Molecular phylogenetics and historical biogeography of Hawaiian Dryopteris (Dryopteridaceae).

The fern genus Dryopteris (Dryopteridaceae) is represented in the Hawaiian Islands by 18 endemic taxa and one non-endemic, native species. The goals of this study were to determine whether Dryopteris in Hawai'i is monophyletic and to infer the biogeographical origins of Hawaiian Dryopteris by determining the geographical distributions of their closest living relatives. We sequenced two chloroplast DNA fragments, rbcL and the trnL-F intergenic spacer (IGS), for 18 Hawaiian taxa, 45 non-Hawaiian taxa, and two outgroup species. For individual fragments, we estimated phylogenetic relationships using Bayesian inference and maximum parsimony. We performed a combined analysis of both cpDNA fragments employing Bayesian inference, maximum parsimony, and maximum likelihood. These analyses indicate that Hawaiian Dryopteris is not monophyletic, and that there were at least five separate colonizations of the Hawaiian Islands by different species of dryopteroid ferns, with most of the five groups having closest relatives in SE Asia. The results suggest that one colonizing ancestor, perhaps from SE Asia, gave rise to eight endemic taxa (the glabra group). Another colonizing ancestor, also possibly from SE Asia, gave rise to a group of five endemic taxa (the exindusiate group). Dryopteris fusco-atra and its two varieties, which are endemic to Hawai'i, most likely diversified from a SE Asian ancestor. The Hawaiian endemic Nothoperanema rubiginosum has its closest relatives in SE Asia, and while the remaining two species, D. wallichiana and D. subbipinnata, are sister species, their biogeographical origins could not be determined from these analyses due to the widespread distributions of D. wallichiana and its closest non-Hawaiian relative.

Efficacy of acitretin in severe psoriasis.

Acitretin (Soriatane, Roche Pharmaceuticals) is an aromatic retinoid, effective in the treatment of severe psoriasis. This study highlights data from two existing clinical trials to capture PASI 50 and PASI 75 responder rates which represent a common metric used in current psoriasis clinical trials. A review of pharmacokinetics, safety and a discussion of relapse rate establish acitretin as an efficacious, convenient, oral treatment for initial and maintenance therapy of severe psoriasis.

Molecular phylogenetics and evolution of the endemic Hawaiian genus Adenophorus (Grammitidaceae).

Recent studies of the phylogeny of several groups of native Hawaiian vascular plants have led to significant insights into the origin and evolution of important elements of the Hawaiian flora. No groups of Hawaiian pteridophytes have been subjected previously to rigorous phylogenetic analysis. We conducted a molecular phylogenetic analysis of the endemic Hawaiian fern genus Adenophorus employing DNA sequence variation from three cpDNA fragments: rbcL, atpbeta, and the trnL-trnF intergenic spacer (IGS). In the phylogenetic analyses we employed maximum parsimony and Bayesian inference. Bayesian phylogenetic inference often provided stronger support for hypothetical relationships than did nonparametric bootstrap analyses. Although phylogenetic analyses of individual DNA fragments resulted in different patterns of relationships among species and varying levels of support for various clades, a combined analysis of all three sets of sequences produced one, strongly supported phylogenetic hypothesis. The primary features of that hypothesis are: (1) Adenophorus is monophyletic; (2) subgenus Oligadenus is paraphyletic; (3) the enigmatic endemic Hawaiian species Grammitis tenella is strongly supported as the sister taxon to Adenophorus; (4) highly divided leaf blades are evolutionarily derived in the group and simple leaves are ancestral; and, (5) the biogeographical origin of the common ancestor of the Adenophorus-G. tenella clade remains unresolved, although a neotropical origin seems most likely.

Is there a reproductive safety risk in male patients treated with acitretin (neotigason/soriatane?

Review of preclinical data including genotoxicity assays and a male rat reproduction toxicology study demonstrates that acitretin (Neotigason)/Soriatane) does not affect the reproductive outcome in naive females mated with treated males. Prospective studies of teratogenic risk or impairment of fertility cannot be ethically conducted in humans. However, it is highly unlikely that any fetal malformation could be induced by an ejaculate containing traces of acitretin. Indeed, worldwide postmarketing surveillance has not revealed any cases of retinoid embryopathy associated with paternal treatment with acitretin. Birth defects seen in pregnancies fathered by male acitretin patients were all events expected to occur in the general population at known frequencies. In conclusion, therefore, available data do not appear to indicate any reproductive safety risk due to paternal treatment with acitretin.

[HIV protease inhibitors: general review]. / Les inhibiteurs de la protéase du VIH: revue générale.

