text:
Use of a compound selected from the group consisting of pentoxifylline, propentofylline and torbafylline for topical treatment of psoriasis or atopic dermatitis and pharmaceutical compositions comprising them.
1. A composition for the topical treatment of psoriasis or atopic dermatitis comprising an effective amount of an active compound selected from the group consisting of propentofylline and torbafylline, and a pharmaceutically acceptable topical carrier, said composition being in the form of lotion, cream, ointment, encapsulated gel or sprayable aerosol.
2. A method for the treatment of a subject suffering from psoriasis or atopic dermatitis, comprising topically applying to said subject a therapeutically effective amount of an active compound selected from the group consisting of pentoxifylline, propentofylline and torbafylline.
3. The method of claim 2, wherein said active compound is pentoxifylline.
4. The method of claim 3, wherein said active substance is applied together with a pharmaceutically acceptable topical carrier.
This is a Continuation of application Ser. No. 07/934,268 filed Aug. 25, 1992, now abandoned.
This invention relates to topical pharmaceutical compositions for and a method of treating inflammatory and proliferative skin diseases such as psoriasis and atopic dermatitis.
Psoriasis is a common chronic relapsing inflammatory skin disease which affects 1-3% of the population. It is characterised by the circumscribed scaling erythematous plaques of various sizes and forms which in some cases may extend to more than 50% of the skin area. The psoriatic condition is composed of two main processes: cellular hyperproliferation and inflammation. Despite extensive research the etiology of the disease is still unknown.
Psoriasis is currently treated by a number of methods which include topical applications consisting of tar derivatives, steroids, vitamin D and its derivatives or vitamin A and its derivatives (J. P. Callen, Drug Therapy, April 1987, pp. 29-35). These therapies are only partially successful and may be accompanied by undesired side affects. Thus although steroids can be very effective, they are also frequently associated with side effects. Other therapies include phototherapy with or without concomitant systemic administration of psoralen derivatives. Additionally, systemic administration of steroids, methotrexate and cyclosporine have been used for treatment of severe cases of psoriasis. All of these therapies are associated with side effects. There is thus an urgent need for new effective, non-toxic therapeutics for psoriasis.
Atopic dermatitis is a chronic skin condition of unknown etiology, and which may be continuous from infancy to adulthood. There is about 4% incidence of atopic dermatitis from birth to 7 years (Halpern et al., J. Allergy Clin. Immunol. 51:139-151 (1973). In childhood, it is characterized by papules, erythema, thickening and lichenification. In the adolescent, the main symptoms are thickening and lichenification with erythema and scaling. Pruritis is a general feature of the disease. Systemic therapy includes antihistamine drugs and steroids, but the latter are reserved for unmanageable cases and used for the shortest period possible. Topical therapy includes fluorinated and fluorochlorinated corticosteroid preparations, but striae and cataracts are likely complications. Clearly there is as yet no satisfactory and safe drug treatment for atopic dermatitis.
Xanthine derivatives have been proposed for the treatment of psoriasis and atopic dermatitis. U.S. Pat. No. 4,141,976 proposes certain pharmaceutical preparations for the topical treatment of psoriasis. Among the compounds described are certain substituted alkylxanthine derivatives and substituted thioxanthines. However data demonstrating effectiveness is shown only for RO 20-1724 (d,1-4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone, which is not a xanthine derivative. There is no data showing that the xanthine derivatives are effective therapeutics when topically administered to patients suffering from proliferative skin disease.
WO 9101730 describes the use of certain xanthine derivatives for the treatment of asthma, urticaria, eczema and rhinitis. Suggested modes of administration are listed as oral, rectal, topical, parenteral, intravenous, or intramuscular or through the respiratory tract. EP 195,496 describes the use of certain xanthine derivatives for treating proliferative skin disease such as psoriasis. The xanthine derivatives are administered orally. U.S. Pat. No. 4,716,165 describes the use of certain theobromine derivatives for treating asthma, allergic rhinitis, atopic dermatitis or eczema. WO 8905145 describes the use of certain xanthine derivatives for the treatment of a wide variety of disease states including psoriasis. EP 260,127 describes the oral administration of certain xanthine derivatives for the treatment of proliferative skin disease. U.S. 4,341,783 describes the use of topical dyphylline for the treatment of psoriasis. There is no teaching or suggestion in any of the above-listed patents and patent applications that the topical administration of the compounds of the instant invention would be more effective in the treatment of psoriasis or atopic dermatitis than the topical application of other xanthine derivatives described in the above-cited patents and patent applications.
Ravid et al. (Ravid et al., J. Allergy Clin. Immunol. 86:881-885 (1990) and J. Clin. Endocrinol. Metab. 70:1687-1692 (1990)) have shown that certain compounds which increase the levels of cyclic adenosine monophosphate (cAMP) are capable of inhibiting the mitogenic induced proliferation of peripheral blood mononuclear cells (PBMC) from both healthy and atopic patients. The only xanthine derivative tested in these articles was isobutylmethylxanthine (IBMX). However, there is no teaching or suggestion in these publications that other xanthine derivatives may have different or superior properties to IBMX. There is certainly no mention of pentoxifylline (PTX), propentofylline (PPF) or torbafylline (TBF).
Pentoxifylline (PTX) (3,7-dimethyl-1-(5-oxohexyl)-xanthine), propentofylline (PPF) (3-methyl-7-propyl-1-(5-oxohexyl)-xanthine) and torbafylline (TBF) (3-methyl-7-ethoxymethyl-1-(5-hydroxy-5-methylhexyl)-xanthine are related methyl-xanthine derivatives which are well known in the art for treatment of a variety of disease states. PTX is widely used systemically for the treatment of peripheral vascular diseases. PTX and PPF have been administered systemically for the treatment of senile dementia while systemic administration of TBF is under investigation for treatment of senile dementia, peripheral vascular disease and myopathy.
PTX has been used systemically for the treatment of various cutaneous lesions associated with or due to impaired or deficient blood flow in the dermis layer of skin and its effectiveness in the treatment of peripheral vascular diseases is described by H. Ely, Dermatologic Clinics 6:585-608 (1988). There is no teaching that PTX, or any of its congeners, PPF or TBF, were effective in the treatment of psoriasis or atopic dermatitis, which are lesions of the epidermis layer of the skin rather than one of the peripheral blood vessels.
In accordance with the present invention it has surprisingly been found that the topical administration of a pharmaceutical composition comprising a compound selected from the group of pentoxifylline, propentofylline and torbafylline dramatically improves the psoriatic lesions of patients. Most surprisingly the improvement is greater than that achieved with other xanthine derivatives such as dyphylline which are taught in the prior art as useful for the topical treatment of psoriatic lesions.
Accordingly, the present invention provides a pharmaceutical composition for the topical treatment of psoriasis or atopic dermatitis comprising an effective amount of an active compound selected from the group of pentoxifylline, propentofylline and torbafylline, and a pharmaceutically acceptable carrier.
Preferably the concentration of the active compound is about 0.5%-5% (w/w). When the active compound is pentoxifylline its concentration is preferably 2% (w/w).
If desired, the compositions according to the invention may additionally contain therapeutically effective amounts of one or more compound which are known to be of use in the topical treatment of psoriasis and atopic dermatitis. These compounds are well known to those skilled in the art and include cyclosporine, methotrexate, tamoxifen, forskolin and analogs, tar derivatives, steroids, vitamin A and its derivatives vitamin D and its derivatives including 1-alpha-hydroxy-cholecalciferol, 1,25-dihydroxy-cholecalciferol, 24,25-dihydroxy-cholecalciferol, 1,24-dihydroxy-cholecalciferol and calcipotriol (MC 903), and beta agonists such as terbutaline.
In addition or instead, the compositions according to the invention may contain one or more of the compounds adenosine and related purines, lipoxygenase inhibitors, substance P antagonists, delta tocopherol, 2-heptanone, and fatty acids and their esters such as heptanoic acid, ethyl heptanoate, 3,3-dimethylbutyric acid, and lipoic acid.
The pharmaceutically acceptable carrier of the compositions according to the invention may contain any of the components which are used in topical compositions and are well known to those skilled in the art.
If desired, the pharmaceutically acceptable carrier of the compositions according to the invention may also contain penetration enhancers such as urea, lactic acid, ammonium lactate, salicylic acid or a C3 -C12 -straight chain alkanoic acid.
The compositions may be in the form of lotions, creams, ointments and gels, and also in the form of sprayable aerosols. Preferred formulations of the compositions according to the invention are creams, which may further contain saturated or unsaturated fatty acids such as stearic acid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleyl alcohols, stearic acid being particularly preferred. Creams of the invention may also contain a non-ionic surfactant, typically polyoxy-40-stearate.
