[Central action of Salmonella typhimurium endotoxin on the hypothalamo-hypophyseal-adrenal axis].
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Adrenal Glands↗
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Intravenous and intrathecal miconazole therapy for systemic mycoses.
Ten patients with systemic mycoses, including five with fungal meningitis, were treated with intravenously or intrathecally administered miconazole, or both. Minimal inhibitory concentrations of miconazole for clinical isolates of Coccidioides immitis, Cryptococcus neoformans and Candida albicans were less than 0.6 microg per ml. Except for pruritus of variable degrees, the drug was well tolerated both intravenously and intrathecally by all patients. No measurable impairment of renal, hepatic or bone marrow function was observed in patients after 4(1/2) months of intravenous therapy. No hematological or biochemical abnormalities and no evidence of recurrent coccidioidal osteomyelitis were observed in 16 months of follow-up in our first patient treated with this drug. Miconazole is apparently an effective antifungal drug of low toxicity and is a potentially useful agent for treatment of human systemic mycoses.
Aged↗
Perilymph penetration of methotrexate in cats.
The perilymph of the inner ear has recently been suggested as a site of frequent leukemic or lymphomatous infiltrates. Experimental evidence supports the existence of barrier mechanisms and explains the attenuated entry of several substances, including chemotherapeutic agents, from either the cerebrospinal fluid or blood into theperilymph. The present study describes the attenuated entry of methotrexate into the perilymph compartment of experimental animals following intrathecal or iv administration.
Animals↗
Evaluation of combined adrenal demedullation and chronic guanethidine treatment as a sympathectomy procedure for metabolic studies.
The usefulness of a combination of adrenal demedullation and treatment with guanethidine (25 mg kg-1 day-1, i.p. for 14 days) as a sympathectomy procedure for metabolic studies was investigated in the rat. The procedure reduced markedly or abolished pressor and positive chronotropic responses to tyramine, nicotine or electrical stimulation of the sympathetic spinal outflow. Hyperglycaemic responses to nicotine or spinal sympathetic stimulation were abolished. Nicotine infusion in intact animals reduced glucose-induced hyperinsulinaemia. On the other hand nicotine infusion in sympathectomized animals produced a marked elevation in glucose-induced hyperinsulinaemia relative to that seen in intact animals. The early hyperinsulinaemic response to glucose infusion during sympathetic stimulation was markedly greater in sympathectomized rats compared with that seen in intact rats. The sympathectomy procedure did not modify the glycaemic responses to adrenaline or insulin or glucose-induced hyperinsulinaemia.
Adrenal Medulla↗
Methotrexate. II. Use in pediatric chemotherapy.
The comprehensive use of methotrexate is possible because there is an easy way of reducing the toxic effects of this drug. Effective in the antidotic action are alkalinization of the urine, increasing hydration of the patient, and "rescue" of purine and pyrimidine metabolism in the tissues by use of reduced folates. Only intravenous administration, by means of infusion given over a long period (24 hours or more), results in reliable and reproducible concentrations in the plasma. Oral administration should be abandoned because of the variable resorption and the different concentrations reached in plasma by different individuals. Local administration, such as by intrathecal injection, is useful only when the interval between two succeeding injections is 14 days or more. On the basis of known pharmacokinetic constants, the dose of methotrexate and of citrovorum factor (leucovorin) which will result in the desired concentration in plasma, and possibly also in tissues, can easily be calculated. Use of the principle of concentration X time in dosage calculations will result in the avoidance of giving unnecessarily high doses of methotrexate.
Administration, Oral↗
[Pharmacokinetics of intrathecal chemotherapy and clinical problems].