Protease inhibitors are a new class of drugs which has demonstrated activity for the treatment of HIV infection. The function of the HIV protease is to split a polyprotein to create smaller proteins which will be incorporated in the structure of the virus. The eight cleavage sites of the polyprotein constitute a template for the synthesis of potential inhibitors. Today, only inhibitors of the Phe-Pro cleavage have shown an antiproteinase activity specific for HIV. Clinical trials in HIV infection with saquinavir, indinavir, and ritonavir have demonstrated a decrease in viral load measured by plasma HIV-RNA PCR and an increase in CD4 lymphocyte counts. The use of protease inhibitors leads to a more or less rapid selection of mutant resistant viruses. However, these new drugs, either used alone or in combination, constitute a new therapeutic approach for the treatment of HIV disease.

Vaginal keratinization during the estrous cycle in rats: a model for evaluating retinoid activity.

A model is described for evaluating the activity of a retinoid based on its effect on the keratinization of the vaginal epithelium that occurs on estrus (day 4) of a 4-day cycle in female rats. This keratinization process is dependent on the endogenous estradiol (E2) secreted between the evening of diestrus 2 (day 2) and that of proestrus (day 3). Various doses of all-transretinoic acid (tRA) were injected at different time points during the estrous cycle and the vaginal keratinization was assessed by microscope examination of unstained native or Papanicolaou-stained smear preparations. Additionally, the preovulatory E2 secretion was measured and ovaries were histologically examined. A single injection of 10 mg/kg tRA either on diestrus 2 (evening) or on proestrus (early morning) was able to induce a complete inhibition of the vaginal keratinization in more than 80% of the cases. This can be considered as a direct effect on the vaginal epithelial differentiation since neither the E2 secretion nor the ovulatory process were affected. The inhibition of vaginal keratinization can be used as a rapid and convenient in vivo model for screening retinoid candidates with antikeratinizing activity.

Oral 9-cis-retinoic acid versus 13-cis-retinoic acid in acne therapy.

BACKGROUND: 9-cis-Retinoic acid (9-cis-RA) is as active as 13-cis-retinoic acid (13-cis-RA) in inhibiting the proliferation of cultured human sebocytes and in reducing the size of sebaceous glands of hamsters. OBJECTIVE: Evaluate the anti-acne effect of 9-cis-RA compared to that of 13-cis-RA in a pilot study. METHODS: Four young male patients with acne were treated in an open study consecutively with 9-cis-RA and 13-cis-RA given at similar doses. RESULTS: No beneficial effects were observed with 9-cis-RA in any of the patients whereas all responded favorably to 13-cis-RA. CONCLUSION: For the two retinoids tested, the anti-acne effect correlates with the sebosuppressive effect in humans.

Sebum excretion rate in subjects treated with oral all-trans-retinoic acid.

BACKGROUND AND OBJECTIVE: It is generally accepted that the inhibition of sebum excretion has a predictive value for anti-acne activity. Whereas oral 13-cisretinoic acid (13-cis-RA) decreases sebum excretion, it has not been shown so far if oral all-trans-retinoic acid (tretinoin, tRA) does so. The aim of this exploratory study was to investigate the effect of oral tRA on the sebum excretion rate (SER) in young male subjects. METHODS: 12 healthy volunteers with a baseline SER above 1.0 microgram/cm2/min were treated with 20 mg/day tRA for 4 weeks. The SER was measured at weeks 2 and 4. Adverse reactions were recorded. RESULTS: The mean SER varied from 1.56 at baseline to 1.65 at week 2 and to 1.49 micrograms/cm2/min at week 4. Comparison with values obtained in the same subjects previously treated with either 13-cis-RA or 9-cis-retinoic acid indicated that tRA less sebosuppressive. Mucocutaneous reactions and headache were the most frequent side effects of oral tRA. CONCLUSION: The lack of effect on the SER suggests that oral tRA would probably be ineffective against acne. The fact that, of the three isomers tested, only 13-cis-RA (which does not bind to nuclear receptors) shows activity may suggest that sebosuppression is not nuclear receptor mediated. We discuss other hypotheses related to pharmacokinetics.

Efficacy of oral low-dose tretinoin (all-trans-retinoic acid) in lichen planus.

BACKGROUND: Retinoids were shown to be effective in the treatment of both oral and cutaneous forms of lichen planus. OBJECTIVE: Confirm the beneficial effect of low doses of oral tretinoin in lichen planus. METHODS: Eighteen patients with lichen planus were treated in an open study for up to 19 months. Efficacy and safety data were recorded. RESULTS: Complete remission was observed in 13 (72%) and marked improvement in 4 (22%) out of 18 patients. Six patients showed moderate and 12 had no side effects. CONCLUSION: Tretinoin is a valuable drug when given at low doses to patients with lichen planus who failed to respond to other therapies.

