PTH improves titanium implant fixation more than pamidronate or renutrition in osteopenic rats chronically fed a low protein diet

Summary   

We evaluated the effects of parathyroid hormone (PTH), pamidronate, or renutrition on osseointegration of titanium implants in the proximal tibia of rats subject to prolonged low-protein diets. PTH improved mechanical fixation, microarchitecture, and increased pull-out strength. Pamidronate or renutrition had lesser effects. PTH can thus improve implant osseointegration in protein-malnourished rats.     

Low protein intake is associated with impaired titanium implant osseointegration.

Low protein intake is highly prevalent among orthopaedic elderly patients. We studied the effects of an isocaloric low protein diet on the resistance to pull-out of titanium rods implanted into rats proximal tibia. Isocaloric low protein intake impairs titanium implant osseointegration, with a decreased strength needed to completely loose the implant and altered bone microarchitecture in its vicinity. INTRODUCTION: Low protein intake is highly prevalent among elderly patients in orthopaedic wards and could retard fracture healing. It was previously shown that reduced protein intake decreases bone strength. Whether dietary protein intake could influence titanium implant osseointegration is unknown. We studied the effects of an isocaloric low protein diet on the resistance to pull-out of titanium rods implanted into rats proximal tibia. MATERIALS AND METHODS: Forty-eight 11-month-old female rats were fed isocaloric diets containing 2.5% (low protein) or 15% (normal protein) casein from 2 weeks before the implantation of a 1-mm-diameter cylindrical titanium rod in the proximal metaphysis of each tibia. Four, 6, and 8 weeks after implantation, the tibias were removed for microCT histomorphometry to quantify bone-to-implant contact and bone trabecular microarchitecture around the implant. Resistance to implant pull-out was tested by recording the maximal force necessary to completely loosen the implant. RESULTS: Pull-out strength was significantly lower in rats fed an isocaloric low protein diet by 6 and 8 weeks after implantation (-43%, p < 0.001 and -42%, p < 0.001, respectively) compared with rats fed a normal protein diet. Bone-to-implant contact was significantly lower in the low protein group 8 weeks after implantation (p < 0.05). Bone-to-implant contact and pull-out strength were correlated (r2= 0.57, p < 0.0001). BV/TV around the implant was 19.9 +/- 2.2% (SE) versus 31.8 +/- 3.3% (p < 0.05) at 6 weeks and 20.1 +/- 1.9% versus 29.8 +/- 3.2% (p < 0.05) at 8 weeks after implantation in the low protein and normal protein intake groups, respectively. Trabecular thickness was 96.2 +/- 3.7 versus 113.0 +/- 3.6 microm (p < 0.01) at 6 weeks and 101.4 +/- 2.7 versus 116.2 +/- 3.3 microm (p < 0.01) at 8 weeks in the corresponding groups. In a structure model index analysis, there was a significant shift to a more rod-like pattern in the low protein diet groups. All these changes were associated with lower plasma IGF-I levels. CONCLUSIONS: Isocaloric low protein intake impairs titanium implant osseointegration, with decreased strength needed to completely loosen the implant and altered bone microarchitecture in the vicinity of the implant.     

Differences in osseointegration rate due to implant surface geometry can be explained by local tissue strains.

Experimental evidence indicates that the surface geometry of bone-interfacing implants influences the nature and rate of tissues formed around implants. In a previously reported animal model study, we showed that non-functional, press-fitted porous-surfaced implants placed in rabbit femoral condyle sites osseointegrated more rapidly than plasma-sprayed implants. We hypothesized that the accelerated osseointegration observed with the porous-surfaced design was the result of this design providing a local mechanical environment that was more favourable for bone formation. In the present study, we tested this hypothesis using finite element analysis and homogenization methods to predict the local strains in the pre-mineralized tissues formed around porous-surfaced and plasma-sprayed implants. We found that, for loading perpendicular to the implant interface, the porous surface structure provided a large region that experienced low distortional and volumetric strains, whereas the plasma-sprayed implant provided little local strain protection to the healing tissue. The strain protected region, which was within the pores of the sintered porous surface layer. corresponded to the region where the difference in the amount of mineralization between the two implant designs was the greatest. Low distortional and volumetric strains are believed to favour osteogenesis, and therefore the model results provide initial support for the hypothesis that the porous-surfaced geometry provides a local mechanical environment that favours more rapid bone formation in certain situations.     

