WO1997033580A1 - Maintien de la fonction renale pendant une intervention chirurgicale ou en situation de trauma - Google Patents

Maintien de la fonction renale pendant une intervention chirurgicale ou en situation de trauma Download PDF

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WO1997033580A1
WO1997033580A1 PCT/US1997/003439 US9703439W WO9733580A1 WO 1997033580 A1 WO1997033580 A1 WO 1997033580A1 US 9703439 W US9703439 W US 9703439W WO 9733580 A1 WO9733580 A1 WO 9733580A1
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general
recited
anesdiesia
kappa opioid
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Daniel R. Kapusta
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Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin

Definitions

  • This invention pertains to diuretics, particularly to diuretics that are used during surgery or severe trauma under general anesthesia.
  • gaseous (volatile) general anesthetics such as isoflurane, enflurane, desflurane, nitrous oxide, halothane, ethylene, cyclopropane, sevoflurane and methoxyfiurane cause an undesirable side effect on the kidneys: the use of gaseous general anesthetics during the stress of surgery or severe trauma causes acute renal failure and the nearly complete shutdown of urine production.
  • urine output antidiuresis
  • urinary sodium excretion antiinatriuresis
  • urinary potassium excretion antioxidantsis
  • Potentially life-threatening conditions that can develop during or after surgery under general anesthesia include pulmonary edema, seizures, angina, myocardial infarction, cardiac arrhythmia, heart failure, renal failure, renal tubular necrosis, sepsis, gastrointestinal hemorrhage, and central nervous system edema or dysfunction.
  • Drugs that function as diuretics in conscious patients often do not function at all, or do not function in the same manner, when used during general anesthesia There are a few drugs that have been used to increase urine output and to try to protect the kidneys from damage during anesthesia and surgery, but the existing drugs have complications. Drugs that have been used as diuretics during major operations and treatments for severe trauma include the following high ceiling loop diuretics such as furosemi e. bumetanide. and ethacrvnic acid. mannitol, an osmotic diuretic; dopamine, a dopaminergic agonist; and clonidine, an alpha-2 adrenoceptor agonist.
  • high ceiling loop diuretics such as furosemi e. bumetanide. and ethacrvnic acid.
  • mannitol an osmotic diuretic
  • dopamine a dopaminergic agonist
  • clonidine an alpha-2 adrenoceptor agonist.
  • these drugs have significant limitations in that either they have a limited ability to increase urine output during anesthesia and surgery, or they cause excessive loss of water and electrolytes.
  • these drugs are largely ineffective as diuretics.
  • the level of water output can be exceedingly high.
  • these agents can cause adverse, potentially life-threatening electrolyte imbalances such as hyponatremia (low plasma sodium) or hyperkalemia (high plasma potassium).
  • Furosemide, bumetanide and ethacrynic acid are short acting loop diuretics (none of which are opioid agonists). Furosemide is currently one of the drugs most frequently selected for increasing urine output during surgery under general anesthesia. Furosemide has been used to treat fluid overload and hypertension in the following settings: (1) following renal transplant, (2) as an adjunct in reducing intracranial pressure in patients undergoing surgery for intracranial hematomas, (3) for the treatment of edema associated with renal failure, and (4) as an adjunct in treating acute pulmonary edema. Furosemide is administered during a surgical procedure, but not before.
  • Adverse effects related to fluid or electrolyte disturbances can include hyperglycemia, hyperuricemia, hypokalemia, hyponatremia, hypovolemia, hypochloremic alkalosis, tachycardia, oliguria (diminished output of urine), and arrhythmias.
  • Furosemide can also cause acute hypotensive episodes during rapid diuresis that can then lead to further impairment of renal function.
  • furosemide can cause excessive losses of water, sodium, potassium, and calcium that can lead to life-threatening complications as severe as those caused by renal shutdown. For example, the marked rise in urine output caused by furosemide can cause renal failure by inducing hypovolemia (abnormally decreased volume of circulating blood).
