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French to English: Composition a base d'inhibiteurs de cysteine-proteases pour retarder la senescence, l'autodestruction et l'hemolyse des erythrocytes
Source text - French Composition a base d'inhibiteurs de cysteine-proteases pour retarder la senescence, l'autodestruction et l'hemolyse des erythrocytes
Translation - English (19) REPUBLIC OF FRANCE (11) Publication No.: 2 778 851
(to be used only for
reproduction orders)
_______
NATIONAL INSTITUTE OF
PATENT RIGHTS (21) National registration no.: 98 06288
______
PARIS
______
(51) Int Cl6: 61 K 38/55
(12) PATENT B 1
(54) CYSTEINE-PROTEASE INHIBITOR-BASED COMPOSITION TO SLOW SENESCENCE, SELF-DESTRUCTION AND HEMOLYSIS OF ERYTHROCYTES
(22) Filing date: 05.19.98. (60) References to other related national documents:
(30) Priority:
(71) Applicant(s): ASSOCIATION POUR L’ESSOR DE LA TRANSFUSION SANGUINE DANS LA REGION DU NORD Association law of 1901 – FR.
(43) Public disclosure date of the patent application: 11.26.99 Bulletin 99/47.
(72) Inventor(s): Ameisen, Jean Claude, Bratosin, Daniela, Estaquier, Jerome, Huart, Jean Jacques and Montreuil, Jean.
(45) Public disclosure date of the patent: 07.02.26 Bulletin 02/30
(56) List of documents cited in search report:
(73) Holder(s):
See end of present document
(74) Attorney(s): Cabinet Lepeudry.
FR 2 778 851 – B 1
The invention is concerned with a composition for slowing senescence, self-destruction and hemolysis of erythrocytes, which consists of cysteine-protease inhibitors, in particular caspase and calpain inhibitors. These inhibitors are preferably chosen from among the tri- or tetrapeptide analogues of the cysteine-protease recognition and cleavage site. They will be used alone or in combination, especially in erythrocyte conservation media intended for use in blood transfusions.
It is known that erythrocytes have a lifespan of 120 days in the blood circulation. They are then phagocytized by the macrophages. This phagocytosis is preceded and provoked by numerous physiologic and morphologic disturbances within the erythrocytes, in particular reduction in size, appearance of pseudopods, emission of vesicles, desialylation of membrane glycoconjugates and externalization of phosphatidylserine (which moves from the inner layer to the outer layer of the lipid leaflets of the membrane).
It has been shown that these last two events, desialylation and appearance of phosphatidylserine, which are considered as markers of senescence, are directly associated with the microphage capture mechanism (Bratosin et al. Glycoconjugate J. 12, 1995, 258-267; Bratosin et al. Comptes Rendus Acad. Sci. 320, 1997, 811-818).
It is also known that after blood transfusions, 30% of the transfused erythrocytes disappear from the circulation after 24 hours, and 70% after 3 days. This phenomenon has also been attributed to senescence of the erythrocytes during storage and to their phagocytosis after transfusion.
In addition, the self-destruction and hemolysis of the erythrocytes already begins in the blood packs during storage.
Any improvement in the storage condition of erythrocytes intended for use in transfusions making it possible to preserve their integrity and physiologic activity would thus represent considerable progress in the area of transfusion. It is a goal of the present invention to provide such an improvement.
Although erythrocytes are cells with no nucleus and no mitochondria, the Applicants have submitted the hypothesis that the phenomena associated with senescence and self-destruction of the erythrocytes could be similar to an apoptosis mechanism that was never considered previously. From the opposite perspective, it has also been published recently that “erythrocytes cannot undergo apoptosis since they lack a nucleus” (Boas et al. Proc. Natl. Acad. Sci. 95-1998-3077). Consequently, the Applicants studied the effect of known inhibitors of apoptosis on senescence markers of erythrocytes.
Among various families of known inhibitors, the Applicants chose oligopeptides, chiefly tri- and tetrapeptides and their analogues or derivatives thereof which have already been described as caspase and calpain inhibitors. These two families of enzymes are proteases that participate in a cascade of reactions associated with cytoplasmic apoptosis.
- Numerous studies have demonstrated the role of various families of intracellular proteases, in particular cysteine-proteases, in modulating the activity of other cellular proteins and in controlling the balance between activators and inhibitors of various cellular functions (see review by Sorimachi et al. Biochem. J. 328, 1997, 721-732).
Among these proteases, the caspases cleave specifically after a residue of aspartic acid (see review by Cohen, Biochem. J. 326, 1997, 1-16). To date, ten caspases have been identified that participate in a cleavage reaction cascade of the proteins in the nucleus and cytoskeleton that characterize the effector phase of apoptosis.
On the other hand, the calpains combine a cysteine-protease activity domain and a domain that binds calcium; they thus participate in several cellular functions. In addition to their well-described role in dysfunction of the brain and muscles, the calpains also seem to participate in the apoptosis process (Sorimachi – same reference).
- Study of the mode of action of the caspases has incorporated the concept of synthetic inhibitors that are oligopeptides, whose sequence resembles that of the tri- or tetrapeptide sequence of the recognition and cleavage site present on the natural substrates of the caspases.
Thus the tetrapeptide DEVD (Asp-Glu-Val-Asp) corresponds to the cleavage site of poly-ADP-ribose polymerase and YVAD (Tyr-Val-Ala-Asp) corresponds to that of the ICE (IL-1β-converting enzyme).
YVAD inhibits caspases 1 and 4; DEVD inhibits caspases 3 and 7. Various derivatives (aldehyde, nitriles, chloromethyl, fluoromethyl, methylketones, etc….) have also been considered (see reviews: Nicholson and Thornberry; TIBS 22, 1997, 299-306; Villa et al. TIBS 22, 1997, 388-393).
A modified tripeptide, Z-VAD k (benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone) exerts an irreversible inhibitory action on the caspases.
Therapeutic applications of these inhibitors have already been considered for the treatment of pathologic states associated with apoptosis phenomena, such as fulminant hepatitis, myocardial infarction and cerebral ischemic accidents.
- Inhibitors of the cysteine-protease function of calpain have also been described (Sorimachi – same reference): the molecule known by the code name E-64 (trans-epoxysuccinyl-4-leukylamido-(4-guanidino)-butane), isolated from an Aspergillus japonicus culture, as a papain inhibitor, as well as two derivatives of E64c (N-[(L-3-trans-carboxyoxirane-2-carbonyl)-L-leucyl] isoamylamine) and E-64d (N-[N-(L-3-trans-ethoxycarbonyloxyoxirane-2-carbonyl)-L-leucyl] isoamylamine) and leupeptin (N-acetyl-Leu-Leu-argininal) isolated from different strains of Actinomycetes, as well as similar analogues or synthetic derivatives such as N-acetyl-Leu-Leu-norleucinal, N-acetyl-Leu-Leu-methioninal, benzyloxycarbonyl-Leu-Leu-leucinal, etc….
These molecules inhibit the cysteine-proteases to different degrees; certain ones have already been used for the treatment of muscular dystrophy linked to these proteases.
These inhibitors are marketed (particularly by the SIGMA and BACHEM companies) and are represented as apoptosis inhibitor reagents.
The Applicants have used these various caspase and calpain inhibitors and have shown that surprisingly they also had an inhibitory effect on four well-defined markers of erythrocyte senescence:
- Morphologic changes
- Externalization of phosphatidylserine
- Erythrophagocytosis
- Hemolysis.
These observations thus support the starting hypothesis and make it possible to compare senescence and self-destruction of erythrocytes to an apoptosis phenomenon.
The Applicants have deduced practical applications from these observations, particularly for improving the conditions for preserving erythrocytes intended for transfusion.
Thus the invention concerns a composition for slowing senescence, self-destruction and hemolysis of erythrocytes, which comprises specific inhibitors of the active cysteine-protease site. The said inhibitors preferably bear a structural resemblance to the peptide motif specifically recognized by the cysteine-proteases. More particularly, a first group of inhibitors bears a structural resemblance to a tetrapeptide motif specifically recognized by caspases. A second group of inhibitors a bears a structural resemblance to a tripeptide motif specifically recognized by calpains. The composition according to the invention preferably consists of a mixture of the type bearing a resemblance to the tetrapeptide motif and inhibitors of the type bearing a resemblance to the tripeptide motif.
The inhibitors of the first type are preferably chosen from among the Asp-Glu-Val-Asp, Tyr-Val-Ala-Asp tetrapeptides or the Z-Val-Ala-Asp tripeptide or derivatives thereof modified upstream or downstream from the specific aforementioned sequence, such as those that have been described in the literature (references cited above); they can be used alone or in combination.
The inhibitors of the second type are preferably chosen from among leupeptin or its derivatives and the E-64 molecule or its derivatives, such as those that have been described in the literature (references cited above); they can be used alone or in combination.
In addition, other molecules could be synthesized or used as inhibitors of the same caspases and calpains, which would act by any mechanism on the active site of these same enzymes. These molecules could also be used as inhibitors in the composition according to the present invention in the same capacity as the structural analogues.
The invention also concerns an erythrocyte preservation process that makes it possible to slow senescence, self-destruction and hemolysis of these cells by adding the inhibitor composition to the preservation medium, to achieve a final inhibitor concentration ranging from 0.1 to 100 mM, for a final hematocrit of approximately 30%.
The composition according to the invention can also be used in the preparation of drugs designed for the treatment of various pathologies linked to early or aberrant signs of senescence or self-destruction and hemolysis of erythrocytes and associated in particular with different forms of anemia.
The following examples illustrate the invention, without nevertheless limiting its scope.
Fig. 1 is a scanning electron microscopy photograph illustrating the effect of inhibitors on the morphology of the erythrocytes.
Fig. 2 is a scanning electron microscope photograph illustrating the effect of inhibitors on the capture of erythrocytes by macrophages.