The invention also provides a method for the treatment of a subject suffering from psoriasis or atopic dermatitis comprising topically applying to the subject a therapeutically effective amount of an active compound selected from the group consisting of pentoxifylline, propentofylline and torbafylline if desired together with a pharmaceutically acceptable carrier.
The preferred active compound for the performance of the method according to the invention is pentoxifylline.
If desired the said active compound may be applied together with a therapeutically effective amount of one or more additional compounds which are known to be of use in the topical treatment of psoriasis and atopic dermatitis. These compounds are well known to those skilled in the art and include cyclosporine, methotrexate, tamoxifen, forskolin and analogs thereof, tar derivatives, steroids, vitamin A and its derivatives, or vitamin D and its derivatives including 1-alpha-hydroxy-cholecalciferol, 1,25-dihydroxy-cholecalciferol24,25-dihydroxy-cholecalciferol,1,24-dihydroxy-cholecalciferol and calcipotriol (MC 903), and beta agonists such as terbutaline.
Also if desired the said active substance may be applied together with an effective amount of at least one member of the group of adenosine and related purines, lipooxygenase inhibitors, substance P antagonists, delta tocopherol, 2-heptanone, and fatty acids and their esters such as heptanoic acid, ethyl heptanoate, 3,3-dimethylbutyric acid, and lipoic acid.
Still further the invention provides for use of a compound selected from the group consisting of pentoxifylline, propentofylline and torbafylline for the preparation of pharmaceutical compositions for the topical treatment of human patients suffering from psoriasis of atopic dermatitis.
In the following Example 1 the advantages achieved in accordance with the invention are described, i.a. with reference to the annexed pictures in which:
FIG. 1 shows photomicrographs of transverse sections of human psoriatic skin transplants before and after treatment; and
FIG. 2 shows two further similar photomicrographs.
Some embodiments of the present invention will now be described and exemplified in the following Examples, it being understood that the invention is not limited thereto.
A. Pentoxifylline was formulated into a cream for topical application as follows:
______________________________________ % w/w______________________________________Stearic Acid 15.0Cetyl Alcohol 1.0White Petrolatum 3.0Polyoxy 40 Stearate 4.0Methyl Paraben 0.025Propyl Paraben 0.015Pentoxifylline (PTX) 2.0Propylene Glycol 9.5Sorbitol 7.5Purified Water To make up 100%______________________________________
This formulation was used in Examples 2 and 5.
B. Additional cream formulations of pentoxifylline suitable for topical application was prepared as follows:
______________________________________ % w/w______________________________________Pentoxifylline (PTX) 2.0Urea 5.0Lactic Acid 2.0Germaben II 1.0Sorbitol 70 solution 4.0Glycerin 4.0White Petrolatum 3.0Glyceryl monostearate 3.0Cetyl alcohol 3.5Heavy mineral oil 10.0Eutanol G-Octyldodecanol 5.0Acetylated lanolin (Modulan ™) 3.0Myrg 52 ™ 3.0Span 60 ™ 1.5Ammonia solution to adjust pH to 4.5Water To make up 100%______________________________________
C. Pentoxifylline was formulated into an ointment for topical application as follows:
______________________________________ % w/w______________________________________Miglyol ™ 840-B Gel 10.0Eutanol G-Octyldodecanol 17.0Cril 6-Glyceryl isostearate 3.0Hard paraffin wax 3.0Zinc stearate 1.0Amphisol K 0.5Germaben II 1.0Magnesium sulfate 0.2Urea 10.0Pentoxifylline (PTX) 2.0Purified water To make up to 100%______________________________________
D. Pentoxifylline was formulated into a gel suitable for topical application as follows:
______________________________________ % w/w______________________________________Pentoxifylline (PTX) 2.0Carbopol 940 ™ 1.5Triethanolamine 1.5Water 95.0______________________________________
Nude Mice with Transplanted Human Skin
Human psoriatic skin from psoriatic patients was transplanted to nude mice essentially according to the method of G. Kreuger et al., Prog. in Dermatol. 12:17-22 (1978) as modified by A. Gilhar et al., Exp. Cell Biol. 54:263-274 (1986). The donors had stable plaque type psoriasis for at least one year preceding biopsy and had not received systemic anti-psoriatic therapy for the 4 weeks preceding biopsy. They had also not received topical therapy or U.V. therapy for the two weeks preceding biopsy. The severity of the psoriatic lesion was evaluated and the PASI index was calculated as described by Fredrikson and Petterson (Dermatologica 157:238-244 (1978)). In this method the area (A) of the psoriasis in four main body parts (head (H), trunk (T), upper extremities (U) and lower extremities (L)) is assigned a value from 0-6 depending on the extent of psoriasis where O reflects no involvement and 6 reflects 90-100% involvement. The severity of the lesion is assessed based on three parameters: Erythema (E), Desquamation (scaling) (D) and Infiltration (I). The severity of each of these parameters is measured on a scale of 0-4 where 0 is no involvement and 4 is very sever. The total severity score is calculated according to the following formula:
Severity score=0.1(EH +IH +DH)AH +0.2EU +IU +DU)AU +0.3(ET +IT +DT)AT +0.4(EL +IL +DL)AL
Split thickness biopsies of nonpustular psoriatic human tissue, 4×5 cm and 0.4 mm thick were obtained from the edge of established plaques from various donor patients. Each specimen was divided into sections as follows: 4-5 sections, 2×2 mm each for thymidine incorporation and subsequent autoradiography in order to assess the rate of proliferation in the epidermis; 1-2 sections 0.5×1 cm each for histological examination prior to grafting in order to evaluate the severity of the disease, as quantitated by the measure of epidermal thickness; and 3 sections 1.5×1 cm each for grafting on the dorsal side of each of three different nude mice. The grafts were allowed to heal for one week prior to topical application of the test preparations.
Outbred Balb/C nude mice, 2 to 3 months of age were used in this study. The mice were obtained from the pathogen free animal breeding facility at the University of Tel Aviv (Israel) and were raised in the pathogen-free animal facility at the Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Following the one week healing period the graft area was treated daily with the test drug in a cream composition according to Example 1 or vehicle alone by applying 200 μl of the preparation, once at 08:00 and once at 21:00 for the duration of 7 days.
On the day following the end of treatment the severity of the psoriatic lesion was assessed and then the animals were sacrificed and the entire graft was excised and divided into two equal sections. One section was used to assess changes in the rate of proliferation by autoradiography (tritiated thymidine incorporation) while the other section was sectioned for microscopic histological assessment, including acanthosis and parakeratosis.
Table 1 shows the effect of the topical preparations tested on human psoriatic skin transplanted in nude mice according to the procedure outlined above. The results of the experiment shown in Table 1 demonstrate that pentoxifylline is almost as effective as steroids in treating psoriasis and far more effective than dyphylline, a related xanthine which was shown to be virtually inactive.
TABLE 1__________________________________________________________________________Epidermal Thickness (Acanthosis) of Psoriatic SkinTransplants (in μm)*% Improvement (Decrease in Thickness) Before and AfterTreatment With Various Preparations.PASI** After 7 Days TreatmentDonor Score Before 0.05% ClobetasolPatient Treatment 2% PTX 8% Dyphylline propionate*** PlaceboNo. μm μm % Improv. μm % Improv. μm % Improv. μm % Improv.__________________________________________________________________________1 3.2 44 65 0 24 452 3.2 68 62 93 7.6 46 28 40 27 414 17.6 54 42 22 24 555 31.3 35 45 0 47 06 3.8 55 39 30 77 0Average Improvement 31% 0% 35% 5%__________________________________________________________________________ *μ= micrometer **PASI = Psoriasis Area Severity Index (see Example 3) ***Dermovate ™-Glaxo
In another series of experiments, human psoriatic skin of various severities was transplanted on each of 28 nude mice. The graft area was treated with various preparations as described above.
Table 2 shows the results of the application of topical skin formulations to transplanted human psoriatic skin in each of the 28 nude mice. The results are expressed as a success ratio where success is defined as a decrease of at least 15% in epidermal thickness (acanthosis) as a result of the 7 day topical treatment. The treatments were applied as creams and were administered as described above.
The experiment shown in Table 2 demonstrates that pentoxifylline is almost as effective as topical steroids in treating psoriasis and far more effective than dyphylline which was inactive.
In summary the experiments performed with the animal model for psoriasis described above present a clear indication that PTX is effective in the treatment of psoriasis.
TABLE 2______________________________________ SUCCESSTREATMENT RATIO______________________________________2% Pentoxifylline* 6/108% Dyphylline 0/20.05% topical steroid** 7/10Placebo 0/6______________________________________ *Cream composition prepared according to the formulation given in Example 1A. **The topical steroid was either 0.05% clobetasol propionate ointment (Dermovate ™-Glaxo) or 0.05% betametasone dipropionate cream (Diproson ™ Schering U.S.A.).