Interrelations of PTH, cAMP, creatinine and uric acid in nephrectomized patients under DNA or PTH application

Patients with reduced renal mass (i.e., nephrectomized) and slightly decreased renal clearance (70-80%) have been treated by 4 g DNA to study uricosuria. Prompt or prolonged renal excretion of uric acid and creatinine have been observed with indirect effects on parathyroid secretion. Urinary cAMP, however, failed to correlate to the change of parathyroid function. Reversely, PTH injection significantly increases uricosuria suggesting interrelated secretion of uric acid and cAMP of the proximal tubules. In some respects this model can be used to investigate increased DNA metabolism and parathyroid function.     

Effect of pamidronate on bone turnover and implant migration after total hip arthroplasty: a randomized trial.

In this trial we studied the effect of pamidronate on periprosthetic bone turnover and pelvic implant migration over 2 years after hybrid total hip arthroplasty (THA). Twenty-two patients received 90 mg of pamidronate and 22 received placebo at randomization 5 days after surgery. Rapid periprosthetic bone loss occurred in the placebo group over the first 6 months and was accompanied by transient increases in biochemical markers of bone turnover. Partial recovery in bone mass occurred in most regions after this period. No recovery of bone mass occurred at the femoral calcar or the medial wall of the acetabulum. Femoral calcar bone loss at 2 years was strongly predicted by acute biomarker changes at week 6. Pamidronate therapy reduced femoral bone loss in the region of the femoral calcar (P = 0.01), but did not affect pelvic bone loss. Pamidronate therapy also inhibited the transient rise in biochemical markers of bone turnover during this period. Pamidronate therapy did not affect acetabular cup migration. Cup migration was inversely related to subject age, but unrelated to initial post-operative bone mineral density, or subsequent bone loss. In summary, early periprosthetic bone loss is associated with a transient expansion of the bone remodeling space. Bisphosphonate therapy reduces femoral calcar bone loss and bone turnover after THA, but did not influence cup migration in this study. Acute changes in biochemical markers predict femoral periprosthetic bone loss.     

Bone mineral density in lung-transplant recipients before and after graft: prevention of lumbar spine post-transplantation-accelerated bone loss by pamidronate.

BACKGROUND: Lung-transplant recipients are at risk of osteoporosis. They may have low bone mass even before posttransplantation immunosuppressive therapy. We studied bone mineral density (BMD) before and after lung transplantation and compared the efficacy of antiresorptive therapies to calcium and vitamin D supplementation. METHODS: Areal BMD was assessed in 42 patients awaiting lung transplantation and measured again after surgery at 6 (n = 29), and at 12 months (n = 20). Nineteen patients received antiresorptive therapy (30 mg pamidronate IV every 3 months (n = 14), or hormonal replacement therapy (n = 5)), and 10 patients received only calcium and vitamin D supplements.RESULTS: Mean age- and gender-adjusted lumbar spine (LS) and femoral neck (FN) BMD was significantly decreased prior to transplantation (- 0.6 +/- 0.2, p< 0.01, and - 1.5 +/- 0.2 standard deviation, p < 0.001, respectively). At that time, 29% were osteoporotic (T-score < - 2.5 below the peak bone mass), while 55% were below - 1.0 T-score. Antiresorptive therapy decreased the rate of LS bone loss during the first 6 months and led to a significant increase of BMD at 1 year, with LS changes of + 0.2 +/- 0.1 vs - 0.4 +/- 0.1 Z-score in the calcium-vitamin D group (p< 0.002), and + 0.2 +/- 0.1 vs - 0.04 +/- 0.1 for FN (NS). One out of 20 patients experienced clinically evident fractures during antiresorptive therapy, and 3 out of 12 in the calcium-vitamin D group. CONCLUSION: A significant proportion of patients awaiting lung transplantation was osteoporotic or osteopenic. Antiresorptive therapy (pamidronate or hormone-replacement therapy (HRT)) prevented accelerated LS bone loss after graft.     

