Comparison of the potential for developmental toxicity of prenatal exposure to two dietary chromium supplements, chromium picolinate and [Cr3O(O2CCH2CH3)(6(H2O)3]+, in mice.

BACKGROUND: Chromium(III) is generally thought to be an essential trace element that allows for proper glucose metabolism. However, chromium(III) picolinate, Cr(pic)3, a popular dietary supplement form of chromium, has been shown to be capable of generating hydroxyl radicals and oxidative DNA damage in rats. The cation [Cr3O(O2CCH2CH3)(6(H2O)3]+, Cr3, has been studied as an alternative supplemental source of chromium. It has been shown to increase insulin sensitivity and lower glycated hemoglobin levels in rats, making it attractive as a potential therapeutic treatment for gestational diabetes. To date, no studies have been published regarding the safety of Cr3 supplementation to a developing fetus. METHODS: From gestation days (GD) 6-17, mated CD-1 female mice were fed diets delivering either 25 mg Cr/kg/day as Cr(pic)(3), 3.3 or 26 mg Cr/kg/day as Cr3, or the diet only to determine if Cr3 could cause developmental toxicity. Dams were sacrificed on GD 17, and their litters were examined for adverse effects. RESULTS: No signs of maternal toxicity were observed. No decrease in fetal weight or significantly increased incidence of skeletal defects was observed in the Cr3 or Cr(pic)3 exposed fetuses compared to the controls. CONCLUSION: Maternal exposure to either Cr(pic)3 or Cr3 at the dosages employed did not appear to cause deleterious effects to the developing offspring in mice.

Exposure of pregnant mice to chromium picolinate results in skeletal defects in their offspring.

BACKGROUND: Chromium(III) picolinate, [Cr(pic)(3)], is a widely marketed dietary supplement. However, Cr(pic)(3) has been associated with oxidative damage to DNA in rats and mutations and DNA fragmentation in cell cultures. In isolated case reports, Cr(pic)(3) supplementation has been said to cause adverse effects, such as anemia, renal failure, liver dysfunction, and neuronal impairment. To date, no studies have been published regarding the safety of chromium picolinate supplementation to a developing fetus, although Cr(pic)(3) has been recommended for pregnant women who are diagnosed with gestational diabetes. METHODS: From gestation days (GD) 6-17, pregnant CD-1 mice were fed diets containing either 200 mg/kg Cr(pic)(3), 200 mg/kg CrCl(3), 174 mg/kg picolinic acid, or the diet only to determine if Cr(pic)(3), CrCl(3), or picolinic acid could cause developmental toxicity. Dams were sacrificed on GD 17, and their litters were examined for adverse effects. RESULTS: The incidence of bifurcated cervical arches was significantly increased in fetuses from the Cr(pic)(3) group as compared to the diet-only group. Fetuses in the picolinic acid-treated group had an incidence double that of the control group; however, this increase was not statistically significant. Fetuses in the CrCl(3) group did not differ from the controls in any variable examined. No maternal toxicity was observed in any of the treatment groups. CONCLUSIONS: High maternal oral exposures to chromium picolinate can cause morphological defects in developing offspring of mice.

Functional interactions between GTP cyclohydrolase I and tyrosine hydroxylase in Drosophila.

Tyrosine hydroxylase requires the regulatory cofactor, tetrahydrobiopterin, for catecholamine biosynthesis. Because guanosine triphosphate cyclohydrolase I is the rate limiting enzyme for the synthesis of this cofactor, it has a key role in catecholamine production. We show that GTP cyclohydrolase and tyrosine hydroxylase (TH) are co-localized in the Drosophila central nervous system. Mutations in the Punch locus, which encodes GTP cyclohydrolase, reduce TH activity; addition of cofactor to crude extracts could not fully rescue this activity in all mutant strains. The decrease in TH activity and the inability to increase it with added cofactor is not due to loss or decreased production of TH protein. We found that TH co-immunoprecipitated with GTP cyclohydrolase when wild type head extracts were incubated with anti-GTP cyclohydrolase antibody. We suggest that regulation of TH by its cofactor may require its association with GTP cyclohydrolase, and that the ability of GTP cyclohydrolase to associate with TH and its role in tetrahydrobiopterin synthesis may be separable functions of this enzyme. These results have important implications for understanding catecholamine-related neural diseases and designing strategies for gene therapy.