FIG. 1 shows photomicrographs of representative examples of transverse human psoriatic skin transplant sections. The transplants were made as described above and were all taken from the same patient.
Panel A shows a transplant before treatment and panels B and C show transplants after daily treatments for seven days with the 2% PTX cream of Example 1 and an 0.05% clobetasol propionate ointment, respectively.
FIG. 2 shows similar photomicrographs before and after daily treatment for seven days with 8% dyphylline.
Inhibition of Human Psoriatic Fibroblast Proliferation
As excess proliferation of fibroblasts is one of the symptoms of psoriasis, the inhibition of fibroblasts proliferation was used as a test to determine the utility of the drugs of the present invention in the treatment of psoriasis. PTX and PPF, alone as well as PTX in combination with other drugs were tested.
Human psoriatic fibroblasts were obtained from skin biopsies of 5 individuals with plaque psoriasis. Cells in the 3-7th passages were used for the experiments. Human psoriatic fibroblasts (4×103 -6×103 cells) were added in 24-well plates and cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal calf serum, 2 mM L-glutamine, 100 u/ml penicillin, 100 μg/ml streptomycin (DMEM+) at 5% CO2 and 95% humidity at 37° C.
After 3 days, medium was replaced with fresh DMEM+(control) or with medium containing various concentrations of compounds alone or in combination with pentoxifylline and incubation was continued for additional 3 days. Stock solutions (10-1 -10-2 M) of the compounds tested were made in ethanol. For these compounds special control (DMEM+ with 1% ethanol) was made. The compounds tested together with pentoxifylline were 3-heptanone, 3,3-dimethylbutyric acid, lipoic acid, 1,25-dihydroxyvitamin D3 betamethasone dipropionate and hydrocortisone-17-butyrate.
On the last day of experiments, the medium was aspirated and the cells were obtained by trypsinization. The number of cells in each well was counted by the use of an hemocytometer.
The percentage of inhibition of fibroblast proliferation was calculated according to the formula: ##EQU1## and the results are shown in Tables 3 and 4.
TABLE 3______________________________________ Concentration of additional % Inhibition of ProliferationCompound drug (M) PTX 10-4 (M) PTX 10-3 (M)______________________________________Pentoxifylline 3.7 16.9(PTX)2-Heptanone 10-5 N.D. 21.3 10-4 21.0 26.4 10-3 18.6 453,3dimethyl 10-4 19.3 17.2butyricacid 10-3 36.3 21Lipoicacid 10-4 14.5 50.21,25(OH)2 D3 10-7 49.5 N.D.Betamethasone 10-7 43.1 N.D.dipropionate 10-4 55.8 77.5hydrocortisone 10-5 N.D. 41.917-butyrate 10-5 N.D. 51.2______________________________________ N.D. = Not Determined 1,25(OH2)D3 is 1,25dihydroxyvitamin D3
TABLE 4______________________________________ Concentration % Inhibition ofCompound (M) Proliferation______________________________________Pentoxifylline 10-4 5.9(PTX) 10-3 16.9 ± 4.8Propentofylline 10-4 20.3 ± 6.6(PPF) 10-3 39.0 ± 7______________________________________
These results show that the drugs of the present invention do inhibit the proliferation of fibroblasts which indicate their potential utility in treating psoriasis. The results are satisfactory both when these drugs are applied as the only active compound and when they are applied in combination with other drugs.
Inhibition of the Mitogenic Stimulation of Human Lymphocytes
Study in the literature have shown that atopic dermatitis is transferable by bone marrow cells indicating that primary site of disease is in the immune and inflammatory cells which infiltrate the skin. Thus the lymphocytes are thought to be one of the targets for treatment of the disease. Also, various cells (including lymphocytes) and organs derived from atopic subjects showed a common impaired response to cAMP agonists. Thus the study of atopic lymphocytes behavior in response to various agents is predictive of the atopic individuals response to these agents.
Studies have shown that cAMP agonists have an inhibitory effect on the mitogenic stimulation of peripheral blood mononuclear cells (PBMC) from atopic subjects (Ravid et al., J. Allergy Clin. Immunol. 86:881-885 (1990)). In these studies it was found that those compounds which have an inhibitory effect on PBMC from atopic subjects have a similar inhibitory effect on PBMC from healthy subjects. The primary difference noted was one of degree; the inhibitory effect on cells from atopic subjects was reduced when compared to healthy individuals. It was also shown that steroids such as dexamethasone, which are used in the treatment of atopic dermatitis, inhibited the mitogenic stimulation of PBMC. Thus the inhibitory effect of certain compounds on the mitogenic stimulation of PBMC isolated from healthy and atopic individuals is predictive of the effect of these compounds in the treatment of atopic diseases, including atopic dermatitis.
All materials and tissue culture media used were obtained from commercial sources.
Buffy coats from the Beilinson Medical Center Blood Bank or 20 mL samples of heparinized venous blood from healthy or atopic donors were used as a source for human peripheral blood mononuclear (PBM) cells. PBM cells were separated by Ficoll-Hypaque density gradient centrifugation. Partial depletion of adherent cells was achieved by incubating PBM cells for 90 min in plastic petri dishes at 37° C. at a concentration of 5×104 cells/mL in RPMI-1640 medium containing 2% heat-inactivated newborn calf serum. The nonadhering cells were stirred gently and carefully collected. The monocyte content of PBM cells was thus reduced to 3-7%.
PBM cells were suspended (1×104 /mL) in RPMI-1640 medium containing 5% heat-inactivated pooled human AB serum supplemented with penicillin (100 U/mL) and streptomycin (100 μg/mL). Cells were incubated at 37° C. in a humidified 5% CO2 -95% air atmosphere in 0.2 mL aliquots in 96-well flat bottomed Cooke microtiter plates. PHA (1 μg/mL), indomethacin (5 μg/mL) and various xanthine derivatives were added at initiation of culture. Indomethacin was dissolved in ethanol. The concentration of ethanol in the cell cultures did not exceed 0.006%, a concentration that, in our hands, has no effect on any of the cellular functions studied in this work. [methyl-3 H]Thymidine (1 μCi/well) was added at 68 h, and the cells were harvested 4 h later using an automated cell harvester (Dynatech, Alexandria, Va.). Unless otherwise stated, all cultures were performed in triplicate.
The inhibition of the mitogenic stimulation of PBMC by pentoxyfilline was found to be similar regardless of whether the source of the cells was patients with atopic dermatitis or healthy volunteers.
The net inhibitory effect on the mitogenic stimulation of human lymphocytes from healthy volunteers was compared for pentoxifylline, propentofylline and two other xanthine derivatives, theophylline and diphylline (Table 5). Surprisingly, pentoxifylline and propentofylline inhibited the mitogenic stimulation to a far greater effect than the other xanthine derivatives.
TABLE 5______________________________________ Xanthine Deriative UsedConcentration (M) PPF PTX THEOP DIPHY______________________________________3 × 10-4 88 46 37 121 × 10-3 89 70 59 24______________________________________ PPF-Propentofylline PTXPentoxifylline THEOPTheophylline DIPHYDiphylline
Clinical Trial
A clinical trial was performed comparing a cream composition of 2% pentoxifylline (formulation A of Example 1) to placebo. The trial was randomized, double blind, placebo controlled, right-left comparison within patient design.
Two similar plaque areas of psoriasis (i.e. both legs or forearms), were selected for treatment in each patient. In each patient one area on one side of the body was treated with 2% pentoxifylline formulated as in Example 1 and the other area on the other side of the body was treated with placebo cream formulated identically but without the pentoxifylline. The cream (formulation A in Example 1) was applied by the patient twice daily.
Patients were selected so that the lesions did not cover more than 30% of the total skin area. Patients stopped all forms of topical psoriatic treatment two weeks before entry into the study.
Systemic psoriatic treatments and phototherapy were stopped one month before entry into the study.
The dermatological assessment was performed as follows. The dermatologist measured the area of the lesion in cm2. The severity of each lesion was evaluated by grading erythema, scaling and thickness on a 0-4 scale where 0=none, 1=slight, 2=moderate, 3=severe and 4=exceptionally severe.
Based on these measurements the Psoriasis Area Severity Index (PASI) was calculated for each of the 2 lesions on each patient as follows:
PASI=Area x (Erythema+Thickness+Scaling)
Patient 1: After 1.5 weeks of treatment the patient showed a 58% decrease in PASI on the pentoxifylline treated side and 0% decrease in PASI on the placebo treated side.
Patient 2: After 2 weeks of treatment the patient showed a 53% decrease in PASI on the pentoxifylline treated side and 34% decrease in PASI on the placebo treated side.
Patient 3: After 2 weeks of treatment the patient showed a 73% decrease in PASI on the pentoxifylline treated side and 45% decrease in PASI on the placebo treated side. After 6 weeks of treatment the decrease in PASI on the pentoxifylline treated side was 90% and on the placebo treated side 56%.