Example I
I-A-induction of self-destruction of erythrocytes in vitro
An erythrocyte population always contains a certain percentage of cells that are senescent or in the process of self-destruction, whose morphologic and physiologic characteristics have been described above.
The senescence process can be accelerated and self-destruction of the erythrocytes can be provoked in vitro by keeping them for 24 to 48 hours at 37ºC. (They are normally preserved at 4ºC for 2 to 6 weeks at transfusion centers).
It is also possible to artificially trigger the self-destruction process by the action of a specific calcium channel ionophore, known by the code number A-23187 (manufactured by Calbiochem-Novabiochem). This ionophore increases the solubility of calcium ions in lipid media and thereby facilitates their penetration of the cellular membranes.
The following senescence markers have been chosen for subsequent studies, since they are easy to observe and/or quantify:
1) Alteration of the discoid aspect and emergence of pseudopods (erythrocytes in the “echinocyte” stage), then filiform pseudopods (erythrocytes in the “spheroechinocyte” stage).
2) Capture and phagocytosis of the erythrocytes by macrophages.
3) Externalization of phosphatidylserine.
4) Hemolysis of the erythrocytes.
The morphologic appearance of the erythrocytes is analyzed by scanning electron microscopy.
Phagocytosis of the erythrocytes by macrophages is measured either by observation and direct counting by viewing through a microscope, or after labeling with fluorescent PKH-26 dye by flow cytofluorimetry, as described by Bratosin et al. (Cytométrie 30, 1997, 269). Peritoneal murine macrophages (Swiss breed females, 6 to 8 weeks old) were used.
Externalization of phosphatidylserine was measured by labeling annexin V conjugated to fluorescein (annexin V-FITC) and [by] flow cytofluorimetry, as described by Kuypers et al. (Blood 87, 1996, 1179).
Hemolysis was evaluated by determination of the hemoglobin released in the preservation medium.
In the tables showing the results, the inhibitory peptides are designated by coding with a letter: DEVD, YVAD, Z-VAD.
I-B-inhibitor study conditions
The erythrocytes are placed in suspension in a HEPES buffer supplemented with CaCl2 2.5 mM, at a concentration of 107 cells per mL.
- The erythrocytes are kept at 37ºC for 48 hours;
- or incubated in the presence of ionophore A-23187 5 μM at 37ºC for 3 hours;
- the Asp-Glu-Val-Asp (DEVD), Tyr-Val-Ala-Asp (YVAD), leupeptin and E-64 inhibitors are added to the erythrocyte suspension at a concentration of 200 μM. The mixture is kept at 20ºC for 30 minutes. Z-Val-Ala-Asp (Z-VAD) is used at 40 μM.
I-C-evaluation of effect of inhibitors on morphology of the erythrocytes
Figure 1 shows the appearance of the erythrocytes observed by scanning electron microscopy:
A. Native erythrocytes
B. Erythrocytes treated with ionophore A-23187
C. Erythrocytes placed in contact with the DEVD inhibitor prior to treatment with the ionophore.
The figure is presented by way of example. The same results are obtained with erythrocytes kept at 37ºC for 48 hours (B) and YVAD, E-64 and leupeptin inhibitors (C).
It clearly appears on Fig. 1C that almost all of the treated erythrocytes have retained their normal discoid appearance, while on Fig. 1B a large proportion of the erythrocytes are spheroechinocytes.
The latter are the only ones to externalize phosphatidylserine and to be phagocytized (Bratosin et al. Comptes Rendus de l’Acad. Sci. Paris, 320, 1998, 811).
I-D-evaluation of effect of inhibitors on capture and phagocytosis of erythrocytes by macrophages
Under the same incubation and inhibitor treatment conditions, the number of erythrocytes captured by cultured murine macrophages was counted using electron microscopy images after a contact period of 2 hours.
Counting was performed on 500 macrophages per sample.
The results are presented in Table I and illustrated in Figure 2. They show a large reduction in capture after treatment with the inhibitors.
Table I
Erythrocyte treatment Number of erythrocytes captured per 100 macrophages
None
Ionophore A 23187
A 23187 + inhibitors:
DEVD
YVAD
Leupeptin
E-64
DEVD + leupeptin 6
500
70
15
25
30
14
Figure 2 shows the capture of human erythrocytes by peritoneal murine macrophages observed by scanning electron microscopy:
A. Native erythrocytes
B. Erythrocytes treated with ionophore A-23187
C. Erythrocytes placed in contact with the leupeptin before treatment with the ionophore.
The figure is presented by way of example.
The same results are obtained with erythrocytes kept at 37ºC for 48 hours (B) and with the other inhibitors (C).
In addition, erythrophagocytosis by macrophages was measured by cytofluorimetry after labeling with PKH-26.
The results are presented in Table II, expressed in percentage inhibition of erythrophagocytosis.
The measurements were performed on 5,000 cells per each condition.
IE-evaluation of effect of inhibitors on externalization of phosphatidylserine
With the same incubation and inhibitor treatment conditions, the capacity of erythrocytes to bind annexin V-FITC was evaluated.
After washing in isotonic phosphate buffer, the erythrocytes (105 cells in 100 μL) were incubated in the presence of 0.1 μg of annexin V-FITC for 15 min at 20ºC, in the dark.
The percentage of fluorescent cells (annexin-positive) was determined by flow cytofluorimetry (on FACScan® Becton-Dickinson cytofluorimeter, with LYSIS program), by counting 5 to 10,000 cells per sample.
The results are presented in the table below.
Table III
Percentage inhibition of externalization of phosphatidylserine
Inhibitors: At 37ºC After treatment with the ionophore A-23187
DEVD
YVAD
Z-VAD
Leupeptin
E-64
DEVD + E-64 83 ± 12
82 ± 4
-
89 ± 8
82 ± 8
96 ± 2 90 ± 6
82 ± 10
71 ± 10
83 ± 13
96 ± 4
94 ± 2
Note: Since Z-VAD supplemented with ethanol or DMSO causes erythrocyte lysis during prolonged incubation, the test at 37ºC was not performed.
I-F-evaluation of effect of inhibitors on self-destruction of erythrocytes by hemolysis
Human erythrocytes were incubated in the presence of ionophore A-23187 at 37ºC for 8 and 20 hours in the absence and presence of inhibitors.
Hemolysis was measured and expressed in mg of hemoglobin released per liter of medium.
The results presented in Table IV show that the inhibitors protect the erythrocytes from lysis.
Table IV
Treatment of erythrocytes Hemoglobin in preservation medium (mg/L)
Incubation
8 hr time
20 hr
- ionophore in absence of inhibitor
- ionophore in presence of inhibitors:
To evaluate the effect of inhibitors on erythrocytes under storage conditions followed by transfusion, a study model was developed for the Balb-c mouse.
Murine erythrocytes are isolated by centrifugation (2,000 g, 5 min at 4ºC) of heparinized blood. After 3 washings in a phosphate buffer at pH 7.2, they were taken up in HEPES buffer supplemented with 0.1 % human serum albumin. The final hematocrit was 10%.
The erythrocytes were incubated for 4 days at 20ºC (instead of 37ºC for human erythrocytes due to the weaker strength of mouse erythrocytes).
Next the erythrocytes were centrifuged and labeled with fluorescent PKH-26 dye (under the same conditions used for human erythrocytes). 100 μL of erythrocyte residue was taken up in 100 μL of phosphate buffer to be injected into the retroorbital sinus of the mice.
Blood samples were then taken over the course of time to measure the presence and then the clearance of the injected erythrocytes.
The measurements were done by flow cytofluorimetry. Each measurement was conducted on 10,000 cells.
The first blood sample was drawn 1 hour after the injection so that all of the erythrocytes injected would have entered the circulation.
The same operating method was applied to the erythrocytes incubated at 20ºC in the presence of inhibitors at a concentration of 2 mM.
Freshly sampled erythrocytes were used as a control.
The results presented in Table V show that the untreated erythrocyte clearance was complete by the 6th hour, while the erythrocytes treated with inhibitors were still present after 48 hours.
Table V
Erythrocyte treatment Number of labeled erythrocytes remaining in the circulation (out of 10,000 counted) after
1 hr 6 hr 20 hr 48 hr
None 364 343 317 305
4 days at 20ºC 34 11 11 10
4 days at 20ºC in the presence of 2 mM of
• DEVD 276 260 220 210
• YVAD cmk 359 340 330 300
• Leupeptin 219 230 250 230
• YVAD cmk + leupeptin 422 377 385 352
• DEVD + leupeptin 293 247 284 292
Example III
Study of action of protease inhibitors on erythrocytes under storage conditions at transfusion centers
A blood sample was taken at the Regional Blood Transfusion Center of Lille under the usual conditions in a “sampling medium” at a pH of 5.6. Leukocytes and platelets were removed. The erythrocytes were transferred to a “preservation medium” at a neutral pH, with a final hematocrit of 30%.
Erythrocytes are normally preserved at 4ºC. For the present experiment, accelerated aging was achieved by incubating them at 37ºC for 3 and 4 days. At the same time, aliquots were incubated in the presence of the inhibitors at a concentration of 3 mM.
After 3 and 4 days, externalization of the phosphatidylserine was measured, as described in example I.
Table VI shows inhibition of phosphatidylserine externalization under the action of inhibitors.
1. Composition for slowing the senescence, self-destruction and hemolysis of erythrocytes, characterized by the fact that it comprises specific cysteine-protease site-active inhibitors.
2. Composition according to claim 1, characterized by the fact that the inhibitors are similar in structure to the peptide motif specifically recognized by the said cysteine-proteases.
3. Composition according to claim 1 or 2, characterized by the fact that the inhibitors are similar in structure to the tetrapeptide motif specifically recognized by caspases.
4. Composition according to claim 1 or 2, characterized by the fact that the inhibitors are similar in structure to a tripeptide motif specifically recognized by calpains.
5. Composition according to claim 1 or 2, characterized by the fact that it comprises a mixture of inhibitors bearing a resemblance to the tetrapeptide motif according to claim 2 and inhibitors bearing a resemblance to the tripeptide motif according to claim 3.
