Biomedical subjects

R K Johnson

Publications and source records attributed to R K Johnson.

At least 109 records · Page 6Linked to original sources

PubMed1994

Comparison of energy intake by semiquantitative food-frequency questionnaire with total energy expenditure by the doubly labeled water method in young children.

We assessed the validity of a semiquantitative food-frequency questionnaire to estimate energy intake in young children by comparison with total energy expenditure (TEE). TEE was measured in 45 children (22 males and 23 females; 4.2-6.9 y of age) by the doubly labeled water method and body composition was estimated from bioelectrical resistance (20.2 +/- 4.0 kg body weight, 4.6 +/- 2.1 kg fat mass, and 15.6 +/- 3.1 kg fat-free mass). The sample included 36 white children and 9 Mohawk Native American children. The children's mothers completed one Willett food-frequency questionnaire to reflect the child's usual dietary intake over the last year. Total energy intake by food-frequency questionnaire (9.12 +/- 2.28 MJ/d) was significantly higher than TEE (5.74 +/- 1.13 MJ/d; P < 0.001). Misreporting of intake by food-frequency questionnaire ranged from 9.57 MJ/d overestimation to 1.58 MJ/d underestimation and was not significantly influenced by sex or body composition of the children. We conclude that use of the food-frequency questionnaire significantly overestimates energy intake in children.

Adult↗

PubMed1994

Ten generations of selection for predicted weight of testes in swine: direct response and correlated response in body weight, backfat, age at puberty, and ovulation rate.

Selection for predicted weight of testes at 150 d of age (PWT) was practiced for 10 generations to determine the effect on reproductive and growth traits in swine. Mass selection among boars (line TS) or random selection (line C) was practiced beginning with the F3 generation of a Large White x Landrace composite population. Population size in each line was 40 to 45 litters by 15 sires per generation. Responses were estimated by regressions on cumulative selection differentials for PWT and on generation number and by mixed-model derivative-free REML procedures. The realized heritability of PWT was .35 +/- .02 and the response per generation was 19 g (P < .01). Correlated responses in body weight were .95 +/- .37 (140 d) and 1.13 +/- .42 kg (160 d) per generation for boars and .70 +/- .32 (130 d) and .64 +/- .46 kg (180 d) per generation for gilts. Response in backfat was .08 +/- .14 mm per generation in boars and .16 +/- .14 mm in gilts. Negative genetic trends occurred in age at puberty in both lines, but the difference between lines was not significant. At Generation 10, ovulation rate was .76 +/- .43 eggs more for gilts of the TS line than for C gilts. Genetic correlations of PWT with other traits are presented. Heritability of PWT was moderately high and its phenotypic variance was large; therefore, a high rate of response of 5.5% per generation occurred. Selection for PWT was not effective in decreasing age at puberty or increasing ovulation rate of daughters.

Adipose Tissue↗

PubMed1994

Comparative activity of oral and parenteral topotecan in murine tumor models: efficacy of oral topotecan.

Studies were performed using several tumor models to determine the oral efficacy of topotecan. These studies were direct comparisons of oral administration with parenteral treatment by the intravenous, intraperitoneal, or subcutaneous routes. Treatment schedules included bolus treatments at 4- or 7-day intervals and a split-dose regimen (q3hx4) repeated at 4- or 7-day intervals. On the various schedules, the maximally tolerated dose of topotecan was either equivalent to or at most 1.7-fold that of parenteral administration, indicative of excellent oral bioavailability in the mouse. Orally administered topotecan was comparable in efficacy to parenteral treatment in four of five tumor models tested (i.v. L1210 leukemia, i.v. B16 melanoma, i.v. and s.c. Lewis lung carcinoma). The M5076 reticulum cell sarcoma implanted i.p. responded to i.p. and s.c. but not to orally administered topotecan. These studies provide convincing support for the clinical evaluation of orally administered topotecan.

Administration, Oral↗

PubMed1993

The inophyllums, novel inhibitors of HIV-1 reverse transcriptase isolated from the Malaysian tree, Calophyllum inophyllum Linn.