Patient 4: After 6 weeks of treatment the patient showed a 91% decrease in PASI on the pentoxifylline treated side and 73% decrease in PASI on the placebo treated side. After 8 weeks of treatment the decrease in PASI on the pentoxifylline treated side was 88% and on the placebo treated side 57%.
Patient 5: After 2 weeks of treatment the patient showed a 73% decrease in PASI on the pentoxifylline treated side and 25% decrease in PASI on the placebo treated side.
In all patients the improvement in erythema was most pronounced. There was also good improvement in the thickness scores.
Clinical Trial
In a different series of tests 5% dyphylline cream was applied in the same vehicle that had been used to apply PTX cream. Thus the formulation used in this series of tests was the same as in Example 1 with the exception that 5% dyphylline was used in place of 2% pentoxifylline. The design of the trial was similar in all respects to the clinical trial of PTX described in Example 5 except that the number of patients was 33. The results shown in Table 6 demonstrate that treatment with dyphylline was nearly ineffective with respect to placebo.
______________________________________Treatment with 5% dyphylline vs. Placebo % Decreasein PASI as a Function of Time (n = 33 patients) 1 week 2 weeks 4 weeks 6 weeks______________________________________5% Dyphylline 12.6 25.9 28.0 26.5Placebo 12.4 30.0 21.5 15.6______________________________________
In summary the clinical trials demonstrate that topical pentoxifylline, a xanthine derivative, is a very effective therapeutic for the treatment of psoriatic lesions. However, dyphylline, a different xanthine derivative is virtually inactive in the treatment of psoriasis. These clinical trials also demonstrate the close correlation between the results obtained in the animal model and the results obtained in the clinical trial.
Clinical Trials
A randomized double blind, vehicle controlled, bilateral comparison study was performed, to determine the effect of pentoxifylline (PTX) in the treatment of atopic dermatitis. The study medication contained 2% pentoxifylline in an oil-in-water cream vehicle, and the control treatment consisted of the same vehicle without the pentoxifylline. The exact formulations appear in Table 7.
Seven patients (aged 3-10 years) were enrolled in the trial and evaluated for pruritus, erythema, dryness/scaling and exudate. Pentoxifylline cream, or the placebo (the identical cream, but without the pentoxifylline) were dispensed in identical tubes that were marked for application to right and left sides. Patients were instructed to apply medication twice a day (morning and evening) for four weeks.
The patients were evaluated at the end of the four week period and the results demonstrated that the pentoxifylline treatment significantly improved each of the four symptoms evaluated.
TABLE 7______________________________________ TEST CREAM PLACEBOINGREDIENT % W/W % W/W______________________________________Pentoxifylline 2.0Urea 5.0 5.0Lactic acid 2.0 2.0Ammonia 1.0 1.0Germaben ii 1.0 1.0Sorbitol 70% 4.0 4.0Glycerol 4.0 4.0White petrolatum 3.0 3.0Glyeryl monostearate 3.5 3.5Cetyl alcohol 3.5 3.5Mineral oil 10.0 10.0Octyldecanol 5.0 5.0Acetylated lanolin 3.0 3.0Polyoxyl 40 stearate 3.0 3.0Sorbitan monostearate 1.5 1.5Purified water 64.5 66.5______________________________________
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Runway o Produce!! Mangaランウェイを☆プロデュース; Runway wo Produce!!; 恋爱路线; 戀愛路線
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1st Wessex Artillery
|1st Wessex Artillery
|United Kingdom
|Territorial Army
|Artillery Regiment
|Garrison Artillery (1860–1908)
Field Artillery (1908–1932)
Heavy Anti-Aircraft Artillery (1932–1967)
Infantry (1967–1971)
- 215th Brigade Royal Field Artillery and 57th (Wessex) Heavy Anti-Aircraft Regiment, Royal Artillery redirect here.
The 1st Wessex Artillery was a volunteer unit of the British Army that existed under various titles from 1860 to 1971, including active service in World War I and World War II
19th century[edit]
Artillery Volunteers (1859-1908)[edit]
An invasion scare in 1859 led to a surge of new Rifle and Artillery Volunteer corps coming into existence across Great Britain, forming a large Volunteer Force. The 2nd Hampshire (2nd Hants) Artillery Volunteers (AV) were formed at Southsea in May 1860 and the following year became part of the 1st (Portsmouth) Administrative Brigade of the Hampshire Artillery, along with the 1st Hants AV at Bitterne, Southampton, and the 3rd Hants (Dockyard) AV raised from civilian staff of Portsmouth Dockyard. In 1871 the 2nd Hants absorbed the Dockyard AV. The 2nd Hants AV drilled on the guns at Southsea Castle and was attached to the Royal Garrison Artillery.[1][2] By 1900 the 2nd Hants had 10 garrison batteries (companies) and a total enrolment of 777 out of an authorised strength of 805 officers and men.[1] The companies were distributed as follows:[3]
- Nos 1–5, 8, 10 at Portsmouth
- No 6 at Gosport
- No 7 at Freshwater, Isle of Wight
- No 9 at Cosham
(an 11th company was raised later).
20th century[edit]
On the creation of the Territorial Force in 1908, Nos 1-9 companies of the 2nd Hants Volunteer Artillery formed 1st (Wessex) Brigade Royal Field Artillery (RFA), organised as follows:[3][4]
- 1st Hampshire Battery at Portsmouth
- 2nd Hampshire Battery at Portsmouth
- 3rd Hampshire Battery at Gosport
- 1st Wessex Ammunition Column, newly raised at Southsea
Nos 10 and 11 Companies were separated to form the nucleus of 2nd Wessex (Howitzer) Brigade RFA on the Isle of Wight.[3][5][6] 2nd Hants Volunteer Artillery also provided the nucleus of The Wessex (Hampshire) Heavy Battery, RGA (TF), with headquarters at Southsea.[7]
As the change of title indicates, 1st Wessex Brigade was now trained and equipped as field artillery rather than garrison artillery. It formed part of the Wessex Division of the TF. When war was declared in August 1914 the whole division was at its annual camp on Salisbury Plain.[8]
World War I[edit]
On mobilisation in 1914, the Territorials of the Wessex Division were sent to India to relieve British and Indian Regular troops for the Western Front. The artillery left behind their horses and their ammunition column, which were needed in France.[8][9][10]
With the expansion of the army, the division was designated 43rd (Wessex) Infantry Division in April 1915 and 1st Wessex Brigade became CCXV (or 215) Brigade RFA. Its three batteries were renamed A, B and C.[8][11][12]
All those Territorials who had not volunteered for overseas service, together with the recruits, were left behind to form Second Line units. The 45th (2nd Wessex) Division containing the CCXXV (2/1st Wessex) Bde RFA resulted from this process, and was ready so quickly that it followed the 43rd to India in December 1914. These units remained in garrison in India, supplying drafts to the First Line and other theatres throughout the war until they had virtually disappeared. CCCXV Bde was broken up in April 1917.[13][14]
Initially, CCXV brigade had been equipped with obsolete 15-pounder field guns, but in July 1916 it re-equipped with 4 x 18-pounders per battery in preparation for front line duty.[8][15]
With a reformed Brigade Ammunition Column, CCXV Bde moved in October 1916 to Basra to take part in the Mesopotamian campaign, and on 8 December 1916 it joined 3rd (Lahore) Division of the Indian Army on the Tigris front. At this time it had 524 (Howitzer) Battery (4 x 4.5-inch howitzers) attached, which remained with the brigade until September 1917.[8][15][16]
From 14 December 1916 until 19 January 1917 the division participated in the advance to the Hai and the capture of the Khudaira Bend. The one-hour bombardment at Khudaira by 3rd Division's guns on 9 January was described by the Turks as 'violent' and caused heavy losses. When the infantry went in they occupied the Turkish front line in minutes with few losses. The Turks counter-attacked under cover of a mist, but when that cleared a 15-minute bombardment enabled the British to secure the position.[17]