6. Composition according to any of claims 1, 2, 3 or 5, characterized by the fact that the inhibitors are chosen from among the Asp-Glu-Val-Asp, Tyr-Val-Ala-Asp tetrapeptides or Z-Val-Ala-Asp tripeptide or derivatives thereof modified upstream or downstream from the specific aforementioned sequence, and [by the fact that] they are used alone or in combination.
7. Composition according to any of claims 1, 2, 4, or 5, characterized by the fact that the inhibitors are chosen from among leupeptin or its derivatives and molecule E-64 or its derivatives, used alone or in combination.
8. Process to slow senescence, self-destruction and hemolysis of erythrocytes, characterized by the fact that it comprises the addition of the composition according to any of claims 1 to 7 to the erythrocyte preservation medium to achieve a final concentration ranging from 0.1 to 100 mM.
9. Use of the composition according to any of claims 1 to 7 for the preparation of drugs designed for the treatment of pathologies connected with early or aberrant symptoms of senescence or self-destruction and hemolysis of erythrocytes.
French to English: Medical syringe equipped with a hinged and interlockable needle.
Source text - French Seringue medicale munie d'une protection d'aiguille articulee et verrouillable
Translation - English Medical syringe equipped with a hinged and interlockable needle.
(19) REPUBLIC OF FRANCE (11) Publication no.: 2 684 004
______ (to be used only for
NATIONAL INSTITUTE OF reproduction orders)
INDUSTRIAL PROPERTY (21) National Registration No. 91 14516
______
PARIS
(51) Int. Cl.5: A 61 M 5/32
(72) Inventor(s): LENOIS Michel.
(43) Public disclosure date of the
patent: 5/28/93 Bulletin 93/21
(56) List of documents cited in the
search report: See end of present
publication.
(60) References to other related (73) Holder(s):
domestic documents:
(74) Attorney:
(54) Medical syringe equipped with a hinged and interlockable needle.
(57) The syringe is composed of a plunger (5), a body (3), and a needle protection system (9) joined by a hinge (12) to the body. The protection system (9) consists of a groove (10) able to contain the needle (1) in its totality. A portion of this groove forms a housing (11) capable of containing and retaining the base (2) of the needle (1).
After use, the end (8) of the protection system (9) is held in a housing (7) fitted in the collar (4). After use, pressure on the component part (6) of the collar releases the protection system (9) which, flattened, contains the needle (1) and is kept locked in this position by engagement of the base (2) in the housing (11).
The present invention concerns a single-use medical syringe equipped with a needle protection system connected by one of its ends to the body of the syringe and having the capability after use of being pressed down against the needle to contain it entirely and interlockably in this position.
After use, by accidentally pricking the user, syringe needles may transmit certain diseases, in particular viral diseases. The only process limiting this risk consists of collecting the syringes immediately after use in a container incapable of being perforated. This manner of proceeding has a drawback: it is necessary that the container consistently be in the immediate vicinity of the user, which is sometimes difficult to accomplish, in particular in home-care situations or when the syringe is used by a drug addict.
The device according to the invention makes it possible to remedy this drawback. It comprises a needle protection system in the form of a bar hollowed out along a portion of its length. One of the ends of this protection system is connected to the end of the body of the syringe containing the needle (which needle may be a fixed needle incapable of being removed from the syringe or a needle attached by fitting onto a standardized cone). Prior to use, the other end of the protection system is kept in a housing fitted into the collar of the syringe. After using the syringe, the user exerts a bending force on the edge of this collar, which releases the end of the protection system. This protection system is then pressed down toward the needle. Part of the groove of the protection system grips the base of the needle, which holds this protection system in place, with the needle contained therein.
According to particular embodiments:
- The base of the needle may have a trapezoidal cross-section in order to ensure that the protection system is held more securely in place; in this case, the lodging designed to accommodate the base also has a trapezoidal cross-section.
- The needle protection system may be equipped with a support surface in the form of a cylinder portion. Before using the syringe, this support surface is laid flat against the body of the syringe whose shape it takes. This support surface makes it possible to facilitate interlocking by engaging the base in the groove of the needle protection system.
- The needle protection system may be fitted on its hollowed-out face and along the entire length thereof with a detachable film of plastic material. This arrangement makes it possible to deliver the syringe with the needle placed in the protection system, which eliminates the need to use a separate protective cap for the needle.
- The end of the needle attached to the body of the syringe may protrude into the said body, which, for example, makes it possible to replace the plunger with a receptacle introduced into the body of the syringe and equipped with a plug that may be easily perforated;
- The support surface in the cylinder portion in one piece with the needle protection system may consist of a cylinder portion, the circumference of which exceeds half the circumference of the body of the syringe. This arrangement makes it possible to lock the protection system onto the body of the syringe by gripping it without having the need for a housing placed in the collar.
- The body of the syringe and the needle protection system can be manufactured in a single piece by milling, wherein a zone of shallow depth ensures interlinking between the two parts.
The attached drawings illustrate the invention:
- Figure 1 represents the arrangement according to the invention
- Figure 2 represents the same arrangement after use
- Figure 3 represents Figure 2 in cutaway according to AA; in order to facilitate interpretation, Figure 3 represents a threefold enlargement
- Figure 4 represents a variant of the arrangement, characterized by the presence of a support zone in the form of a cylinder portion and a trapezoidal cross-sectional base
- Figure 5 represents Figure 4 in cutaway along CC
- Figure 6 represents Figure 4 in cutaway along BB; in order to facilitate interpretation, Figure 6 represents a threefold enlargement
- Figure 7 represents a variant of the arrangement, characterized by the fact that the needle protection system is held on the body of the syringe by containment of the support surface
- Figure 8 represents Figure 7 in cutaway along DD
In reference to these drawings the arrangement according to the invention is composed of a syringe body (3), a plunger (5), and a needle protection system (9). This needle protection system has a groove (10) capable of containing the needle in its entirety (1). One part (11) of this groove may hold and lock the base (2) of the needle. The protection system (9) is connected to the body (3) by an interlinking system (12) forming a hinge.
Prior to use, the protection system (9) is held by one of its ends (8) engaged in a housing (7) fitted in the collar (4).
After use, the user puts bending pressure on the part (6) of the collar (4), which releases the end (8) from its housing (7). He then presses the protection system (9) down against the needle (1). One push makes it possible to engage the base (2) in the portion (11) of the groove (10) designed to accommodate it and to lock it. The protection system (9) is then in place with the needle (1) contained in its entirety in the groove (10). The engagement of the base (2) in its lodging (11) is facilitated by a sloping (13) and (14) of the edges of the said housing.
In a variant illustrated by Figures 4, 5, and 6, the arrangement may have a support zone (15) in the form of a cylinder portion in one piece with the protection system (9). Prior to use, this support zone is laid flat against the body (3) of the syringe. The base (2’) may have a trapezoidal cross-section, facilitating its retention in the housing (11’), with this lodging itself having a trapezoidal cross-section. In a variant illustrated by Figures 7 and 8, retention of the protection system (9) against the body (3) of the syringe prior to use is ensured by the support zone (15’) in cylinder portion form holding the body (3) of the cylinder in place over more than half of its circumference.
The dimensions of the system depend on the capacity of the syringe. By way of nonlimiting example, for a capacity of 5 milliliters, the diameter of the body of the syringe will be on the order of 14 millimeters and its length on the order of 80 millimeters.
Possible manufacturing method:
- The plunger may be manufactured by the molding of plastic materials by injection;
- The body (3) of the syringe and the protection system (9) may be produced in a single piece manufactured by molding of plastic material by injection, wherein a zone of shallow depth forms the interlinking hinge system (12). In the case where the needle (1) is fixed and cannot be removed from the body, the end of this needle is set in the plastic material during molding.
CLAIMS
1) Single-use medical syringe, characterized by the fact that the body (3) is equipped with a needle protection system (9) connected to this body via a hinge (12) and having the capacity to contain the needle in its entirety (1) in a groove (10), wherein a portion (11) of this groove may contain and lock the base (2) of the needle. One end (8) of the protection system (9) can be held in a housing (7) fitted in the collar (4) and released by bending a part (6) of this collar. The needle (1) is a fixed needle designed by manufacturing of the body to be nonremovable (3).
2) Arrangement according to claim 1, characterized by the fact that instead of being a nonremovable needle, needle (1) is a needle fixed by interlocking by means of a standardized cone.
3) Arrangement according to claim 1 or claim 2, characterized by the fact that the end of the needle (1) attached to the body (3) protrudes within the interior of the said body.
4) Arrangement according to claim 1 or claim 2, characterized by the fact that the base (2’) and the housing (11’) both are of trapezoidal cross-section.
5) Arrangement according to claim 1 or claim 2, characterized by the fact that the free surface of the groove (10) can be covered along its entire length with a film of detachable plastic material.
6) Arrangement according to claim 1 or claim 2, characterized by the fact that the protection system (9) may be equipped with a support surface (15) in cylinder portion form capable of being fitted onto the body (3).
7) Arrangement according to claim 6, characterized by the fact that the support surface (15) may consist of a cylinder portion of a circumference exceeding half of the circumference of the body (3), wherein the collar (4) no longer acts as a housing (7).
8) Arrangement according to claim 1 or claim 2, characterized by the fact that the body (3) of the syringe and the needle protection system (9) are manufactured in a single piece obtained by molding, wherein a zone of shallow depth forms the interlinking hinge system (12).
Spanish to English: Aditivo refinador de grano para la electro-obtencion y electro-refinacion de cobre que mejora el deposito en calidad y cantidad, entre otros beneficios.
Source text - Spanish Aditivo refinador de grano para la electro-obtencion y electro-refinacion de cobre que mejora el deposito en calidad y cantidad, entre otros beneficios.
Translation - English SPECIFICATIONS
Grain refining additive for the electrowinning and electrorefining of copper which improves the deposit in terms of quality and quantity, among other benefits.
