text:
A novel and effective treatment of psoriatic arthritis is provided using biologically active forms of vitamin D analogues and metabolites, and preferrably 1,25-dihydroxy vitamin D3. The administration of vitamin D analogues and metabolites may be made orally, topically, or parenterally. Substitive improvements in both the arthritic condition and skin lesions result after approximately two month's treatment when effective dosages are provided and maintained.
1. A therapeutic method for treating psoriatic arthritis in an afflicted living subject as a distinct pathological entity different and distinguishable from the pathologies of psoriasis and rheumatoid arthritis, said psoriatic arthritis treatment method comprising the steps of:
obtaining an anti-psoriatic arthritis compound having the formula ##STR6## wherein the bond between positions 22 and 23 is a single or double bond; Y is H, F, CH3, or CH2 CH3 ;
Z is F, H, or OH;
Qa is CF3, CH3, CH2, CH2 OH, H, or OH;
Qb is CF3, CH2, or CH3 ;
X is H, F, or OH;
W22 is CH2, CH, or O;
W20 is CH;
M is a double bond or an epoxy group; and
administering an effective amount of said anti-psoriatic arthritis compound to the afflicted living subject.
2. A therapeutic method for treating psoriatic arthritis is an afflicted living subject as a distinct pathological entity different and distinguishable from the pathologies of psoriasis and rheumatoid arthritis, said psoriatic arthritis treatment method comprising the steps of:
obtaining an anti-psoriatic arthritis compound having the formula ##STR7## wherein the bond between positions 22 and 23 is a single or double bond; Y' is H, F, CH3, or CH2 CH3 ;
Z' is F, H, or X';
Qa is CF3, CH3, CH2, CH2 OH, H, or OH;
Qb is CF3, CH2, or CH3 ;
M' is a double bond or an epoxy group;
X' is H, F, or OR;
W22 ' is CH2, CH, or O;
W20 ' is CH;
R is hydrogen, straight or branched chainglycosidic residue containg 1-20 glycosidic units per residue, or is an orthoester glycoside moiety having the structure ##STR8## wherein A represents a glucofuranosyl or glucopyranosyl ring; R1 is hydrogen or an alkyl, aralkyl, or aryl group; and
R2 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glucosidic units per residue, provided that at least one R entity is a glycosidic residue or an orthoester glycoside moiety; and
administering an effective amount of said anti-psoriatic arthritis compound to the afflicted living subject.
3. The therapeutic method as recited in claim 1 or 2 wherein said compound is one selected from the group consisting of 1-hydroxy vitamin D3 ; 1-hydroxy vitamin D2 ; 1.25-dihydroxy vitamin D3, 1,25-dihydroxy vitamin D2 ; 24,25-dihydroxy vitamin D3, 24,25-dihydroxy vitamin D2 ; 25,26-dihydroxy vitamin D3 ; 25,26-dihydroxy vitamin D2 ; 1,24,25-trihydroxy vitamin D3 ; 1,24,25-trihydroxy vitamin D2 ; 1 ,24-dihydroxy vitamin D2 and D3 ; 24,24-difluro,1,25-dihydroxy vitamin D3 ; 26,27-hexafluoro,1,25-dihydroxy vitamin D3 ; 5,6-epoxy derivatives of vitamin D and its metabolites, and fluoro derivatives of 1 -hydroxy vitamin D and of 1,25-dihydroxy vitamin D.
4. The therapeutic method as recited in claim 1 or 2 wherein said compound is administered to the skin of the subject.
5. The therapeutic method as recited in claim 1 or 2 wherein said compound is orally administered to the subject.
6. The therapeutic method as recited in claim 1 or 2 wherein said compound is parenterally administered to the subject.
7. The therapeutic method as recited in claim 1 or 2 wherein said compound is administered to the subject at a concentration ranging from about 0.001-100.0 micrograms per kilogram of body weight.
This application is a continuation of application Ser. No. 320,028, filed Mar. 6, 1989, now abandoned.
The present invention is concerned with specific disease states and pathological disorders, and is particularly directed to therapeutically treating psoriatic arthritis as a singular disease and pathological state.
Although psoriatic arthritis is today recognized and as a distinct disease and pathological state based on its natural evolution, prognosis, and response to available modes of treatment, its consideration and present status as a distinct and separate clinical entity separate from either psoriasis and/or rheumatoid arthritis required both time and in-depth medical knowledge. In retrospect, the first detailed description of psoriatic arthritis appeared in the doctoral thesis of Charles Bourdillion [Psoriasis et Arthropathies, These de Paris, Volume 298, 1988]; and in several mid-19th century case reports of a unique relationship between psoriasis and arthritis published by 1904 [Menzen, J., Arch. Dermatol. Syph. 70:239-240 (1904)]. For about 30 years thereafter, the idea of psoriatic arthritis being an individual and discrete entity, as opposed to the coincidental occurrence of rheumatoid arthritis and psoriasis, was not generally accepted. Consequently, it was not until the demonstration of rheumatoid factor (RF) in the serum of most patients with typical rheumatoid arthritis in 1948 that the distinction became firmly established. The demonstration and meaning of rheumatoid factor (RF) divided inflammatory arthritis into seropositive and seronegative groupings. Consequently, the realization that the majority of patients with coincident psoriasis and arthritis were in fact seronegative, coupled with the introduction of specific and reliable criteria for the diagnosis of rheumatoid arthritis itself, then firmly established psoriatic arthritis as a separate and distinct disease entity [Rose et al., Proc. Soc. Exp. Biol. Med. 68:1-6 (1948); Ragan, C., Arthritis And Allied Conditions, (J.L. Hollander and D.J. McCarthy, editors) 8th Edition, Lee & Febiger, Philadelphia, 1972; Ropes et al., Bull. Rheum. Dis. 7:121-124 (1956); and Ropes et al., Bull. Rheum. Dis. 9:175-176 (1959)].