The Central Nervous System has often been classified as a "drug sanctuary" as most anticancer drugs do not achieve effective penetration of the blood-brain barrier. With more effective systemic chemotherapy programs (especially in acute leukemia in children), the incidence of meningeal tumor involvement has increased. Even though a number of systemically administered agents might be used in treating the CNS, only three have been used intrathecally with good clinical results: the antimetabolites methotrexate (MTX) and cytosine arabinoside (Ara-C) and the alkylating derivative thiophosphoramide (thio-TEPA). Drug distribution in the CSF which is injected by lumbar puncture does not generally allow for delivery of effective quantities of drug to the cisternae nor the ventricles. Thus direct intraventricular injection via a subcutaneously implanted (Ommaya) reservoir is necessary to achieve adequate drug levels in the higher CNS cavities. The peak ventricular concentration of MTX, which was administered by Ommaya reservoir, at a dose of 15mg/m2, was 2.5 +/- 0.9 X 10(-4)M, and remained as a level of 10(-6)M for 72 hours with a half-life of 10.5 hours. During an intravenous 6 hour-infusion at a dose of 750-3,000mg/m2, MTX concentration in CSF reached 8.2 X 10(-7)M to 2.7 X 10(-6)M. The drug content in CSF had a linear concentration related to the drug level in plasma. Intrathecal MTX and Ara-C frequently cause symptoms of meningeal irritation. Occasionally cases of weakness and paralysis and rare instances of severe encephalopathy may occur. The best established causes of these symptoms is high concentration of these drugs in the CSF, or prolonged exposure of the brain to low CSF concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Vancomycin for treatment of bacterial meningitis.
Clinical experience with vancomycin for the treatment of bacterial meningitis has not been extensive. Presently available data indicate that when meningeal inflammation is present intravenously administered vancomycin penetrates into cerebrospinal fluid and therapeutically effective levels of drug therein are frequently attained. Treatment of meningitis with vancomycin has been effective in clinical situations that precluded the use of the commonly administered agents, i.e., in infections due to resistant strains or to unusual organisms, in patients allergic to penicillin, and in patients for whom therapy with a first-choice antibiotic has failed. When response to intravenously administered vancomycin was unsatisfactory, the addition of intrathecal therapy resulted in a favorable outcome in some patients. Combination therapy with agents that act synergistically with vancomycin has been beneficial. Vancomycin warrants serious consideration as a useful alternate antibiotic for the treatment of bacterial meningitis.
Adult↗
Amphotericin B: Ten common questions.
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Amphotericin B↗
The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia.
Although central nervous system (CNS) leukemic relapse is frequent in adult acute lymphocytic leukemia (ALL), the need for prophylaxis in different risk groups for CNS relapse, the value of high-dose systemic and intrathecal (IT) chemotherapy, and the timing of prophylaxis are not well defined. This analysis was conducted to investigate these questions and to assess the value of a risk-oriented CNS prophylaxis approach. We analyzed the incidence of CNS leukemia after initiation of therapy in patients treated on 4 consecutive trials for adult ALL including different CNS prophylactic modalities. The treatment groups included (1) the program preceeding the vincristine-Adriamycin-dexamethasone (VAD) regimen, with no CNS prophylaxis; (2) the VAD regimen with prophylaxis using high-dose systemic chemotherapy; (3) the modified VAD program with high-dose systemic chemotherapy to all patients and IT chemotherapy for high-risk patients after achieving complete remission; and (4) the hyperCVAD program with early high-dose systemic and IT chemotherapy starting during induction to all patients, with more IT injections (16IT) administered to the high-risk group for CNS relapse compared with the low-risk group (4IT). A total of 391 patients were included, 73 of whom were treated with preVAD, 112 with VAD, 114 with modified VAD, and 92 with hyperCVAD. The overall CNS relapse rates were 31%, 18%, 17%, and 3%, respectively for the 4 groups (P < .001). For the high-risk group for CNS relapse, they were 42%, 26%, 20%, and 2%, respectively (P < .001). The differences in CNS relapse rates in the low-risk group were not statistically significant. At 3 years, the overall CNS leukemia event-free rates were 48%, 76%, and 98%, respectively (P < .001). In the high-risk group, the CNS event-free rates were 38%, 66%, 75%, and 98%, respectively (P < .001); however, there was no difference in the low-risk group. We conclude that (1) high-dose systemic chemotherapy is a useful prophylactic measure; (2) early IT chemotherapy is necessary to reduce the incidence of CNS leukemia overall and in the high-risk group; and (3) a risk-oriented approach is appropriate to tailor the intensity of CNS prophylaxis.