Expression of PTH1R constructs in LLC-PK1 cells: protein nuclear targeting is mediated by the PTH1R NLS

This study demonstrates that the PTH1R NLS can target a fusion protein to the nucleus, and that this is blocked by sequences downstream of the NLS. GFP fused to the NLS showed a significant increase in nuclear targeting compared to GFP alone or GFP fused to a peptide of the same length. In previous studies, we demonstrated that the type I PTH/PTHrP receptor (PTH1R) localizes to the nucleus of cells within rat liver, kidney, uterus, ovary and gut. Similarly, nuclear localization of the PTH1R was observed in the cultured osteoblast-like cells MC3T3-E1, UMR106, ROS 17/2.8 and SaOS-2. We have identified a putative bipartite nuclear localization signal (NLS), from residues 471-488 in the protein sequence of the PTH1R. In this study, several PTH1R constructs were made in the Enhanced Green Fluorescent Protein (EGFP) expression vector (Clontech), transiently transfected into LLC-PK1 Clone 46 cells, and the resultant fusion protein expression followed by fluorescence microscopy. This particular clone of LLC-PK1 shows no biochemical response in vitro to parathyroid hormone. Constructs included the entire PTH1R sequence (PTH1R-GFP), the putative NLS fused to the C-terminus of GFP (GFP-NLS) or the NLS through to the C-terminus of the PTH1R fused to GFP (GFP-NLSCT). Deconvolution fluorescence microscopy of cells transfected with PTH1R-GFP showed abundant fluorescent signal throughout the cells with distinctly fluorescing plasma membranes. These cells also exhibited an increase in cAMP production in response to (0-10(-8) M) hPTH(1-34), with an increase in cAMP from 11 fmol/mug of protein to 101 fmol/microg. In contrast, cells transfected with the GFP-NLS construct showed significant nuclear sequestration of fluorescence as compared to GFP alone, GFP-NLSCT, or a short amino acid sequence fused to GFP (GFP-FFVAIYCFCNGEVQAEI). These results indicate that the NLS at residues 471-488 of the mature rat PTH1R is functional and plays a role in targeting the PTH1R the nucleus, also the addition of GFP to the C-terminus of the PTH1R still allows cAMP generation which will be useful for further studies.     

Selective Modification of Bone Quality by PTH,Pamidronate, or Raloxifene

Bone strength, a determinant of resistance to fracture, depends on BMD, geometry, microarchitecture, bone turnover rates, and properties of the bone at the material level. Despite comparable antifracture efficacy, anti‐catabolics and bone anabolic agents are likely to modify the various determinants of bone strength in very different ways. Eight weeks after ovariectomy (OVX), 8‐mo‐old osteoporotic rats received pamidronate (APD; 0.6 mg/kg, 5 days/mo, SC), raloxifene (3 mg/kg, 5/7 days, tube feeding), PTH(1–34) (10 μg/kg, 5/7 days, SC), or vehicle for 16 wk, and we measured vertebral BMD, maximal load, stiffness and energy, microarchitecture, and material properties by nanoindentation, which allows the calculation of the elastic modulus, tissue hardness, and working energy. Markers of bone turnover, plasma osteocalcin, and urinary deoxypyridinoline (Dpd) were also determined. PTH induced greater maximal load than APD or raloxifene, as well as greater absorbed energy, BMD, and increased bone turnover markers. PTH markedly increased trabecular bone volume and connectivity to values higher than sham. Animals treated with APD had BV/TV values significantly higher than OVX but lower than sham, whereas raloxifene had no effect. Tissue hardness was identical in PTH‐treated and OVX untreated controls. In contrast, APD reversed the decline in strength to levels not significantly different to sham, reduced bone turnover, and increased hardness. Raloxifene markedly increased material level cortical hardness and elastic modulus. These results show the different mechanisms by which anti‐catabolics and bone anabolics reduce fracture risk. PTH influences microarchitecture, whereas bisphosphonates alter material‐level bone properties, with probable opposite effects on remodeling space. Raloxifene primarily improved the material stiffness at the cortical level.     