De la acción comunicativa a la sociedad democrática / From communicative action toward a democratic society

Defendendo uma ética da comunicaçäo como condiçäo da construçäo de uma sociedade democrática de indivíduos emancipados, o texto traz uma reflexäo sobre os fundamentos da ética comunicativa de Habermas, a partir da distinçäo entre dois campos de desenvolvimento discursivo: o discurso teórico e o discurso prático.

Maternal restraint stress-enhanced teratogenicity of all-trans-retinoic acid in CD-1 mice.

The present study combined maternal restraint stress with a teratogenic agent, all-trans-retinoic acid (tRA). Five treatment groups were used initially: (1) vehicle (corn oil) control [C], (2) food/water-deprived [FWD], (3) tRA only [tRA], (4) restraint only [R], and (5) tRA plus restraint [tRA+R]. Mated CD-1 mice in groups 3 and 5 were given 20 mg/kg tRA po. Mice in groups 4 and 5 were restrained in the supine position for 12 hr (9:00 a.m. to 9:00 p.m.), and the FWD group mice were deprived during the same time period. The tRA+R mice were dosed immediately prior to the 12-hr restraint period. All treatments were administered on gestation day (GD) 9 (copulation plug = day 1). On GD 18, all females were killed and subjected to teratological examination. The incidences of resorptions, short tails, bent tails, fused ribs, and fused vertebrae were significantly increased in the tRA+R group, in comparison with all other groups. Spina bifida was observed only in the tRA+R group. The current results, combined with those of earlier studies with other agents, support the likelihood that maternal stress can exacerbate adverse effects of chemical teratogens on mouse development.

Enhancement of the teratogenicity of all-trans-retinoic acid by maternal restraint stress in mice as a function of treatment timing.

In CD-1 mice, maternal restraint stress was combined with all-trans-retinoic acid (tRA) given during the restraint period (9:00 a.m. to 9:00 p.m.) to determine in what manner and to what degree teratogenesis might be affected by treatment timing within the stress period and to determine the optimum timing for stress-enhanced production of fetal defects. Eleven groups were treated on gestation day 9 (copulation plug = day 1): group 1, vehicle (corn oil) control (C); group 2, food/water deprived (FWD); group 3, restraint only (R); group 4, tRA plus food/water deprivation (tRA+FWD); groups 5 and 6, tRA at 0 or 4 hr after 9:00 a.m., i.e., tRA(0) and tRA(4), respectively; and groups 7-11, restraint plus tRA at 0, 2, 4, 8, or 12 hr after 9:00 a.m., (i.e., R+tRA(0), R+tRA(2), R+tRA(4), R+tRA(8), and R+tRA(12), respectively). The tRA dose was 20 mg/kg, PO; mice were restrained in the supine position. FWD mice were deprived for the same 12 hr as the restrained mice. All stated differences were significant (P < or = 0.05), based on litter incidences. The incidences of short tails (65%), fused ribs (62%), and fused vertebrae (37%) were elevated in the R+tRA(4) group in comparison with all others, and there appeared to be more exencephalies in R+tRA(2) litters than in any others. The incidence of supernumerary ribs was elevated in the R group in comparison with C and FWD; it was further elevated by tRA at all treatment times.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effect of restraint procedure on incidence of restraint-stress-induced rib fusion in CD-1 mice.

In an investigation of the effects of specific maternal stressors on development of the conceptus, pregnant mice were exposed to restraint stress on gestation day 9 (plug = day 1). Mated females were either unrestrained (C), unrestrained and food/water deprived (FWD), or restrained with surgical tape in a supine position for 12 h by one of two methods: I. 1-inch wide tape reaching from each shoulder across the body to the opposite thigh, or II. 1-inch wide tape placed over one shoulder, across the thorax, and over the opposite shoulder and similar tape placed over each thigh and across the intervening pelvic area. For both methods, an additional tape was placed across the tail and a 2-inch wide tape secured the upper abdominal area. There were 32 to 62 litters in each treatment group, and all fetuses were examined on day 18 for gross and skeletal defects. With regard to rib fusion, the percentage of affected fetuses and litters was increased (P < or = 0.05) by Method I (3.5% and 27%, respectively) vs. Method II. (0.5% and 4%), C (0.1% and 1%), or FWD (0%). Incidences of supernumerary ribs, however, did not differ between the restrained groups but were higher in both such groups than in the FWD and C groups. These results suggest that different methods of restraint may result in differences in incidence of rib fusion. Such data suggest that development of the offspring of stressed dams may be significantly influenced by what might appear to be minor differences in the stress techniques used.