  • hypovolemia is a particular problem in patients who are only minimally euvolemic (normal blood volume).
  • Y. Hamaya et al. "Diuretic Effect of Clo ⁇ idine during Isoflurane, Nitrous Oxide, and Oxygen Anesthesia," Anesthesiology, vol. 81, pp. 811-819 (1994) discussed the diuretic effect of clonidine (not an opioid agonist) during general anesthesia and surgery in human patients.
  • clonidine was administered 90 minutes before anesthesia it caused significant diuresis during surgery, but also produced substantial losses of sodium and potassium.
  • Clonidine also produced a substantial decrease in mean arterial pressure and heart rate in these patients.
  • clonidine can alter the pharmacological action of other drugs mat are frequently co- administered during various surgical operations. For example, the heart rate response to intravenous administration of atropine is attenuated. Moreover, the pressor response to intravenous ephedrine is augmented by clonidine pretreatment.
  • Mannitol (not an opioid agonist) is extensively employed as an osmotic diuretic. Mannitol is sometimes used to decrease intracranial pressure and fluid volume. Mannitol has also been used for prophylaxis and the treatment of acute renal failure during cardiovascular operations and in treating severe traumatic injury. However, mannitol causes extracellular (e.g., intravascular and interstitial) volume expansion, and it can precipitate congestive heart failure and pulmonary edema in patients with limited cardiac reserve. Mannitol can cause other major adverse reactions including hypernatremia, hyperkalemia, hyperosmolality, circulatory overload, renal failure, allergic reactions, and seizures. Mannitol's effects on plasma potassium and sodium can produce potentially life-threatening complications in surgical patients with underlying conditions such as cardiac or renal disease, or in patients with preexisting electrolyte abnormalities.
  • Dopamine is an inotropic agent that stimulates dopaminergic and alpha-adrenergic receptors. Dopamine is sometimes used in surgical settings to improve renal blood flow in an attempt to augment urine flow. Dopamine is also a natriuretic agent; it produces an increase in urine sodium excretion. Adverse effects of dopamine infusion in surgical patients can include hypotension, hypertension, tachycardia, hyponatremia, and cardiac arrhythmias. Dopamine can also cause renal artery vasoconstriction, thereby reducing urinary sodium and water excretion. Dopamine is contraindicated in patients receiving cyclopropane or halothane anesthesia.
  • diuretic compounds that may be used during surgery or treatment for severe trauma under a general, gaseous anesthetic.
  • diuretic compounds that induce a constant level of urine flow, that protect the kidneys, from damage, and that do not cause excessive loss of water or electrolytes.
  • diuretic compounds that preserve kidney function while maintaining homeostasis of intravascular volume, electrolyte concentration, and osmolality.
  • Endogenous opioid receptors have been identified in both the central nervous system (brain and spinal cord), and in the periphery. These receptors have been classified into three major subtypes: mu, delta, and kappa receptors. Morphine and related compounds are often called "mu opioids,” because they bind to mu receptors. The so-called “kappa opioid agonists,” first discovered about fifteen years ago, bind instead to kappa receptors with high selectivity. A compound is considered a kappa opioid agonist if it binds to kappa receptors in a binding assay, or if it demonstrates kappa agonist activity in functional assays. The kappa agonists are as effective as morphine in relieving pain. But unlike morphine, kappa agonists are not addictive, and do not cause cardiovascular or respiratory depression at the doses required for analgesia.
  • kappa opioids which are unique in being analgesic without being addictive, were initially regarded as a potential breakthrough in the therapeutic management of chronic pain.
  • no kappa opioid agonists have been approved in any country for any indication to date.
  • the reason is that kappa agonists cause dysphoria that is not well tolerated by patients during chronic use.
  • the sensation of dysphoria differs between individuals, variously including dizziness, fatigue, paresthesia, headache, feeling "high,” thinking abnormally, emotional lability, facial flushing, nausea, and vomiting. Unsuccessful attempts have been made to separate the analgesic and dysphoric properties of kappa agonists.