Additive manufacturing of porous titanium metaphyseal components: Early osseointegration and implant stability in revision knee arthroplasty

AimsMetaphyseal cones and sleeves are components used in revision knee arthroplasty to ensure load transfer, encourage bone on-growth and prevent stress shielding. Additive manufacturing of titanium alloy implants is a novel technique with limited clinical outcome reports in the literature. The aim of this study was to determine radiographic evidence of osseointegration and early results of a single manufacturer porous titanium metaphyseal components in the proximal tibia.MethodsWe retrospectively reviewed the prospectively collected database of two institutions. Patients who underwent revision knee arthroplasty using porous titanium components by a single manufacturer were identified. Immediate post-operative and latest follow-up radiographs were independently analysed by 2 reviewers to determine metaphyseal bone contact and level of osseointegration in relevant Knee Society Radiographic Evaluation and Scoring System zones.Results22 patients (15 males; 7 females) with a mean age of 71 (49–92) years were included. The mean follow-up period was 14 months (2–44 months). Cones were used in 16 patients and sleeves in 6. Interobserver reliability assessment showed substantial agreement (weighted Kappa 0.71, (95% CI: 0.60, 0.81). There was significant correlation between the bone contact in the immediate postop radiograph and osseointegration at final follow-up (kendall’s tau-b: 0.698, p < 0.001). Infection free prosthetic joint survival was 20/22 at final follow-up.ConclusionPorous titanium metaphyseal components produced with additive manufacturing provided excellent osseointegration and no early clinical failures. Partial or complete contact of the cone with native bone in the immediate postoperative radiograph resulted in osseointegration in all cases.     

Fracture repair: modulation of fracture-callus and mechanical properties by sequential application of IL-6 following PTH 1-34 or PTH 28-48

Fracture healing presents a sequence of three major stages: inflammation and granulation tissue formation, callus formation and remodeling. Our working hypothesis was that fracture-repair might be enhanced by stimulating proliferation of chondrocytes and osteoblasts in the early stages of fracture healing followed by sequential acceleration of the remodeling process. In the present study we employed a novel device developed by us implementing a standardized fracture in rat tibiae. We investigated the effect of PTH 28-48 or PTH 1-34 alone or in sequence combination with IL-6 together with its soluble receptor (IL-6sR) on fracture repair. PTH 28-48 or PTH 1-34 was applied locally into the hematoma of fractures on days 4, 5 and 6 and IL-6+ its soluble receptor on days 7, 9, and 11. Post-fracture callus volume as measured 14 days post-fracture was increased significantly only by PTH 1-34 (20%; P<0.01). When one of the PTH fragments and IL-6+IL-6sR were applied sequentially callus volume was increased significantly (33%; P<0.01). X-rays radiography at 5 weeks post-fracture showed enlarged callus volume following treatment by either PTH fragments alone, and complete union following the sequential injection of both PTH fragments and IL-6+IL-6sR, only. Only the combination of one of the PTH fragments with IL-6+IL-6sR, as measured 6 weeks post-fracture by three point bending, changed dramatically the quality of the regenerating bone as presented by a 300% increase in mechanical resistance when PTH 1-34 was combined and 200% when PTH 28-48 was combined relative to vehicle-treated fractured bones. We conclude that the sequential application of IL-6+IL-6sR with both PTH fragments has the potential of enhancing fracture healing in long bones and should be further explored in preclinical and in clinical studies.     