Effects of maternal restraint stress and sodium arsenate in mice.

Either maternal restraint stress or sodium arsenate treatment during pregnancy can cause adverse effects on the mouse conceptus. The current study assessed the effects of both factors administered concurrently. Five treatment groups were used initially: (1) vehicle (H2O) control [C], (2) feed/water deprived [FWD], (3) sodium arsenate [SA], (4) restraint only [R], and (5) sodium arsenate plus restraint [SA+R]. A sixth group, arsenate plus feed/water deprived [SA+FWD], was added later, along with (7) a concurrent arsenate-only control [SAC]. Mated female CD-1 mice in Groups 3, 5, 6, and 7 were injected ip with sodium arsenate (20 mg/kg) on gestation day (GD) 9 (plug = day 1). Group 5 mice were restrained for 12 h beginning immediately after dosing. Groups 4 and 5 were restrained in the supine position from 9:00 a.m. to 9:00 p.m. on GD 9; FWD mice were deprived during that time. All females were killed on GD 18 and subjected to teratologic examination. Significantly increased exencephaly and decreased fetal weight were seen in SA+R Group fetuses. The incidence of supernumerary ribs was significantly higher in the SA+R Group than in the SA Group but did not differ from the R Group. These results add to the evidence that maternal stress combined with a chemical teratogen may have a greater effect on the conceptus than would exposure to either agent alone.

Antimalarial activities of the 4-quinolinemethanols WR-184,806 and WR-226,253.

WR-184,806 and WR-226,253, two 4-quinolinemethanols structurally similar to WR-142,490 (mefloquine), have been studied in depth in owl monkeys infected with various drug-resistant and drug-susceptible strains of Plasmodium falciparum and P. vivax in an effort to provide support and guidance for projected evaluations in human volunteers. The results of these studies, confirmatory of preliminary appraisals, showed that WR-184,806 was approximately one-third as active as WR-142,490 against infections with a multidrug-resistant strain of P. falciparum, whereas WR-226,253 was twice as active. Additionally, the current studies showed: (i) that both WR-184,806 and WR-226,253 were significantly more active against infections with blood schizonts of P. vivax than against those of P. falciparum; (ii) that their activities against established infections with either Plasmodium species were functions of the total doses delivered, single doses being as effective as three or seven fractional doses given on successive days; (iii) that WR-184,806 could be administered intravenously as the phosphate salt and was curative via this route in single doses; and (iv) that based on comparative curative doses, WR-184,806 was slightly more active and WR-226,253 was seven times more active against infections with a multidrug-resistant strain of P. falciparum than was chloroquine against infections with a 4-aminoquinoline-susceptible strain.

Antimalarial activities of various 9-phenanthrenemethanols with special attention to WR-122,455 and WR-171,669.

Pilot appraisals of the activities of 16 specially selected 9-phenanthrenemethanols against acute infections with Plasmodium falciparum in owl monkeys showed that all were more active than the reference compound, WR-33,063. WR-122,455, the most active derivative, and WR-171,669, ranked sixth, were selected for study in human volunteers. To assist this undertaking, appraisals of both compounds in owl monkeys infected with various strains of P. falciparum were expanded. These assessments showed: (i) that WR-122,455 was four times as active as chloroquine against infections with chloroquine-sensitive strains and that WR-171,669 equalled chloroquine in activity; (ii) that these compounds were fully active against infections with strains resistant to chloroquine, pyrimethamine, or quinine, or to all three standard drugs; (iii) that the activity of WR-122,455 was a function of total dose, single doses being as effective as the same amounts delivered in three or seven daily fractions; and (iv) that a single dose of WR-122,455 conferred extended, although only partial, protection against challenges with trophozoites. Complementary experiments in rhesus monkeys inoculated with sporozoites of P. cynomolgi showed that the activity of WR-122,455 was limited to blood schizonts and did not extend to early or late tissue schizonts. These evaluations were compatible with the results of preliminary studies of the activities of WR-122,455 and WR-171,669 in human volunteers.

Antimalarial activities of various 4-pyridinemethanols with special attention to WR-172,435 and WR-180,409.