  • the urine flow rate in the conscious rats increased to 118 ⁇ 22 / tl/min after 15-30 minutes, an increase of 78 ⁇ l/min over the baseline flow rate.
  • a barbiturate not a gaseous anesthetic
  • the basal urine flow rate dropped substantially, to 4.0 ⁇ 0.5 ⁇ l/min.
  • 50 ⁇ g of E-2078 was administered i.v. to the anesthetized rats, the urine flow rate increased, but only slightly, to 6.3 + 1.0 ⁇ l/min, still well below die basal rate in the conscious animals.
  • Pentobarbital anesthesia dramatically reduced the ability of the kappa agonist to increase urine output.
  • the intravenous (i.v.) administration of 50 ⁇ g E-2078 was also reported to decrease urinary sodium excretion from 3.0 ⁇ 0.6 ⁇ Eq/min (basal) to 1.4 ⁇ 0.4 ⁇ Eq/min (at 30-45 min) in conscious rats.
  • basal urinary sodium excretion was reported to drop to 0.2 ⁇ Eq/min.
  • Barbiturates modulate the action of neurotransmitters at specific receptor sites. For example, it is known that barbiturates bind to 7-aminobutyric acid (GABA) receptors, thereby enhancing the inhibitory action of GABA on the central nervous system.
  • GABA 7-aminobutyric acid
  • gaseous anesthetics do not directly bind to specific receptor sites. Instead, gaseous anesthetics act on the lipid matrix of the cell membrane to distort the channels involved in sodium conductance, thereby stabilizing nerve membranes and reducing nerve activity.
  • Barbiturates are metabolized by liver enzymes to active metabolites. Gaseous anesthetics are eliminated, largely unchanged, through expiration. Barbiturates and gaseous anesthetics have different effects on die release of circulating hormones (e.g., epinephrine, histamine, angiotensin II, vasopressin, aldosterone, adrenocorticotropic hormone). Barbiturates increase renal vascular resistance, while gaseous anesthetics decrease renal vascular resistance. Barbiturates cause central nervous system stimulation and can induce seizures, whereas gaseous anesthetics do not cause seizure activity.
  • hormones e.g., epinephrine, histamine, angiotensin II, vasopressin, aldosterone, adrenocorticotropic hormone.
  • Barbiturates increase renal vascular resistance, while gaseous anesthetics decrease renal vascular resistance. Barbiturates cause central nervous system stimulation
  • barbiturates and gaseous anesthetic agents operate through separate mechanisms, have different effects on neural and hormonal systems, and produce different central and peripheral nervous system responses, results obtained with one type of anesthetic cannot be extrapolated to the other.
  • barbiturates and gaseous anesthetics use different mechanisms to produce acute renal failure and to decrease urine and electrolyte output during surgery.
  • the same physiological result e.g. impaired renal function during anesthesia and surgery
  • control urine flow rates in these groups of dogs before U-50,488 administration only ranged from 0.031 ⁇ 0.007 (in the lowest dose group, 0.2 mg/kg) to 0.063 ⁇ 0.020 ml/min/kg (in the middle dose group, 1 mg/kg).
  • the administration of U-50,488 caused a dose-dependent increase in urine flow rate, peaking within two hours.
  • the lowest dose (0.2 mg/kg) produced about a 2.5-fold increase in urine flow rate (i.e. to approximately 0.078 ml/min kg).
  • kappa agonists could be developed that did not have analgesic/dysphoric properties, but that could still produce a diuretic response
  • the compounds might be useful as water diuretics for chronic hyponatremic disorders.
  • Conscious rats were infused intravenously with saline at 10 l/min, and were hydrated by a bolus administration of lukewarm water intragastrically. The effects of kappa opioids on the rats were then studied. When urinary output exceeded the infusion rate by 2 ml, it was replaced by lukewarm tap water via the stomach catheter.
