Quingestanol Acetate from Sesame Oil Solution and Its Determination in Combinations withEthinyl Estradiol or Quinestrol

Quingestanol acetate, norethindrone acetate 3-cyclopentyl enol ether, was not separable from its sesame oil dosage form vehicle as the intact compound using chromatography procedures that depend on differences in polarity. The steroid can be retained quantitatively on a Florisil column treated with a relatively high concentration of ammoniacal silver nitrate and then quantitatively eluted with ethanolic ammonium chloride. The progestin can be determined selectively in the presence of its products of solvolytic or oxidative degradation by UV spectrophotometry after treatment with sodium borohydride; the chromophore of the decomposition products is eliminated by this process while that of the intact compound is unaffected. Quinestrol or ethinyl estradiol, which may be coformulated with the progestin, does not interfere with its determination. Methods for the quantitative determination of the declared steroids in quingestanol acetate formulations and for the estimation of degradation products of the progestin are presented.

EFFECT OF ESTROGEN ON COPPER-INDUCED OVULATION IN THE RABBIT.

Studies were performed on copper-induced ovulation in female adult rabbits of Japanese mongrel breed. No superovulation such as that which occurs in gonadotropin-induced ovulation was noted in copperinduced ovulation. The average number of ova discharged by x*abbits subjected to copperinduced ovulation did not increase with doses of copper salts greater than the minimally effective dose (3 mg/kg). The optimal pretreatment of these animals proved to be 20 Mg of 17/3-estradiol benzoate daily for 4 days. (Endocrinology 76: 1205, 1965.) E in rabbits, which do not show cyclic spontaneous ovulation, estrogen seems to be closely related to ovulation. Appropriate treatment may facilitate the induction of ovulation by glass-rod stimulation of the vagina (1), although high doses of estrogen have been found to inhibit the ovulatory response to electrical stimulation (2). Estrogen pretreatment, or priming, has also been found to facilitate the induction of ovulation by injection of copper salts into the anestrous rabbit (3, 4), and estrogen injections may even cause rabbits to ovulate spontaneously, i.e., without any other extrinsic stimulus (1, 5). These findings suggest that the effect of estrogen treatment on ovulation depends on the mode of administration and size of dose, as well as the physiological state of the recipient. The study reported here was undertaken to provide more quantitative information about the influences of these factors on both spontaneous and copper-induced ovulation. Materials and Methods One hundred eighty Japanese mongrel adult female rabbits weighing from 2.5 to 3.3 kg were maintained, each in a separate cell, for at least 3 weeks. Then, after ruling out ovulation by exploratory laparotomy, they were used in these experiments. 1. A sesame oil solution of 17/3-estradiol benzoate was injected subcutaneously (100 ^g/day for 2 days). On the 3rd day, 2, 4 or 8 mg/kg of Received November 30, 1964. This investigation was supported by Grant M6365 from the Population Council, New York. cupric sulfate (CuSO4-5H2O) was injected into the marginal ear vein. These rabbits were examined for ovulation and the number of corpora lutea, if present, were counted 48 hr after the copper injection. The 8 mg/kg dose of cupric sulfate was given in 2 equal portions 30 min apart to reduce toxicity. 2. Sesame oil containing 20, 100 or 500 ng of 17/3-estradiol benzoate was injected daily for 2 or 4 days. Controls were given only sesame oil. Each rabbit was laparotomized a few days after the last injection and the ovaries were examined. In parallel, comparably injected rabbits were also injected intravenously (marginal ear vein), 24 hr after the last estrogen injection, with 3 mg/kg of 0.3 % cupric sulfate in 0.9 % NaCl solution. These animals were examined at laparotomy 48 hr later. The period of the above-mentioned experiments was from December, 1963, to June, 1964. For minimizing seasonal influences on ovulation, 14 rabbits (1 rabbit from each of the 14 treatment groups) were used in each of 10 replicate studies. Results Ovulation was not observed among controls or rabbits given only 2 mg/kg of cupric sulfate, but was observed in all the rabbits given 4 or 8 mg/kg. The total numbers of ova discharged in the 4 and 8 mg/kg groups were 57 and 40, respectively (Table 1). The difference between average ova counts in these 2 groups is not statistically significant. Ovulation following the administration of 17/3-estradiol benzoate alone was observed in only one (10 %) of the 10 rabbits given 100 /xg daily for 4 days, and not at all in any of the other groups. Copper treatment induced 1205 1206 NOTES AND COMMENTS Volume 76 TABLE 1. Number of rabbits classified by number of ruptured ova following various doses of injected cupric sulfate (the numerals in parentheses indicate the number of rabbits classified by the total number of ruptured ova and hemorrhagic follicles) Doses of cupric sulfate (mg/kg) 0 (Control, saline) 2 4

TOXICITY OF PROGESTERONE TO MOUSE FETUSES.

