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PubMed1992

The history and development of the fentanyl series.

In the last two decades, opioid analgesics have assumed an important place in general anesthetic practice in the United States. Part of the reason for this has been the introduction of the potent new agonists fentanyl, sufentanil, and alfentanil. Because of problems with morphine-oxygen anesthesia (incomplete amnesia, occasional histamine-related reaction, marked increases in intra- and postoperative respiratory depression), a suitable alternative was sought but not found among existing opioids. A breakthrough came in 1960, when fentanyl was synthesized, laying the foundation for a better understanding of the structure-activity relationships of narcotic analgesics and stimulating interest in developing compounds with even greater potency and safety margins. Investigators interested in opioid anesthesia began to study fentanyl in animals and then in humans. Fentanyl (50-100 micrograms/kg) with oxygen (100%) was evaluated as an anesthetic in patients undergoing mitral valve and coronary artery surgery. Changes in cardiovascular dynamics with induction doses ranging from 8 to 30 micrograms/kg consisted of small decreases in heart rate and arterial blood pressure. All other cardiovascular variables studied, including cardiac output, remained unchanged, even with additional doses up to 100 micrograms/kg. It was determined that fentanyl had use as a narcotic anesthetic, despite its potential for cardiovascular depression and stimulation, respiratory depression, muscle rigidity, and, occasionally, incomplete anesthesia. Since the introduction of fentanyl, two other potent synthetic opioids have been introduced into clinical practice--sufentanil and alfentanil.

Combined Modality Therapy↗
PubMed1991

Evidence for genetic heterogeneity in malignant hyperthermia susceptibility.

Malignant hyperthermia susceptibility (MHS) is a clinically heterogeneous pharmacogenetic disorder characterized by accelerated metabolism, hyperthermia, and frequently muscle rigidity. MHS is elicited by all commonly used potent inhalation anesthetics and depolarizing neuromuscular blockers and remains an important cause of death due to anesthesia. Recent linkage studies suggest a single genetic locus for this disorder on chromosome 19q13.1. The results of our linkage analyses exclude several loci on 19q13.1 as a site for the gene(s) that produces the MHS phenotype in three unrelated families and clearly establish genetic heterogeneity in this disorder. These results are consistent with the hypothesis that the genetic defect that alters thermoregulation may vary in MHS and that clinical variability in the expression of MHS may be explained by genetic heterogeneity.

Chromosomes, Human, Pair 19↗
PubMed2005

A case of late-onset Segawa syndrome (autosomal dominant dopa-responsive dystonia) with a novel mutation of the GTP-cyclohydrase I (GCH1) gene.

We report a case of a 46-year-old Japanese woman with hereditary progressive dystonia with marked diurnal fluctuations and dopa-responsive dystonia (HPD/DRD). She developed difficulty in walking at the age of 44 years due to bradykinesia as well as hand tremors, muscle rigidity, increased tendon reflexes and mild dystonia in the lower extremities, all of which responded remarkably to low doses of levodopa (150 mg/day). Biopterin and neopterin concentrations in the cerebrospinal fluid (CSF) were decreased. Analysis of the guanosine 5'-triphosphate cyclohydrolase I (GCH1) gene revealed a novel mutation (W53X) in one allele. The GCH1 activity that was expressed in mononuclear blood cells was almost half the normal value (usually 2-20% of the normal value (39.0+/-9.2 pmol/ml) in patients with HPD/DRD). The relatively conserved GCH1 activity that is expressed in stimulated peripheral blood mononuclear cells may be related to the late clinical symptoms in this patient.

Biopterins↗
PubMed2005

Role of inflammation in gastrointestinal tract in aetiology and pathogenesis of idiopathic parkinsonism.