After the capture of Baghdad, 524th (Howitzer) Battery was lent to 7th (Meerut) Division for the advance on Hassaiwa and Fallujah, which was captured on 19 March 1917.[16][18] In parallel, the rest of CCXV Bde was with another force advancing towards Khaniqin, where they were supposed to link up with Russian troops. There was no sign of the Russians, but the Turks were present in force in the Jabal Hamrin hills. A brigade group including B Battery CCXV was ordered to outflank this position, and at one point B/CCXV was engaging the enemy at 1500 yards' range from open positions in the plain. But the Turkish position was too strong and the British force had to fall back towards Baghdad.[19]
In July the British resumed their advance, making for Ramadi. CCXV had its own A and B Batteries, 66th Battery and 524 (Howitzer) Battery under command. Contact was made at Mushaid Ridge, where the force was held by heavy fire from the banks of the Euphrates Canal and from the Regulator House. 2nd Battalion 7th Gurkha Rifles and CCXV Bde were ordered to try a left flanking movement. The Turks had about six guns firing very accurately, but 66th and 524th Batteries got the upper hand and by 1830 hours the Gurkhas were across the canal, only to come under heavy fire from the Ramadi trenches. Forward artillery observers saw signs of a Turkish retirement and brought down fire on the Aziziya Ridge to cut them off. But now confusion set in: Turkish shells cut telephone wires, two forward observers were wounded, and a dust storm blew up. Then two guns of B Battery were hit. No effective artillery bombardment was possible and the attack had to be called off. The flanking force had lost 566 casualties, 321 from the effects of heat.[20]
On 7 August 1917 CCXV's 18-pounder batteries were renamed again, as 1086, 1087 and 1088, and 1087 Battery was then broken up (probably to make the other batteries up to 6 guns each).[16] CCXV Bde transferred to 15th Indian Division on 4 October 1917 and gained an extra battery: 2/1st Nottinghamshire Royal Horse Artillery (renumbered 816 Battery RFA in February 1918).[8][16][21][22]
With 15th Indian Division on the Euphrates front, CCXV Bde participated in the occupation of Hīt on 8 March 1918 and the Action of Khan Baghdadi on 25 March 1918.[21][23] At the latter battle, CCXV and CCXXII Brigades advanced by alternate batteries over rough country under heavy enemy fire. 1088 Battery lost a gun and many casualties, but they continued moving forward and kept the momentum of the infantry advance going. By now the gunners were so far forward that they were engaging at ranges of 1800–2200 yards, putting down a steady barrage on the Turkish trenches followed by 15 minutes of intense fire, described by the RA's historian, Gen Sir Martin Farndale, as 'the most accurate seen so far' on the Mesopotamian Front. The infantry were able to enter these trenches with few casualties, taking many prisoners and enemy guns.[23]
After Khan Baghdadi, CCXV was sent to the rear to ease supply problems, and therefore took no part in the pursuit to Kirkuk through April and May. 15th Indian Division played little part in the final battles in Mespotamia.[21][24] CCXV Bde was placed in suspended animation in 1919.[4]
Interwar years[edit]
In 1920 the Territorial Army was reformed and prewar TF units reconstituted. 1st Wessex reabsorbed the Wessex Heavy Battery and now became 54th (Wessex) Field Brigade, Royal Artillery (RA), organised as follows:[3][4]
- 213 (Hampshire) Battery at Portsmouth
- 214 (Hampshire) Battery at Southsea
- 215 (Hampshire) Battery at Gosport
The unit was given a new role and title in 1932 as 57th (Wessex) Anti-Aircraft Brigade RA, (TA), taking over 219 (Isle of Wight) Battery from 95th (Hampshire Yeomanry) Field Regiment – this battery had originally been part of 2nd Wessex Bde, soon it absorbed 216 Battery at Cosham which had a similar history.
On the eve of World War II, 57th (Wessex) Bde was organised as follows:[3]
- 213 (Portsmouth) Battery at Southsea
- 214 (Southsea) Battery at Southsea
- 215 (Gosport and Fareham) Battery at Gosport
- 219 (Isle of Wight and Cosham) Battery at Newport.
World War II[edit]
Early in WWII, the unit – now designated 57th (Wessex) Heavy Anti-Aircraft Regiment, RA – was part of Home Forces. During the Battle of Britain and Blitz it served in 65 AA Brigade of 5 AA Division, defending Portsmouth and Southampton.[25][26]
In October 1942, 57 (Wessex) HAA Regt was sent to North Africa to join Eighth Army, and it served with that formation through the rest of the North African Campaign and the Italian Campaign until the end of the war.[25][27] 57 (Wessex) HAA was placed in suspended animation in 1946.[4]
Postwar years[edit]
On the reconstitution of the TA in 1947, the regiment was designated 457 (Wessex) HAA Regiment RA. In 1955 it absorbed 428 HAA Regiment, formerly Princess Beatrice's Isle of Wight Rifles, which formed P (Princess Beatrice's Isle of Wight) Battery alongside Q (Portsmouth) and R (Gosport) Batteries. In 1963, the regiment absorbed 295 (Hampshire Carabiniers Yeomanry) HAA Regiment, and became 457 (Wessex) Heavy Air Defence Regiment, RA, (Hampshire Carabiniers Yeomanry).[2][3]
In 1967 the regiment became infantry as C Company (Wessex Royal Artillery Princess Beatrice's) in the Hampshire and Isle of Wight Territorials, but when that regiment was subsumed into the Wessex Regiment the Royal Artillery and Hampshire Yeomanry links were discontinued. However, when 106 (Yeomanry) Regiment Royal Artillery was created in 1999, the old number '457' was revived for 457 (Hampshire Yeomanry) Battery.
There is a memorial plaque on the seafront at Hayling Island to 219 Batty, 57 HAA Regiment. Unveiled in July 1994, it lists the names of six men of the battery killed during a German air raid on Portsmouth and Hayling Island on the night of 17/18 April 1941.[28]
Re-enactment group[edit]
The Palmerston Forts Society has a re-enactment group, the Portsdown Artillery Volunteers, based on the 2nd Hants Artillery Volunteers.[29]
- ^ a b http://www.victorianforts.co.uk/HantsArtillery.htm
- ^ a b http://www.nationalarchives.gov.uk/nra/onlinelists/GB0042%201153A-2.pdf
- ^ a b c d e f "1st Wessex Regiment, RA (TA) [UK]". Web.archive.org. Retrieved 2013-02-05.
- ^ a b c d Litchfield, pp. 89–92.
- ^ "2nd Wessex Regiment, RA [UK]". Web.archive.org. Retrieved 2013-02-05.
- ^ Litchfield, p 93.
- ^ Litchfield, p 92.
- ^ a b c d e f The Long, Long Trail. "The Royal Field Artillery of 1914-1918". 1914-1918.net. Retrieved 2013-02-05.
- ^ "Royal Field Artillery Batteries". Web.archive.org. Retrieved 2013-02-05.
- ^ Farndale, p. 334.
- ^ "The 43rd (Wessex) Division of the British Army in 1914-1918". 1914-1918.net. Retrieved 2013-02-05.
- ^ "43rd (Wessex) Division". Web.archive.org. Retrieved 2013-02-05.
- ^ The Long, Long Trail. "The 45th (2nd Wessex) Division of the British Army in 1914-1918". 1914-1918.net. Retrieved 2013-02-05.
- ^ Fardndale p 335.
- ^ a b Farndale, p. 242.
- ^ a b c d Perry, 3rd (Lahore).
- ^ Farndale, p. 243.
- ^ Farndale p. 255
- ^ Farndale, p9. 255–6
- ^ Farndale, p. 264.
- ^ a b c Perry, 15th Indian
- ^ The Long, Long Trail. "The Royal Horse Artillery of 1914-1918". 1914-1918.net. Retrieved 2013-02-05.
- ^ a b Farndale, p. 272.
- ^ Farndale, p. 275.
- ^ a b "RA 1939-45 57 HAA Rgt". Ra39-45.pwp.blueyonder.co.uk. Retrieved 2013-02-05.
- ^ "RA 39-45 5 AA Div". Ra39-45.pwp.blueyonder.co.uk. Retrieved 2013-02-05.
- ^ Joslen, pp. 467, 486.
- ^ UKNIWM Ref 21275
- ^ "Portsdown Artillery Volunteers Re-enactment". Palmerstonfortssociety.org.uk. 1908-03-31. Retrieved 2013-02-05.
- Farndale, General Sir Martin (1988). The Forgotten Fronts and the Home Base, 1914–18. History of the Royal Regiment of Artillery. Woolwich: The Royal Artillery Institution. ISBN 1-870114-05-1.
- Lt-Col H.F. Joslen, Orders of Battle, United Kingdom and Colonial Formations and Units in the Second World War, 1939–1945, London: HM Stationery Office, 1960/Uckfield: Naval & Military, 2003, ISBN 1-84342-474-6.
- Litchfield, Norman E H, and Westlake, R, 1982. The Volunteer Artillery 1859-1908, The Sherwood Press, Nottingham. ISBN 0-9508205-0-4
- Norman E.H. Litchfield, The Territorial Artillery 1908–1988 (Their Lineage, Uniforms and Badges), Nottingham: Sherwood Press, 1992, ISBN 0-9508205-2-0.
- F.W. Perry, History of the Great War: Order of Battle of Divisions, Part 5B: Indian Army Divisions, Newport, Gwent: Ray Westlake Military Books, 1993, ISBN 1-871167-23-X.