Parathyroid adenomectomy under local anesthesia with intra-operative monitoring of UcAMP and/or 1-84 PTH

Because 80% of patients with primary hyperparathyroidism have a single adenoma and because most adenomas are now visualized by ultrasonography, we have attempted to remove these suspected single adenomas under local anesthesia with intra-operative monitoring of urinary cAMP (UcAMP) and 1-84 parathyroid hormone (PTH) serum levels. In the last 2 years, 45 patients (mean age 65 years) with primary hyperparathyroidism underwent surgery with local anesthesia when a single adenoma was strongly suspected by ultrasonography. Patients with equivocal or misleading ultrasonography, e.g., those with associated thyroid or multiglandular pathology and those who were non-cooperative, were excluded from this procedure. UcAMP and 1-84 PTH were determined prior to the incision, at the time of removal of the adenoma, and at regular intervals until 120 minutes after the operation. Results were available 45 min to 60 min after sampling for PTH and 60 min to 80 min for UcAMP. Forty-two adenomas were removed through a 2 cm to 3 cm skin incision in a mean time of 25 minutes, with no adverse effect, no morbidity, and minimal discomfort. The 42 patients were normocalcaemic on follow-up. The monitorings always predicted the success of the operation. In the 3 remaining patients, because the monitorings remained elevated at the end of the procedure, the patients underwent classical bilateral neck dissection under general anesthesia. This new approach can be safely accomplished with short operative time and hospital stay. The absence of general anesthesia is reassuring for the patients who are reluctant to undergo general anesthesia. The intra-operative monitoring which predicts the cure of primary hyperparathyroidism with high accuracy allows the surgeon to conclude the operation with confidence.

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Resumen Teniendo en cuenta que 80% de los casos de hiperparatiroidismo primario se deben a un adenoma único, y puesto que actualmente la mayoría de los adenomas pueden ser visulizados con ultrasonografía, hemos intentado resecar posibles adenomas únicos bajo anestesia local con monitoría intraoperatoria de la AMPc urinaria y de los niveles séricos de PTH 1-84. En los últimos dos años hemos operado 45 pacientes (65 años de edad en promedio) con hiperparatiroidismo primario bajo anestesia local y la demostración ultrasonográfica de un muy posible adenoma único. Se excluyeron de la serie los pacientes con ultrasonografía equívoca, así como los casos asociados con patología tiroidea o enfermedad multiglandular y los pacientes poco cooperadores. Se hizo la determinación de UcAMP (AMP urinaria cíclica) y de 1-84 PTH antes de efectuar la incisión, en el momento de la remoción del adenoma y a intervalos regulares hasta 120 minutos luego de terminada la operación. Los resultados estuvieron disponibles a los 45 a 60 minutos de la toma de la muestra para PTH y a los 60 a 80 minutos para la UcAMP. Se resecaron 42 adenomas a través de una incisión de 2–3 centímetros en un tiempo promedio de 25 minutos, sin efectos adversos, sin morbilidad y con mínima incomodidad para el paciente. Los 42 pacientes aparecieron mormocalcémicos en el seguimiento postoperatorio. La monitoría intraoperatoria predijo regularmente el éxito de la operación. Los tres pacientes restantes, y porque los niveles de las sustancias utilizadas para la monitoría continuaban elevados al final del procedimiento, fueron sometidos a la operación clásica bajo anestesia general, con disección bilateral del cuello. Este novedoso aproche, que puede ser practicado con seguridad, resulta en un tiempo operatorio muy breve y una corta permanencia en el hospital. Evitar la anestesia general resulta satisfactorio para aquellos pacientes que son reacios a aceptar la anestesia general. La monitoría intraoperatoria, que predice la cura del hiperparatiroidismo con un elevado grado de certeza, permite al cirujano completar la operación con la confianza de un buen resultado.