Idiopathic parkinsonism (IP) is a common disorder, conventionally regarded as neurodegenerative. Its cardinal features, poverty and slowness of movement, muscle rigidity, postural abnormality and a characteristic tremor, are associated with loss of dopaminergic neurones in the substantia nigra of the brain. Genetic factors explain only a minority of cases, and a common toxic environmental insult remains elusive. We propose that IP is a systemic disorder resulting from a ubiquitous peripheral infection, and that only the tip of the iceberg comes to diagnosis. There is evidence for inflammatory/immune activation peripherally and in the brain. We have used statistical modelling to explore links with non-specific and specific systemic markers of inflammation/infection in IP probands, and explore whether their partners and siblings have a frank or pre-presentation parkinsonian state. Critical to this approach is continuous objective measures of the facets of IP. Hypotheses on causality and mechanism are based on the statistical models. There is pathological and clinical evidence for direct involvement of the gastrointestinal tract in IP. The candidacy of Helicobacter pylori infection as a trigger event or driving infection is relatively high. We have found that eliminating infection in late parkinsonism with cachexia, a stage usually considered intractable, can result in a U-turn. However, eradication therapy may not provide a complete solution. Persistence of antibody against cytotoxin-associated antigen (CagA), increases the predicted probability of being labelled as having parkinsonism. Evidence for autoimmunity and immunocompromise is used to build schemes for the natural history. We conclude that current classifications of neuropsychiatric disease may not prove the best with respect to defining sub-clinical disease, prophylaxis or halting progression.

Gastroenteritis↗
PubMedDate not supplied

Interaction of serotonergic antidepressants and opioid analgesics: Is serotonin syndrome going undetected?

OBJECTIVES: To describe the potential for interaction between opioids and serotonergic antidepressants leading to the development of serotonin syndrome (SS), mechanism of the interaction, and the spectrum of SS in elderly residents of a long-term care facility. DESIGN: Case series. SETTING: Long-term care facility (LTCF) in California. PARTICIPANTS: Four elderly LTCF residents treated with serotonergic antidepressants including selective serotonin reuptake inhibitor (SSRI) or mirtazapine and opioids. MEASUREMENTS: Signs and symptoms suggestive of SS. RESULTS: We describe 4 cases of probable SS among elderly residents of a LTCF. The spectrum of serotonin toxicity ranged from visual hallucinations, muscle rigidity, myoclonus, or hypertension in patients taking an opiate with an SSRI to lethargy, hypotension, and hypoxia in a patient taking tramadol and mirtazapine. CONCLUSION: While many can benefit from coadministration of serotonergic antidepressants and opioids, it appears that some individuals are at increased risk for SS. Since SS is a clinical diagnosis, heightened clinician awareness of the possibility of SS among patients receiving SSRI or mirtazapine in combination with opioids may lead to earlier detection and avoidance of potentially lethal consequences.

Aged↗
PubMed2006

Role of reflex dynamics in spinal stability: intrinsic muscle stiffness alone is insufficient for stability.

Spinal stability is related to both the intrinsic stiffness of active muscle as well as neuromuscular reflex response. However, existing analyses of spinal stability ignore the role of the reflex response, focusing solely on the intrinsic muscle stiffness associated with voluntary activation patterns in the torso musculature. The goal of this study was to empirically characterize the role of reflex components of spinal stability during voluntary trunk extension exertions. Pseudorandom position perturbations of the torso and associated driving forces were recorded in 11 healthy adults. Nonlinear systems-identification analyses of the measured data provided an estimate of total systems dynamics that explained 81% of the movement variability. Proportional intrinsic response was less than zero in more than 60% of the trials, e.g. mean value of P(INT) during the 20% maximum voluntary exertion trunk extension exertions -415+/-354N/m. The negative value indicated that the intrinsic muscle stiffness was not sufficient to stabilize the spine without reflex response. Reflexes accounted for 42% of the total stabilizing trunk stiffness. Both intrinsic and reflex components of stiffness increased significantly with trunk extension effort. Results reveal that reflex dynamics are a necessary component in the stabilizing control of spinal stability.

Humans↗
PubMed2005

Toxin-induced hyperthermic syndromes.