- Land Forces of Britain, the Empire and Commonwealth
- The Long, Long Trail
- The Regimental Warpath 1914–1918
- The Royal Artillery 1939–45
- UK National Inventory of War Memorials
- Victorian Forts and Artillery


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SunPower, PG&E Enter Contract For 100-Megawatt Henrietta Solar Project
SunPower Corp. (SPWR) has signed a power purchase agreement with Pacific Gas and Electric or PG&E for delivery of the 100-megawatt (AC) Henrietta Solar Project in Kings County, Calif. According to the company, the project is likely to create nearly 200 jobs during construction and inject $72.7 million into the local economy.
Report: U.S. Solar Market Spikes in Q2 2012, More than Doubling Q2 2011 Market Size
GTM Research and the Solar Energy Industries Association® (SEIA®) today released U.S. Solar Market Insight: 2nd Quarter 2012. The report finds that U.S. solar achieved its second-best quarter in history, having installed 742 megawatts of solar power, and the best quarter on record for the utility market segment.
Solar Tree that Doubles as an EV Charger Going Up at GM Site
Envision Solar International announced on Thursday that one of its Tracking Solar Trees®, which includes a SunCharge™ electric vehicle charging station as its trunk, will be going up at GM's Milford Proving Ground.
Sun Peeks Through in Solar
The solar-power business is expanding quickly in the U.S., helping lift the cloud that has surrounded the industry since the demise of Solyndra LLC a year ago. But the growth isn't coming from U.S. solar-panel manufacturing, despite the money and rhetoric devoted to the industry by the Obama administration. Instead, it is in installations of largely foreign-made panels, whose falling price has made solar more competitive with other forms of power.
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It's true—amazing solar tech innovations just keep coming. Some advances come in the form of new handheld devices and applications. Others promise to elevate solar into a mainstream energy source that may one day replace greenhouse-gas-emitting fossil fuels. Here are five recent innovations that have left both solar experts and newbies in a daze.
Renewables From Vestas to Suntech Plan Profit Without Subsidy
Renewable energy companies are approaching the point where they can generate electricity at a price competitive with fossil-fuels without subsidies, the biggest wind and solar manufacturers said.
In Defense of Clean Energy
After months of standing by as Republicans tried to gut environmental laws and discredit his clean energy initiatives, President Obama took the offensive in his State of the Union address.
Au revoir D.C.! Solar Decathlon relocates to sunny Southern California
Well, it looks like the Solar Decathlon officially has a new home and it's not exactly a big shocker that the 2013 edition will not be held in or around Washington, D.C.
Four Market Niches In The Solar Boom
After a summer hearing about the death of Solyndra, you couldn't be blamed for not knowing that the solar industry is exploding in this country. And it's not just selling panels--an entire industry is springing up around people getting energy from the sun.


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I am delighted to announce that Irish transport data is now integrated with Bing, meaning when you use Bing to get directions you can choose to see transport options for that journey. This is a fantastic example of local Microsoft staff working with the National Transport Authority to integrate the appropriate data feeds into Bing to make Bing search more relevant in Ireland.
As an example, I searched for directions from St. Stephen's Green to our sales office on Carmanhall road in Sandyford.
The results show all of my transport options including the number 11 bus as well as the green Luas line, so cool! I can also see this on the map and track exactly what route each option takes.
And, of course, I can see the exact directions and steps I need to take
If you are a Windows Phone user then you may have heard of Nokia Here Transit. It pulls it's data from the NTA services, and has done for a while now, so all of this works just as nicely on Here Transit.
I think this is a great example of the Bing team, Microsoft Ireland and NTA working together and there are plans to integrate even more local services like this into Bing soon.
Any plans for adding the Translink unified public transport system informatino for buses/trains in Northern Ireland?
Hi Niall,
Just noticed, I wanted to get to bing maps. And there was no link on bing.com which could take me to bing.com/maps. I searched for maps on bing and it turned out to be google maps came first.
@keith its a different organisation but we are investigating. I will keep you posted.
@jose I've passed your comment on to the team. Thanks


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Fire Escape
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Originally Posted by
No. She is NOT comfortable on her DR!
I would very much like it 1 to 2 inches lower still. I actually don't think the gel seat is quite as comfy as the stock seat was, but the lower height wins out. I still can't get my feet flat on the ground when the bike (and I) are on level ground, and that's something I really want to be able to do.
Hi everybody! I am Matt's (aka Hesaid's) other half, and the rider of the second (lower) DR in the household.
Unfortunately, despite all our best efforts to start out and stay safe, sane, mature and responsible while cutting our teeth and getting the hang of riding-- the almost very first thing I did was "shatter" (Dr.'s words) my left wrist in a sloppy dismount after losing balance and realizing the bike was going over whether I stayed on it or not.
And so all those people who were utterly disgusted at us for getting motorcycles for various reasons have had a chance to "tsk tsk" at us and point at my fancy new scar from the ORIF surgery as if that proves them right. And I have the unfortunate luck to contribute to motorcycle statistics.
Which is just pathetic because the bike was stalled at a dead stop when I did it.
Shouldn't even have mentioned the bike... it was the tripping and falling down that did all the damage.
He promises not to go riding without me, so according to the orthopedist, we hope to be back on 2 wheels early in 2013. Which is good, because I'm looking forward to some back country roads to enjoy the fruit orchards in full bloom come mid-February.
Alrighty-- that is my introductory post, tieing me in with Hesaid so hopefully y'all will associate us with with eachother now.
BTW: Thank you, Sarah, for both the thought and the link!
I was having a grand time-- and not feeling too intimidated at all-- puttering around the parking lot in 1st gear before I hit that curb and broke my wrist. Really looking forward to getting just a little bit lower... and back on the bike.
Your mention of "stalled at a dead stop" caught my attention. Was the engine actually stalled? It is pretty easy to fall over if the engine stalls when trying to get underway (or stopping if the clutch timing is off a little), the motion you were expecting and that your body was already adjusting to ... doesn't happen and it is hard to 'readjust' to the new direction of travel (that being down) quickly enough.
For all it's attributes, the DR isn't a really forgiving engine at low rpms, it likes to rev to run smoothly. The bike is also not geared particularly low. I did not notice this very much until I had the DR and a Triumph Scrambler that I pretty much rode on alternate days. I often enjoy just puttering along
slowly on a back road with NO traffic, I mean slow as in single digit speeds. My DR, despite being a "thumper" would not actually allow me to go as slow as the Scrambler. I changed my countershaft sprocket down one tooth to a 14 and it helped a lot in that regard. I then did a bit more by replacing the rear sprocket with a 43T (up one). I can't say that it 'transformed' the bike but it sure made the low speed 'puttering along' much more enjoyable and the bike is noticeably easier to get in motion from a stop.
Perhaps my DR will no longer cruise the highway at 85 or 90 mph, so be it, that isn't what I bought it for. I can still travel on the interstate if really necessary but would use another bike by choice. Some will say that I fixed a non-existent problem, that it isn't a hard bike to ride stock, they are correct, I just made it more suitable to MY desires.
It might make your riding more enjoyable and reduce one of the challenges of getting used to riding. There isn't a lot of cost involved and it is all reversible if you don't like it. Might be worth some consideration.
Of course if you didn't actually mean that the engine had stalled, perhaps none of this is appropriate or needed. Good luck and have fun!
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This paper presents the mechanical design, kinematic modeling and simulation of a robotic dolphin. The mechanical structure of robotic dolphin was designed according to the bionics. The motion equation of the robotic dolphin was established by reference to the motion equation of submarine. Then, the motion simulation of the sinusoidal movement mechanism and the caudal fin was achieved using SolidWorks. The motion equation of the robotic dolphin was the basis of the robotic dolphin's motion control. The analysis results of motion simulation confirmed the effectiveness of the robotic dolphin in propulsion.
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Discover Erykah Badu's Neo-Soul at American Airlines Arena
Forget what it says on the marquee — the venue is undoubtedly Amerykahn Airlines Arena when queen of neo-soul Erykah Badu's in town. The striking singer, recognizable by her beehive headgear and enormous Afro wigs, is touring in support of the freshly released New Amerykah Part Two (Return of the Ankh). It's a gritty R&B collection that trumps her formidable Part One (4th World War) and nearly any album released so far in 2010.
The new single, "Window Seat," finds Badu holding her own broken-beautiful voice as confidently as anything since her 1997 debut, Baduizm. In the brash, NSFW "Window Seat" video, she takes off all of her clothes on the Dallas street where JFK was assassinated — a stunt falling right in line with her artistic intensity. Elsewhere on the album, she boasts that she's 20 feet tall. No argument here.
Badu's support for the night is strong. In Bilal, she has the silver pipes providing backing vocals on much of her last release as well as just a soulful stud who added his touch to Common, J Dilla, and Jay-Z records. Artistically, the past couple of years have been good to Erykah Badu, so it's the right time to reward her by reveling in her greatness in person.