As part of a search for novel inhibitors of HIV-1 reverse transcriptase, the acetone extract of the giant African snail, Achatina fulica, was shown to be active. Fractionation of the extract yielded inophyllums A, B, C, and E and calophyllolide (1a, 2a, 3a, 3b, and 6), previously isolated from Calophyllum inophyllum Linn., a known source of nutrition for A. fulica. From a methanol/methylene chloride extract of C. inophyllum, the same natural products in considerably greater yield were isolated in addition to a novel enantiomer of soulattrolide (4), inophyllum P (2b), and two other novel compounds, inophyllums G-1 (7) and G-2 (8). The absolute stereochemistry of inophyllum A (1a) was determined to be 10(R), 11(S), 12(S) from a single-crystal X-ray analysis of its 4-bromobenzoate derivative, and the relative stereochemistries of the other inophyllums isolated from C. inophyllum were established by a comparison of their 1H NMR NOE values and coupling constants to those of inophyllum A (1a). Inophyllums B and P (2a and 2b) inhibited HIV reverse transcriptase with IC50 values of 38 and 130 nM, respectively, and both were active against HIV-1 in cell culture (IC50 of 1.4 and 1.6 microM). Closely related inophyllums A, C, D, and E, including calophyllic acids, were significantly less active or totally inactive, indicating certain structural requirements in the chromanol ring. Altogether, 11 compounds of the inophyllum class were isolated from C. inophyllum and are described together with the SAR of these novel anti-HIV compounds.

Acetylation↗

PubMed1993

The tyrosine89 residue of yeast FKBP12 is required for rapamycin binding.

Rapamycin (Rm) is a macrolide antifungal agent related to FK506 that exhibits potent immunosuppressive properties which are mediated through interaction with specific cytoplasmic receptors (FKBPs or RBPs, for FK506- and Rm-binding proteins, respectively). These proteins possess peptidyl-prolyl cis-trans isomerase (PPIase) activity in vitro which is inhibited by the binding of Rm and FK506. In Saccharomyces cerevisiae, Rm sensitivity (Rms) is mediated by binding of the drug to RBP1, a homolog of the 12-kDa human FK506-binding protein (FKBP12); null mutations in the yeast RBP1 gene result in a recessive drug resistance phenotype. To identify missense mutations that define amino acid (aa) residues in RBP1 involved in drug sensitivity, we selected and genetically characterized over 250 independent RmR rbp1 mutants and screened them for both RBP1-specific mRNA and protein expression. Whereas all rbp1 mutants expressed abundant levels of RBP1 mRNA, stable RBP1 protein production was detected in only one mutant strain. The RBP1 gene was PCR-generated (in triplicate) from several rbp1 mutants and independent clones were sequenced. Most of the immunoblot-negative alleles were found to contain various types of null mutations; however, some alleles contained specific missense mutations that apparently affect protein stability in vivo. The single immunoblot-positive allele was found to contain a mutation altering a specific residue (Tyr89) which is conserved among the known FKBPs, and which, based on the solution and x-ray structures of human FKBP12, has been proposed to be part of a hydrophobic drug-binding pocket for FK506 and Rm.(ABSTRACT TRUNCATED AT 250 WORDS)

Antifungal Agents↗

PubMed1993

A screen for inhibitors of DNA recombination: identification of two new spirostanol glycosides from Chamaedorea linearis.

Two new glycosides have been isolated from the MeOH extract of the stem wood and stem bark of an Ecuadorian plant Chamaedorea linearis, and their structures have been determined by spectroscopic means and X-ray analysis of the aglycone to be 1-O-[beta-L-fucopyranosyl-(4'-sulfate)]-25R,5 alpha-spirostane-1 beta, 3 beta-diol [1]) and 1-O-[beta-L-fucopyranosyl-(4'-sulfate)]-25R,5 alpha-spirostane-1 alpha, 3 beta-diol [2]. These compounds were identified in a screen for inhibitors of recombinational DNA repair. Cytotoxic activity was also demonstrated.

Animals↗

PubMed1993

Bioactive furanonaphthoquinones from Crescentia cujete.