Toxin-induced hyperthermic syndromes are important to consider in the differential diagnosis of patients presenting with fever and muscle rigidity. If untreated, toxin-induced hyperthermia may result in fatal hyperthermia with multisystem organ failure. All of these syndromes have at their center the disruption of normal thermogenic mechanisms, resulting in the activation of the hypothalamus and sympathetic nervous systems.The result of this thermogenic dysregulation is excess heat generation combined with impaired heat dissipation. Although many similarities exist among the clinical presentations and pathophysiologies of toxin-induced hyperthermic syndromes, important differences exist among their triggers and treatments. Serotonin syndrome typically occurs within hours of the addition ofa new serotonergic agent or the abuse of stimulants such as MDMA or methamphetamine. Treatment involves discontinuing the offending agent and administering either a central serotonergic antagonist, such as cyproheptadine or chlorpromazine, a benzodiazepine, or a combination of the two. NMS typically occurs over hours to days in a patient taking a neuroleptic agent; its recommended treatment is generally the combination of a central dopamine agonist, bromocriptine or L-dopa, and dantrolene. In those patients in whom it is difficult to differentiate between serotonin and neuroleptic malignant syndromes, the physical examination may be helpful:clonus and hyperreflexia are more suggestive of serotonin syndrome,whereas lead-pipe rigidity is suggestive of NMS. In patients in whom serotonin syndrome and NMS cannot be differentiated, benzodiazepines represent the safest therapeutic option. MH presents rapidly with jaw rigidity, hyperthermia, and hypercarbia. Although it almost always occurs in the setting of surgical anesthesia, cases have occurred in susceptible individuals during exertion. The treatment of MH involves the use of dantrolene. Future improvements in understanding the pathophysiology and clinical presentations of these syndromes will undoubtedly result in earlier recognition and better treatment strategies.

Anesthesia, General↗
PubMed2005

Malignant catatonia with severe bronchorrhea and its response to electroconvulsive therapy.

A 21-year-old female presented excitement, auditory hallucination, monologue, and insomnia. After 1 week of risperidone administration, she showed hyperthermia, salivation, and muscle rigidity. Risperidone was discontinued, but stupor, convulsions, and respiratory distress developed. In the intensive care unit where she was transferred, catatonic symptoms such as stupor or excitement, catalepsy, and negativism were prominent. In addition, severe bronchorrhea causing respiratory failure was observed. Her catatonic symptoms, hyperthermia, and bronchorrhea resolved by ECT. After recovery, affective flattening, alogia, and avolition remained. The final diagnosis was MC associated with schizophrenia. This report suggests that MC may be complicated by severe bronchorrhea, but this condition responds to ECT.

Adult↗
PubMed2006

Possible neuroleptic malignant syndrome related to concomitant treatment with paroxetine and alprazolam.

A 74-year-old man with depressive symptoms was admitted to a psychiatric hospital due to insomnia, loss of appetite, exhaustion, and agitation. Medical treatment was initiated at a daily dose of 20 mg paroxetine and 1.2 mg alprazolam. On the 10th day of paroxetine and alprazolam treatment, the patient exhibited marked psychomotor retardation, disorientation, and severe muscle rigidity with tremors. The patient had a fever (38.2 degrees C), fluctuating blood pressure (between 165/90 and 130/70 mg mm Hg), and severe extrapyramidal symptoms. Laboratory tests showed an elevation of creatine phosphokinase (2218 IU/L), aspartate aminotransferase (134 IU/L), alanine aminotransferase (78 IU/L), and BUN (27.9 mg/ml) levels. The patient received bromocriptine and diazepam to treat his symptoms. 7 days later, the fever disappeared and the patient's serum CPK levels were normalized (175 IU/L). This patient presented with symptoms of neuroleptic malignant syndrome (NMS), thus demonstrating that NMS-like symptoms can occur after combined paroxetine and alprazolam treatment. The adverse drug reaction score obtained by the Naranjo algorithm was 6 in our case, indicating a probable relationship between the patient's NMS-like adverse symptoms and the combined treatment used in this case. The involvement of physiologic and environmental aspects specific to this patient was suspected. Several risk factors for NMS should be noted in elderly depressive patients whose symptoms often include dehydration, agitation, malnutrition, and exhaustion. Careful therapeutic intervention is necessary in cases involving elderly patients who suffer from depression.

Aged↗
PubMed1997

Stereotactic pallidotomy for treatment of Parkinson's disease.

There has been a resurgence of interest in surgical treatment of Parkinson's disease in the past five years due to the large number of patients who have medically intractable symptoms and because significant improvements in neuroimaging and stereotactic techniques have made surgical procedures safer and more accurate. Stereotactic pallidotomy procedures allow neurosurgeons to destroy a portion of the globus pallidus, and thereby, decrease patients' muscle rigidity from Parkinson's disease. These surgical procedures primarily involve magnetic resonance-guided stereotactic targeting and microelectrode recording techniques. To ensure successful patient outcomes, stereotactic pallidotomy procedures require special perioperative nursing interventions discussed in this article.