Today, rheumatologists have generally accepted the concept of distinctive clinical and radiological features for psoriatic arthritis; and employ them to identify subjects suffering from psoriasis alone and to distinguish those persons suffering from either seronegative or seropositive rheumatoid arthritis without psoriasis. A series of clinical characteristics suggestive of psoriatic arthritis have been developed and verified. Similarly, a detailed description and evaluation of the pathology, etiology, clinical features, patterns of disease onset and distribution, laboratory tests, and radiographic findings of psoriatic arthritic have been extensively investigated and documented. A comprehensive and well documented description of these diagnostic, clinical, and pathological developments and findings identifying psoriatic arthritis as a distinctive disease state and entity is provided by Robert N. Bennett in Arthritis And Allied Conditions, A Textbook Of Rheumatology, (Daniel J. McCarthy, Editor) Lee & Febiger, 11th Edition, 1989, pages 954-971, the text of which is expressly incorporated by reference herein.
Psoriatic arthritis can afflict humans with varying degrees of suffering and debilitation. Most patients with psoriatic arthritis have mild disease states affecting only a few joints and follow a rather episodic course. The range of symptoms and duration of disease may extend to forms considered mild, or acute, or even severe in the extreme cases. Many cases of mild disease are well controlled using aspirin or non-salicylic acid substitutes available without prescription as anti-inflammatory agents. In patients with only a few involved joints, corticosteroids injected locally, both into joints and into tendon sheaths have been effective. In the small number of patients (about 5%) developing severe, destructive inflammation that leads to marked disability, a number of different therapeutic approaches have been attempted. Photochemotherapy using oral 8-methoxypsoralenes, followed 2 hours later by photosensitization using ultraviolet light type A (PUVA) has been occasionally successful [Perlman et al., Ann. Intern. Med. 91:717-722 (1979)]. Similarly, high dose methotrexate administered parenterally [Black et al., JAMA 189:743-747 (1964)]has proven useful. More recent approaches and therapeutic compositions have included: chiral ester compounds of naproxen and naproxol [British Publication No. 2,204,868 printed Nov. 23, 1988]; the inhibiting of interleukin-1 production by monocytes [U.S. Pat. No. 4,778,806]; new substituted phenol compositions useful as anti-inflammatory and anti-arthritic compositions [U.S. Pat. No. 4,708,966]; a polyvalent non-specific immunostimulating vaccine comprising purified protein derivatives from rabies and snake venom [U.S. Pat. No. 4,657,761]; the treating of adrenal glands and affected joints daily with decimetre band electromagnetic fields [Soviet Union Patent No. 1,210,847 printed Feb. 15, 1986]; 6-alkoxy-2-naphthohydroxamic acid compounds useful as lipoxygenase inhibitors [U.S. Pat. No. 4,605,669]; 3-dimetblycarbamoylthyazolo-(4,5-a)-pyridine derivatives [British Patent No. 2,151,623]; pyrazolo-pyridine 3-carboxylic acid derivatives [British Patent No. 2,153,818]; immunosuppressive agents including tetrahydro-1,3-thiazine-4-one compounds [U.S. Pat. No. 4,352,929]; 2(4-(4-chlorophenyl)-benzelyoxy)-2-phenyl-acetic acid derivatives [U.S. Pat. Nos. 4,304,788 and 4,310,544]; and omega-hydroxy-carbonyl-alkyl substituted-dithio-carbanilates active as immunosuppressive agents [U.S. Pat. No. 4,166,866].
The mode and manner of developments and therapeutic treatments for effectively treating psoriatic arthritis thus is markedly different from the comparably intense investigations for effectively treating hyperproliferative skin disorders such as psoriasis itself. Exemplifying the degree of difference and approach has been the therapeutic development of using biologically active vitamin D analogues and metabolites as therapeutic agents.
The initial breakthrough in this field was the demonstration that topical application of radiolabelled 1,25-dihydroxy-7-dehydrocholesterol followed by phototherapy resulted in the detection of tritiated 1,25-dihydroxy vitamin D3 in the circulation. The topical application of such vitamin D analogues has been suggested as an effective method of therapy for diseases involving calcium, phosphorous, and bone metabolism problems [Holick et al., New England Journal Of Medicine 303:349-354 (1980); U.S. Pat. No. 4,230,701 and 4,335,210]. Subsequently, a specific biological function for 1 ,25-dihydroxy-vitamin D3 intracutaneously was demonstrated [Clemens et al., J. Clin. Endocrinol. Metab. 56:824-830 (1983); Morimoto et al., Arch. Dermatol. 125:231-234 (1989)]. In addition, it has been shown that the topical application of 1 -hydroxycholecalciferol, 1,25-hydroxychole-calciferol, 24,25-dihydroxycholecalciferol, and other derivative forms individually are directly effective agents in the skin of persons afflicted with contact dermatitis [European Patent Publication No. 0129003; see also Vitamin D Molecular, Cellular, And Clinical Endocrinology, Walter deGruyter & Company, Berlin, Germany, 1988, pp 300-319].
The most recent developments and therapeutic uses for vitamin D analogues and metabolites have been extended to include a variety of other clinical conditions including osteoporosis, rickets, rheumatism, and anti-proliferative agents effective against tumors. Representative of the variety and degree of these vitamin D developments are the following printed publications: European Patent Publication Nos. 250,755 (880107); 1184112 (860611); 205028 (861217); 85112679 (851007); and 87115258 (871019); Japanese publication No. 62004262 (870110); U.S. Pat. Nos. 4,341,774; 4,610,978; 4,613,594; 4,728,643.