Bioassay-directed fractionation of the MeCOEt extract of Crescentia cujete (Bignonaceae) resulted in the isolation of (2S,3S)-3-hydroxy-5,6-dimethoxydehydroiso-alpha-lapachone [1], (2R)-5,6-dimethoxydehydroiso-alpha-lapachone [2], (2R)-5-methoxydehydroiso-alpha-lapachone [3], 2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione [4], 5-hydroxy-2-(1-hydroxyethyl)naphtho[2,3-b]furan-4,9-dione [5], 2-isopropenylnaphtho[2,3-b]furan-4,9-dione [6], and 5-hydroxydehydroiso-alpha-lapachone [7]. Compounds 1-3 are new, and all compounds are bioactive, showing selective activity towards DNA-repair-deficient yeast mutants. The isolation, structure elucidation, and biological activities of these compounds are reported.

Animals↗

PubMed1993

Two bioactive pterocarpans from Erythrina burana.

Bioactivity-directed fractionation of the CHCl3 extract of the bark of Erythrina burana afforded phaseollidin [1] and cristacarpin [2]. Both 1 and 2 exhibited moderate but selective activity towards DNA repair-deficient yeast mutants, whereas only 1 was found to be cytotoxic. 13C-nmr spectra of both compounds were assigned.

Animals↗

PubMed1993

Dominant missense mutations in a novel yeast protein related to mammalian phosphatidylinositol 3-kinase and VPS34 abrogate rapamycin cytotoxicity.

Rapamycin is a macrolide antifungal agent that exhibits potent immunosuppressive properties. In Saccharomyces cerevisiae, rapamycin sensitivity is mediated by a specific cytoplasmic receptor which is a homolog of human FKBP12 (hFKBP12). Deletion of the gene for yeast FKBP12 (RBP1) results in recessive drug resistance, and expression of hFKBP12 restores rapamycin sensitivity. These data support the idea that FKBP12 and rapamycin form a toxic complex that corrupts the function of other cellular proteins. To identify such proteins, we isolated dominant rapamycin-resistant mutants both in wild-type haploid and diploid cells and in haploid rbp1::URA3 cells engineered to express hFKBP12. Genetic analysis indicated that the dominant mutations are nonallelic to mutations in RBP1 and define two genes, designated DRR1 and DRR2 (for dominant rapamycin resistance). Mutant copies of DRR1 and DRR2 were cloned from genomic YCp50 libraries by their ability to confer drug resistance in wild-type cells. DNA sequence analysis of a mutant drr1 allele revealed a long open reading frame predicting a novel 2470-amino-acid protein with several motifs suggesting an involvement in intracellular signal transduction, including a leucine zipper near the N terminus, two putative DNA-binding sequences, and a domain that exhibits significant sequence similarity to the 110-kDa catalytic subunit of both yeast (VPS34) and bovine phosphatidylinositol 3-kinases. Genomic disruption of DRR1 in a mutant haploid strain restored drug sensitivity and demonstrated that the gene encodes a nonessential function. DNA sequence comparison of seven independent drr1dom alleles identified single base pair substitutions in the same codon within the phosphatidylinositol 3-kinase domain, resulting in a change of Ser-1972 to Arg or Asn. We conclude either that DRR1 (alone or in combination with DRR2) acts as a target of FKBP12-rapamycin complexes or that a missense mutation in DRR1 allows it to compensate for the function of the normal drug target.

Alleles↗

PubMed1993

Changes in ovulation rate, uterine capacity, uterine dimensions, and parity effects with selection for litter size in swine.

This study was conducted with random samples of pigs of a line (LS) selected for eight generations for litter size and a randomly selected control line (RS) in the Nebraska Gene Pool population and of crosses of these lines with a Large White-Landrace composite line (I) that was selected for an index of ovulation rate and embryonic survival to 50 d of gestation. Two experiments were done to obtain information on ovulation rate, uterine dimensions, and uterine capacity. In Exp. 1, 103 gilts were slaughtered 9 to 16 d after their second estrus to obtain reproductive tracts for evaluation of ovulation rate and uterine dimensions. In Exp. 2, unilateral hysterectomy-ovariectomy was performed 3 to 10 d after puberty in 109 gilts that were then mated at their next estrus and slaughtered at 93 to 100 d of gestation to recover reproductive tracts for evaluation. Litter size at birth was recorded at first (n = 414), second (n = 159), and third (n = 143) parity of pureline and crossline gilts. The cumulative response to eight generations of selection for litter size pooled over type of cross and parity was 1.21 +/- .38 pigs, in good agreement with the realized response of 1.06 pigs previously estimated for the period of selection. This response was due to an increase of 1.30 +/- .54 eggs in ovulation rate (measured by the number of corpora lutea in cyclic and pregnant gilts) and .66 +/- 1.28 pigs in uterine capacity (measured after unilateral hysterectomy-ovariectomy). No significant changes were found in uterine dimensions in cyclic gilts. Approximately 25% of the increase in litter size could be explained by a reduction in number of mummified pigs at birth, an indication that uterine capacity in late gestation was increased. Estimated differences between lines (gLS - gRS) were not significantly different for pureline and crossline gilts and sows, and no interactions of these estimates with parity were detected. Estimates of heterosis for LS x I and RS x I did not differ significantly, nor were interactions of heterosis with parity significant.