Pilot appraisals of the activities of 10 specially selected 2,6-substituted-4-pyridinemethanols against acute Plasmodium falciparum infections in owl monkeys identified three derivatives that were two to three times as active as chloroquine against infections with a 4-aminoquinoline-susceptible strain and, at the same doses, were equally effective against infections with a strain fully resistant to treatment with maximally tolerated doses of chloroquine, quinine, and pyrimethamine. Two of these derivatives, WR-172,435 and WR-180,409, deemed worthy of evaluation in human volunteers, were studied in greater depth in owl monkeys infected with either the multidrug-resistant Smith strain of P. falciparum or the pyrimethamine-resistant Palo Alto strain of P. vivax. These studies showed (i) that at the same total oral dose, 3-day and 7-day treatment schedules were equally effective and slightly superior to a single-dose schedule; (ii) that WR-172,435 was slightly more active than WR-180,409 in each treatment regimen; (iii) that intravenous delivery of WR-180,409 phosphate was feasible and effective; (iv) that both compounds effected control of parasitemia more rapidly than any standard or newly discovered antimalarial drug; and (v) that WR-172,435 and WR-180,409 had therapeutic indexes at least four to eight times those exhibited by chloroquine in infections with 4-aminoquinoline-susceptible strains, indexes retained by these pyridinemethanols against infections with various drug-resistant strains.

Antimalarial activities of various 4-quinolonemethanols with special attention to WR-142,490 (mefloquine).

Pilot appraisals of the activities of a selected group of 4-quinolinemethanols against acute Plasmodium falciparum infections in owl monkeys indicated that compounds of this class are equally active against infections with chloroquine-resistant and chloroquine-susceptible strains and that this efficacy is not compromised by concomitant resistance to pyrimethamine, and in addition, identified three derivatives with outstanding activity (WR-226,253; WR-142,490; and WR-184,806). WR-142,490, the second 4-quinolinemethanol evaluated in the above model, was five times as active as chloroquine against infections with the chloroquine-susceptible, pyrimethamine-resistant strain and had a much larger therapeutic index. Expanded evaluations designed to support projected studies in human volunteers provided full confirmation of the pilot appraisals and in addition showed: (i) that the activity of WR-142,490 was a function of the total dose delivered, single doses being as effective as three or seven fractional doses administered over as many days; (ii) that intravenous administration of this agent was feasible and effective; and (iii) that the compound was at least as active against infections with P. vivax as against infections with P. falciparum. Companion studies in rhesus monkeys infected with P. cynomolgi showed that WR-142,490 lacked prophylactic or radical curative activity, but that it was as effective as chloroquine as a companion to primaquine in a combination curative drug regimen. The results of human volunteer and field trials agree well with comparable segments of these experimental evaluations.

Low atmospheric pressure effects on wearing soft contact lenses.

The majority of all research in the field of contact lenses has taken place in a normal, ground-level environment. The purpose of this study was to determine if any changes occurred in wearing hydrophilic soft lenses under conditions of low atmospheric pressures. The effects on visual acuity, refraction, keratometry, and biomicroscopy were investigated with eight naval volunteers while wearing soft contact lenses at simulated altitudes up to 30,000 ft (9144 m) in an aviation hypobaric chamber. The results indicated that the low atmospheric pressure at high atitude in itself did not affect the fit of soft contact lenses.

Comparison of the curative antimalarial activities and toxicities of primaquine and its d and l isomers.

This investigation was undertaken to determine whether either d-primaquine or l-primaquine has sufficient advantage over primaquine to warrant evaluation for curative activity in human volunteers infected with Plasmodium vivax. It was found: (i) that the capacities of the isomers and the racemate to cure infections with Plasmodium cynomolgi in rhesus monkeys were essentially identical; (ii) that the subacute toxicities of the isomers and racemate for this monkey were qualitatively the same, but that l-primaquine was three to five times as toxic as d-primaquine and at least twice as toxic as primaquine; and (iii) that the acute single-dose toxicities of the isomers for mice were not only qualitatively different, but that the d isomer was at least four times as toxic as l-primaquine. Since previous appraisals of curative activity and tolerability of 8-aminoquinolines in rhesus monkeys have correlated well with appraisals in human volunteers, attention was focused on results acquired with these test subjects. The relevant evaluations showed that d-primaquine had a therapeutic index at least twice that of primaquine. If this advantage carries over to man, problems that now complicate routine use of primaquine might be obviated. Therefore, a critical comparison of d-primaquine and primaquine in human volunteers seems indicated.