  • Urinary flow for rats given U-50,488 increased from a baseline rate of about 150 ⁇ l/min (about equal to the rate of the hypotonic saline infusion), to a peak of about 220 ⁇ l/min at 60 minutes after injection. The increased urine flow was not sustained, however, and urine flow dropped below baseline to about 90 ⁇ l/min at 200 minutes after injection. Tifluadom produced a similar diuresis.
  • kappa-opiox ⁇ agonists may be used to prevent the impairment of renal function mat occurs during surgery or treatment of severe trauma under gaseous anesthesia. Not only do kappa opioid agonists preserve renal function and maintain a constant level of urine output during anesthesia and surgery, but they also preserve sodium, potassium, calcium, and total osmolality, thereby helping to keep plasma electrolyte levels constant.
  • Kappa agonists may be used in heal y patients, but are particularly useful for surgical patients with compromised cardiovascular or renal function, or otherwise having a prior condition of water or electrolyte imbalance.
  • This invention encompasses the use of kappa opioid agonists to induce diuresis in anesthetized mammals (including humans) during surgery or treatment of severe trauma, where the anesthesia is induced by a volatile, inhaled anesthetic, including one or more of the following: isoflurane, enflurane, desflurane, nitrous oxide, halothane, ethylene, cyclopropane, sevoflurane, and metiioxyflurane.
  • a volatile, inhaled anesthetic including one or more of the following: isoflurane, enflurane, desflurane, nitrous oxide, halothane, ethylene, cyclopropane, sevoflurane, and metiioxyflurane.
  • prior diuretics can be ineffective in modifying urine output in surgical patients with certain pre-existing conditions (e.g., cirrhosis with ascites, congestive heart failure, or chronic renal failure, or hypotension following severe traumatic injury or shock).
  • urine flow rate remained constant during infusion of U-50,488H (60 minutes) at approximately 50-70 ⁇ l/min, a level similar to that observed before administration of anesthesia and surgery. After stopping the infusion of U-50.488H, the urine flow rate remained elevated at a similar level for an additional 100-120 minutes.
  • dysphoric response to is kappa opioid pretreatment is possible, mis potential adverse response is likely to be masked by the actions of other drugs or the anesthetic agent.
  • drugs such as diazepam (Valium), morphine, meperidine (Demerol), codeine, oxycodone, etc.
  • drugs such as diazepam (Valium), morphine, meperidine (Demerol), codeine, oxycodone, etc.
  • drugs such as diazepam (Valium), morphine, meperidine (Demerol), codeine, oxycodone, etc.
  • pre-, peri-, and post-operative medications are typically used as pre-, peri-, and post-operative medications in the surgical patient, and should conceal any dysphoria otherwise resulting from the kappa opioid.
  • persistent dysphoric effects make intolerable the chronic administration of kappa opioids for other uses.
  • Figures 1(a), 1(b), and 1(c) depict the levels of urine flow rate, urinary sodium excretion, and urinary potassium excretion, observed in conscious control rats infused with saline.
  • Figures 2(a)-(d) depict me renal responses of rats upon invasive surgery and isoflurane anesthesia, without any diuretic.
  • Figures 3(a)-(d) illustrate the ability of the kappa opioid agonist U-50,488H to reverse the impairment of urine flow rate produced by the combination of surgery and isoflurane anesthesia.
  • Figures 4(a)-(d) demonstrate the effect of U-50,488H pretreatment on renal response during surgery and isoflurane anesthesia.
  • Figures 5(a)-(c) illustrate the effects of continuous intravenous infusion of U-50.488H on renal excretory function in a rat during surgery under isoflurane anesthesia.
  • Figs. 6(a)-(d) depict the effects of pretreatment of a rat with the cis enantiomer of U- 50,488H.
  • Figs. 7(a)-(d) depict the effects of pretreatment with the kappa opioid agonist U-62,066E.
  • Figs. 8(a)-(c) show the effects of a long-duration intravenous infusion of U-62.066E on renal function in a rat during surgery under isoflurane anesmesia.
  • Figs. 9(a)-(d) depict the effects of pretreatment with the kappa opioid agonist U-69,593 on renal function in a rat.
