Treatment of raynaud's phenomenon using botulinum toxin type b
|発明の名称 （英語）||Treatment of raynaud's phenomenon using botulinum toxin type b|
|発明の概要（英語）||An effective amount of botulinum toxin type B is administered to a subject in need thereof for treating Raynaud's phenomenon. Botulinum toxin type B may be in a form of an injection, and may be locally administered to a disease affected site, in a dose of 200 to 400 units per disease affected site.|
Raynaud's phenomenon is a phenomenon in which the color tone of fingers suddenly changes, as a result of arteriolar spasm in fingers, transient ischemia in the distal portion, and subsequent reperfusion. This phenomenon is induced by cold stimulation or psychological stress. The arteriolar ischemia-reperfusion in fingers causes triphasic changes in the color into white (ischemia), purple (cyanosis), and red (reperfusion). Since the phenomenon accompanies pain and numbness for a long period, the daily life of the patient is seriously affected, leading to a remarkable decrease in QOL. Due to decreased peripheral blood flow, circulatory disturbance easily occurs, and even a mild injury is likely to cause an ulcer. Fingertip ulcers due to Raynaud's phenomenon are often intractable. If bacterial infection occurs, the ulcer may be enlarged, and osteomyelitis and arthritis may occur, resulting in amputation of digits in some cases. Since bacterial infection of a wound may cause sepsis to affect survival prognosis, appropriate treatment at an early stage is important.
Common examples of current pharmacotherapy for Raynaud's phenomenon include use of a drug having a vasodilator action or antiplatelet action such as a vitamin E preparation (tocopherol nicotinate etc.), calcium antagonist (Nifedipine etc.), prostaglandin preparation (oral drug: limaprost or beraprost; injection: alprostadil), scrotonin antagonist (sarpogrelate hydrochloride), or platelet aggregation inhibitor (cilostazol or dipyridamole); infusion of an anticoagulant argatroban; and use of an endothelin receptor antagonist (bosentan). However, these oral drugs and infusions are poorly effective.
In recent years, there were some reports on remarkable amelioration of symptoms of Raynaud's phenomenon by local injection of botulinum toxin type A (Non-patent Documents 1 to 6). Botulinum toxin is a neurotoxin produced from Clostridium botulinum. Botulinum toxin is incorporated from nerve endings by endocytosis, and cleaves a specific site of a protein complex which is directly involved in fusion of synaptic vesicles to the presynaptic membrane (fusion complex). This causes inhibition of Ca-dependent acetylcholine release from synaptic vesicles. As a result, neuromuscular transmission is inhibited and muscle paralysis is induced. Depending on the type of the toxin, the protein cleaved varies. Botulinum toxin type B specifically cleaves VAMP (vesicle-associated membrane protein: synaptobrevin: one of the synaptic vesicle membrane proteins), and botulinum toxin type A specifically cleaves SNAP-25 (synaptosome-associated protein of molecular weight 25,000 dalton: one of the membrane-bound proteins present in the presynaptic membrane), to suppress acetylcholine release from the peripheral cholinergic nerve endings, causing inhibition of neuromuscular transmission, resulting in muscle paralysis. Thus, although these toxin types have different mechanisms of suppression of acetylcholine release, they are considered to have the same inhibitory action on neuromuscular transmission.
In Raynaud's phenomenon, suppression of arteriolar spasm (transient contraction) in digits and improvement of peripheral circulation can be expected by allowing botulinum toxin to block signal transduction to vascular smooth muscle. Further, amelioration of pain and numbness in Raynaud's phenomenon can be expected by allowing botulinum toxin to suppress neurotransmitters (for example, substance P) that cause the pain and the numbness.
The inventor of the present invention carried out an investigator-initiated independent study in which botulinum toxin type A was injected into the base of a finger in each of 10 patients with Raynaud's phenomenon. One finger exhibiting Raynaud's phenomenon was selected, and 10 units of botulinum toxin type A was subcutaneously injected at each of the left and right on the base of the finger (20 units in total). Four weeks after the administration, severity (frequency, color, duration, and the like) of Raynaud's symptoms according to the Raynaud's score, as well as pain and numbness (VAS), were significantly lower than those before the administration, and the effect could be continuously observed for 16 weeks. The degree of recovery of the skin temperature during the 20-minute period immediately after application of cold water load was significantly higher at Week 4 compared to that before the administration. Total epithelialization of fingertip ulcers (5 cases) was achieved by Week 12. In all cases, no side effect such as muscle weakness or pain was found. By this independent study, safety and effectiveness of local injection of 10 units of botulinum toxin type A could be confirmed (Non-patent Document 7).
Botulinum toxin type B is known, for example, to be less expensive than type A by about 40%, to show the effect quickly, and to be highly effective for pain. However, there has been no report on a test of a therapeutic effect of botulinum toxin type B on Raynaud's phenomenon. Although Patent Document 1 discloses utilization of botulinum toxin for Raynaud's phenomenon, it was mainly utilization of type A, and the document does not show actual clinical data.
It has been thought that an almost equivalent effect can be produced when botulinum toxin type B is used in an amount (units) corresponding to the ratio A:B=1:20 to 40 (Non-patent Document 8), but the concentration at which a therapeutic effect is produced against Raynaud's phenomenon is not clear.
1. A method of treating Raynaud's phenomenon, comprising administering an effective amount of botulinum toxin type B to a subject in need thereof.
2. The method according to claim 1, wherein said botulinum toxin type B is in a form of an injection.
3. The method according to claim 1, wherein said botulinum toxin type B is locally administered to a disease affected site.
4. The method according to claim 3, wherein the dose of the botulinum toxin type B is 200 to 400 units per site.
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