It is abundantly clear, therefore, to clinical practitioners and research investigators in the art, that because of the major clinical and pathological distinctions and characteristics which identify and separate psoriatic arthritis from the related pathologies of psoriasis and rheumatoid arthritis individually, there has accordingly been no reason or expectation that the developments and uses of vitamin D analogues and metabolites might have any value or effectiveness on the clinical condition recognized distinctively as psoriatic arthritis. For this reason, and, because effective therapeutic treatments and compositions for psoriatic arthritis continue to be needed especially for those patients suffering from severe, debilitating forms, the possibility of applying vitamin D therapeutic treatments and compositions as therapies for psoriatic arthritis, stands as both unforeseen and unexpected developments and achievements of merit.
The present invention is a therapeutic method for treating psoriatic arthritis comprising the steps of: ##STR1## wherein the bond between carbon atoms C-22 and C-23 is a single or double covalent bond;
Y is H, F, CH3, or CH2 CH3 ;
Z is F, H, or OH;
Qa is CF3, CH3, CH2, CH2 OH, H, or OH;
Qb is CF3, CH2, or CH3 ;
X is H, F, or OH;
W is CH2, CH, or O;
M is a double bond or an epoxy group; and
administering an effective amount of the compound to the subject.
The present invention is a therapeutic method for oral, topical, and/or parenteral treatment of psoriatic arthritis using vitamin D2, vitamin D3, and biologically active analogues and metabolites of vitamin D. This therapeutic method utilizes active compositions of specified chemical formula which are administered in effective quantities to the afflicted subject for beneficial treatment. While the methodology is empirically demonstrated hereinafter to be especially effective in the treatment of acute or chronic psoriasis arthritis) it is intended for general use in therapeutically treating all degrees of this disease and pathological state. The present invention allows the user to employ quantities of biologically active vitamin D analogues and metabolites in concentrations up to 1,000.0 microgram (hereinafter "ug") preferably, but not exclusively, in a single dose before the subject retires at night to sleep. The timing of the therapeutical regimen for the afflicted subject is not critical.
Conventional knowledge and expectations in this art recognize that application of biologically active vitamin D analogues and metabolites to the subject may cause a substantial increase of calcium uptake in the blood of the subject and/or the release of increased quantities of calcium into the urine. Such side effects are directly attributable to the presence of ingested calcium-containing food (solid or liquid) in the digestive system of the subject at the time the therapeutic dose of biologically active vitamin D analogue or metabolite is administered. One mode of controlling such hypercalcemia and hypercalciuria is by administration of the vitamin D analogue or metabolite at a time when little or no calcium-containing food lies within the digestive system--that is, by fasting, by careful food discrimination, or by administration immediately before sleeping.
The biologically active vitamin D analogues and metabolites useful as therapeutic agents in the present invention are those embodying Formula I or Formula II below. ##STR2## wherein the bond between carbons C-22 and C-23 is single or double; Y is hydrogen, F, CH3, or CH2 CH3 ;
Z is F, H, or OH;
Qa is CF3, CH3, CH2, CH2 OH, OH, or hydrogen;
Qb is CF3, CH2, or CH3 ;
M is a double bond or an epoxy ##STR3## X is H, F, or -OH; and W is CH2, CH, or O.
When the compounds for Formula I have a double bond at position C-22, they are derivative of vitamin D2 ; whereas if the bond at that position is single, and there is no alkyl group at C-24, they are derivatives of vitamin D3.
Preferred embodiments of Formula I are those compounds derived from vitamins D3 or D2 ; 1-hydroxy-vitamins D3 or D2 ; 1,25-dihydroxy vitamins D3 and Db 2 ; 24,25-dihydroxy vitamins D3 or D2 ; 25,26-dihydroxy vitamins D3 or D2 ; 1,24,25-trihydroxy vitamins D3 and D2. Most preferred among these are 1-hydroxy-vitamins D3 or D2 ; 1 ,24-dihydroxy vitamin D2 or D3 ; 24,24-difluoro,1,25-dihydroxy vitamin D3 ; 26,27-hexafluoro,1,25-dihydroxy vitamin D3 ; and 1,25-dihydroxy vitamins D3 or D2 and the side chain fluoro derivatives of 1,25 (OH)2 vitamin D and 1 (OH) vitamin D.
The synthesis and purification of compositions embodying Formula I are known and conventional in this art. The epoxy derivatives of vitamin D3 are obtained as described in Jpn. Kokai Tokkyo Koho JP 58,216,178 [83,216,178], Dec. 15, 1983. Other derivatives are described in Vitamin D Molecular, Cellular, And Clinical Endocrinology, Walter deGruyter & Company, 1988, pp 300-319.
The fluoro derivatives are made or obtained as described in Shiina et al., Arch. Biochm. Biophy. 220:90 (1983).
Formula II is: ##STR4## wherein Y' is hydrogen, fluorine, methyl, or ethyl; Z' is F, H, or X';
Qa, Qb, and W have the same meanings as in Formula I;
M' is a double bond or an epoxy group;
X" is hydrogen, fluorine, or OR;
R is hydrogen, a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, or is an orthoester glycoside moiety. ##STR5## where A represents a glucofuranosyl or glucopyranosyl ring;
R1 is hydrogen or an alkyl, aralkyl, or aryl group and
R2 is hydrogen or a straight or branched chain glycosidic residue containing 1-20 glycosidic units per residue, with the proviso that at least one R entity is either a glycosidic residue or an orthoester glycoside moiety.
Such compounds are water soluble derivatives of Formula I obtained by attaching thereto glycosidic residues preferably by the reactions disclosed in Holick, U.S. Pat. No. 4,410,515. Alternative methods of solubilization comprise conjugating compounds for Formula I to glycosyl orthoester residues as disclosed in U.S. Ser. No. 607,117 by Holick et al., filed May 3, 1984. The disclosures of the aforementioned issued patent and patent application are expressly incorporated by reference herein.