  • Figs. 10(a)-(d) depict the effects of pretreatment with e kappa opioid agonist bremazocine in a rat.
  • Figs. 11 (a)-( ) depict the effects of pretreatment with the kappa opioid agonist tifluadom in a rat.
  • Figs. 12(a)-(c) demonstrate the renal effects of an intravenous U-50,488H infusion in a rat during surgery and anesmesia, where the kappa agonist was dissolved in a solution of 5% dextrose in water instead of saline.
  • Figs. 13(a)-(c) illustrate the renal responses produced by the high-ceiling loop diuretic furosemide in isoflurane-treated rats under surgery.
  • Figs. 14(a)-(c) illustrate the effects of furosemide infusion on renal response during surgery and anesthesia.
  • Figs. 15(a)-(c) illustrate the effects of the osmotic diuretic mannitol on renal response during surgery and anesthesia.
  • V urine flow rate
  • U N ,V urinary sodium excretion
  • U K V urinary potassium excretion
  • the levels of urine flow rate, urinary sodium excretion, and urinary potassium excretion were 42 ⁇ 7 ⁇ l/min, 7.6 ⁇ 0.5 ⁇ Eq/min, and 3.3 ⁇ 0.5 ⁇ Eq/min, respectively.
  • urine flow rate, urinary sodium excretion, and urinary potassium excretion remained approximately steady in me conscious rats throughout the duration of study.
  • me experiments depicted in Figure 1 an intravenous infusion of isotonic saline at a rate of 55 ⁇ l/min was started in the conscious state, and. was continued for the duration of the surgery and isoflurane anesthesia (200 minutes total). After 15 minutes of isotonic saline infusion while conscious, the rats were anesthetized by intravenous bolus administration of thiopental (25 mg/kg).
  • FIGs 3(a)-(d) illustrate the ability of the kappa opioid agonist U-50,488H (a benzeneacetamide derivative) to reverse the impairment of urine flow rate produced by the combination of surgery and isoflurane anesthesia.
  • the U-50,488H was a gift from Upjohn Pharmaceuticals (Kalamazoo, Michigan).
  • this kappa opioid agonist caused an "overshoot" in urine flow rate to about 120 ⁇ l/min, compared wi the isotonic saline infusion rate of 55 ⁇ l/min. It is likely that the "overshoot” resulted from the large volume of fluid retained since the beginning of surgery and isoflurane administration. Despite the increase in urine flow rate, urinary sodium and potassium excretion remained at low levels throughout the duration of die study. These effects are novel; all current, clinically-used diuretics, whether used in surgical patients or conscious patients, cause increases not only in urine flow, but also in urinary sodium and potassium excretion rates.
  • Figures 4(a)-(d) demonstrate the effect of kappa agonist pretreatment on renal response during surgery and isoflurane anesthesia.
  • Rats were infused intravenously for 15 minutes with the kappa opioid U-50.488H (100 ⁇ g/kg/min) (a benzeneacetamide derivative) while conscious.
  • U-50.488H 100 ⁇ g/kg/min
  • anesthesia was induced by intravenous bolus administration of thiopental (25 mg/kg), and invasive surgery (tracheotomy and bladder catheter implantation) was performed.
  • urine a 5 minute sample
  • Anesthesia was thereafter maintained by administering isoflurane to the animals through the tracheotomy tube.
  • FIGs 5(a)-(c) illustrate the effects of continuous intravenous infusion of U-50,488H on renal excretory function in a single female Sprague-Dawley rat during surgery under isoflurane anesmesia.
  • the experimental procedure was similar to that described for the experiments of Figure 4, with me exception mat U-50,488H was continuously infused intravenously for 10 hours after the. start of isoflurane anesthesia. Abbreviations are as in Figure 2.
  • Pretreatment with U-50,488H prevented the initial anesthesia and surgery-induced shutdown of urine flow rate that normally results from these stressors at time 0-1 hours.
  • intravenous infusion of U-50,488H continued to protect the kidneys from renal impairment over time.