The history of modern copper hydrometallurgy began in the 1960s with the introduction of oximes as copper extractants to the solvent extraction process and guar gum as a grain refiner to the electrowinning process (1962, General Mills, now Cognis). The first industrial application of this process was introduced at the Bluebird Plant in Arizona in 1968. In the 1970s, there were new industrial applications in the United States and Zambia (Nchanga plant, 1974), while in Chile the new extraction process was introduced in 1969 (Chuquicamata)
In hydrometallurgical processes the metals present in the minerals are extracted by physicochemical processes in aqueous media at moderate temperatures. The basic steps are:
• Mechanical preparation: This consists of a reduction in size of the mineral to facilitate the release of the mineral species (desired metals)
• Chemical attack: This consists of the release of the metal species of interest and of the mineral impurities by the chemical action of acid or basic solutions, which transform them into a soluble state.
• Purification or concentration: These are methods used to isolate the species of interest and to increase the content thereof per unit volume. One such procedure that may be used is (liquid/liquid) ion exchange, which selectively extracts the metal of interest; this step is called solvent extraction.
• Production of metal: this is the achievement of the final product, using electrolytic deposition techniques, wherein the metal takes the form of high-purity metal sheets.
As the years passed, the term “chemical attack” came to include leaching, acid curing and agglomeration, non-flooded beds, shallow leaching piles and bacterial leaching. At present, due to its characteristics and qualities, the application and development of solvent extraction has achieved widespread expansion and rapid growth, especially in our country, with 30 plants in operation. Solvent extraction has advanced based on the need to optimize the process, which involves improvements in the extractant (oximes), broadening the range of applications and being more selective in the process. Profound improvements have not been made in the electrowinning process (process derived from electroplating), but one of the most important is the use of the grain refining additive generically called guar gum.
Guar gum is a water-soluble polysaccharide; guar gum is a bland white powder that forms a viscous gel when mixed with water. The viscosity of the solution depends on the length of the galactomanan chain that it contains. Although in electroplating the best yield occurred when using alkaline electrolytes, in the mining industry guar gum was introduced as a grain refiner using an acid electrolyte, which reduces its viscosity, thereby shortening its working life. Another problem that has been experienced with guar gum is its poor efficiency at low temperatures, since it tends to gelatinize; in addition, it produces an accumulation of residue in the electrolyte. This results in severe organic contamination, with a serious impact on the quality of the copper cathode.
Based on the preceding information, various grain refining additives have appeared on the market in the past decade in the search to replace a natural refining agent that has been used for more than 100 years in electrowinning processes (beginning with electroplating). However, attempts to find a replacement for guar gum have proved unsuccessful, since such products have proved harmful to the extractant, which is the main component in the solvent extraction process. Despite the fact that attempts have been made to introduce synthetic additives such as modified starches, in the long run these also ended in failure, causing degradation of the extractant, since synthetics lose their natural properties when modified with alcohol.
As a fact of great relevance in the electrowinning process, in 2006 experiments were conducted with a new 100% natural grain refiner exhibiting a more highly branched molecular structure compared with that of guar gum, a property which has led it to be recognized as an effective grain refiner. The product in question is dextrin, never before used in hydrometallurgical processes, let alone as a grain refiner in electrowinning processes. This development was advanced by the Process Company Ltd., which, together with the Cognis Company, a leader in the solvent extraction process, has conducted various tests in Chile and the United States, confirming the effectiveness of this new grain refiner.
There are various advantages of dextrin, since not only does it act as an efficient grain refiner, regardless of the temperature of the medium in which it is used, but also it has been found to have a greater tolerance to higher current densities. Taking this into account, plus the fact that it is highly soluble in the aqueous phase and considering its physical properties, dextrin improves the electrical efficiency of the system, in addition to reducing the emission of acid mist due to the low surface tension of the electrolyte. These qualities, which exceed those of guar gum, will have a real impact on the world’s copper production.
Copper electrowinning processes use an electrolyte from the solvent extraction (SX) step: an aqueous solution that contains copper sulfate, sulfuric acid and other impurities.
Electrowinning electrolysis cells are connected to a direct current supply source. The negative pole is connected to a stainless steel plate comprising the cathode, and the positive pole to a lead plate comprising the anode. At present the aforementioned electrodes have a smooth surface.
The anode provides the positive charge so that the copper sulfate molecules are electrically charged; this phenomenon takes place in the area of the electrolyte that is in contact with the solution, i.e., at the electrolyte-anode interface.
After the molecules are charged, they are attracted toward the negative pole, and upon coming into contact with it, are immediately reduced to metallic copper, causing the copper to be deposited on the cathode.
A fundamental part of the aforementioned process is the use of additives, which improve the quality of the deposit on the final product according to the existing metallurgical parameters. For this purpose, a grain refiner generically called guar gum has been used.
Guar gum is used widely in the field of copper metallurgy, for example as a flocculent in the process of solid-liquid separation by filtration, sedimentation and clarification in the area of mineral concentration; guar gum accelerates the sedimentation of suspended sludge and facilitates its removal. It is also used as a polarizing agent to prevent the formation of nodules causing short circuits in the electrowinning of copper.
The guar gum in the copper deposit acts by the adsorption of the gum on the cathode, where a high electric field is found at some points. On the other hand, guar gum undergoes degradation as a result of the hydrolysis reaction. The degradation rate depends on the temperature of the electrolyte and the concentration of the acid present.
It should be pointed out that there is a broad range of grain refining additives, which are listed below:
- Galactasol 20H3C.
- Guarc Mimflo 100.
- Guarfloc 66.
- Dynafloc 210.
- Guar OPT-43.
- Guar Gum 66.
With regard to the quality of the cathode, emphasis should be placed on the growth of the crystals, for which it is useful to consult Fisher’s classification. Fisher determined five types of deposits that cover all cases of electrodeposition; Table 1 describes the three most important types. These types of deposits are affected by the grain refining additive.
Table No.1
Types of Crystals
N° Type of growth Abbreviation Characteristics
1 Basic reproduction crystals BR Form under high diffusion and low density conditions
Form under low current density conditions
Crystals grow with regular surfaces
2 Field-oriented type crystals FT Formation by predominantly bidimensional nucleation
3 Unoriented dispersion type crystals UD Crystals grow from smaller grains
On the other hand, as mentioned at the beginning of this description, the Solvent Extraction step is very important and costly in the copper recovery process. In this step the so-called PLS solution is purified, and the copper quantity contained therein is concentrated. In order for the aforementioned process to succeed, a so-called extractant reagent is used, which is so expensive that it is necessary to analyze the effect that the grain refining additive has on it. In the electrowinning step the copper deposit is also affected by various parameters that have an impact on its subsequent classification according to production quality and variability. The crystal structure of the deposit deteriorates in proportion to an increase in current density. In addition to the formation of nodules representing a poor deposit, short circuits may occur.
With the aforementioned procedure, a grain refining additive that solves the problems mentioned in the preceding paragraph is used for copper electrowinning and solvent extraction. In addition, the grain refining additive can be used in its native form (solid) or in an aqueous solution with the following formulation per liter of additive:
Yellow dextrin: 500 to 520 grams, corresponding to 50% of the mixture.
Deionized water: 500 ml, corresponding to 50% of the mixture.
In addition, the grain refining additive may contain other components in the mixture without the loss of its organic structure and properties; these components are: ethylene diamine [tetraacetic] acid (C10H12N2O8*4Na), tetrasodium (EDTA) (a carboxylic acid derivative), diacetone alcohol, dibutyl carbonyl, dibutyl glycol, ethers, esters, carboxylic acids in general and alcohols (derivatives).
Yellow dextrin is a derivative of starch, which itself is made up of polysaccharide chains, which generically form glycogen, starch, cellulose, hemicellulose, chitin, the pectins and the guar gums.
Starch is a storage form of homopolysaccharide and is composed of from 73 to 78% amylopectin and from 22 to 27% amylose. It originates from potatoes, tapioca, corn, wheat and rice. It is used as an adhesive, binder, foam stabilizer, [or] texturizer, among other applications.
Products derived from starch include corn syrups (mixture of dextrin, maltose and glucose), yellow dextrin (non-crystallizing) and modified starches. Starch is modified by etherification with propylene oxide or polyphosphates, while yellow dextrin is not a modified starch. In addition, modified starch is a synthetic product, since its composition is modified by etherification, while yellow dextrin is a purely natural product, since its original structure is not altered.
Yellow dextrin is composed of a group of low-molecular-weight carbohydrates produced by the hydrolysis of starch. They have the same general formula as the carbohydrates, but are of shorter chain length. Keeping in mind that there are various types of modified starches, yellow dextrin is the only one that offers advantages for electrowinning. The aforementioned chain is presented in Figure No. 1, and its chemical formula is given below:
(C6H10O5)n x H2O
To determine the effect of the grain refining additive in the extractant, an evaluation is performed, which is described below:
The main parameters affecting the grain refining additive in the SX process are described in the following protocol:
A.- Materials:
- Organic Solution (extractant plus solvent) for a metallurgical process, 10 liters.
- Poor Electrolyte (PE) for a metallurgical process, 10 liters.
- Rich Solution (PLS) for a metallurgical process, 10 liters.
- Grain refining additive, 50 ml.
- Sodium sulfate, volume according to number of tests.
- Cannon-Fenske viscometer.
- Mechanical Stirrer with a variable speed motor that permits an agitator speed of (1750 ± 25 rpm); equipped with a 316L stainless steel stirring rod with a width of 23 cm. The rod has an impeller 4.45 cm in diameter with 6 grooves measuring 0.32 in depth and width.
- 1000 ml beaker with a stainless steel baffle, clean and free of soap or detergent.
- Chronometer.
Two methods can be used to evaluate the mentioned solutions and materials; these are described in items B and C.
B.- Method No.1:
1.- Prepare 500 ml [each] of PE with concentrations of 0, 2, 5, 10, 15, 20, 50 and 100 ppm of grain refining additive.