Injection of 3.5 mg progesterone in 0.05 ml sesame oil into each of 2 amniotic sacs on the 15th day of pregnancy in mice resulted in 61 % mortality by day 18 in the fetuses in the injected sacs. In a second group of pregnant mice, intra-amniotic injection of oil without other treatment was associated with 13% mortality by the 18th day in fetuses in injected sacs. In a third group, intra-amniotic injection of oil alone and subcutaneous injection of the mother on days 15, 16 and 17 of pregnancy with 3.5 mg progesterone in oil/day was followed by 65% mortality by day 18 in the fetuses in the injected sacs. Since the mortality rate in the injected sacs was about the same whether progesterone was administered intra-amniotically or via the maternal circulation and the placenta, it appears that this hormone is directly toxic to the mouse fetus in late pregnancy. Fetal mortality on day 18 in 15 untreated control litters was 2%. {Endocrinology 75: 145, 1964) A DMINISTRATION of large amounts of J\. progesterone to the pregnant mouse has usually been followed by fetal death, particularly in the later stages of gestation (1-5). Similar treatment of pregnant rats resulted in an eclampsia-like condition in the mothers and death of the fetuses (6, 7). Progesterone was sufficiently toxic to newborn mice that the estimated LD50 was 0.1 mg/mouse on the first, 0.4 mg on the second, and 2.5 mg on the third neonatal day (4). Mouse blastulae in vitro succumbed when the concentration of the hormone in the culture medium was 8 /ug/ml or more (8, 9). The present experiments were undertaken to determine whether in the mouse progesterone causes fetal death indirectly through an effect on the mother or placenta or, as seemed more likely, by direct action on the fetus. Materials and Methods Female mice of the Brown Belt stock were mated and were inspected each morning for the presence of vaginal plugs. The day of finding a plug was counted as day 1 of pregnancy. A solution of 70 mg of progesterone/ml of sesame oil was prepared. Precipitation of the hormone was prevented by keeping the solution in an oven at 65 C. On day 15 of pregnancy the mice were partially anesthetized with a subcutaneous injection of sodium amytal. Anesthesia was completed by administration of ether, and the abdomen was opened by a mid ventral incision. The amniotic sacs were drawn into or through Received February 3, 1964. This research was supported by Grant HD00456-14 from the National Institute of Child Health and Human Development, USPHS. the incision, and their condition was noted. The progesterone solution, cooled just before use to 40 C or a little less, was then injected through a 27or 30-gauge needle into the 2 most cephalad amniotic sacs in 1 uterine horn. Great care was employed to avoid touching the fetus or tearing the sac during this process; leakage of oil or amniotic fluid was very slight or did not occur. When the injections had been completed, the amniotic sacs were returned to the abdominal cavity and the muscle and skin layers were sutured separately. The mothers tolerated the procedure very well. Each of 2 amniotic sacs in 48 mothers was injected once with 0.05 ml of solution (3.5 mg of progesterone). Each of 2 sacs in 49 control mothers was injected once with 0.05 ml of sesame oil only. In a third group of 20 mothers 2 amniotic sacs were injected once with 0.05 ml of oil only and each mother was injected subcutaneously with 0.10 ml of a 35 mg/ml sesame oil solution on days 15, 16 and 17 of pregnancy. Each mother thus received a total of 10.5 mg of hormone in subcutaneous sites. A fourth group of 15 pregnant mice served as untreated controls. All mice were autopsied on day 18 (Brown Belt mice usually deliver on day 20 or 21).

STUDIES ON THE PHYSICOCHEMICAL PROPERTIES OF ALUMINUM SOAPS. V. STRUCTURAL VISCOSITY OF ALUMINUM STEARATES IN VEGETABLE OILS

The structural viscosity of aluminum stearate was measured in either sesame or peanut oil solution in the similar way observed in benzene solution, but the concentration, at which the structural viscosity appeared, was found to be higher than that of benzene solution. Concentration dependency of ηN (=ηr(1/Q→0)) in oil solution was weaker than that in benzene solution. Intrinsic viscosity [ηN] was much lower than that in benzene solution and there was not found such a sharp peak in the relation between [ηN] and St/Al ratio as observed in benzene solution. As to the result, it was considered that polymer chains of aluminum stearate were less extended in these oils than in benzene, or that polymer chains of aluminum stearate, especially of disoap, were broken either by a required heating for a preparation of oil solution, or by coordination of a certain component in the oil.It was also found that structural viscosity, concentration dependency of ηN and intrinsic viscosity [ηN] were varied with the soap composition in oil solution, and these properties are observed most remarkably in disoap solution as compared with the other soap solutions.In addition, no essential difference between sesame oil and peanut oil was observed.