  • urinary potassium excretion levels were low during die first hour of U-50,488H infusion. After the first hour, urinary potassium excretion rose slowly for a time (time 1-3 hours), and men more rapidly (time 4-10 hours). Urinary sodium excretion remained low for several hours (time 0-5 hours), but increased substantially after urinary potassium excretion had reached its peak (time 6-10 hours). It appeared that the changes in urinary sodium and potassium excretion were dissociated from one another, and that they occurred as different physiological mechanisms acted to override the action of U-50,488H on renal handling of sodium and potassium.
  • Kappa agonists are thus uniquely beneficial in mat they can protect die kidneys from shutdown while maintaining constant urine output, without substantially inhibiting physiological compensatory mechanisms for the excretion of sodium and potassium when appropriate. Put differently, kappa opioid agonists do not substantially interfere wim the regulatory mechanisms governing electrolyte homeostasis.
  • Figs. 6(a)-(d) depict the effects of pretreatment of a single Sprague-Dawley rat wim the cis enantiomer of U-50.488H.
  • the active kappa opioid agonist trans-(+/-)- U-50,488H
  • the c/.r-U-50,488H enantiomer has previously been shown to be devoid of activity at kappa opioid receptors.
  • the same experimental protocol was used as described above for the experiments of Figure 4, except that the study was terminated after 60 minutes of intravenous infusion (55 ⁇ l/min) of the inactive cw-U-50,488H enantiomer.
  • Abbreviations are as for Figure 2.
  • Figs. 7(a)-(d) depict me effects of pretreatment with a different kappa opioid agonist, U-62.066E (spiradoline, a benzeneacetamide derivative).
  • U-62.066E was purchased from Research Biochemicals International (Natick, MA). Rats (two male and two female) underwent the same experimental protocol as described for the experiments of Figure 4, except mat the kappa agonist U-62,066E was infused intravenously (55 ⁇ l/min) instead of U-50,488H. Since U-62,066E evoked similar responses in male and female rats in diese studies, data for bo sexes were pooled together in Figs. 6(a)-(d). Abbreviations are as for Figure 2.
  • Figs. 8(a)-(c) show die effects of a long-duration intravenous infusion of U-62,066E on renal excretory function in a single male Sprague-Dawley rat during surgery under isoflurane anesmesia.
  • the experimental procedure was similar to that described for the experiment of Figure 6, except that the kappa agonist infusion was continued for 6 hours after the start of isoflurane anesthesia.
  • Abbreviations are as in Figure 2.
  • Pretreatment with U-62,066E prevented impairment of urine flow rate during surgery and anesmesia.
  • urine flow rate remained elevated mroughout me 6 hours of the study.
  • Figs. 9(a)-(d) depict the effects of pretreatment with a different kappa opioid agonist, U-69,593 (a benzeneacetamide derivative) in a single rat.
  • U-69,593 was purchased from Research Biochemicals International, Natick, MA.
  • Figs. 10(a)-(d) depict me effects of pretreatment with a different kappa opioid agonist, bremazocine (a benzomorphan derivative) in a single rat.
  • Bremazocine was a gift from the research technology branch of die National Institute for Drug Abuse (NIDA).
  • NIDA National Institute for Drug Abuse
  • the same experimental protocol was used as described above for the experiment of Figure 9, except that the kappa agonist bremazocine was infused intravenously (55 ⁇ l/min) instead of U-69,593 for a total of 120 minutes.
  • Abbreviations are as for Figure 2.
  • benzomorphan derivative kappa agonists also provide renal protection during surgery under general anesthesia.
  • Figs. U(a)-(d) depict me effects of pretreatment with a different kappa opioid agonist, tifluadom (a benzodiazepine derivative) in a single rat. Tifluadom was a gift from Dr. Joseph M. Moerschbaecher, Department of Pharmacology, Louisiana State University Medical Center (New Orleans, LA).
  • Urinary sodium and potassium excretion and urine osmolality remained low throughout the study.