Biomechanical comparison of anterior instrumentation for the cervical spine.

Metal fixation has been advocated to achieve immediate local stabilization during anterior cervical fusion surgery. Screw loosening, screw backout, and breakage of screws or plates remain clinical complications that warrant concern. This study examined the biomechanical characteristics of a prototype anterior cervical plating system with unique screw and plate geometries in comparison to a fixation system currently used clinically. Compared with a standard screw design, a taper screw design resulted in increased ultimate strength and fatigue life. The addition of a locking pin hole in the tapered screw made the screw's fatigue life comparable to the standard design. Pullout strength was comparable in all screw designs. The prototype fixation system had higher strength in pure compression and compression with bending than the comparative system, while also demonstrating improved fatigue characteristics. The tensile bending stiffness of the prototype was double that of the comparative system and within the anatomical range of cervical vertebrae, the bending moment was greater. Torsional yield strength was greater than the reported breaking strength of cervical disc in situ for both systems. The unique designs of the screw and plate geometry resulted in an anterior cervical plate fixation system that is stronger with decreased risk of fatigue failure than a currently used system. Clinical evaluation in patients requiring immediate stabilization is warranted.

Retinoids and sebaceous gland activity.

BACKGROUND AND OBJECTIVE: The marked efficacy of isotretinoin in the treatment of acne is undoubtedly due to its potential to inhibit sebaceous gland activity. The question arises if the anti-acne effect of new oral retinoids can be predicted by using the currently available experimental models. METHODS: We reviewed the effects of various oral retinoids on sebum excretion in humans and their efficacy in acne. The human data were compared to the results obtained from in vitro and animal models. RESULTS: Oral retinoids such as etretinate, acitretin and the so-called arotinoids were not able to inhibit the sebum production in humans and were ineffective against acne. In various animal models (i.e. sebum production in rats, flank organ size in hamsters, ear sebaceous gland size in hamster, most of these retinoids were shown to be effective. Furthermore, in addition to isotretinoin, some retinoids were able to suppress the proliferation of human sebocytes in vitro. CONCLUSIONS: The elucidation of the mechanism of action of isotretinoin on the sebocyte biology is critical for the search of more reliable models and for the discovery of new retinoids with anti-acne activity.

Determination of acitretin in the skin, in the suction blister, and in plasma of human volunteers after multiple oral dosing.

Several HPLC methods for quantification of acitretin and its 13-cis isomer in biological fluids have been described. Only limited data are available on determination of this drug in skin samples. Our objective was to improve the sensitivity and selectivity of existing methods to measure drug in small skin samples from humans treated with acitretin. With a new optimized mobile phase [methanol: acetonitrile (7:3, v/v), purified water with 1.5% (v/v) acetic acid, mixed in a 85:15 ratio (v/v)] and a new internal standard (arotinoid ethyl sulfone), a limit of quantification of 1 ng/g tissue was reached. Nine male volunteers were given an oral daily dose of 50 mg acitretin for up to 28 days. Blood and skin samples (punch and shave biopsies, suction blister skin, and fluid) were taken at various time points during and after treatment. Drug concentration and metabolism in plasma and skin samples appeared to be linked in that the trans-isomer concentration was always higher than the cis-isomer concentration during dosing and 3 h after the last dose. However, 7 and 14 days after the last dose in plasma and in all tissue samples (except the shave biopsy), the all-trans-acitretin concentration rapidly decreased and approached the detection limit. In the shave biopsy, the all-trans-acitretin concentration remained higher than the 13-cis-acitretin concentration. Furthermore, the elimination of two isomers from the shave biopsy was delayed.(ABSTRACT TRUNCATED AT 250 WORDS)

Acitretin in the treatment of severe lichen sclerosus et atrophicus of the vulva: a double-blind, placebo-controlled study.

BACKGROUND: Promising results have been reported from treatment with oral retinoids in patients with severe lichen sclerosus et atrophicus (LSA) of the vulva. OBJECTIVE: The aim of our study was to determine the efficacy of acitretin (20 to 30 mg/day) for 16 weeks in LSA. METHODS: Seventy-eight patients were enrolled into a multicenter, randomized, placebo-controlled, double-blind trial. The primary measure of efficacy was the "responder" rate based on the assessment of characteristic clinical features of LSA of the vulva (pruritus, burning, atrophy, hyperkeratosis, and secondary features such as erosions, ulcers, edema, or lichenification) and on the extent of the lesions. RESULTS: From the 46 patients eligible for efficacy analysis, a significantly higher number of responders was observed in the acitretin-treatment group (14 of 22 patients) as compared with the placebo-treatment group (6 of 24 patients). Typical retinoid adverse reactions were observed in all patients receiving active drug. CONCLUSION: Acitretin is effective in treating women with severe LSA of the vulva.