Adolescent↗
Can high-dose methylprednisolone be diluted?
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Acute Disease↗
Possible involvement of the activation of voltage-sensitive calcium channels in the ameliorating effects of nefiracetam on scopolamine-induced impairment of performance in a passive avoidance task.
We investigated the effects of various types of calcium channel antagonists on the amelioration by nefiracetam [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide, DM-9384] of scopolamine-induced impairment of performance in a passive avoidance task in mice. The reversal of the scopolamine-induced impairment of performance by nefiracetam showed a bell-shaped plot. Both i.p. and i.c.v. injection of L-type calcium channel antagonists such as nifedipine and flunarizine attenuated the ameliorating effects of nefiracetam, although diltiazem had no effect. Neomycin, an N-type calcium channel antagonist, also attenuated these effects of nefiracetam in a dose-dependent manner. Further, LaCl3 but not NiCl2 showed inhibitory effects on the amelioration by nefiracetam. These results suggest that the activation of high-voltage-activated, but not low-voltage-activated, calcium channels is involved in the ameliorating effects of nefiracetam on scopolamine-induced impairment of performance in a passive avoidance task.
Animals↗
[Treatment of spasticity by intrathecal baclofen treatment].
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Baclofen↗
Toxicity following concurrent intrathecal and moderate-dose intravenous methotrexate.
To evaluate factors predisposing children with non-Hodgkin's lymphoma to toxicity from moderate dose methotrexate (MTX) (300 mg/m2 per 4 hours), we reviewed the medical records of 15 patients treated at our institution according to two similar protocols. Five patients experienced hyperemesis and/or severe mucositis. In two of these patients, pharmacokinetic analysis demonstrated delayed terminal excretion of methotrexate with a half-life of 3-3.5 days, compared to a previously reported t1/2 of 8-15 hours in subjects with normal clearance. All affected patients were large (body surface area 1.6-1.9 m2), and MTX toxicity was seen only during courses where intravenous MTX was given concurrently with intrathecal MTX. Four patients also received simultaneous prophylactic doses of oral trimethoprim-sulfamethoxazole (trimethoprim 5 mg/kg per day). We recommend that, in protocol design, consideration be given to avoiding concurrent use of intravenous and intrathecal MTX, and possibly trimethoprim-sulfamethoxazole. Where high doses of MTX are given based on large body surface area, urine alkalinization may be indicated.
Adolescent↗
[Intravenous anesthesia with perfused propofol combined with loco-regional spinal anesthesia].
The authors review the advantages and disadvantages of general and regional anesthesia in bad clinical conditions. The purpose of this study was to evaluate the efficacy of Blended Anesthesia (association of general anesthesia with a regional technique) in 25 patients belonging to ASA classes II-III-IV, undergoing surgery for various disease. General anesthesia was provided by perfusion of propofol, after a peridural or subarachnoid continuous anesthesia was started. Patients were either in spontaneous or controlled ventilation. There were no cases of hypotension or other important side effects and the majority of patients judged good the anesthetic technique in regard to lack of pain, exhaustion and recall of operation.
Aged↗
Blockade of cannabinoid-induced antinociception by norbinaltorphimine, but not N,N-diallyl-tyrosine-Aib-phenylalanine-leucine, ICI 174,864 or naloxone in mice.