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Résumé Puisque 80% des hyperparathyroïdies primaires sont dues à un adénome solitaire, et puisqu'il est actuellement possible de bien visualiser les parathyroïdes par échographie, nous avons essayé d'opérer sous anesthésie locale en dosant la concentration urinaire d'AMPc (UAMPc) et de PTH 1-84 dans le sérum pendant l'intervention. Dans les deux dernières années, 45 patients (âge moyen 65 ans) ayant une hyperparathyroïdie primaire ont été opérés sous anesthésie locale car l'échographie laissait soupçonner l'existence d'un adénome solitaire. Les critères d'exclusion étaient l'absence d'échographie formelle ou typique, la notion de pathologie multiendocrininne gandulaire (dont l'association à une pathologie thyroïdienne) et la mauvaise coopération des patients. Les dosages de l'U AMPc et la PTH 1-84 étaient déterminés avant l'incision, au moment de l'exérèse de l'adénome et à intervalles réguliers jusqu'à 120 minutes après l'opération. Les résultats étaient disponibles en 45 à 60 minutes en ce qui concerne la PTH, et en 60 à 80 minutes pour l'U AMPc. Quarante-deux adénomes ont été enlevés ainsi par une incision de 2–3 cm. La durée de l'intervention était de 25 minutes; il n'y a eu aucun effet secondaire, pas de morbidité et l'inconfort a été minimal. Les 42 patients ont tous été normocalcémiques. Le monitorage a toujours prédit le succès de l'opération. Chez les trois autres patients, les valeurs de calcémie sont restées élevées en fin d'intervention et ces patients ont été opérés sous anesthésie générale avec une dissection cervicale classique. Cette nouvelle approche est compatible avec un temps d'intervention et d'hospitalistaion courts. L'absence d'anesthésie générale présente un attrait certain pour le malade qui y est réticent. Le monitorage peropératoire qui prédit la cure d'hyperparathyroïdie avec une grande précision permet au chirurgien de terminer l'intervention en toute confiance.

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Presented at the International Association of Endocrine Surgeons in Stockholm, Sweden, August, 1991.     

Inhibition of bone healing by pamidronate in calvarial bony defects.

OBJECTIVE: Pamidronate has been studied as a therapeutic drug for various osteopenic diseases. However, avascular osteonecrosis in the jawbone has been recently reported in patients receiving pamidronate. The objective of this study was to examine the effect of pamidronate on bone regeneration in a controlled animal model. MATERIALS AND METHODS: To determine the effect of parmidronate on bone healing in a local bony defect area, a rabbit calvarial bony defect model was used and poly L-lactide-co-glycolide (PLGA) used as a drug carrier material. Four defect groups were made in each rabbit calvaria and the defects were treated as follows: untreated bony defect (group 1), PLGA only (group 2), 2 mg of pamidronate with PLGA (group 3), and 3 mg of pamidronate with PLGA (group 4). Bone healing was evaluated by radiography and histology at 1, 2, 4, 6, and 8 weeks after surgery. RESULTS: In radiographic analysis, radiopacity was lower in pamidronate groups than non-operated rabbit calvarial bone at all observation points (P < .05). In histological analysis, the initial bone formation at 1 week was not different among groups, but it was much lower in the pamidronate groups than in the control or PLGA group after 2 weeks. Newly formed bone at 1 week underwent avascular necrosis after 2 weeks in both pamidronate groups. Avascular necrosis was not observed until 8 weeks in both topically applied pamidronate groups. CONCLUSION: Collectively, pamidronate inhibits bone healing in rabbit calvarial bony defect and it may explain the avascular necrosis of the jaws in patients receiving pamidronate.     

Exogenous PTH-related protein and PTH improve mineral and skeletal status in 25-hydroxyvitamin D-1alpha-hydroxylase and PTH double knockout mice.

