1. A method of producing analgesia in a subject comprising administering a synergistic combination of an effective amount of a selective inhibitor of the neuronal norepinephrine transporter and an effective amount of an analgesic agent, wherein administration of said synergistic combination produces analgesia in said subject; wherein the selective inhibitor of the neuronal norepinephrine transporter comprises the following sequence of amino acids:
(SEQ\u2003ID\u2003NO:\u20035)
Xaa0\u2003Xaa1\u2003Xaa2\u2003Xaa3\u2003Xaa4\u2003Cys1\u2003Cys2\u2003Gly\u2003Tyr\u2003Lys\u2003Leu
Cys3\u2003Xaa8\u2003Xaa9\u2003Cys4,
where
Xaa0 is selected from Tyr, Trp, hPhe and a deletion;
Xaa1 is a deletion;
Xaa2 is selected from Arg, Ala, Asn, Lys, Phe, BHK, Orn, DArg, Nle, DLys, DMK, DAsn, Thr, ABZ, Nap, Cit, Val, Tyr, Trp, pGlu, DpGlu, Gln, Thr, Glu, Asp and a deletion;
Xaa3 is selected from Gly, Asp, and Ala;
Xaa4 is selected from Val, Leu, Nle, Ile, and Ala;
Xaa8 is selected from His, Arg, Trp, Nal, and a deletion;
Xaa9 is selected from Hyp, Pro, Ala, Tic, Pip, MeY, DMD, Phe, THZ, Glu, Nle, Tyr, and a deletion; and
wherein Cys1 is connected to Cys4 and Cys2 is connected to Cys3 by disulfide bonds.
2. A method according to claim 1 wherein Xaa8 is Arg or His.
3. A method according to claim 1 wherein Xaa9 is Hyp or Pro.
4. A method according to claim 1 wherein Xaa2 is selected from the group consisting of pGlu, Glu, Gln, Asn and Asp.
5. A method according to claim 1 wherein Xaa4 is selected from the group consisting of Leu, Nle, Ala, Ile and Val.
6. A method according to claim 1 wherein the selective inhibitor of the neuronal norepinephrine transporter comprises the following sequence of amino acids:
(SEQ\u2003ID\u2003NO:\u20036)
pGlu\u2003Gly\u2003Val\u2003Cys1\u2003Cys2\u2003Gly\u2003Tyr\u2003Lys\u2003Leu\u2003Cys3\u2003His
Hyp\u2003Cys4
wherein Cys1 is connected to Cys4 and Cys2 is connected to Cys3 by disulfide bonds.
7. A method according to claim 1 wherein the analgesic agent is an opioid analgesic or an N-type calcium channel blocker.
8. A method according to claim 7 wherein the opioid analgesic is selected from the group consisting of propoxyphene, meperidine, hydromorphone, hydrocodone, morphine, codeine, methadone, fentanyl, sufentanil, alfentanil, oxymorphone, oxycodone, hydrocodeine, levorphanol, heroin, morphine-6-glucuronide, levallorphan, 6-monoacetylmorphine and tramodol; their pharmaceutically active salts and their optical isomers.
9. A method according to claim 1 wherein the analgesic agent is a \u03c9-conotoxin.
10. A method according to claim 9 wherein the \u03c9-conotoxin is selected from:
and derivatives and pharmaceutically acceptable salts thereof.
11. A method according to claim 1 wherein the effective amount of the inhibitor of the neuronal norepinephrine transporter is a sub-analgesic amount.
12. A method according to claim 1 wherein the effective amount of the analgesic agent is a sub-analgesic amount.
13. A method for the treatment or control of pain comprising administering a synergistic combination of an effective amount of a selective inhibitor of the neuronal norepinephrine transporter and an effective amount of an analgesic agent, wherein administration of said synergistic combination treats or controls pain in said subject; wherein the selective inhibitor of the neuronal norepinephrine transporter comprises the following sequence of amino acids:
(SEQ\u2003ID\u2003NO:\u20035)
Xaa0\u2003Xaa1\u2003Xaa2\u2003Xaa3\u2003Xaa4\u2003Cys1\u2003Cys2\u2003Gly\u2003Tyr\u2003Lys\u2003Leu
Cys3\u2003Xaa8\u2003Xaa9\u2003Cys4
where
Xaa0 is selected from Tyr, Trp, hPhe and a deletion;
Xaa1 is a deletion;
Xaa2 is selected from Arg, Ala, Asn, Lys, Phe, BHK, Orn, DArg, Nle, DLys, DMK, DAsn, Thr, ABZ, Nap, Cit, Val, Tyr, Trp, pGlu, DpGlu, Gln, Thr, Glu, Asp and a deletion;
Xaa3 is selected from Gly, Asp, and Ala;
Xaa4 is selected from Val, Leu, Nle, Ile and Ala;
Xaa8 is selected from His, Arg, Trp, Nal and a deletion;
Xaa9 is selected from Hyp, Pro, Ala, Tic, Pip, MeY, DMD, Phe, THZ, Glu, Nle, Tyr, and a deletion; and
wherein Cys1 is connected to Cys4 and Cys2, is connected to Cys3 by disulfide bonds.
14. A method according to claim 13 wherein Xaa8 is Arg or His.
15. A method according to claim 13 wherein Xaa9 is Hyp or Pro.
16. A method according to claim 13 wherein Xaa2 is selected from the group consisting of pGlu, Glu, Gln, Asn and Asp.
17. A method according to claim 13 wherein Xaa4 is selected from the group consisting of Leu, Nle, Ala, Ile and Val.
18. A method according to claim 13 wherein the selective inhibitor of the neuronal norepinephrine transporter comprises the following sequence of amino acids:
(SEQ\u2003ID\u2003NO:\u20036)
pGlu\u2003Gly\u2003Val\u2003Cys1\u2003Cys2\u2003Gly\u2003Tyr\u2003Lys\u2003Leu\u2003Cys3\u2003His
Hyp\u2003Cys4
wherein Cys1 is connected to Cys4 and Cys2 is connected to Cys3 by disulfide bonds.