Globus Pallidus↗
PubMed1997

Surgical treatment for thyroid cancer.

Thyroidectomy procedures are the mainstay treatment for thyroid cancer and are safe and effective when they are performed by experienced surgeons. Preoperative evaluation of patients with suspected thyroid cancer consists of ultrasonography, radioisotope scanning, and computed tomography scans. Postoperative complications of thyroidectomy procedures include hemorrhage, edema of the glottis, muscle rigidity and spasm (ie, tetany), acute thyrotoxicosis, and damage to the laryngeal nerve. Most surgical patients are discharged home within three days after surgery, and many patients require lifelong thyroid hormone replacement to prevent hypothyroidism.

Carcinoma, Papillary↗
PubMed1997

Malignant hyperthermia.

Malignant hyperthermia (MH) is a medical emergency that all perioperative nurses should be prepared to handle. Patients with the inherited MH trait have a rare skeletal muscle disease that causes them to develop life-threatening hyperthermia (ie, body temperatures of 43.3 degrees C [110.0 degrees F] or higher) at the time MH-triggering agents are administered to induce general anesthesia or shortly thereafter. The incidence of MH episodes is reported to be 1 in every 12,000 pediatric anesthetic procedures and 1 in every 40,000 adult anesthetic procedures. The MH syndrome also is characterized by continuous skeletal muscle rigidity, hypermetabolism, hypercapnia, tachypnea, and tachycardia that result in cardiac arrest and death if left untreated. Perioperative staff members' knowledge of MH, the care of MH-susceptible patients, and adequate preparation for MH crises are the cornerstones of successful patient outcomes to this life-threatening syndrome.

Adult↗
PubMed2002

Structural features of cross-bridges in isometrically contracting skeletal muscle.

Two-dimensional x-ray diffraction was used to investigate structural features of cross-bridges that generate force in isometrically contracting skeletal muscle. Diffraction patterns were recorded from arrays of single, chemically skinned rabbit psoas muscle fibers during isometric force generation, under relaxation, and in rigor. In isometric contraction, a rather prominent intensification of the actin layer lines at 5.9 and 5.1 nm and of the first actin layer line at 37 nm was found compared with those under relaxing conditions. Surprisingly, during isometric contraction, the intensity profile of the 5.9-nm actin layer line was shifted toward the meridian, but the resulting intensity profile was different from that observed in rigor. We particularly addressed the question whether the differences seen between rigor and active contraction might be due to a rigor-like configuration of both myosin heads in the absence of nucleotide (rigor), whereas during active contraction only one head of each myosin molecule is in a rigor-like configuration and the second head is weakly bound. To investigate this question, we created different mixtures of weak binding myosin heads and rigor-like actomyosin complexes by titrating MgATPgammaS at saturating [Ca2+] into arrays of single muscle fibers. The resulting diffraction patterns were different in several respects from patterns recorded under isometric contraction, particularly in the intensity distribution along the 5.9-nm actin layer line. This result indicates that cross-bridges present during isometric force generation are not simply a mixture of weakly bound and single-headed rigor-like complexes but are rather distinctly different from the rigor-like cross-bridge. Experiments with myosin-S1 and truncated S1 (motor domain) support the idea that for a force generating cross-bridge, disorder due to elastic distortion might involve a larger part of the myosin head than for a nucleotide free, rigor cross-bridge.

Actins↗
PubMed2003

Rigor-force producing cross-bridges in skeletal muscle fibers activated by a substoichiometric amount of ATP.