We examined the effect of NH2-terminal fragments of PTHrP and PTH in young mutant mice deficient in both PTH and 1,25-dihydroxyvitamin D. Both proteins prolonged murine survival by increasing serum calcium, apparently by enhancing renal calcium transporter expression. The dominant effect on the skeleton was an increase in both endochondral bone and appositional formation without increased bone resorption. INTRODUCTION: PTH-related protein (PTHrP) was discovered as a hypercalcemic agent responsible for the syndrome of humeral hypercalcemia of malignancy, and PTH is the major protein hormone regulating calcium homeostasis. Both proteins have skeletal anabolic actions when administered intermittently. We examined effects of exogenous PTHrP(1-86) and PTH(1-34) in double null mutant mice deficient in both PTH and 25-hydroxyvitamin D-1alpha-hydroxylase [1alpha(OH)ase] to determine the action of these proteins in the absence of the two major regulators of calcium and skeletal homeostasis. MATERIALS AND METHODS: Mice heterozygous for the PTH null allele and for the 1alpha(OH)ase null allele were mated to generate pups homozygous for both null alleles. PTHrP(1-86) and PTH(1-34) were administered subcutaneously starting 4 days after birth. Serum biochemistry and skeletal radiology, histology, and histomorphometry were performed, and indices of bone formation, resorption, and renal calcium transport were determined by real time RT-PCR, Western blot, and immunohistochemical approaches. RESULTS: In the double mutant mice, which die within 3 weeks after birth with severe hypocalcemia, tetany, and skeletal defects, exogenous PTHrP and PTH enhanced survival of the animals by improving serum calcium. Both proteins increased renal calcium transporter expression and long bone length and augmented growth plate chondrocyte proliferation, differentiation, and cartilage matrix mineralization. Cortical and trabecular bone mass was increased with augmented osteoblast number and activity; however, bone resorption was not increased. CONCLUSIONS: PTHrP and PTH reduced hypocalcemia by enhancing renal calcium reabsorption but not by increasing bone resorption. The major skeletal effects of exogenous PTHrP and PTH were to increase bone anabolism.     

Adverse effects of suxamethonium. Failure of prevention by atracurium or fazadinium

One hundred patients were allocated randomly to pretreatment with atracurium 2.5 mg, atracurium 5 mg, fazadinium 3.75 mg or saline 3 minutes before the injection of suxamethonium. The effect upon neuromuscular conduction was studied by recording the mechanical response of the adductor pollicis muscle to indirect stimulation of the ulnar nerve using repeated 2 Hz train of four stimuli. Blood samples were taken at intervals for the measurement of serum potassium. There was no significant difference in the incidence of postoperative muscle pains between the groups in the first 72 hours following anaesthesia. The use of the larger pretreatment dose of atracurium resulted in clinically significant neuromuscular blockade in three of the subjects. Minimal changes in serum potassium occurred in all patients but there was no statistical difference between the groups.     

Succinylcholine: mechanism of fasciculations and their prevention by d-tubocurarine or diphenylhydantoin

Administration of d-tubocurarine (dTC) or diphenylhydantoin (DPH) was evaluated as a pretreatment to prevent succinylcholine (Sch) evoked fasciculations. Experiments were designed to determine the nature of the drug-drug interactions, sites of interaction, and site of fasciculation suppression. Sch is known to evoke repetitive discharge generation by motor nerve terminals (MNTs). Transmission of these prejunctional discharges causes fasciculations. A cat soleus neuromuscular preparation in situ, which enables recording of nerve action potentials initiated by MNTs, their transmitted muscle action potentials, and the resultant contractile responses, was used to explore Sch effects before and after iv pretreatment with dTC or DPH. dTC is known to act prejunctionally to suppress repetitive discharges initiated by facilitatory drugs and tetanic conditioning of MNTs. Accordingly, pretreatment with dTC 50 micrograms X kg-1 suppressed the Sch-induced MNT repetitive discharging and correspondingly suppressed generalized fasciculations without affecting twitch. This dTC dose, however, also reduced Sch blocking potency by 33%, slowed its rate, and shortened block duration. These latter effects represent competitive postjunctional antagonism. DPH is also known to suppress MNT repetitive discharging. Correspondingly, Sch-induced repetitive firing and ensuing fasciculations were suppressed by DPH (30 mg X kg-1) without affecting twitch. Unlike dTC, this DPH dose increased Sch blocking potency by 50%, increased the initial rate of block, and did not alter block duration. These DPH effects were dose-dependent and within the anticonvulsant range for cats. Therefore, patients with anticonvulsant levels of DPH may not require pretreatment before Sch.(ABSTRACT TRUNCATED AT 250 WORDS)