Compounds embodying Formulas I and II respectively of the invention can be administered in any appropriate carrier for oral, topical, or parenteral administration. They can be introduced by any means that effects conditions of psoriatic arthritis in humans. The dosage administered will vary and be dependent upon the age, health, and weight of the recipient; the kind of concurrent treatment, if any; the frequency of treatment; and the nature of the therapeutic effect desired. Generally, daily oral dosage at bedtime of active compounds will be from about 0.001 micrograms/kg to 100 micrograms/kg. Normally, from 0.5 to 50.0 micrograms per day, in one or more oral administrations per day, is effective to yield the desired results.
If the vitamin D analogues and metabolites for Formulas I and II are to be applied topically, they can be admixed in a concentration from about 0.001 to 1,000.0 ug per gram of a pharmacologically inert topical carrier such as a gel, an ointment, a lotion, or a cream; and include such carriers as water, glycerrol, alcohol, propylene glycol, fatty alcohols, triglycerides, fatty acid esters, or mineral oils. Other possible topical carriers are liquid petrolatum, isopropylpalmitate, polyethylene glycol ethanol 95%, polyoxyethylene monolaurate 5% in water, sodium lauryl sulfate 5% in water, and the like. Materials such as anti-oxidants, bumectants, viscosity stabilizers, and the like may be added, if necessary. Also, the active vitamin D composition may be disposed within devices placed on, in, or under the skin; such devices include patches and implants which release the active material into the skin or body either by diffusion or by an active release mechanism.
Similarly, if the vitamin D analogues and metabolites of Formulas I and II are to be given parenterally, they will be prepared in sterile form; in multiple or single dose formats; and dispersed in a fluid carrier such as sterile physiological saline or 5% dextrose solutions commonly used with injectables. In addition, other methods of administration such as transdermal applications can be advantageously employed as well.
The unique and unexpected benefits of therapeutically administering biologically active vitamin D analogues and metabolites conforming to either of Formulas I or II respectively is demonstrated by the individual case histories of the human patients identified hereinafter.
As part of a study being conducted at the Boston University Clinical Research Center at the School of Medicine for the experimental treatment of psoriasis, a 56 year old male patient was treated in an open, uncontrolled trial--initially for psoriasis over a period of 1 calendar year. Prior to beginning the trial treatment at the Center, the subject (over a three month period of time) discontinued medications of any and every kind previously used to treat his affliction except for orally taking a multi-vitamin supplement once a day. Recognizing that the trial treatment was intended initially for treating psoriasis alone, the subject's skin lesions were treated topically with 1,25-dihydroxy vitamin D3 and the treatments monitored individually over a two week time period. The topical administration was made using a petroleum based composition and employed an initial dosage of 3.0 micrograms of 1,25-dihydroxy vitamin D3 per total weight of 1.0 grams of petroleum base, each administration to be made over a two week duration. Concurrently, 0.5 micrograms of 1,25-dihydroxy vitamin D3 was taken orally by the subject once a day before bedtime. The oral dosage was increased incrementally over a four month time by individual increases of 0.25 micrograms every two weeks until the maximum dose of 2.0 micrograms of activated vitamin D3 was orally taken each night. After the sixth month of treatment, the topical dose administered was also increased from 3.0 micrograms to 15.0 micrograms per gram of petrolatum.
By the end of the fourth month of the trials, the subject experienced and observed an unexpected and beneficial side-effect. In addition to being afflicted with psoriasis, the subject male had been previously diagnosed as having arthritis, a condition present since the age of 25. The arthritic condition was present in the ankles, feet, toes, knees, elbows, hands, and left shoulder of the subject. In particular, the left shoulder condition was quite severe and prevented the subject from raising his arm above shoulder length. The unexpected and beneficial side-effects of this therapy were noticed by the subject at the end of the fourth month of treatment during which the subject found he had complete mobility of the left shoulder without any accompanying pain as a result of the oral administration. By the fifth month of treatment, the subject found he was able to freely exercise. Such exercise included walking approximately 1.5 miles daily within about 25 minutes time; and being able to bicycle about 3 miles within 17-18 minutes every other day. By the end of the sixth month of treatment, all other arthritic areas in the body were markedly and substantially improved with major reductions in pain and increased joint mobility; this improvement was so enhanced that at the end of the seventh month of treatment, the subject was able to wear normal, penny-loafer style shoes and walked without discomfort for the first time in over 20years. At the end of the full calendar year of treatment, the subject had significant clearing of skin lesions as the result of topical application. Some treated areas had completely healed with no visible trace and no subsequent occurrence of lesions; other skin areas were completely cleared but required periodic additional topical treatment to remain lesion free. A very few skin areas, most notably on the toes, were cleared of lesions but had resisted complete healing even at the maximum dosage levels then being topically administered.
The subject male also had been routinely monitored on a monthly basis using a Chem 20 profile and a urine test for presence of calcium. Over the one year trial period, the calcium levels remained within normal limits.
Subsequent to the individual subject trial study, the Arthritis Center at the Boston University School of Medicine conducted an open, uncontrolled trial of 5 patients with active psoriatic arthritis using orally administered 1,25-dihydroxy vitamin D3 to determine if this had any beneficial effect on their condition; and, if so, to determine if there was a corresponding improvement in their skin lesions as well. The treatment of these 5 patients was conducted over a period of 3 calendar months and the subjects comprised both males and females with documented individual histories of psoriatic arthritis ranging from less than 1 year to over 25 years of affliction. Each patient was evaluated and individually traced, before treatment to establish a pre-treatment baseline of personal condition. Subsequently, each began a therapeutic regimen beginning with 0.5 micrograms of activated vitamin D3 which was incrementally increased every two weeks until a maximum dosage of 2.0 micrograms was taken orally once a day.