Analysis of Variance↗

PubMed1993

Animal model estimation of genetic parameters and response to selection for litter size and weight, growth, and backfat in closed seedstock populations of large white and Landrace swine.

Records from 2,495 litters and 14,605 Landrace and Large White pigs from two farms, but established from the same base population and run as replicated selection lines, were analyzed. Selection within herd was on estimated breeding values weighted by economic values. Animal models and REML procedures were used to estimate genetic, phenotypic, and environmental parameters for the number of pigs born alive (NBA), litter weight at 21 d (LW), average daily gain form approximately 30 to 104 kg (ADG), and backfat thickness adjusted to 104 kg (BF). Random animal genetic effects (o), permanent (NBA and LW) or litter (ADG and BF) environmental effects, maternal genetic effects (m), and the covariance between o and m were sequentially added to the model. Estimates of total heritability calculated from all data (ht2 = sigma o2 + 1/2 sigma m2 + 3/2 sigma om) ranged from .01 to .14 for NBA, from .18 to .22 for LW, from .23 to .34 for ADG, and from .40 to .50 for BF. Maternal genetic variance was from 2.4 to 3.8% of phenotypic variance in NBA, from 1.2 to 3.6% in LW, from .5 to 1.5% in ADG, and from 1.9 to 3.4% in BF. The correlation between o and m was -.07 for NBA, -.25 for LW, -.34 for ADG, and -.26 for BF. Permanent environmental effects explained from 16 to 17% of total phenotypic variation for NBA and from 1.6 to 5.3% for LW. Approximately 7% of the variation in ADG and 5% in BF was due to litter environmental effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1993

Challenges and opportunities for integrating genetically modified animals into traditional animal breeding plans.

Techniques have been developed to introduce specific genes from one species into the germplasm of another, including livestock. This paper reviews reports on evaluation, selection, and breeding procedures for introduction and multiplication of transgenes in breeding populations of livestock. Before transgenes are introduced and multiplied in commercial breeding populations, it is necessary to test transgenics extensively for both favorable and unfavorable transgene effects. Parent stock used to produce transgenic founder animals should be selected to excel in polygenic breeding value for economically important traits, especially if founder animals or their sons are to be used directly by AI in commercial populations. However, polygenic breeding value of founder transgenic animals and inbreeding depression are of negligible importance if a transgene is introgressed into a selection nucleus population from three or four generations of backcrossing. Transgenic development should be economically viable for traits with major effects on net merit, especially in the dairy industry, where transgenic sires can be used extensively by AI. A minimum effect of about 10% of the mean (or one phenotypic standard deviation) is a reasonable approximation of the minimum transgene effect that would be necessary to justify introgression into a nucleus swine population. A transgene effect of 10 to 20% of the mean would be required for most economic traits in beef cattle.

Animals↗

PubMed1993

In vitro and in vivo effects of clinically important camptothecin analogues on multidrug-resistant cells.