Enhancement of Myotrophic and Androgenic Responses by Aqueous Suspension of Steroids.

SummaryAn aqueous microcrystalline suspension of testosterone was 3 times more effective in stimulating the growth of the temporal muscles and 9-16 times more effective on the accessory sex organs than an olive oil solution of testosterone and as effective as a sesame oil solution of testosterone propionate. An aqueous microcrystalline suspension of androstanediol-3 a, 17 a was slightly more effective on the temporal muscle and less effective on the accessory sex organs than a similar suspension of testosterone.

Effects of Various Estrogenic Preparations: IV. Alpha-Estradiol Administered Intraorally in a Polyethylene Glycol Wax: Objective and Subjective Effects in Climacteric Women

Abstract 1.1. Forty-one women were treated with one or more injections of equivalent amounts of seven estrogenic preparations to a total of 57 tests. In thirty-nine tests, changes occurred in the vaginal mucosa; of these, however, seven were difficult to evaluate in relation to the administration of the estrogen. No objective response followed any of the remaining eighteen injections. 2.2. Free estrone, free estradiol, and the benzoic acid and dipropionic acid esters of the latter were the estrogens employed in these tests. Estrone was given in doses of 4 mg. and each estradiol preparation in amounts of 1 mg. per injection. Estrone was used as an equeous suspension only. Free estradiol was similarly employed, and also as a solution in propylene glycol and sesame oil, respectively. Estradiol dipropionate was prepared as a solution in sesame oil only; the benzoate was administered in menstrua of peanut oil and propylene glycol, respectively. 3.3. Daily vaginal smears were taken for a control period of approximately one week prior to therapy and for an average period of ten days thereafter. Approximately 900 smears were studied. 4.4. The average lag-time (hours between injection and vaginal response) for each preparation was as follows: estradiol dipropionate in sesame oil, 88; estradiol benzoate in peanut oil, 90; estradiol in aqueous suspension, 90; estrone in aqueous suspension, 100; estradiol in sesame oil, 108; estradiol in propylene glycol, 114; and estradiol benzoate in propylene glycol (one case), 120. 5.5. The average duration in hours of the vaginal response initiated by estradiol dipropionate in sesame oil was 100; by estradiol benzoate in peanut oil, 82; by estradiol in sesame oil, 36; by estradiol in propylene glycol, 120; by estradiol in aqueous suspension, 109; and by estrone in aqueous suspension, 110. 6.6. The degree of follicular activity varied widely with the preparation used and from subject to subject, but in any given instance, was directly proportional to the duration of the vaginal changes. 7.7. Climacteric patients reported symptomatic relief starting one to three days following injection and persisting for from three to ten days thereafter.

The effects of various estrogenic preparations: III. The influence of equivalent amounts of several estrogens on the vaginal mucosa of nonmenstruating women

1.1. Forty-one women were treated with one or more injections of equivalent amounts of seven estrogenic preparations to a total of 57 tests. In thirty-nine tests, changes occurred in the vaginal mucosa; of these, however, seven were difficult to evaluate in relation to the administration of the estrogen. No objective response followed any of the remaining eighteen injections.2.2. Free estrone, free estradiol, and the benzoic acid and dipropionic acid esters of the latter were the estrogens employed in these tests. Estrone was given in doses of 4 mg. and each estradiol preparation in amounts of 1 mg. per injection. Estrone was used as an equeous suspension only. Free estradiol was similarly employed, and also as a solution in propylene glycol and sesame oil, respectively. Estradiol dipropionate was prepared as a solution in sesame oil only; the benzoate was administered in menstrua of peanut oil and propylene glycol, respectively.3.3. Daily vaginal smears were taken for a control period of approximately one week prior to therapy and for an average period of ten days thereafter. Approximately 900 smears were studied.4.4. The average lag-time (hours between injection and vaginal response) for each preparation was as follows: estradiol dipropionate in sesame oil, 88; estradiol benzoate in peanut oil, 90; estradiol in aqueous suspension, 90; estrone in aqueous suspension, 100; estradiol in sesame oil, 108; estradiol in propylene glycol, 114; and estradiol benzoate in propylene glycol (one case), 120.5.5. The average duration in hours of the vaginal response initiated by estradiol dipropionate in sesame oil was 100; by estradiol benzoate in peanut oil, 82; by estradiol in sesame oil, 36; by estradiol in propylene glycol, 120; by estradiol in aqueous suspension, 109; and by estrone in aqueous suspension, 110.6.6. The degree of follicular activity varied widely with the preparation used and from subject to subject, but in any given instance, was directly proportional to the duration of the vaginal changes.7.7. Climacteric patients reported symptomatic relief starting one to three days following injection and persisting for from three to ten days thereafter.