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The Library of Hebrew Bible/OT Studies: JSOTS on Torah collection offers the scholar explorations of issues pertaining to the first five books of the Old Testament. Written with the academic in mind, the six volumes capture a variety of fascinating thoughts on these foundational … more
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MaxLinear, Inc. (MXL)
February 25, 2013 7:00 pm ET
Kishore Seendripu - Co-Founder, Chairman, Chief Executive Officer and President
Adam C. Spice - Chief Financial Officer and Vice President
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Vidya Adala - Morgan Stanley, Research Division
» Logitech's Management Presents at Morgan Stanley 2013 Technology, Media & Telecom Conference (Transcript)
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Before I kick off, I just need to read the disclosure. Please note that all important disclosures, including personal holding disclosures and Morgan Stanley disclosures, appear on the Morgan Stanley public website at www.morganstanley.com/resourcedisclosures or at the registration desk.
With that, I thought the best thing for us to do to kick off is to -- for either of you to give us a very brief overview of the story, and we can then jump into different specifics following that.
Kishore Seendripu
Okay. Thank you, Vidya. So it's a pretty exciting time to be at MaxLinear. I think as a semiconductor fabless or a mixed-signal company, we have recorded some of the industry best growths. We had about 36% revenue growth last year. And we did that while stabilizing the gross margin, and in fact growing the gross margin to about 63% in the last quarter. We made some disciplined investments to really increase the TAM. Move the company away from consumer markets with short product cycles to operative class markets where product cycles are longer, 2 to 3 years. And then now making more disciplined R&D investments to move the company more towards the infrastructure markets where the revenue cycles are much longer, 6, 7 years.
What we do at MaxLinear is basically the access at the home. By that I mean that if you really look how you receive your multimedia content or your broadband data via [ph] cable, so whenever you have something coming off your coaxial cable at your home or a terrestrial TV antennae at your home or even a satellite dish, first, it goes into a very tough radio mixed signal product called the -- traditionally called the tuner, but today they're called broadband receivers for a variety of reasons, later I'll tell you that. We do this very tough broadband RF mixed-signal chips that make it possible for you to receive the exploding multimedia content out there, and whether it's over-the-top content or through regular traditional linear video sources such as cable operators or satellite operators. So that's what we do as of today.
But as we move forward, look forward, the company is spending more money and investment into how to get into infrastructure market, be it satellite or cable or outside of it where the plumbing for the content that comes to your home has to be changed or overhauled. And there's a lot of range [ph] radio mix-signal content in the infrastructure side. For example, cable had an infrastructure satellite outdoor units and even data centers and maybe wireless infrastructure. And that's where we propose to play.
So that's the overview of what MaxLinear is about. We have a very, very strong team. One of the world's best, I would say, radio mixed-signal and comm systems technology of about 200-plus R&D engineering staff. We have about 30% are PhDs and 85%, 90% are pretty advanced degree holders. It's a very, very world-class caliber R&D technology team.
And we augmented that over the last 18 months with what I call one of the best management teams for a company of our size, with the senior management having broad experience taking companies from tens of millions of dollars to billions of dollars in revenues. Adam Spice was one of the early employees of Broadcom and he saw Broadcom scale from some billion dollars to several billions of dollars in revenue and be our VP of Operations and so on and so forth.
So we feel really good. I think there's never been a greater opportunity to be a participant, whether as an equity holder or as an employee inside MaxLinear. I firmly believe that.
Adam C. Spice
Yes, I'd like to add one thing to what Kishore is mentioning that's very important. In my career at Broadcom, I was involved in about 50 acquisitions. And I think the one thing that always came through and would made us walk away from more acquisitions than anything else was really kind of was there a core strength or capacity on the analog design side? And we look at all these companies, they might have 75 or 100 employees or engineers and of which you might have 1 or 2 really good analog designers. And if -- you'd actually be lucky if you found that. And I think the one unrecognized gem within MaxLinear, which is allowing us to get into all these markets that Kishore mentioned earlier, is the fact that we have this incredibly talented, very big scale team of analog art designers, which is incredibly rare to find. I think, if anything, that gates companies' abilities to enter new markets. And I think that's the one factor that we don't have limiting us right now, is that scale of that very rare hard-to-find analog design resource.
Question-and-Answer Session
Vidya Adala - Morgan Stanley, Research Division
And just because you brought up Broadcom, they are one of your competitors in some of these end markets out there. And surely, they have these capabilities, too, it's probably a gating factor maybe for other people to enter the markets. But how do you think about how you've got -- you've put in the door already, which is established and you have a good track record of that? But also going forward, how do you remain ahead of these guys with deeper pockets in a way?
Read the rest of this transcript for free on seekingalpha.com


text:
A method and apparatus (10) for the secure transmission of static data (16) from a tag (11) to a remote reader (12). Each time the static data (16) is to be transmitted to the reader (12), the 10 bits of static data (16) are combined with 54 bits of binary data (21), which constantly change from one transmission to the next, into a 64-bit number (22). This number is then encrypted and transmitted to the remote reader (12) where it is decrypted (26) to produce the same 64 bit number that was encrypted in the tag (11). With a continual change in the value of the 64 bit number (22) in the tag, the encrypted numbers transmitted to the reader (12) will appear to be dynamic in character rather than being static.
1. A tag adapted to be affixed to a device and adapted to be interrogated from a remote location, said tag comprising:
means for generating m number of binary bits having a static value unique to the device to which the tag is affixed,
means for generating n number of binary bits of binary data, with the value of the n number of binary bits being different on each interrogation of said tag,
means responsive to an interrogation of said tag for combining said m number of bits and said n number of bits into a combined number having m+n number of bits and with said n number of bits being at a predetermined location in said number,
encryption keys in said tag,
means for encrypting said combined number in accordance with said encryption keys for transmission to said remote location.
2. A tag as set forth in claim 1, wherein said means for generating n number of binary bits comprises a cycle counter, and wherein said tag further includes means for changing the count in said cycle counter on each interrogation of said tag.
3. A tag as set forth in claim 1, wherein said means for generating m number of binary bits comprises a random number generator.
4. A system for secure communication of static information comprising:
a tag adapted to be affixed to a device and adapted to be interrogated from a remote location,
means in said tag for generating m number of binary bits having a static value unique to the device to which the tag is affixed,
means in said tag for generating n number of binary bits of binary data, with the value of the m number of binary bits being different on each interrogation of said tag,
means in said tag responsive to an interrogation of said tag for combining said m number of bits and said n number of bits into a combined number having m+n number of bits and with said n number of bits being at a predetermined location in said number,
encryption keys in said tag,
means in said tag for encrypting said combined number in accordance with said encryption keys for transmission to said remote location,
a reader adapted to be at said remote location,
means in said reader for interrogating said tag,
decryption keys in said reader, said decryption keys being the same as said encryption keys in said tag,
means in said tag for receiving said encrypted number from said tag and for decrypting said encrypted number in accordance with said decryption keys to produce a decrypted number of n+m binary bits with said n number of bits being in the same location in said decrypted number as they were in the number in said tag prior to encryption.
5. A system as set forth in claim 4 wherein said means in said tag for generating n number of binary bits comprises a cycle counter, and wherein said tag further includes means for changing the count in said cycle counter in each interrogation of said tag.
6. A system as set forth in claim 4 wherein said means in said tag for generating m number of binary bits comprises a random number generator.
The Government has rights in this invention pursuant to Contract No. W-7405-ENG-48 awarded by the United States Department of Energy.
The invention relates to the secure transmission of static information. The term "secure" implies that an adversary has access to the communication channels and a functional knowledge of the system but cannot extract desired information.
Numerous secure communication systems exist that employ some form of encryption of the data before it is transmitted to a remote receiving station. However, if the data to be transmitted is static, i.e. of constant value, then the encrypter will produce a common output for each transmission of the data. Although an adversary without knowledge of the encryption keys could not decode the information he would be able to tell whether the information was static or dynamic. This knowledge could aid the adversary, as in the following situation.
Electronic tagging devices are in common usage for inventory control in both commercial and governmental applications. In some instances, a donor may put a device in the custody of an adversary to be kept at a given location from which the donor is excluded. In such a case, an electronic tag will be affixed to the device, the tag having a tamper detector, often referred to as a seal, which is integrated with a device to ensure that the tag has not been removed from the device and transferred to a surrogate. When such a tag is interrogated from a remote location, it will uniquely identify itself and provide tamper sensor status. This information is encrypted and can only be decrypted by a interrogator that has knowledge of the particular encryption keys.