Acitretin biotransformation into etretinate: role of ethanol on in vitro hepatic metabolism.

The aim of this study was to investigate the possible esterification of acitretin into etretinate by using hepatocytes in primary culture from the rat, monkey, dog and man. With rat and human hepatocytes, etretinate was detectable only when ethanol was co-administered with acitretin. With monkey and dog cells, traces of etretinate were found without ethanol addition, but the esterification of acitretin was highly enhanced by ethanol. The metabolic profile was not changed when cells were pre-incubated with ethanol. Therefore acitretin seems to act rather as a substrate than an enzymatic inducer.

Teratogenic risk with etretinate and acitretin treatment.

Etretinate (Tigason, Tegison) and its active metabolite acitretin (Neotigason, Soriatane) are known teratogens. Pregnancy should be avoided during treatment and until 2 years after treatment discontinuation. The question is discussed whether a dose or a blood concentration of the drug below which there is no teratogenic risk can be determined. Animal experimental and human pharmacokinetic data are reviewed. An evaluation of the outcomes of pregnancies which occurred in mothers exposed to etretinate or acitretin was performed. A threshold dose in human therapy below which there is no risk of congenital malformation cannot be determined based on animal experimental data. With regard to pharmacokinetics, there are currently no data suggesting that blood levels of the drug below the detection limit of 2 ng/ml are associated with a teratogenic risk. The most useful information is given by reports in women who were exposed to either retinoid before or during pregnancy. The data indicate that the risk of spontaneous abortion or congenital malformation is high when the drug is administered during the first trimester of pregnancy. After treatment discontinuation, the risk is low since the number of abnormalities seems not to exceed those observed in a general population. There are currently no available data which suggest that the pregnancy warnings are inappropriate in terms of duration of contraception.

[Distribution of acitretin in human skin]. / Distribution de l'acitrétine dans la peau humaine.

Acitretin has recently been introduced for the systemic treatment of dermatologic diseases such as psoriasis and congenital disorders of keratinization. At present, only an oral form of this drug is available. However results from recent studies have shown that considerable drug concentrations can be delivered to the skin by topical administration of acitretin. Based on this data we addressed the question whether the topical administration of acitretin can produce in humans a drug concentration in the skin which exceeds the drug concentration that is found in the skin after multiple oral acitretin dosing and is reported to be clinical effective. Drug concentrations in the skin were investigated under conditions in which the maximum dose that can be administered in a therapeutic situation was applied. Additionally, three different skin sampling techniques, the punch biopsy, the shave biopsy and the suction blister technique were validated to quantitate acitretin in the skin. The drug concentrations in skin after systemic application in a steady state situation were comparable with the drug concentration reached after a single 24 hours topical application of a saturated acitretin/isopropylmyristate formulation. However, no unequivocal effects in psoriasis and disorders of keratinization were observed up to now by the topical administration of acitretin. The inverse drug concentration gradients which are present in the skin, depending on the route of administration, may explain differences in activity. The skin samples in our and other studies were homogenized or dissolved and thus much of the anatomical information is lost. The latter may be most important for the understanding of the local events.

Acitretin and etretinate. How and when they should be used.

Nearly two decades after the advent of synthetic retinoids for the treatment of many severe and incapacitating dermatologic conditions, the usefulness of these drugs is not universally accepted. The safety profile is well established. Other than teratogenicity, which can be avoided if the recommended precautions for use are followed, serious or unexpected adverse reactions rarely occur. This article concisely addresses some questions about etretinate and acitretin therapy that are most pertinent for the dermatologist.

Practical use of retinoids in psoriasis.

In two decades, retinoids have nearly revolutionized some aspects of dermatologic practice. The dramatic response of severe acne to isotretinoin therapy is equally matched at times by the rapid response of pustular psoriasis treated with etretinate. Many other psoriatic patients, especially those who have failed the standard therapeutic regimens, have immensely benefited by the addition of retinoids to the therapeutic armamentaria. The use of etretinate or acitretin where available has repeatedly shown their utility, general safety, and cost effectiveness. Additionally, the advent of combination therapy with UV light has allowed better response using less retinoid and less light, eg, in retinoid-light combinations. With careful attention to the safety profile of retinoids, especially in the area of pregnancy prevention, a powerful therapy option is available for even the most recalcitrant patients. These responses would be sufficient reason for interest in retinoids but, when coupled with the exciting developments in molecular biology of retinoids, lead one to look with excitement on the dermatologic horizon for a new generation of significant breakthroughs.