Isometric skinned muscle fibers were activated by the photogeneration of a substoichiometric amount of ATP and their cross-bridge configurations examined during the development of the rigor force by x-ray diffraction and electron microscopy. By the photogeneration of approximately 100 microM ATP, approximately 2/3 of the concentration of the myosin heads in a muscle fiber, muscle fibers originally in the rigor state showed a transient drop of the force and then produced a long-lasting rigor force (approximately 50% of the maximal active force), which gradually recovered to the original force level with a time constant of approximately 4 s. Associated with the photoactivation, muscle fibers revealed small but distinct changes in the equatorial x-ray diffraction that run ahead of the development of force. After reaching a plateau of force, long-lasting intensity changes in the x-ray diffraction pattern developed in parallel with the force decline. Two-dimensional x-ray diffraction patterns and electron micrographs of the sectioned muscle fibers taken during the period of 1-1.9 s after the photoactivation were basically similar to those from rigor preparations but also contained features characteristic of fully activated fibers. In photoactivated muscle fibers, some cross-bridges bound photogenerated ATP and underwent an ATP hydrolysis cycle whereas a significant population of the cross-bridges remained attached to the thin actin filaments with no available ATP to bind. Analysis of the results obtained indicates that, during the ATP hydrolysis reaction, the cross-bridges detached from actin filaments and reattached either to the same original actin monomers or to neighboring actin monomers. The latter cross-bridges contribute to produce the rigor force by interacting with the actin filaments, first producing the active force and then being locked in a noncycling state(s), transforming their configuration on the actin filaments to stably sustain the produced force as a passive rigor force.

Adenosine Triphosphate↗
PubMed1983

Lateral forces in the filament lattice of vertebrate striated muscle in the rigor state.

The repulsive pressure between filaments in the lattice of skinned rabbit and frog striated muscle in rigor has been measured as a function of interfilament spacing, using the osmotic pressure generated by solutions of large, uncharged polymeric molecules (dextran and polyvinylpyrrolidone). The pressure/spacing measurements have been compared with theoretically derived curves for electrostatic pressure. In both muscles, the major part of the experimental curves (100-2,000 torr) lies in the same region as the electrostatic pressure curves, providing that a thick filament charge diameter of approximately 30 nm in rabbit and approximately 26 nm in frog is assumed. In chemically skinned or glycerol-extracted rabbit muscle the fit is good; in chemically skinned frog sartorius and semitendinosus muscle the fit is poor, particularly at lower pressures where a greater spacing is observed than expected on theoretical grounds. The charge diameter is much larger than the generally accepted value for thick filament backbone diameter. This may be because electron microscope results have underestimated the amount of filament shrinkage during sample preparation, or because most of the filament charge is located at some distance from the backbone surface, e.g., on HMM-S2. Decreasing the ionic strength of the external solution, changing the pH, and varying the sarcomere length all give pressure/spacing changes similar to those expected from electrostatic pressure calculations. We conclude that over most of the external pressure range studied, repulsive pressure in the lattice is predominantly electrostatic.

Animals↗
PubMed1984

Stiffness of glycerinated rabbit psoas fibers in the rigor state. Filament-overlap relation.

The stiffness of glycerinated rabbit psoas fibers in the rigor state was measured at various sarcomere lengths in order to determine the distribution of the sarcomere compliance between the cross-bridge and other structures. The stiffness was determined by measuring the tension increment at one end of a fiber segment while stretching the other end of the fiber. The contribution of the end compliance to the rigor segments was checked both by laser diffractometry of the sarcomere length change and by measuring the length dependence of the Young's modulus; the contribution was found to be small. The stiffness in the rigor state was constant at sarcomere lengths of 2.4 microns or less; at greater sarcomere lengths the stiffness, when corrected for the contribution of resting stiffness, scaled with the amount of overlap between the thick and thin filaments. These results suggest that the source of the sarcomere compliance of the rigor fiber at the full overlapping of filaments is mostly the cross-bridge compliance.

Animals↗
PubMed1984

Is the SII portion of the cross-bridge in glycerinated rabbit psoas fibers compliant in the rigor state?

To see whether the SII portion of the cross-bridge in rigor fibers is longitudinally compliant, we chemically cross-linked with dimethyl suberimidate the entire rod portion (including the SII portion) of myosin onto the surface of thick filaments in glycerinated rabbit psoas fibers, and studied the effect of the SII fixation on the stiffness of the rigor fibers. The cross-linking of fiber segments with full filament overlap increased the rigor stiffness by approximately 25%. Almost the same absolute amount of the stiffness increase was also observed in rigor fibers with half- or no filament overlap after the cross-linking, and a similar but somewhat larger increment of stiffness was observed in fiber segments cross-linked in relaxing solution. These results indicate that the stiffness increase is not produced by the fixation of the SII portion onto the thick filament surface, but is caused instead by the cross-linking of some parallel elastic elements in muscle, and therefore indicate that the SII portion of the cross-bridge is hardly longitudinally compliant in rigor fibers.

Actins↗