At the end of three calendar months of vitamin D3 therapy, one patient found no meaningful improvement and withdrew from the study because of ineffectiveness and an inability to achieve a maximum therapeutic dose secondary to hypercalciuria. Of the remaining 4 patients, each was able to achieve the maximum dosage of 2.0 micrograms taken orally, and 2 of 3 showed a marked improvement in their arthritic condition manifested by a decrease in tender joint count of greater than 80% improvement. Each person also showed improvements in skin lesions but the degree of skin lesion improvement was not correlatable with the degree of arthritic improvement as such. The 2 subjects for whom the activate vitamin D3 therapy was effective have continued using the orally administered 1,25-dihydroxy vitamin D3 therapeutic mode of treatment long term and achieved substantial improvement at the continuing dosage level of 2.0 micrograms taken orally once a day.
A male subject aged 35 years with a history of psoriatic arthritis in both elbows for over ten years, was treated topically with 1.0 micrograms of 1,25-dihydroxy vitamin D3 dispersed in 10 grams of petroleum base. After two months of topical treatment, the male patient observed and experienced significant improvement in both his skin lesions and his arthritis.
These case histories individually and cumulatively empirically demonstrate and document the ability of activated vitamin D analogues and metabolites to be therapeutically effective in the treatment of psoriatic arthritis. The case histories demonstrate effective improvement and therapeutic results when the mode of treatment is oral or topical, or oral and topical treatment concurrently. However, it is expected and deemed that the best and most effective mode of treatment is by oral administration of the activated vitamin D analogue and metabolite in an amount of at least 0.5 micrograms taken once as a single dose on a daily basis; however, because of the oral administration preferred route, it is most desirable to reduce the side-effects of calcium build-up (hypercalcemia and hypercalciuria) by administering the active vitamin D compositions immediately prior to bed time in the evening.
The present invention is not to be restricted in form nor limited in scope except by the claims appended hereto.
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In its recent third quarter reporting, the company posted a 7% decrease in user engagement and a slide in growth of monthly active users: growth increased 23%, but that was down from 24% posted in the second quarter of 2014 and down from 38% reported in the third quarter of 2013. Consequently, Twitter's stock price has fallen in recent weeks, and the S&P downgraded Twitter's debt to junk status, describing the company's risk as significant. So, how did it come to this? Where did Twitter go wrong, and, more importantly, what can it do to right the ship and recruit new users?
Dec 01, 2006
Broadband Enterprises, an online video sales and syndication company, has announced an agreement with The HealthCentral Network, an online resource for health and wellness information. Made up of a collection of consumer-oriented health and wellness destinations, The HealthCentral Network takes a Web 2.0 approach for community networking. The company's library of online video featuring medical advice and news from America's Doctor, Dr. Dean Edell, and medical news reports from Ivanhoe Broadcast News and other sources, will be syndicated through select websites from Broadband Enterprises' online website network. This agreement is designed to allow Broadband Enterprises to fill a programming niche in their content offerings to the advertising community. The syndication agreement will allow Broadband Enterprises to deliver HealthCentral Network's programming to new audiences as well as monetize the site's collection of rich media through pre and post roll advertising sales.
(www.broadbandenterprises.com; www.thehealthcentralnetwork.com)

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Log cabins longmountaincentre
Log cabin | 6 bedrooms | sleeps 15
|Key Info
The home of Jackie Gavyn and family, Long mountain centre offers you a self-catering holiday with a difference; a real home from home close to a area of outstanding natural beauty in the heart of the Shropshire hills
Our traditional family-run centre on the edge of the Shropshire Area of outstanding natural beauty and right on the Welsh border is situated between Shrewsbury and Welshpool with the Historic town of Oswestry only 30mins away and 1 hrs drive to Chester Approximately1 1/2 hours from Manchester, Birmingham and Liverpool Airports, a 1½ hour drive to the spectacular welsh coastal areas. The nearest train station is approx 6 miles away at Welshpool if you want to reduce your carbon footprint and leave the car at home
A great rural retreat holiday
An ideal central base from which to explore the wonders of the South Shropshire hills and the welsh border towns and to meet up with friends and family. Stay with us in our luxurious self-catering log cabins with stunning views of the beautiful and dramatic Shropshire and welsh border countryside. An idyllic rural retreat, where you can relax and unwind from the stresses and strains of everyday life. Why not come to rural Shropshire and try our fantastic accommodation, and "hospitality second to none" for yourself.
Lavender, Honeysuckle Bluebell Poppy Iris and Violet cabins can be rented together to sleep up to 30 people. They are fully equipped with everything you could possibly need for a relaxing holiday including bed linen, tea towels, fridge, TV with DVD.
|Sleeps up to 15, 6 bedrooms
|Nearest beach
|Borth 75 km
|Will consider
|Corporate bookings, Short breaks (1-4 days)
|Car advised
|Nearest Amenities
|3 km
|Nearest travel links
|Nearest airport: Birmingham, Nearest railway: Welshpool 10 km
|Family friendly
|Great for children of all ages
|Pets welcome, No smoking at this property
Features and Facilities
|Internet access, DVD player
|Central heating, TV, Wi-Fi available
|Kettle, Toaster, Iron
|Cooker, Microwave, Fridge, Freezer
|6 bedrooms, 6 bathrooms of which 6 Family bathrooms
|Single beds (8), Double beds (3), Cots (2), Dining seats for 16, Lounge seats for 15
|Linen provided, High chair
|Balcony or terrace
|Secure parking
|Further details outdoors
Situated close to the border with Wales, the surrounding area is one of both outstanding natural beauty and historical interest. For those who enjoy walking and the great outdoors, we are a short distance away from the Stiperstones National Nature Reserve, famous for the "Devil's Chair" at its rock-strewn summit. Visit the newly-opened Lead mines at Snail beach.
ideal for walking cycling horse riding
Great deals for Nov DEC jAN
free wifi
|Further details
Click through to our website at the bottom of the page for booking conditions.