However, if the tamper sensor's status response is static, the encrypted data will likewise be static. With the tagged device in the custody of the adversary, the communication channels would be available to the adversary and the encrypted response would be known to the adversary. The adversary could transfer the tag to a surrogate device and make adjustments until the tamper sensor returns to its pre-transfer encrypted readings. This is possible even though the adversary has no knowledge of what the encrypted tamper sensor data actually represents. For many applications where security is of paramount importance, this inherent problem presents unacceptable risks. This problem also exists if the tamper sensor produces quasi-dynamic readings of limited range.
It is the primary object of the present invention to provide a system which will preclude even a very sophisticated adversary from extracting static or quasi-dynamic tamper sensor date from an encrypted wavetrain.
Additional objects, advantages and novel features will be set forth in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations pointed out in the appended claims.
To achieve the foregoing and other objects, and in accordance with the present invention as described and broadly claimed herein, a tag is provided which will combine dynamic information with the static tamper sensor status information from the seal prior to encryption and transmission, so that all transmissions appear to be fully dynamic and only by decrypting the transmitted message can the static information be separated from the masking effect of the appended dynamic information.
In one aspect of the invention a continually changing cycle counter in the tag is used to provide the dynamic information to be combined with the static information from the seal.
In another aspect of the invention, a random number generator in the tag is used to provide the dynamic data.
The accompanying drawings, which are incorporated and form part of the application, together with the description serve to explain the principles of the invention.
FIG. 1 is a block diagram of the components of a tag and a reader in accordance with the present invention.
FIG. 2 is similar to FIG. 1, but illustrates the components of an alternate form of tag 11.
Referring now to FIG. 1 of the drawings, the communication system 10 comprises a tag 11 adapted to be affixed to a particular device (not shown) and a reader 12 remotely located from the tag and in communication with the tag by channels 13 and 14. The tag 11 includes a seal 16 which is uniquely related to the device to which the tag is affixed and which will provide a unique multi-bit tamper sensor data signal identifying the device. For purposes of description the tamper sensor data signal is assumed to be a unique binary number of 10 bits in length. The sequence of the 10 bits will be the same every time that the tag 11 is interrogated, as long as the tag remains affixed to the particular device that is being monitored.
In operation of the system, an external "Execute" signal is applied to terminal 17 of the reader 12 which causes the interrogation signal generator 18 to send a signal over communication channel 13 to sequencer 19 of tag 11. The sequencer 19 causes the cycle counter 21 to send 54 bits of data, and the seal 16 to send its 10 bits of data to holding register 22 to form a 64-bit number therein. The location of the 10 bits of tamper sensor data in register 22 is a matter of choice. For example, the first 54 bits of the number in register 22 may come from the cycle counter 22, with the tamper sensor data being the last 10 bits of the 64 bit number.
The 64-bit number is then sent to the encrypter 23 which will encrypt the number in accordance with the encryption keys 24, to produce a 64-bit encrypted number. In accordance with present encryption technology, a change in only one of the bits of the 64-bit number in register 22 will produce a substantially changed encrypted number, with the change in the encrypted number being unpredictable. The degree of change and of the unpredictability will, of course, depend upon the quality of the encryption keys 24.
The encrypted number then passes by way of communication channel 14 to the decrypter 26 of the interrogator 12, and the number is decrypted in known manner in accordance with the decryption keys 27. The keys 27 are, of course, the same as keys 24. The decrypted number is now sent to holding register 28, and the 64 bits in register 28 will be the same as was in tag register 22 prior to encryption. The contents of register 28 will now be sent through mask 29 to the tamper sensor data register 31. The mask 29 will remove the data bits from the cycle counter in tag 11. For example, the mask 29 may function to multiply the first 54 bits in register 29 by "0" and the last 10 bits by "1". By so doing, all of the first 54 bits from register 29 will become "0" while the data in the last 10 bits will be unchanged. Thus, the data passing through mask 29 to register 31 will be identical to the data in the tag seal 16.
The data in register 31 may be sent to a data display device 32 or to a comparator 33 for comparison with the known value of the data that the tag seal 16 should produce.
In tag 11, the encrypted word detector 34 will sense the completion of the transmission of the encrypted number to the decrypter 26 and will send a signal to the cycle counter 21 causing it to advance one count for the next interrogation. With 54 bits of data going from the cycle counter 21 to the register 22, and with the count being increased by "1" on each successive cycle of operation, 254 interrogations must occur before any repetition of data from the cycle counter can occur. If interrogations are made at one second intervals, only about 225 interrogation cycles would occur in a year's time. Accordingly, for all practical purposes, the output of the cycle counter 21 will not repeat.
Tags 10 generally do not have any internal power sources and are powered only from the reader 12 during interrogation. As a consequence, the cycle counter 21 of FIG. 1 must have a nonvolatile memory to prevent the counter from being reset between interrogations.
FIG. 2 discloses a secure communication system 100 wherein the reader 12 is as described above but the tag 110 uses a random number generator 121 in place of the cycle counter 21 of FIG. 1 to provide the first 54 bits of data to the holding register. The operation of the system of FIG. 2 is as described above, with a different arrangement of bits being fed from the random number generator 121 (and the same arrangement of 10 bits from seal 16) to register 22 on each interrogation of the tag.
The system of FIG. 2 does not require a non-volatile memory since the random number generator does not reset. However, the security of this system is limited by the quality of the random numbers.
The foregoing description of the preferred embodiments has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise forms described, and obviously many other modifications are possible in light of the above teaching. The embodiments were chosen in order to explain most clearly the principles of the invention and its practical applications thereby to enable others in the art to utilize most effectively the invention in various other embodiments and with various other modifications as may be suited to the particular use contemplated. It is intended that the scope of the invention be defined by the claims appended hereto.
Patent Citations
Referenced by
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text:
That Chargers game really was something last year. Would have liked to have seen if it was a fluke or something to build on with the young receivers.
We are all in the gutter, but some of us are looking at the stars.
--Oscar Wilde
Huge Bengals fan here... have bought two Carson Palmer jerseys in his time with the team. I do not know if I can accept him back. You signed a extension and now you like to make threats about quitting. You care more about yourself than the team. Screw you pretty boy.
Small market fan... always hoping, but never expecting.
If he sits out the season, then he is "manning up" IMO.
Frankly I think he's manning up by standing up to Mike Brown.
A NFL "contract" isn't worth the paper is printed on. If Brown feels he has been shortchanged he can take that up with the NFL/court system.
For the time being, Palmer has plainly stated he would rather retire than play. This gives Brown the opportunity to trade him if he'd like. Brown has to play hardball with Palmer because he runs that team so shabbily that the setting the precident that you can force your way out of Cincinnati would start a bumrush for the exit. If Palmer comes back to play for the Bengals, I'll think very little of him.
If he is willing to sacrifice a truckload of cash and a year of his career for his beliefs, that is manning up IMO, on a path that few are willing to tread.
/Bengals fan. *sigh*
If you say yes, then fine. If no, and the argument is that the contract allows the team to do that, then, the contract also allows the player to retire.
For those who believe, no proof is necessary. For those who don't believe, no proof is possible
That said, I agree this isn't much of a stand. It's more a realization that he didn't want to play for the Bengals anymore.
When people say that I dont know what Im talking about when it comes to sports or writing, I think: Man, you should see me in the rest of my life.
---Joe Posnanski
Tough call for me. As a rule, I'm not a fan of the variants of "gimme or I'll hold my breath until I pass out." But playing in the NFL is a terrific grind, and if a guy doesn't need the money and doesn't believe in his organization and can't get out of his organization, then yeah, I can see where he could start to wonder why he's still playing. Players always have the right to walk away from the game, just as the game inevitably closes the door on players.
The one thing I don't believe will happen is a trade. So either Palmer retires, which is his right, or he'll come back with an explanation that they cleared up some misunderstandings and he now believes in the future direction of the team, blah blah blah.
For those who believe, no proof is necessary. For those who don't believe, no proof is possible
Does anyone really want Carson back anyway? He's simply not very good.
He should come back and force Brown to make a decision.
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text:
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Originally written on Fox Sports Ohio | Last updated 2/22/13
GOODYEAR, Ariz. When Devin Mesoraco sorts through a pile of personal DVDs, hell throw away any showing him dancing with a lamp shade on his head, any showing him as a toddler in diapers and any showing him batting in a major-league game last season. For the 24-year-old Cincinnati Reds catchers, it was a most forgettable year .212 over 54 games and 165 at-bats. And extremely few of those at-bats came in September when he mostly sat in the dugout and watched the baseball world pass by. Yes, I watched a lot of video, said the No. 1 pick out of Punxutawney, Pa. in 2007. I didnt watch last year, but past video when I was going good and I watched different guys who have similar swings throughout the league to see what works for them and what I need to do. He watched Josh Willingham from the Minnesota Twins and Aaron Hill from the Arizona Diamondbacks, so that what works for them I might be able to mold into my swing. Im just trying to get back the swing I had in the past, he said. L...
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