19. A method according to claim 13 wherein the analgesic agent is an opioid analgesic or an N-type calcium channel blocker.
20. A method according to claim 19 wherein the opioid analgesic is selected from the group consisting of propoxyphene, meperidine, hydromorphone, hydrocodone, morphine, codeine, methadone, fentanyl, sufentanil, alfentanil, oxymorphone, oxycodone, hydrocodeine, levorphanol, heroin, morphine-6-glucuronide, levallorphan, 6-monoacetylmorphine and tramodol; their pharmaceutically active salts and their optical isomers.
21. A method according to claim 13 wherein the analgesic agent is a \u03c9-conotoxin.
22. A method according to claim 21 wherein the \u03c9-conotoxin is selected from:
and derivatives and pharmaceutically acceptable salts thereof.
23. A method according to claim 13 wherein the effective amount of the inhibitor of the neuronal norepinephrine transporter is a sub-analgesic amount.
24. A method according to claim 13 wherein the effective amount of the analgesic agent is a sub-analgesic amount.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A drilling apparatus comprising:
a drill rotatable about a center axis and capable of advancing and retracting along the center axis; and
a pressing unit for pressing a work in an advancing direction of the drill,
the drilling apparatus advancing the drill while rotating the drill about the center axis to form a hole in the work, in a state in which the work is pressed by the pressing unit, wherein
a pressing force applied on the work by the pressing unit is set to a predetermined pressing force on the basis of machining reaction applied to the drill from the work during drilling and the pressing force causing deformation of the work in the advancing direction of the drill, the predetermined pressing force being capable of suppressing deformation of the work and displacement of the drill due to the machining reaction, the machining reaction and the pressing force being calculated in a drilling test performed in advance.
2. The drilling apparatus according to claim 1, further comprising a pressing force detector for detecting a pressing force applied on the work by the pressing unit.
3. The drilling apparatus according to claim 1, wherein the pressing unit presses the work via a drilling jig that comes into contact with the work in an area larger than the area of a pressing surface of the pressing unit.
4. The drilling apparatus according to claim 2, wherein the pressing unit presses the work via a drilling jig that comes into contact with the work in an area larger than the area of a pressing surface of the pressing unit.
5. The drilling apparatus according to claim 3, wherein
the drilling jig includes a positioning hole for positioning a hole formed in the work, and
the pressing unit includes a fitting unit of which relative position to the drill in a plane orthogonal to the center axis of the drill is fixed and which is capable of fitting in the positioning hole of the drilling jig, the drilling jig being pressed in a state in which the fitting unit is fit in the positioning hole.
6. The drilling apparatus according to claim 4, wherein
the drilling jig includes a positioning hole for positioning a hole formed in the work, and
the pressing unit includes a fitting unit of which relative position to the drill in a plane orthogonal to the center axis of the drill is fixed and which is capable of fitting in the positioning hole of the drilling jig, the drilling jig being pressed in a state in which the fitting unit is fit in the positioning hole.
7. The drilling apparatus according to claim 1, wherein the drilling apparatus is an end effector mounted at a distal end of a multi-joint robot.
8. A drilling method using a drilling apparatus including: a drill rotatable about a center axis and capable of advancing and retracting along the center axis; and a pressing unit for pressing a work in an advancing direction of the drill, to form a hole in the work by advancing the drill while rotating the drill about the center axis in a state in which the work is pressed by the pressing unit,
the drilling method comprising:
calculating, in a drilling test performed in advance, pressing reaction applied to the drill from the work during drilling, and a pressing force applied by the pressing unit and causing deformation of the work in the advancing direction of the drill; and
setting a predetermined pressing force, on the basis of the calculated machining reaction and the calculated pressing force causing the deformation of the work, the pressing force applied on the work by the pressing unit, the predetermined pressing force being capable of suppressing deformation of the work and displacement of the drill due to the machining reaction.
9. The drilling method according to claim 8, wherein, as the drilling apparatus, a drilling apparatus including a pressing force detector for detecting a pressing force applied on the work by the pressing unit is used.
10. The drilling method according to claim 8, wherein the pressing unit presses the work via a drilling jig that comes into contact with the work in an area larger than the area of a pressing surface of the pressing unit.
11. The drilling method according to claim 9, wherein the pressing unit presses the work via a drilling jig that comes into contact with the work in an area larger than the area of a pressing surface of the pressing unit.
12. The drilling method according to claim 10, wherein
the drilling jig includes a positioning hole for positioning a hole formed in the work, and
the pressing unit includes a fitting unit of which relative position to the drill in a plane orthogonal to the center axis of the drill is fixed, the fitting unit being capable of fitting in the positioning hole of the drilling jig, the drilling jig being pressed in a state in which the fitting unit is fit in the positioning hole.
13. The drilling method according to claim 11, wherein
the drilling jig includes a positioning hole for positioning a hole formed in the work, and
the pressing unit includes a fitting unit of which relative position to the drill in a plane orthogonal to the center axis of the drill is fixed, the fitting unit being capable of fitting in the positioning hole of the drilling jig, the drilling jig being pressed in a state in which the fitting unit is fit in the positioning hole.
14. The drilling method according to claim 8, wherein the drilling apparatus is an end effector mounted at a distal end of a multi-joint robot.