  • the effects of tifluadom were similar to those shown in Figure 4, Figure 7, Figure 9 and Figure 10 for rats treated with U-50,488H, U-62.066E, U-69,593, and bremazocine, respectively.
  • kappa agonists of the benzeneacetamide e.g. U-50.488H, U-62,066E, U-69,593, etc.
  • benzomorphan e.g. bremazocine
  • me benzodiazepine derivative kappa opioid agonists also provide renal protection during surgery under general anesmesia.
  • the experimental mediods were otherwise the same as those described for Figure 8. Abbreviations are as in Figure 2.
  • FIGs. 13(a)-(c) illustrate me renal responses produced by die high- ceiling loop diuretic furosemide in isoflurane-treated rats under surgery.
  • rats were infused intravenously wim isotonic saline at a rate of 55 ⁇ l/min for the duration of die study.
  • Thirty minutes after e start of isoflurane anesthesia consecutive 10- minute urine samples were collected during two isotonic saline control periods (C), and after an intravenous bolus injection of furosemide (F1-F6).
  • C isotonic saline control periods
  • F1-F6 furosemide
  • furosemide As shown in Fig. 13(a), following bolus administration of furosemide, die urine flow rate initially increased to extremely high levels (about 300 ⁇ l/min), and dien declined rapidly. As shown in Figs. 13(b) and (c), furosemide caused a large urinary loss of sodium and potassium. Al ough furosemide can induce a diuretic response during surgery and anesmesia, it also causes large changes in body fluid compartments. In addition, unlike die kappa opioids, furosemide causes a substantial loss of sodium and potassium. Such large shifts in body water and electrolyte composition are undesirable during surgery.
  • Figs. 14(a)-(c) illustrate me effects of furosemide infusion on renal response during surgery and anesmesia.
  • the protocol described in connection wim Figure 5 was repeated, except mat furosemide (instead of a kappa agonist) was infused intravenously over the duration of the study.
  • Intravenous infusion of furosemide caused large increases in urine flow rate (up to about 200 ⁇ l/min), in urinary sodium excretion, and in urinary potassium excretion. These renal responses were immediate in onset.
  • furosemide infusion caused the urine flow rate, urinary sodium excretion, and urinary potassium excretion to remain at high levels for about 110 minutes (periods Fl-Fl l).
  • Fl-Fl l the excretion rates of water, sodium, and potassium returned to die impaired pre-drug levels.
  • FIGs. 15(a)-(c) illustrate the effects of i.v. bolus administration of the osmotic diuretic mannitol on renal response during surgery and anesmesia.
  • the protocol described above for Figure 13 was repeated in isoflurane-anesmetized rats under surgery, except mat mannitol (instead of a kappa agonist or a loop diuretic) was injected intravenously.
  • Bolus injection of mannitol caused a large increase in urine flow rate (up to 135 ⁇ l/min) that was immediate in onset.
  • Mannitol also caused an increase in urinary sodium and potassium excretion, but the magnitude of diese changes was considerably less than that produced by furosemide (see Figs. 13 and 14).
  • the profound diuretic response initially produced by mannitol die increase in urine flow rate was not maintained and declined to the impaired levels observed before drug administration.
  • Kappa opioid agonists may be administered to humans or other mammals in pharmaceutical compositions or formulations in combination with one or more pharmaceutically acceptable carriers known in the art.
  • suitable pharmaceutical adjuvants for injecting solutions include stabilizing agents, solubilizing agents, buffers, and viscosity regulators. Examples of these adjuvants include but are not limited to ethanol, emylenediamine tetraacetic acid, tartrate buffers, citrate buffers, and high molecular weight polyethylene oxide viscosity regulators.
  • These pharmaceutical formulations may be injected intramuscularly, intraperitoneally, or intravenously, although intravenous injection/infusion is preferred.
  • the preferred doses of kappa agonist pretreatments will depend on the particular compound used, and are typically about 2-10 times, preferably about 4-5 times e dose required to produce a substantial diuretic response in a conscious individual.