Reduced rates for group bookings
Long mountain
Unique private and secluded romantic cabins
If you long for peace and quiet ,privacy amidst beautiful scenic countryside ,in a magical location, read on.
Long mountain centre is hidden away on a secluded South Shropshire hillside ,Wildlife is in abundance, buzzards,red kite owls skylark and curlew often visit
Local pubs and hearty meals. Riding facilities only 50yards away come and explore the shropshire hills on horseback pony trekking for the more adventuress and Long mountain centre has stables and grazing for those who wish to bring their own horses .The location is ideal for walking cycling
Set in 80 acres with many walks and rides Long mountain centre offers a magnificent rural setting in a calm secluded position, offering peace quiet and complete escapism from the mad rush of everyday life. Relax and watch the badgers and rabbits playing on the hill or catch a glimpse of a fox in the woods.
The cabins have , a double bed room and a twin or triple room. It has toilet, shower and sink and separate kitchen, gas cooker, full gas central heating electric and a television, dining table comfortable leather sofas Bed linen, towels, electric and water are all included. Well behaved Dogs are welcome.
Take drinks on the decking balcony , which gets the sun all day long, whilst relaxing and breath in the countryside enjoying the peaceful wonderful setting. All in all this is a wonderfully quiet peaceful relaxing break in the wonderful Shropshire countryside .
Postcode Sy59ry
Minimun stay is 2 nights.
Continental Breakfast pack - from £20
Start your well deserved break with a freshly baked continental breakfast all delivered to your cabin before your arrival. Includes: 1 x teabags 1 x coffee 1 x bag of sugar 1 x white loaf 1 x butter 1 x litre semi-skimmed milk 4 x fresh baked butter Croissants 1 x locally sourced jam 1 x litre pure orange juice
free wi fi
CONTACT US for more details
The Heart of England/Peak District
To the South-west we look onto the ancient hills of the Stiperstones and Callow Hill where famous local authoress, Mary Webb, got inspiration for her books. Offer places of interest include the Long Mountain with the derelict site of Caus Castle and the historical Rowley fort
Close to a network of existing and permissive bridleways, cycle routes and walks linking up with other slow travel venues offering pony trekking on site. Feel free to bring your own horses - livery rates apply.
Situated close to the border with Wales, the surrounding area is one of both outstanding natural beauty and historical interest. For those who enjoy walking and the great outdoors, we are a short distance away from the Stiperstones National Nature Reserve, famous for the "Devil's Chair" at its rock-strewn summit. Visit the newly-opened Lead mines at Snail beach.Why not try your hand at shooting on the nearby Minsterley Ranges.
Or quad trekking at Border quad trekking just a few miles away or even a golf driving range
There are also a number of castles to explore, from the fantastic Powys, Shrewsbury and Chirk Castles to the ruins at Montgomery, Ludlow and Stokesay. 2 miles from Stokesay at Craven Arms is the highly acclaimed Shropshire Hills Discovery Centre where you can see the famous Shropshire Mammoth and experience a simulated balloon flight. Nearby is the Acton Scott Historic Working Farm, an ideal day out for both adults and children. pony trekking on site
* Shrewsbury flower show
* West midland show
* Ludlow food festival
* Offas dyke
* Welshpool
horse riding
Availability Your dates are available
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9 Nov 2014
"Excellent stay, beautiful cabin, amazing surroundings!"
My friends and me booked a night in one of the cabins for a reunion get-together, and we were all thoroughly impressed with the standard of the facilities. Not only are these cabins in a beautiful loc… More
30 Jul 2014
"Excellent stay!"
Myself and my partner got a great deal of eBay for this! Jackie was a really nice lady and went out of her way to help us... Especially when we ran out of lemonade for our pimms! The place is excellen… More
23 Feb 2014
We had a wonderful family break in two adjoining cabins. The log cabins are very comfortable, spacious and have fantastic views. Jackie and her colleagues were extremely friendly and helpful and my grandson thoroughly enjoyed brushing and leading Edward the miniature Shetland pony.
2 Jan 2014
"A perfect weekend"
We hired three cabins, for a total of six adults and six children. It was a weekend break celebrating my 40th birthday. The cabins were lovely, very cosy and big enough for us all to spend the evening… More
30 Jul 2013
"Absolutely Ideal Location"
WOW!! what a brilliant and beautiful location. We hired all 3 cabins for a long weekend, they were clean and well stocked with freshly laid eggs on arrival! There are horses kept in the field right in… More
you where all very welcome hope you can come back soon
1 Sep 2012
"Excellent accomodation in a lovely setting."
With ages ranging from 5 to 70 success was far from guaranteed. However the stunning setting and the close proximity of the friendly horses impressed everyone, even the four teenagers. In fact the pony trekking was the highlight of most people's stay.
The tranquillity and lovely view made many of us reluctant to leave the site. Nevertheless we managed a visit to Portmeirion, white water rafting at Llangollen, a climb to the top of Snowden and much more.
Evenings were spent cooking on the barbeque and in the kitchens, then gathered on the veranda of the middle cabin to discuss the day's activities. I have rarely heard so much laughter and conviviality.
The cabins were exactly as described, comfortable and well equipped.
A very memorable holiday that I am sure we will all talk about for a long time .
The highest praise I can give is that everyone wants to come back.
so glad you and your family enjoyed your stay with us
24 Apr 2012
"Fantastic Place For a Family Break!"
We booked all 3 cabins for my Mum and Dad's Golden Wedding Anniversary, we arrived to glorious sunshine (The forecast had been for rain all weekend?) and after unpacking we had a chance to take i… More
so glad you and your family enjoyed your stay with us hope some or all of you can make it back to Long mountain centre so time
12 Jan 2012
"Home away from home."