The cytotoxic alkaloid camptothecin (CPT) and several of its analogues, including the clinically relevant topotecan (TPT), irinotecan (CPT-11), and 9-aminocamptothecin, were evaluated for differential cytotoxic effect and DNA damage induction in multidrug-sensitive (AuxB1) and multidrug-resistant (MDR) (CHRC5) Chinese hamster ovary cells. CPT, 10-hydroxycamptothecin, and 10,11-methylenedioxycamptothecin produced equivalent amounts of cell growth inhibition and/or DNA single-strand breakage in the two cell lines. TPT, SN-38 (the active metabolite of CPT-11), and 9-aminocamptothecin were 12-, 9-, and 10-fold, respectively, less toxic to the MDR than to the wild-type cells. These findings are consistent with differences in yields of DNA single-strand breaks produced in AuxB1 and CHRC5 cells by 2-hr incubations with the various compounds. In both assays, the resistance ratios of the topoisomerase I inhibitors were approximately one-tenth those of known MDR drugs such as vinblastine or amsacrine. Thus, cultured cells that overexpress P-glycoprotein have the potential to develop some level of cross-resistance to all three topoisomerase I inhibitors currently in the clinic. The chemical basis for cross-resistance of cultured MDR cell lines to certain CPT analogues is not yet understood, but is likely more complex than positive charge alone. TPT had a reasonable therapeutic effect on B6D2F1 female mice implanted with MDR sublines of P388 leukemia, compared with its effect on mice implanted with wild-type P388 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Psychologic assessment of patients with industrial hand injuries.

The benefits and rationale for including a psychologic assessment of a patient with an industrial hand injury are discussed. Issues of compliance and malingering in patients are addressed. The role of pre-existing conditions in understanding an injured patient's current emotional state is explored and contrasted with posttraumatic stress disorders. Recent trends in psychologic assessment techniques are highlighted.

Accidents, Occupational↗

PubMed1992

Activity of topotecan, a new topoisomerase I inhibitor, against human tumor colony-forming units in vitro.

BACKGROUND: Topotecan [(S)-9-dimethylaminomethyl(10-hydroxy-camptothecin), NSC 609699, SK&F 104864A], a semisynthetic analogue of the natural product camptothecin, is a cell cycle-specific drug that exerts antineoplastic activity through inhibition of topoisomerase I. Currently, topotecan is undergoing phase I and early phase II clinical trials. The dose-limiting toxicity for topotecan is myelosuppression. PURPOSE: Our purpose was to determine plasma concentrations and exposure times necessary for optimal clinical activity and tumor types that may be responsive in phase II clinical studies of topotecan. METHODS: A soft-agar cloning system assay was used to determine the in vitro effects of topotecan against cells from biopsy specimens of colorectal, breast, lung, ovarian, renal cell, and gastric cancers and cancers of unknown primary origin. We studied 141 freshly explanted tumor specimens, using 1-hour exposure to topotecan, and 80 were studied using continuous exposure. A decrease in tumor colony formation resulting from drug exposure was considered an in vitro response if survival of colonies was up to 50% of that in controls. RESULTS: With 1-hour exposure, in vitro responses were seen in 10% and 25% of assessable tumor specimens at final topotecan concentrations of 1.0 and 10.0 micrograms/mL, respectively. With continuous exposures at concentrations of 0.1 and 1.0 micrograms/mL, in vitro response rates were 34% and 76%, respectively. Specific activity was seen against colorectal, breast, non-small-cell lung, ovarian, and renal cell cancers, with responses observed in 27%, 25%, 32%, 39%, and 83%, respectively, of assessable tumor specimens after continuous exposure to 0.1 micrograms/mL topotecan. A subset of tumor specimens resistant to doxorubicin or fluorouracil was sensitive to topotecan, and the difference in sensitivity was statistically significant. In addition, some of the tumor specimens resistant to cyclophosphamide and etoposide were also sensitive to topotecan. CONCLUSIONS: Topotecan appears to be active in vitro against a variety of human tumors, including a subgroup resistant in vitro to standard antineoplastic agents. If plasma levels of 0.1 micrograms/mL can be achieved for prolonged periods of time in ongoing clinical trials, topotecan should have substantial clinical activity. IMPLICATIONS: Further clinical development of topotecan is warranted.

Antineoplastic Agents↗

PubMed1992

Response of rat and human prostatic cancers to the novel 5 alpha-reductase inhibitor, SK&F 105657.