2.- Pour 400 ml of organic phase into a beaker and place the impeller in the center of the beaker at a depth of 1 cm from the surface. Set the agitation speed (1750 ± 25 rpm) and pour 400 ml of PE onto the organic phase. Then continue mixing for 3 minutes. Stop rotating the agitator and start to measure the time that it takes for the two phases to separate until a single layer of bubbles remains at the interface.
3.- Determine the viscosity and interfacial tension of the resulting organic phase obtained after step number 3 at 20°C. The interfacial tension is determined using an 0.1 g/mL sodium sulfate solution as reference. A Cannon-Fenske viscometer is used to measure the viscosity.
C.- Method No. 2.
1.- Prepare 500 ml [each] of PE with concentrations of 0, 2, 5, 10, 15, 20, 50 and 100 ppm of grain refining additive.
2.- Pour 400 ml of organic phase into a beaker and place the impeller in the center of the beaker at a depth of 1 cm. from the surface. Set the agitation speed (1750 ± 25 rpm) and pour 400 ml of PE onto the organic phase.
3.- Discard the aqueous phase and introduce a an additional dose of PE with freshly added grain refining additive.
4.- Repeat the previous step at least three times.
5.- Determine the viscosity and interfacial tension of the resulting organic phase obtained after step number 4 at 20°C. The interfacial tension is determined using an 0.1 g/mL sodium sulfate solution as reference. A Cannon-Fenske viscometer is used to measure the viscosity.
D.- For both methods, retrieve the resulting data, archive the results, perform an analysis, and note the relationships found and conclusions reached based on the information.
After conducting the protocol, examine the results obtained regarding phase separation time, surface tension and interfacial tension. The data found are listed in Tables No. 2 through Table No. 9.* Based on the findings, the grain refining additive does not affect any of the principal properties of the extractant, which means that it does not affect the SX process.
Table No. 2
Surface Tension of the [SX] Plant Electrolytes in Dynes/cm[2]
With regard to the effect of grain refining additives in electrowinning, it should be pointed out that Guarfloc 66 works well at low current densities (220 and 250 A/m2), while Galactasol is effective at high current densities (250 y 300 A/m2). In contrast, grain refining additives work at both low and high current densities, reaching values of up to 700 A/m2, a value that is not applicable to the copper industry. With regard to these density values, it should be noted that the behavior of guar gum is not stable, i.e., nodules or a fine fragile deposit may form with densities exceeding 400 A/m2, in comparison to grain refining additives, which produce a compact, uniform deposit, with no increase in impurities due to occlusion or secondary reactions.
Compared to guar gum, the grain refining additive features a larger deposit and greater current efficiency [as was demonstrated] in a battery of tests. These differences are shown in Table No. 9. In addition, Figure No. 2 shows the difference of 10% on average between the tests conducted on current efficiency. On the other hand, when there is an increase in current efficiency, this results in a harvest time that is closer to the optimal or theoretical. Finally, Figure No. 3 shows the losses in percent decreases in harvest times for the tests conducted.
Table No. 9
Comparative Results between Grain Refining Additive and Guar Gum
Theoretical Harvest Rea;
Time Real Mass Delta Time Additive Efficiency Loss
----- (g) (g) (g) (hours) Used (%) (%)
07-04-2007 147.3 177 -29,7 5 Guar 83.2 15.8
07-06-2007 153.6 177 -23,4 5 Guar 86.8 12.3
07-09-2007 150.2 177 -26,8 5 Guar 84.9 14.2
07-13-2007 157.1 177 -19,9 5 DXG 88.8 10.3
07-17-2007 157.2 177 -19,8 5 DXG 88.8 10.2
07-18-2007 175.3 177 -1,7 5 DXG 99.0 0.0
Based on the aforementioned findings, grain refining additives are grain refiners that increase the copper deposit, work at low and high current densities, produce a more uniform and compact deposit, improve the current efficiency (Figure No. 2), prevent the occlusion of impurities and improve cathode quality, i.e., reduce the impurities present in the cathode to be marketed.
CLAIMS
1. Grain refining additive CHARACTERIZED BY THE FACT that it has the following formulation per liter of additive;
Yellow dextrin: 500 to 520 grams, corresponding to 50% of the mixture.
Deionized water: 500 ml, corresponding to 50% of the mixture.
2. Grain refining additive CHARACTERIZED BY THE FACT that it is used in its solid (native) form.
3. Grain refining additive CHARACTERIZED BY THE FACT that it features polysaccharide chains produced from starch.
4. Grain refining additive CHARACTERIZED BY THE FACT that it is mixed with components such as ethylene diamine [tetraacetic] acid (C10H12N2O8*4Na), tetrasodium (EDTA) (a carboxylic acid derivative), diacetone alcohol, dibutyl carbonyl, dibutyl glycol, ethers, esters, carboxylic acids in general and alcohols (derivatives).
5. Grain refining additive in accordance with claim 2, CHARACTERIZED BY THE FACT that it is mixed in a 1:1 ratio of the solid additive with the dilution water.
6. Grain refining additive CHARACTERIZED BY THE FACT that it is mixed for 60 minutes with no colloid formation.
7. Grain refining additive CHARACTERIZED BY THE FACT that it is effective at both low and high current densities.
8. Grain refining additive CHARACTERIZED BY THE FACT that [it is used] for the electrowinning and electrorefining of copper.
Figure No. 1
Figure No. 2
Key to Figure No. 2: Differences in current efficiency Grain refining additive
% efficiency Number of tests Guar gum
Figure No. 3
Key to Figure No. 3: Losses of Time Grain refining additive
(%) Number of tests Guar gum
French to English: Loss of Consciousness in a Child Due to Loperamide
maladies chroniques de l’intestin et du côlon (notamment les poussées aiguës de rectocolite hémorragique). Il ne doit pas non plus être utilisé en cas de diarrhée survenant au cours d’un traitement antibiotique (risque de colite pseudomem¬braneuse).
Les effets indésirables décrits sont de type allergique digestif (constipation, distension abdominale, douleurs, bal¬lonnement, nausées, vomissements, sécheresse buccale, voire iléus paralytique) ou neurologique (asthénie, somno-lence, vertiges). C’est en cas de surdosage que peut apparaî¬tre une dépression du système nerveux central avec diminu¬tion de la vigilance, somnolence, myosis, hypertonie, dépression respiratoire ou incoordination motrice. Les en¬fants sont plus sensibles à ces effets sur le système nerveux central.
S. Chanzy et al. / Archives de pédiatrie 11 (2004) 826–827
827
1. Observation
Cette enfant, âgée de 26 mois, a été hospitalisée pour perte de connaissance. Depuis la veille, elle présentait une gas¬troentérite avec une débâcle diarrhéique et des vomisse-ments. Le médecin traitant avait prescrit de l’Imodium® à dose habituelle (dose 14 kg, 3 fois par jour). Elle avait reçu trois prises d’Imodium®, soit 0,09 mg/kg au total. Le lende-main à midi, alors que la dernière prise d’Imodium® datait de la veille au soir, elle a présenté aux toilettes une perte de connaissance avec pâleur, mais sans mouvement convulsif. Les parents ont alors appelé le Samu qui a constaté une somnolence.
À son arrivée aux urgences, elle présentait une réactivité orientée aux stimulations, ouvrait les yeux à la demande mais sans réponse verbale, et se rendormait. Elle n’était pas fé¬brile, ni déshydratée.
La glycémie, l’ionogramme sanguin étaient normaux, et il n’y avait pas de cétonurie.
La tomodensitométrie cérébrale sans injection était nor-male, la recherche de toxiques était négative, le LCR était normal, l’ECG et le réflexe oculocardiaque étaient normaux.
Devant ce trouble de conscience persistant, une crise épi-leptique a été suspectée et elle a reçu du Valium® intravei¬neux, sans aucune modification des symptômes.
Une possible intolérance à l’Imodium® a alors été évo-quée et l’enfant a reçu quatre heures après son arrivée, deux ampoules intraveineuses à cinq minutes d’intervalle de na-loxone à 0,4 mg/ml, qui ont entraîné un réveil total immédiat sans récidive de somnolence. L’enfant a ensuite été sur¬veillée sans présenter de manifestations particulières en de¬hors d’un syndrome post-ponction lombaire transitoire. L’EEG réalisé trois jours plus tard était normal. Cet accident a été déclaré au centre de pharmacovigilance.
2. Discussion
Le lopéramide est un antidiarrhéique dont l’utilisation est autorisée chez l’enfant au-dessus de deux ans, en complé¬ment de la réhydratation orale, dans le traitement symptoma-tique des diarrhées aiguës et dans le traitement symptomati-que des diarrhées chroniques. Il reste cependant assez peu utilisé (en dehors de certaines indications particulières) par la communauté médicale en raison des risques d’iléus et de prolifération microbienne liés à l’inhibition du péristaltisme intestinal.
Les effets secondaires neurologiques sont très rares en cas d’utilisation à la posologie habituelle, et même en cas d’in¬toxication. Il convient alors d’éliminer une hypoglycémie en rapport avec les troubles digestifs motivant la prescription de lopéramide.
L’antidote à utiliser est la naloxone intraveineuse (Na-lone® solution injectable à 0,4 mg/ml) à la posologie d’une ampoule (pour l’adulte et l’enfant de plus de 3 ans, quel que
soit le poids) pouvant être répétée trois fois, à cinq minutes d’intervalle. S’il s’agit d’une intoxication neurologique due uniquement aux morphiniques, les symptômes doivent s’amender. À noter que l’effet de la naloxone est bref (durée d’action 30 minutes en moyenne) et que l’enfant doit être surveillé pendant plusieurs heures en milieu hospitalier pour dépister une éventuelle récidive du trouble de conscience.