The wooden cabins are really really nice and i was pleasantly suprised, with the interior size. The location is well out the way from everything and very secluded. Once we arrived and unloaded the cars the cabins were just a short walk from the car park.
Once we were bedded in we shut the paddock gate the place was ours. We let the dogs out of the balcony doors and the kids followed and just played for hours in a safe, clean and happy environment.
We booked the 3 cabins over the new year period and this was a brilliant change of pace to bring the new year in.
There was no wifi and the telephone reception was very poor.
18 Jul 2011
"Fresh air, plenty of space, stunning views and comfortable cabins"
14 of us hired out all 3 cabins. We had a great time messing about on the ample lawns surrounding the cabins, the children even running their own mini olympics! Pony riding was very enjpyable for those who wanted (steady mounts all round, well supervised), as was the match on telly seen from the leather sofas for others! 2 Big BBQ's provided were appreciated. Jackie and Gavin were supportive but not intrusive. We'll be back again (again).
12 Jul 2011
My friends and I rented out all three cabins for my 30th birthday weekend. The location is beautiful and the cabins were lovely too.
We all agreed that we would return for another weekend in the future.
The host was excellent and there wasn't one fault that anyone could find. Best birthday ever!!
thank you we are so glad you enjoyed your birthday it was great to have you staying and thank you to you and your group for respecting the cabins and leaving them so clean and tidy
come back soon
This advert is created and maintained by the advertiser; we can only publish adverts in good faith as we don't own, manage or inspect any of the properties. We advise you to familiarise yourself with our terms of use.
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Jackie T.
- 5 Years listed
90% Response rate
Calendar last updated:27 Nov 2014
Based in United Kingdom
- English
Payment accepted
Credit cards accepted
- Landline
- +44(0)1743891274
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- 447813008486
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Cyclist, 32, dies in hospital following crash with 'car racing down Commercial Road'
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Published: 30 January 2013
An official report today cleared oil giants of ripping off motorists — and blamed the cost of motoring on sky-high fuel taxes instead.
The Office of Fair Trading declared competition was "working well" in the petrol and diesel industry, and said that if VAT and fuel duty were stripped out of prices, the UK would enjoy some of the cheapest road fuel in Europe.
Petrol has soared from 76p a litre in 2003 to 136p last year, but the OFT said almost all the 60p rise was down to oil wholesale prices and tax rises. For every £30 paid at the till for petrol, about £18 goes on fuel duty and VAT. Only £12 pays for the fuel, including £1 for the retailer.
Clive Maxwell, OFT chief executive, said: "Our analysis suggests competition is working well, and rises in pump prices over the past decade or so have largely been down to increases in tax and the cost of crude oil." Peter Carroll, founder of the FairFuel campaign, said drivers pay 80p a litre just in taxes. "The only silver lining in this disappointing report is it refocuses attention on the dreadful levels of taxation."
Others were angry the OFT decided no further inquiry was needed into the market. TV presenter and campaigner Quentin Willson said: "Every motorist in the land knows savings are not being passed on to consumers."
However, the OFT said there was "very limited evidence" of so-called rocket-and-feather pricing — where pump prices soar when the wholesale price goes up, but drift down slowly when prices fall.
It identified concerns including a lack of pricing information on motorways, but it said the market was healthy, and praised the big four supermarkets for driving down petrol prices.
That contrasted with energy minister Baroness Verma who told the Lords yesterday that reports of another round of petrol price increases were "worrying". She added: "Perhaps we should look — I was going to say at how we make it easier for consumers not to be ripped off at the petrol pump, but I shall not — at how we can encourage retailers to pass down a drop in price if it comes through the crude oil route."
In Whitehall, the OFT report was being called "wishy-washy". Harlow Tory MP Robert Halfon who led a Commons campaign to stop the annual rise in fuel duty, said high fuel prices "are crushing families across Britain".
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"Star Trek" and "Go On" star John Cho is a dad again!
According to People, the actor and his wife Kerri Higuchi recently welcomed a baby girl.
The details surrounding the actor's new baby are still being kept private by the couple.
The 40-year-old actor is dad to a 4-year-old son. John and Kerri wed in 2006.
John, who made his mark in the "Harold and Kumar" films, is currently starring in "Identity Thief" and will next be seen on the big screen in May in "Star Trek Into Darkness."
-- Jesse Spero
Copyright 2014 by NBC Universal, Inc. All rights reserved.This material may not be published, broadcast, rewritten or redistributed.


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Wilh. Wilhelmsen Holding ASA reports profit growth lifted by high total income and operating profit in the shipping segment.
Operating profit amounted to USD 106 million for the first quarter of 2012, up 84% year over year from USD 58 million in the corresponding quarter of 2011. Total income increased 26% and ended at USD 946 million (USD 753 million).
"With all time high revenue in the shipping segment, the group's earnings improved considerably year over year. Despite a seasonally weaker quarter, we also recorded a positive development quarter on quarter," says Thomas Wilhelmsen, group CEO of WWH. "Our shipping activities benefitted from favourable trade balance and a sound balance between auto and high and heavy volumes. Introduction of new and larger vessels contributed to more efficient operations with a positive effect on earnings," says Wilhelmsen.
The group's maritime services segment continued to show a positive development.
"Sales to the merchant fleet have improved and we have increased the number of vessels on management. This contributes to increased total income both quarter on quarter and year over year. The activity level related to newbuildings and retrofits have been slower, with reduced income albeit an increase in order reserve," says Wilhelmsen.
"Following the withdrawal of the ballast water treatment system earlier this year, the operating profit for the segment was negatively impacted by a loss of USD 15 million. Adjusted for the loss, the maritime services segment recorded a 60% year over year increase in operating profit. The profit improvement plan accomplished last year has lifted the segment back to a 9% operating margin."