The response of two androgen-responsive rat prostatic cancers (i.e., Dunning R-3327 H and G sublines) and one androgen-responsive human prostatic cancer (i.e., PC-82) to the 5 alpha-reductase inhibitor, SK&F 105657, was tested in vivo. SK&F 105657 was administered orally twice a day at a dose of 25 or 50 mg/kg/dose. The rat R-3327 G tumor and the human PC-82 tumor have a low to undetectable level of tissue 5 alpha-reductase activity and both responded to SK&F 105657 treatment with a reproducible inhibition of tumor growth. Associated with this antitumor effect was a major decrease (i.e., greater than 70%) in tissue dihydrotestosterone (DHT) content in both tumors. By contrast, the rat R-3327 H prostatic cancer has a much higher level of tissue 5 alpha-reductase activity, and neither tumor DHT content nor growth of the tumor was inhibited by treatment with SK&F 105657. Drug treatment of rats bearing R-3227 H tumors resulted in a similar reduction in the DHT content, wet weight, and DNA content of the ventral prostate as that produced in R-3327 G tumor-bearing rats which experienced an antitumor response. These results suggest that SK&F 105657 can produce antitumor effects if a substantial reduction in tissue DHT is achieved. Such reduction in tissue DHT, secondary to inhibition of the tissue 5 alpha-reductase enzyme, appears to be more difficult to achieve in tumors than in the normal prostate. In order to achieve such a DHT reduction in tumor tissue, prostatic cancers with low 5 alpha-reductase activity could be treated with SK&F 105657 on a dose regimen that lowers serum DHT to surgical castration levels, while concomitantly inhibiting the already low tumor tissue 5 alpha-reductase activity.

5-alpha Reductase Inhibitors↗

PubMed1992

Bioactive ergost-5-ene-3 beta, 7 alpha-diol derivatives from Pseudobersama mossambicensis.

Bioactivity-directed fractionation of the methyl ethyl ketone extract of Pseudobersama mossambicensis resulted in the isolation of ergosta-5,24(28)-diene-3 beta,7 alpha-diol [1], 24,28-epoxyergost-5-ene-3 beta,7 alpha-diol [2], and ergost-5-ene-3 beta,7 alpha,24,28-tetraol [3]. All three sterols showed selective activity towards DNA repair-deficient yeast mutants. The sterol 1 also showed cytotoxicity towards wild-type P-388 murine leukemia cells. The isolation, structural elucidation, and biological activities of these sterols are reported. The sterol 3 is most probably an artifact formed from 2 during the isolation process.

Animals↗

PubMed1992

Prostatic involution in rats induced by a novel 5 alpha-reductase inhibitor, SK&F 105657: role for testosterone in the androgenic response.

Within the prostate, androgen stimulates glandular cell secretion and proliferation while inhibiting glandular cell death. Due to its predominant nuclear localization, higher affinity for the androgen receptor, and more than 10-fold higher intracellular concentration than testosterone, dihydrotestosterone (DHT), not testosterone, appears to be the active intracellular androgen within the prostate of intact male hosts. The issue has remained unanswered, however, whether testosterone itself, without irreversible conversion to DHT by the 5 alpha-reductase enzyme, is capable of androgenic effects in the prostate. To address this issue, a novel dead end (i.e. product) inhibitor of the 5 alpha-reductase enzyme, SK&F 105657, was administered to intact or castrated male rats treated with either exogeneous testosterone or DHT. When administered twice a day orally at 25 mg/kg.dose, SK&F 105657 reduced the prostatic DHT content of either intact or castrated rats maintained with exogeneous testosterone to the same low level as that produced by surgical castration. Unlike castration, however, such SK&F 105657 treatment increased the prostatic testosterone content by more than 5-fold. The decrease in prostatic DHT coupled with a raise in testosterone are specifically due to the in vivo inhibition of the 5 alpha-reductase activity, since they were not observed in castrated rats maintained with exogeneous DHT. Treatment of intact or castrated male rats with exogeneous testosterone and oral SK&F 105657 (25 mg/kg, twice daily) resulted in a substantial inhibition of prostatic secretion, an inhibition of prostatic glandular cell proliferation, and an increase in prostatic glandular cell death. The magnitude of the changes, however, was not as great as that observed after surgical castration. The results are, however, specific for 5 alpha-reductase inhibition, since they were not observed in castrated rats given exogeneous DHT. These results demonstrate that if the prostatic testosterone content is elevated to sufficient levels, androgenic effects are induced without a requirement for an elevation in prostatic DHT content. Thus, the conversion of testosterone to DHT appears to function as a means of amplifying androgenic stimulation in the prostate.

5-alpha Reductase Inhibitors↗