Dès 1980, Friedli et Haenggeli [1] rapportent un cas d’in-toxication accidentelle au lopéramide avec coma et bradyp-née chez une enfant de quatre mois, traitée favorablement par naloxone intraveineuse. Litovitz et al. ont repris en 1997 [2] 216 cas (adultes et enfants) d’intoxication au lopéramide. Seuls trois patients (deux enfants, un adulte) ont eu besoin de naloxone du fait d’effets secondaires neurologiques, avec une réponse favorable pour les deux plus jeunes et une réponse non connue pour le patient adulte. Il existe aussi de rares cas décrits dans la littérature de toxicité neurologique grave au lopéramide chez l’enfant en dehors d’une intoxica¬tion, dont un cas chez une enfant de cinq semaines, chinoise (non traitée par naloxone), repris par Tan en 1983 [3] ; et un cas chez une enfant de 15 mois britannique (traitée par naloxone ) repris par Minton et Smith en 1987 [4]. On peut noter que ces enfants étaient très jeunes et que la prescription ne correspondait pas aux dispositions de l’autorisation de mise au marché française actuelle du lopéramide, pour l’âge de l’enfant. Notre patiente n’avait que 26 mois et était donc très proche de la limite inférieure d’âge de 24 mois à partir de laquelle ce traitement est autorisé.
3. Conclusion
Le lopéramide est donc un antidiarrhéique analogue struc¬turel des opiacés avec des effets secondaires neurologiques possibles mais rares, même en dehors d’un contexte d’intoxi¬cation. Les restrictions d’utilisation doivent être impérative¬ment respectées en raison notamment de la susceptibilité des jeunes enfants. La survenue de troubles de conscience lors d’un traitement par lopéramide doit faire utiliser la naloxone à visée diagnostique et thérapeutique afin de les imputer éventuellement à la prise de ce traitement. La survenue d’ac¬cident similaire chez d’autres jeunes patients pourrait faire discuter la restriction d’utilisation du lopéramide à des en¬fants plus âgés.
Références
[1] Friedli G, Haenggeli CA. Loperamide overdose managed by nalox-one. Lancet 1980;1:1413.
[2] Litovitz T, Clancy C, Korberly B, Temple AR, Mann KV. Surveillance of loperamide ingestion: an analysis of 216 poison center reports. J Toxicol Clin Toxicol 1997;35:11–9.
[3] Tan SH. Loperamide toxicity in an infant. Aust Paediatr J 1983;19:55.
[4] Minton NA, Smith PG. Loperamide toxicity in a child after a single dose. Br Med J (Clin Res Ed) 1987;294:1383.
Translation - English Loss of Consciousness in a Child Due to Loperamide
by
S. Chanzy, S. Moretti, H. Mayet, M.C. Routon, C. De Gennes, J.C. Msélati
Translated from the French by
Medical Documentation Service
College of Physicians
Philadelphia, Pennsylvania
Clinical Report
Loss of Consciousness in a Child Due to Loperamide
by
S. Chanzy*, S. Moretti, H. Mayet, M.C. Routon, C. De Gennes, J.C. Msélati
Department of Pediatrics and Neonatology, Orsay Hospital Center, P.O .Box 27, 91401 Orsay cedex, France
Date of receipt June 12, 2003; date of acceptance March 20, 2004
Loperamide is an antidiarrheal agent, analogous in structure to the opiates, with possible but rare neurologic side effects. We report the case of a twenty-six-month-old infant girl who presented loss of consciousness following treatment with loperamide, and was treated successfully with naloxone. A certain amount of caution must be exercised in prescribing loperamide to young children due to their sensitivity. Naloxone can be used in the case of impaired consciousness for both diagnostic and therapeutic purposes.
® 2004 Elsevier SAS. All rights reserved.
Loperamide is a structural analog of the opiates, classified as an antidiarrheal. For use in children, it is marketed under the name Imodium®, a 0.2 mg/mL oral solution (90 mL bottle with a dispenser graduated in kg. It is reserved for 2- to 8-year-old children, at the dosage of one dose corresponding to the weight of the child two to three times per day. It can only be obtained with a prescription. Its half-life is 10 to 15 hours, and it is chiefly metabolized by the liver.
The contraindications of loperamide are children under 2 years of age, hypersensitivity to one of the constituents, and chronic diseases of the intestine and colon (especially acute episodes of hemorrhagic rectocolitis). It also should not be used in the case of diarrhea occurring during treatment with antibiotics (risk of pseudomembranous colitis).
The side effects described are of the gastrointestinal allergic type (constipation, abdominal distention, pains, flatulence, nausea, vomiting, dry mouth, even paralytic ileus) or the neurologic type (asthenia, drowsiness, dizziness). In the case of overdosage depression of the central nervous system may develop, with a diminished level of alertness, drowsiness, miosis, hypertonia, respiratory depression or lack of motor coordination. Children are more sensitive to these effects on the central nervous system.
1. Case report
This female child, 26 months old, was hospitalized for impaired consciousness. Since the night before, she presented gastroenteritis with severe diarrhea and vomiting. The attending physician had prescribed Imodium® at the usual dose (14-kg dose, 3 times per day). She had received 3 doses of Imodium®, i.e., 0.09 mg/kg in total. At midday the next day, although the last dose of Imodium® had been taken the night before, upon going to the toilet she presented impaired consciousness with pale skin tone, but without convulsive movement. The parents then called the paramedics, who observed drowsiness.
Upon arriving in the emergency room, the child presented reactivity directed toward stimulation, opened her eyes upon request but without verbal response, and went back to sleep. She was not febrile or dehydrated.
The blood glucose and electrolyte determination were normal, and there was no ketonuria.
The brain CT scan without injection was normal, the toxic agent search was negative, the CSF was normal, and the ECG and oculocardiac reflex were normal.
With the impaired consciousness persisting, an epileptic seizure was suspected and Valium® was given intravenously, with no change in the symptoms.
A possible intolerance to Imodium® then came under consideration, and 4 hours after her arrival the child received 2 intravenous ampules of 0.4 mg/mL naloxone at 5-minute intervals, which triggered immediate, complete recovery without recurrence of drowsiness. The child was then monitored without developing particular symptoms aside from a transient post-puncture lumbar syndrome. The EEG performed 3 days later was normal. This accident was reported to the drug monitoring center.
2. Discussion
Loperamide is an antidiarrheal authorized for use in children above 2 years of age in conjunction with oral rehydration in the symptomatic treatment of acute diarrhea and the symptomatic treatment of chronic diarrhea. However, it is not used much by the medical community (outside of certain particular indications) due to the risk of ileus and microbial proliferation connected with inhibition of intestinal peristalsis.
Neurologic side effects are very rare when it is given at the usual dose and even in the case of poisoning. It is advisable to rule out hypoglycemia when confronted with gastrointestinal problems prompting the prescribing of loperamide.
The antidote to be used is intravenous naloxone (Nalone® 0.4 mg/mL injectable solution) at the dosage of 1 ampule (for adults and children over 3 years of age regardless of their weight), which can be repeated 3 times at 5-minute intervals. If it is a case of neurologic poisoning due solely to the opioid, the symptoms should resolve. It should be noted that the effect of naloxone is brief (duration of action 30 minutes on average) and that children should be monitored for several hours in a hospital to track a possible recurrence of impaired consciousness.
As early as 1980, Friedli and Haenggeli [1] reported a case of accidental poisoning due to loperamide with coma and bradypnea in a 4-month-old female infant, treated successfully with intravenous naloxone. In 1977 Litovitz et al. [2] reviewed 216 cases (adults and children) of loperamide-induced poisoning. Only 3 patients (2 children, 1 adult) required naloxone as a result of neurologic side effects, with a favorable response for the 2 children and an unknown response for the adult. There are also rare cases described in the literature of severe loperamide-induced neurologic toxicity in children outside of the poisoning context, including one case in a 5-week-old female Chinese infant (not treated with naloxone) reported by Tan in 1983 [3]; and one case in a 15-month-old female British infant (treated with naloxone) reported by Minto and Smith in 1987 [4]. It may be noted that these children were very young and that the product was not prescribed according to the current French marketing authorization provisions applicable to loperamide based on the age of the child. Our patient was only 26 months old and was thus very close to the lower age limit of 24 months starting from which this treatment is authorized.
3.Conclusion
Loperamide is thus an antidiarrheal structural analog of the opiates, with possible but rare side effects, even in the absence of the poisoning context. It is imperative to heed the restrictions of use due particularly to the susceptibility of young children. The occurrence of impaired consciousness under treatment with loperamide calls for the use of naloxone as a diagnostic and therapeutic tool to assess the possible culpability of loperamide in connection with the consciousness disorder. Restricting the use of loperamide to older children could be a topic for discussion if a similar accident occurs in other young patients.
References
[1] Friedli G, Haenggeli CA. Loperamide overdose managed by naloxone. Lancet 1980;1:1413.
[2] Litovitz T, Clancy C, Korberly B, Temple AR, Mann KV. Surveillance of loperamide ingestion: an analysis of 215 poison center reports. J Toxicol Clin Toxicol 1997;35:11-9.
[3] Tan SH. Loperamide toxicity in an infant. Aust Paediatr J 1983;19:55.
[4] Minton NA, Smith PG. Loperamide toxicity in a child after a single dose. Br Med J (Clin Res Ed) 1987;294:1383.