Net financials for the quarter amounted to an expense of USD 9 million (expense of USD 23 million), positively affected by a USD 10 million gain from investment management (gain of USD 4 million) and a gain of USD 2 million from sale of 12 million shares in Qube. WWH owned approximately 8.4% of Qube by the end of the quarter.
Net profit after tax and minority interest was USD 69 million (USD 22 million) for the first three months of 2012, an increase of USD 10 million from the fourth quarter of 2011.
The annual general meeting held on 26 April approved a dividend of NOK 3.50 per share paid on 9 May. The group intends to pay dividend semi-annually.
The board maintains a cautiously optimistic view on medium term prospects, but underlines that prospects will depend on the development of the world economy.
W&O, a global supplier to the marine and upstream oil and gas markets for pipe, valves and fittings, valve automation and engineered solutions, has partnered with
Fednav Limited held a reception on board one of its vessels, the Federal Mayumi, at the Port of Cleveland yesterday to celebrate a trio of anniversaries: the 70th
Karl Senner, LLC (KS) has reached a new strategic representation agreement with Electronic Power Design (EPD).
Karl Senner, LLC now represents EPD in the United States marine and offshore Markets.
MacGregor, part of Cargotec, has secured a deck equipment contract from New Times Shipyard in China for Intership Navigation Co Ltd.'s three new 36,500 dwt laker-class bulk carriers.
Seacor Marine is building ever larger and more powerful mono-hull crew/supply boats. The first of these to be delivered is the 202x34-foot Alex F. McCall with some very impressive statistics.
It isn't always about the rate.
In a robust boatbuilding market – like the one we see now – even the most successful, financially stable operators need to borrow.
Keppel AmFELS LLC, a wholly owned US subsidiary of Keppel Offshore & Marine Ltd (Keppel O&M), has delivered the jackup rig, Coatzacoalcos, to Mexico's Central Panuco S.
Woodside advises that it has entered into a contract for an exclusive Reconnaissance Licence
(RL) with the Office National des Hydrocarbures et des Mines, the
Companies operating in the North Sea require a cultural shift to make the most of the its potential, according to a new report from Deloitte, the business advisory firm.
OW Tanker, a unit of bankrupt OW Bunker and owner of its marine fuel supply ships, has been taken over by a newly-created company, the fleet manager told Reuters on Wednesday.
A Creative Combination for Financing Inland Waterways Infrastructure
Earlier this year, the U.S. maritime industry in general, and the inland waterways industry in particular,
Classification society ClassNK has granted approval to the design of the new 28AHX-DF dual-fuel engine developed by Niigata Power Systems Co., Ltd. The new engine
Overnight operations are certainly not unusual on America's inland waterways, but that doesn't make them any less hazardous. Onboard activities that seem so straightforward
The CMA CGM Group has acquired the German shipping company Oldenburg-Portugiesische Dampfschiffs-Rhederei GmbH & Co. KG (OPDR), CMA CGM founder, chairman and CEO Jacques R.


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Biotech Covered Call Picks (SRPT,NAVB,AMRN,DNDN,ALXA)
What's a Covered Call?
The covered call is a strategy where an investor writes a call option contract (sells an option) while at the same time owning an equivalent number of shares of the underlying stock.If this stock is purchased simultaneously with writing the call contract, the strategy is commonly referred to as a buy-write.
While you may have heard that trading options is risky business, covered calls are actually a very conservative strategy, and most brokerages even allow retirement IRA accounts to write covered calls.
Sarepta Therapeutics Inc (SRPT) is currently trading at $14.92. Its 52 week range is between $2.6 and $16.32.
Navidea Biopharmaceuticals Inc (NAVB) is currently trading at $3.8. Its 52 week range is between $2.05 and $4.77.
Amarin Corporation PLC (AMRN) is currently trading at $14.64. Its 52 week range is between $5.99 and $15.96.
Dendreon Corp (DNDN) is currently trading at $4.98. Its 52 week range is between $4.17 and $17.04.
Alexza Pharmaceuticals Inc (ALXA) is currently trading at $4.55. Its 52 week range is between $2.55 and $14.8.
MASTERY Bottom line:
There are pros and cons to writing covered calls. In theory, this strategy will out perform outright stock ownership if the stock price declines, remains the same, or slightly increases in price. The principal disadvantage of this strategy, on the other hand, is that profit potential can be limited if the underlying stock price advances sharply.
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The Changeling—EPISODE 02
Available on Kindle NOW.
Matt Zero has been knocked out cold, and the half-animal changelings who bashed in his head want to finish the job and execute the FooL for the one crime that Betsey is no longer guilty of: being human. But both sides think Betsey is their enemy, and before she can come to anyone's rescue (including her own), she's going to need to figure out a way to transform from her wolf form and back into a human body.


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Talk:Original Floater
From Wikipedia, the free encyclopedia
|WikiProject Fisheries and Fishing
|(Rated Start-class, Mid-importance)
I just created this page (as it had a red link in another article, Rapala) and this was honestly only the second article I have created on here, so I am still getting it down how it should be done. I have redone this article basically from scratch, removing anything that I thought probably could have been taken as advertisement. So I'll be more careful next time. Michael 03:56, 11 April 2007 (UTC)
Deletion request?[edit]
This page was marked for speedy deletion. I removed the tag. Here is why this product is notable:
- This same lure has been produced for 71 years - a classic.
- This lure is the basis for most modern wobblers. They are either copies or made by Rapala.
For reference, you can see the German Wikipedia: de:Wobbler (Angeln). It claims that the first wobler was developed by Lauri Rapala in 1936.
-- Petri Krohn 05:29, 11 April 2007 (UTC)