  • kappa opioid agonist Any pharmacologically acceptable kappa opioid agonist will function the present invention, as die underlying mechanism appears to depend upon binding to and stimulating kappa opioid receptors.
  • kappa opioid agonists There are at least five major categories of kappa opioid agonists: (1) the dynorphins, which are endogenous peptides and their derivatives; (2) the benzodiazepine derivatives, such as tifluadom; (3) the benzomorphan derivatives, such as ediylketocyclazocine, ketocyclazocine, and bremazocine; (4) die benzeneacetamide derivatives, such as U-50,488H, U-62.066E, U-69,593, CI-977, and PD 117302; and (5) the aminomethylpyridines, such as BRL 52537, BRL 52656, BRL 53114, GR89696, GR86014, and GR91272.
  • kappa opioid agonists are listed below. In many cases die listings include references to a commercial source, a citation for the synthesis of a compound, or bodi.
  • BRL 53114 (-)-l-(4-trifluoromethylphenyl)-acetyl-2-(l-pyrrolidinylmethyl)-3,3-dimethyl- piperidine hydrochloride
  • BRL 52974 4-( 1 -pyrrol idinylmethyl)-5-(3 ,4-dichl or ophenyl)acety 1 -4 , 5 ,6,7- tetrahydroimidazo-[4,5-c]-pyridine
  • EMD 60400 iV-methy I -N-[( 1 S)- 1 -phenyl-2-((3.?)-3-hydroxypyrrolidine- 1 -yl)-ethyl]-2- amino-phenylacetamide 2HC1 A. Barber etal., Br. J. Pharmacol, vol. Ill, pp.843-851 (1994).
  • Dynorphin A-(l-17) Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-
  • Dynorphin A-(l-13) Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys
  • ketocyclazocine (+ )-3-(cyclopropylmethyl)-8-keto-5-(eq)-9(ax)-dimethyl-6,7- benzomorphan bremazocine [5R-(5,7,8- / S)]-/V-methyl-N-[7-(l -pyrrol idinyl)-l -oxaspiro]-4, 5- [dec-8-yl]- 4-benzofuranacetamide

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Abstract

Des agonistes Kappa-opioides préviennent l'insuffisance de la fonction rénale provoquée par la combinaison d'une anesthésie gazeuse et d'une intervention chirurgicale ou d'un trauma grave. Ces agents non seulement préservent la fonction rénale et maintiennent l'expulsion d'urine, mais ils maintiennent également la concentration et l'osmolalité d'électrolyte du plasma par réduction de la perte rénale de sodium et de potassium comparés à d'autres agents diurétiques.
PCT/US1997/003439 1996-03-11 1997-03-05 Maintien de la fonction renale pendant une intervention chirurgicale ou en situation de trauma WO1997033580A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6506762B1 (en) 1999-09-30 2003-01-14 Neurogen Corporation Certain alkylene diamine-substituted heterocycles
WO2019197594A1 (fr) * 2018-04-13 2019-10-17 Blumentech, S.L. Produit de combinaison pour l'induction et/ou la maintenance d'une anesthésie générale

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5384113A (en) * 1991-08-29 1995-01-24 Mallinckrodt Medical, Inc. Stabilizers to prevent autoradiolysis of radiolabeled peptides and proteins

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5384113A (en) * 1991-08-29 1995-01-24 Mallinckrodt Medical, Inc. Stabilizers to prevent autoradiolysis of radiolabeled peptides and proteins

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6506762B1 (en) 1999-09-30 2003-01-14 Neurogen Corporation Certain alkylene diamine-substituted heterocycles
US6696445B2 (en) 1999-09-30 2004-02-24 Neurogen Corporation Certain alkylene diamine-substituted heterocycles
US7074929B2 (en) 1999-09-30 2006-07-11 Neurogen Corp. Certain alkylene diamine-substituted heterocycles
WO2019197594A1 (fr) * 2018-04-13 2019-10-17 Blumentech, S.L. Produit de combinaison pour l'induction et/ou la maintenance d'une anesthésie générale

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