Spanish to English: ADDENDUM TO THE INFORMATION AND CONSENT FORM FOR THE RESEARCH SUBJECT
Source text - Spanish APROBADO 13 Mar 2006
WIRB® Olympia, WA
APÉNDICE DEL FORMULARIO DE INFORMACIÓN Y DE CONSENTIMIENTO
PARA EL SUJETO EN UNA INVESTIGACIÓN
Investigación genética en el tejido tumoral
TÍTULO:
Estudio en fase II del fármaco GW786034 que utiliza un diseño de interrupción aleatoria en sujetos con carcinoma localmente recurrente o metastásico de células renales claras
N° DEL PROTOCOLO:
VEG102616
Protocolo de WIRB® #20051869
Institución #AAAB7519
PATROCINADOR:
GlaxoSmithKline
Research Triangle Park, North Carolina
United States
INVESTIGADOR:
Daniel P. Petrylak, M.D. Herbert Irving Pavilion 9th Floor Room 919
161 Fort Washington Avenue New York, New York 10032 United States
LOCALIDAD(ES):
Columbia University Medical Center Herbert Irving Pavilion 9th Floor Room 919
161 Fort Washington Avenue New York, New York 10032 United States
N° DEL TELÉFONO PARA EL ESTUDIO:
Daniel P. Petrylak, M.D. 212-305-1731 (las 24 horas)
Gary Shelton, R.N. 212-305-5275
Número del sujeto:
Versión 1.0, 21 Junio 2005
1
Iniciales del sujeto
APROBADO 13 Mar 2006
WIRB® Olympia, WA
Introducción:
Este apéndice del formulario de consentimiento tiene más información acerca del estudio de investigación. Puede que añada o que cambie la información del formulario de consentimiento que usted firmó al comenzar este estudio. Usted recibirá una copia firmada y fechada de este apéndice del formulario de consentimiento para guardarla en sus archivos.
Este formulario puede que contenga palabras que usted no entienda. Por favor pídale al médico encargado del estudio o al personal del estudio que le explique cualquier palabra o información que usted no entienda claramente. Usted puede llevarse una copia sin firmar de este apéndice del formulario de consentimiento para su casa para pensarlo o para discutirlo con sus familiares o amigos antes de que tome una decisión.
Este apéndice del formulario de consentimiento complementa el formulario de consentimiento que usted ya firmó para el estudio clínico del GW786034.
Consentimiento para la investigación genética en el tejido tumoral
Como parte de este estudio, GlaxoSmithKline (GSK) está llevando a cabo una investigación en el carácter genético de las células cancerosas para ayudarnos a comprender lo que determina si el medicamento en estudio llamado GW786034, funcionará o no en contra del tipo de cáncer que usted tiene. El objetivo general de esta investigación es tratar de hacer medicinas contra el cáncer que sean seguras y más eficaces para todas las personas que las toman. La participación en esta investigación es voluntaria. Usted no tiene que participar en la investigación genética del cáncer para participar en el estudio principal.
• No será necesario una biopsia del tumor adicional fuera del estudio principal.
• Los científicos estudiarán el material genético (por ejemplo, el ADN) de la muestra del tumor obtenida en el estudio principal para ayudar a entender cómo responde su tumor al GW786034.
• GSK puede estudiar la información clínica, las muestras de los tumores y los resultados de la investigación de usted y de otros sujetos para hacer medicinas o para pruebas para entender la respuesta del cáncer al GW786034.
• En algunos casos, puede que no se use la muestra de su tumor. Por ejemplo, esto pudiera suceder si no hubiera suficientes sujetos o si el estudio es suspendido por otros motivos.
• GSK y/o sus socios tienen la intención de reclamar la propiedad exclusiva de cualquier resultado de la investigación consistente con este consentimiento. Los resultados de esta investigación pueden tener valor comercial o de propiedad intelectual. No hay planes para que usted reciba ningún beneficio financiero que pudiera resultar de esta investigación genética del cáncer.
• Usted puede decidir no participar en esta investigación genética (retirar su consentimiento) en cualquier momento y todavía participar en el estudio principal.
Versión 1.0, 21 Junio 2005
2
Iniciales del sujeto
APROBADO 13 Mar 2006
WIRB® Olympia, WA
• Si usted decide no participar o retirar su consentimiento para la investigatión genética después de haber comenzado el estudio, usted no tiene que dar un motivo y no habrâ cambios en su tratamiento médico ni en su participatión en el estudio principal. Si usted se retira de esta investigatión, la muestra de su tumor será destruida y GSK solamente guardarâ la informatión del estudio obtenida y generada hasta ese momento. Todas las muestras que ya se hayan analizado para obtener la informatión de los marcadores biolôgicos no serân devueltas ni destruidas, ya que sirven como fuente de informatión.
• Todos los resultados son con motivos de investigatión y no de diagnosis clínica. Los resultados no se divulgarân a terceros, como companias de seguro, empleadores, o miembros familiares, a no ser que lo requiera la ley.
• Su informatión personal (por ejemplo, su sexo, edad, detalles de su conditión clínica) y la otra informatión (la informatión reunida por GSK como parte del estudio), será identificada solamente con un núméro (codificada).
• Esta investigatión puede ser emprendida con otras companias o universidades, y/o con otras oficinas de GSK en este país y en otros países. Si la informatión es enviada a otro país, GSK usarâ el mismo nivel de protectión con su informatión.
• Después de completar el estudio, la muestra restante del tumor se guardarâ por 2 años como mínimo y 15 años como mâximo, con el propôsito de la posibilidad de llevar a cabo pruebas adicionales consistentes con los objetivos del plan del estudio.
Consentimiento:
Me han comunicado que todas las otras condiciones del estudio permanecen iguales. He revisado el formulario de consentimiento del estudio original y continûo aceptando todos los términos expresados en él.
He leído (o me han leído) la informatión en este apéndice del formulario de consentimiento y he tenido la oportunidad de hacer preguntas acerca de las cosas que no entendía. Mis preguntas han sido contestadas satisfactoriamente.
Favor de marcar una casilla:
□ Yo doy mi consentimiento para participar en la investigación genética usando el tejido tumoral.
□ Yo no doy mi consentimiento para participar en la investigación genética usando el tejido tumoral.
Yo autorizo la entrega de mis registros médicos para propôsitos reglamentarios ô de investigaciôn, al patrocinador, a la FDA, a las agendas del DHHS, las agendas gubernamentales en otros países, y a WIRB»
Versión 1.0, 21 Junio 2005
3
Iniciales del sujeto
APROBADO 13 Mar 2006
WIRB® Olympia, WA
Al firmar este formulario de consentimiento, no renuncio a ninguno de mis derechos legales.
Nombre del sujeto: Firma del sujeto:
(en letras de imprenta) Fecha:
(día/ mes/ año)
Persona explicando el consentimiento informado: Nombre:
(en letras de imprenta)
Firma:
Fecha:
(día/ mes/ año)
Firma del
investigador (si es diferente al anterior)
Fecha:
(día/ mes/ año)
Nombre del
investigador (si es diferente al anterior)
(en letras de imprenta)
Fecha:
(día/ mes/ año)
Use lo siguiente sólo si es pertinente
Si este apéndice del formulario de consentimiento se lee al sujeto porque él mismo no es capaz de leerlo, un testigo imparcial que no esté afiliado ni con la investigación ni con el investigador, debe presenciar el consentimiento y firmar la declaración siguiente:
Confirmo que la información en este apéndice del formulario de consentimiento y toda otra información escrita ha sido explicada al sujeto con exactitud y aparentemente fue entendida por el mismo. El sujeto consiente libremente en participar en el estudio de investigación.
Nombre del testigo imparcial:
(en letras de imprenta)
Fecha:
Firma del testigo imparcial:
(día/ mes/ año) Nota: Esta sección de firmas no puede usarse para traducciones a otro idioma. Es necesario un formulario de consentimiento traducido para inscribir a los sujetos que no hablen inglés.
wirb/gsk/20051869/genetic add./trans. 03-22-2006/mo
Versión 1.0, 21 Junio 2005
4
Iniciales del sujeto
Translation - English ADDENDUM TO THE INFORMATION AND CONSENT FORM FOR THE RESEARCH SUBJECT
Genetic research on tumor tissue
Translated from the Spanish by
Medical Documentation Service
College of Physicians
Philadelphia, Pennsylvania
ADDENDUM TO THE INFORMATION AND CONSENT FORM FOR THE RESEARCH SUBJECT
Genetic research on tumor tissue
TITLE: Phase II study of the drug GW786034 utilizing a randomized discontinuation design in subjects with locally recurrent or metastatic clear cell renal cell carcinoma
SPONSOR: GlaxoSmithKline
Research Triangle Park, North Carolina
United States
INVESTIGATOR: Daniel P. Petrylak, M.D.
Herbert Irving Pavilion 9th Floor
Room 919
161 Fort Washington Avenue
New York, New York 10032
United States
LOCATION(S): Columbia University Medical Center
Herbert Irving Pavilion 9th Floor
Room 919
161 Fort Washington Avenue
New York, New York 10032
United States
TELEPHONE NO.
FOR STUDY: Daniel P. Petrylak, M.D.
212-305-1731 (24 hours)
Gary Shelton, R.N.
212-305-5275
Subject number: _________________________________
Introduction:
This addendum to the consent form contains more information about the research study. It may add or change the information on the consent form that you signed at the beginning of this study. You will receive a signed and dated copy of this addendum to the consent form to keep in your files.
This form may contain words that you do not understand. Please ask the doctor in charge of the study or the study staff to explain any word or information that is not clear to you. You may take an unsigned copy of this addendum to the consent form home to discuss it with your family or friends before making a decision.
This addendum to the consent form complements the consent form that you already signed for the clinical study of GW786034.
Consent for genetic research on tumor tissue
As part of this study, GlaxoSmithKline (GSK) is conducting an investigation on the genetic nature of cancer cells to help us understand what determines whether the study drug called GW786034 will or will not work against the type of cancer that you have. The general goal of this investigation is to try to make medicines against cancer that are safe and more effective for all people who take them. Participation in this investigation is voluntary. You do not have to participate in the genetic investigation of cancer to participate in the main study.
• An additional biopsy of the tumor besides that taken in the main study will not be necessary.
• The scientists plan to study the genetic material (for example, the DNA) of the tumor sample obtained in the main study to help understand how your tumor responds to GW786034.
• GSK may study the clinical information, the samples of the tumors, and the results of the research conducted on you and other subjects to produce medicines or to use in tests to understand how cancer responds to GW786034.
• In some cases, it is possible that your tumor sample may not be used. For example, this could happen if there were not enough subjects or if the study was discontinued for other reasons.