Previous studies showed that cannabinoids administered intrathecally (i.t.) produced antinociception and synergism with the antinociceptive effects of morphine. Low doses of naloxone that appear selective for the mu receptor failed to block the antinociceptive effect of the cannabinoids. The present studies evaluated the interaction of the cannabinoids with kappa and delta opioid antagonists and agonists. Antinociception produced by delta 9 tetrahydrocannabinol (THC) and delta 8-THC (i.v., ED80 doses) was blocked by the kappa antagonist, nor-BNI (10 and 20 micrograms/mouse). The effects of CP 55,940 administered i.v. were blocked by norbinaltorphimine (nor-BNI; i.v. but not i.t.). The delta antagonist, N,N-diallyl-Tyr-Aib-Phe-Leu (ICI 174,864; 10 micrograms/mouse administered i.t.), failed to block the effects of any of the cannabinoids administered i.v. Nor-BNI administered i.t. blocked the antinociception produced by the cannabinoids (administered i.t., ED80 doses). The AD50s generated for nor-BNI vs. i.t. administered delta 9-THC, delta 8-THC, levonantradol and CP 55,940 were 3.5, 1.1, 3.8 and 4.5 micrograms/mouse, respectively. Nor-BNI (10 micrograms/mouse i.t.) shifted the dose-effect curve for delta 9-THC to the right in a parallel manner. delta 9-THC was additive with the kappa agonist, U50,488H, whereas delta 9-THC produced a parallel 37-fold shift to the left in the dose-effect curve of the delta agonist, DPDPE. Nor-BNI (70 micrograms/mouse i.c.v.) or ICI 174,864 (10 micrograms/mouse i.t.) failed to block the effects of the cannabinoids administered i.t. The exact nature of the nor-BNI/cannabinoid interaction is yet to be determined.
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
Continuous cervical intrathecal administration of morphine with a new infusion pump, the Anschütz IP 35.1: a case report.
The continuous intrathecal administration of low-dose morphine is an effective treatment for chronic neuropathic pain. Several implantable devices can be used for such treatments but they all have limitations. In this case report we opted for a new type of implantable pump, the Anschütz, for the combined cervical intrathecal administration of morphine and clonidine in a patient with severe cervicobrachialgia.
Adult↗
[Intrathecal administration of morphine and bupivacaine in the treatment of severe pain in chronic pancreatitis].
A 25-year-old male with idiopathic chronic pancreatitis suffered from severe pain not reacting to medical therapy. Intractable pain persisted after the following procedures: subtotal resection of the pancreas, interpleural administration of bupivacaine, epidural administration of bupivacaine, and thoracoscopic sympathectomy. Eventually, adequate pain relief was achieved with intrathecal administration of morphine and bupivacaine. An infusion pump, externally controlled by radiotelemetry, was implanted subcutaneously for intrathecal drug administration. With this pump the patient was fully ambulant. Intrathecal administration of morphine and bupivacaine through an implanted pump is a possible new technique for pain management in chronic pancreatitis.
Adult↗
Current status of patient-controlled analgesia in cancer patients.
Patient-controlled analgesia (PCA) is a relatively new technique in which patients are able to self-administer small doses of opioid analgesics when needed. Many different devices are available for opioid infusion, including a syringe pump, disposable plastic cylinder, and battery-operated computer-driven pump. These devices allow patients to choose an intermittent (demand) bolus, continuous infusion, or both modes of administration. Parameters, such as route, drug concentration dose, frequency, and maximum daily or hourly dose, are programmed by the physician. The patient decides whether or not to take a dose. Devices can be used to deliver the drug into a running intravenous infusion, the epidural space, or subcutaneously. Controlled trials indicate that PCA is probably superior to regular opioid administration in postoperative pain. Reported advantages include greater patient satisfaction, decreased sedation and anxiety, and reduced nursing time and hospitalization. Preliminary experience suggests that PCA is also useful and safe for cancer pain, but further research is greatly needed.
Administration, Oral↗