• GSK and/or its partners intend to claim exclusive ownership of any research results consistent with this consent. The results of this research may have commercial or intellectual property value. There are no plans for you to receive any financial benefits that may result from this genetic investigation of cancer.
• You may decide not to participate in this genetic investigation (withdraw your consent) at any time and still participate in the main study.
• If you decide not to participate or withdraw your consent to participate in the genetic investigation after having started the study, you do not have to give a reason and there will be no resulting changes in your medical treatment or your participation in the main study. If you withdraw from this investigation, your tumor sample will be destroyed and GSK will only keep the information from the study that has been obtained and generated up to that point. All samples that have already been analyzed to obtain information on the biologic markers will not be returned or destroyed, since they serve as a source of information.
• All of the results are to be used for research purposes and not for clinical diagnosis. The results will not be disclosed to third parties, such as insurance companies, employers, or family members, unless required by law.
• Your personal information (for example, sex, age, details of your medical condition) and other information (information collected by GSK as part of the study), will be identified only by a (code) number.
• This research can be shared with other companies or universities, and/or with other GSK offices in this country or in other countries. If the information is sent to another country, GSK will apply the same level of protection to your information.
• After completion of the study, the tumor sample will be kept for a minimum of 2 years and a maximum of 15 years, for the purpose of possibly carrying out additional tests consistent with the goals of the study plan.
Consent:
I have been informed that all of the other conditions of the study will remain the same. I have reviewed the original study consent form and still agree to all of the terms set forth there.
I have read (or had read to me) the information contained in this addendum to the consent form, and I have had the opportunity to ask questions about things that I did not understand. My questions were answered satisfactorily.
Please check a box:
I give my consent to participate in the genetic investigation using tumor tissue.
I do not give my consent to participate in the genetic investigation using tumor tissue.
I authorize the delivery of my medical records for regulatory or research purposes to the sponsor, to the FDA, to the DHHS agencies, government agencies in other countries, and to the WIRB®.
I do not waive any of my legal rights by signing this consent form.
Name of subject: ________________________ (in printed letters)
Signature of subject: ________________________ Date: __________
(month/ day/ year)
Person explaining the informed consent:
Name: ________________________ (in printed letters)
Signature of _________________________ Date:___________
investigator (if different from the preceding) (month/ day/ year)
Name of ________________________ Date:__________
investigator (if different from the preceding) (month/day/ year)
(in printed letters)
----------------------------------------Use the following only if applicable ------------------------------------------
If this addendum to the informed consent is read to the subject because he or she is not capable of reading it, an impartial witness not affiliated either with the investigation or with the investigator must witness the consent and sign the following statement:
I confirm that the information contained in this addendum to the consent form and any other written information has been accurately explained to the subject and appeared to be understood by the latter. The subject freely consents to participate in the research study.
Name of impartial witness: (in printed letters)
Signature of impartial witness: Date:____________
(month/day/year)
Note: This signature section cannot be used for translation to another language. A translated consent form is necessary in order to enroll subjects who do not speak English.
ADDENDUM TO THE INFORMATION AND CONSENT FORM FOR THE RESEARCH SUBJECT
Genetic research on tumor tissue
Translated from the Spanish by
Medical Documentation Service
College of Physicians
Philadelphia, Pennsylvania
ADDENDUM TO THE INFORMATION AND CONSENT FORM FOR THE RESEARCH SUBJECT
Genetic research on tumor tissue
TITLE: Phase II study of the drug GW786034 utilizing a randomized discontinuation design in subjects with locally recurrent or metastatic clear cell renal cell carcinoma
SPONSOR: GlaxoSmithKline
Research Triangle Park, North Carolina
United States
INVESTIGATOR: Daniel P. Petrylak, M.D.
Herbert Irving Pavilion 9th Floor
Room 919
161 Fort Washington Avenue
New York, New York 10032
United States
LOCATION(S): Columbia University Medical Center
Herbert Irving Pavilion 9th Floor
Room 919
161 Fort Washington Avenue
New York, New York 10032
United States
TELEPHONE NO.
FOR STUDY: Daniel P. Petrylak, M.D.
212-305-1731 (24 hours)
Gary Shelton, R.N.
212-305-5275
Subject number: _________________________________
Introduction:
This addendum to the consent form contains more information about the research study. It may add or change the information on the consent form that you signed at the beginning of this study. You will receive a signed and dated copy of this addendum to the consent form to keep in your files.
This form may contain words that you do not understand. Please ask the doctor in charge of the study or the study staff to explain any word or information that is not clear to you. You may take an unsigned copy of this addendum to the consent form home to discuss it with your family or friends before making a decision.
This addendum to the consent form complements the consent form that you already signed for the clinical study of GW786034.
Consent for genetic research on tumor tissue
As part of this study, GlaxoSmithKline (GSK) is conducting an investigation on the genetic nature of cancer cells to help us understand what determines whether the study drug called GW786034 will or will not work against the type of cancer that you have. The general goal of this investigation is to try to make medicines against cancer that are safe and more effective for all people who take them. Participation in this investigation is voluntary. You do not have to participate in the genetic investigation of cancer to participate in the main study.
• An additional biopsy of the tumor besides that taken in the main study will not be necessary.
• The scientists plan to study the genetic material (for example, the DNA) of the tumor sample obtained in the main study to help understand how your tumor responds to GW786034.
• GSK may study the clinical information, the samples of the tumors, and the results of the research conducted on you and other subjects to produce medicines or to use in tests to understand how cancer responds to GW786034.
• In some cases, it is possible that your tumor sample may not be used. For example, this could happen if there were not enough subjects or if the study was discontinued for other reasons.
• GSK and/or its partners intend to claim exclusive ownership of any research results consistent with this consent. The results of this research may have commercial or intellectual property value. There are no plans for you to receive any financial benefits that may result from this genetic investigation of cancer.
• You may decide not to participate in this genetic investigation (withdraw your consent) at any time and still participate in the main study.
• If you decide not to participate or withdraw your consent to participate in the genetic investigation after having started the study, you do not have to give a reason and there will be no resulting changes in your medical treatment or your participation in the main study. If you withdraw from this investigation, your tumor sample will be destroyed and GSK will only keep the information from the study that has been obtained and generated up to that point. All samples that have already been analyzed to obtain information on the biologic markers will not be returned or destroyed, since they serve as a source of information.
• All of the results are to be used for research purposes and not for clinical diagnosis. The results will not be disclosed to third parties, such as insurance companies, employers, or family members, unless required by law.
• Your personal information (for example, sex, age, details of your medical condition) and other information (information collected by GSK as part of the study), will be identified only by a (code) number.
• This research can be shared with other companies or universities, and/or with other GSK offices in this country or in other countries. If the information is sent to another country, GSK will apply the same level of protection to your information.
• After completion of the study, the tumor sample will be kept for a minimum of 2 years and a maximum of 15 years, for the purpose of possibly carrying out additional tests consistent with the goals of the study plan.
Consent:
I have been informed that all of the other conditions of the study will remain the same. I have reviewed the original study consent form and still agree to all of the terms set forth there.
I have read (or had read to me) the information contained in this addendum to the consent form, and I have had the opportunity to ask questions about things that I did not understand. My questions were answered satisfactorily.
Please check a box:
I give my consent to participate in the genetic investigation using tumor tissue.
I do not give my consent to participate in the genetic investigation using tumor tissue.
I authorize the delivery of my medical records for regulatory or research purposes to the sponsor, to the FDA, to the DHHS agencies, government agencies in other countries, and to the WIRB®.
I do not waive any of my legal rights by signing this consent form.
Name of subject: ________________________ (in printed letters)
Signature of subject: ________________________ Date: __________
(month/ day/ year)
Person explaining the informed consent:
Name: ________________________ (in printed letters)
Signature of _________________________ Date:___________
investigator (if different from the preceding) (month/ day/ year)
Name of ________________________ Date:__________
investigator (if different from the preceding) (month/day/ year)
(in printed letters)
----------------------------------------Use the following only if applicable ------------------------------------------
If this addendum to the informed consent is read to the subject because he or she is not capable of reading it, an impartial witness not affiliated either with the investigation or with the investigator must witness the consent and sign the following statement:
I confirm that the information contained in this addendum to the consent form and any other written information has been accurately explained to the subject and appeared to be understood by the latter. The subject freely consents to participate in the research study.
Name of impartial witness: (in printed letters)
Signature of impartial witness: Date:____________
(month/day/year)
Note: This signature section cannot be used for translation to another language. A translated consent form is necessary in order to enroll subjects who do not speak English.
French to English (BA French + Grad School) Spanish to English (UPenn Grad Linguistics ) Spanish to English (UPenn Grad Linguistics ) Spanish to English (US State Department) Italian to English (US State Department)
Italian to English (UPenn Italian Studies) Italian to English (Delaware Valley Translators Association)
Focus: Topics related to the pharmaceutical industry, medicine, chemistry, engineering, industry in general, contracts, patents and other miscellaneous technical subjects.
Over 40 years working as a free-lance translator mainly from French and Spanish, but also Italian and Portuguese into English. Highly skilled at proofreading material in English.
Over the years have coordinated an extensive corps of technical translators, editors, and word-processing personnel working in a variety of language groups.
Topics covered: pharmaceutical, medicine, chemistry, metallurgy, engineering and other technical subjects; also commercial translations.
Past or present clients: a large number of companies and agencies, including Thomson Reuters, The College of Physicians, Rohm and Haas, The Institute for Scientific Information, Thomson Scientific (US) Headquarters, and several patent attorneys.
Following is a list of the medical/pharmaceutical documents I have worked with:
Clinical trials
Package inserts
Adverse reaction reports
Informed Consents
Pharmaceutical articles on drug treatment assessments
Pharmaceutical patents
HIPAA documents
Back translations
Editing/proofreading.
Keywords: pharmaceutical industry/ medicine/ chemistry/ plant construction / patents
CV/Resume (DOC)