Local Intramuscular Injection Research Articles

A dose–response relationship research on botulinum toxin type A local intramuscular injections of lower extremity spasticity in children with cerebral palsy

To observe the dose-response relationship of intramuscular injections of botulinum toxin A (BTX-A) in the spastic cerebral palsy. One hundred fifty cases (age between 2 and 12 years) were randomly divided into three groups. The patients were injected with different dose of BTX-A. The movement function was evaluated with modified Ashworth scale (MAS) and physician's rating scale (PRS) at entry and 1 month after injection. The analyses were conducted with one-way analysis of variance and chi (2) test. The evaluation of MAS and PRS revealed a significant increase of movement function. No statistically significant differences of the side effects among three groups could be demonstrated. The study suggested that the movement function was more significantly improved with relatively higher dose of BTX-A, which was safe and effective.

MRI findings of Tietze's syndrome mimicking mediastinal malignancy on MDCT

Tietze's syndrome is a relatively rare disorder, characterized by non-suppurative inflammation affecting the costo-sternal and sterno-clavicular joints. We describe the case of a patient affected by Tietze's syndrome clinically presenting with sudden onset of chest pain, initially diagnosed as anterior mediastinal malignancy on multidetector computer tomography. In order to characterize the nature of the lesion, we performed an open biopsy that disclosed no malignant cells. The patient was treated with non-steroidal anti-inflammatory drugs and local intramuscular injections; a progressive decrease of the mass was observed. MRI of the anterior thoracic wall disclosed spongious edema of the left sterno-clavicular joint, cortex preserved and soft-tissue edematous thickening. These findings were consistent with Tietze's syndrome.

Autologous Bone Marrow-Derived Stem Cell Therapy in Patients with Severe Peripheral Arterial Disorders: A Pilot Study.

Introduction. Amputation is the only current option for relief of rest pain or gangrene in patients with severe peripheral arterial disease (SPAD). Up to now, no effective blood-flow enhancement therapies are available. Autologous bone marrow-derived stem cell transplantation (ABMSCT) is an arising therapy modality with an option of building new blood vessels through endothelial stem and/or progenitor cells. Methods. Five patients with SPAD (4 with Buerger's disease and 1 with arteriosclerosis obliterans) were treated by ABMSCT. CD34+/CD133+ cell counts were determined in aspirated bone marrow, CD34+ cells were isolated by magnetic separation and collected into a 10 ml sample. The stem cell suspension was administered by local intramuscular injections (0.5–1.0 ml injections in the musculus gastrocnemius). The follow-up (before; 1−, 3− and 6 months after ABMSCT) based on clinical (rest pain, walking distance without pain, changes of non-healing ulcers, ABI) and laboratory (DS-angiography, Color- and Laser-Doppler scan, TcPO2 measurement and endothel function test) parameters was documented and analyzed. Our goal was to treat the worse limb of all the 5 patients.Results. Therapeutic benefit was shown by complete regression of rest pain in all 5 patients, and by the significant increase of pain-free walking distance (36 m vs. 440 m). Six months after ABMSCT the ischemic ulcers disappeared in 2 patients, and in another 2 patients the large and deep ulcers became smaller and thinner (from 8 cm2 to 2.6 cm2 in one case, and from 30 cm2 to 8 cm2 in another case), and in 1 case no change was realized, where osteomyelitis of the affected toe was diagnosed. The average of ABI improved significantly on the treated lower limb (before: 0.41, 3 and 6 months after: 0.64/0.82). ABI values of the contra-lateral legs did not change. The clinical improvement started 1 months after ABMSCT, it became more prominent after 3 months, and the best clinical results were observed after 6 months of transplantation. Confirmed by post-trial observations obtained at 9 months the clinical improvement was evaluated as stable and long lasting. Using angiography we realized improvement in 3 cases, but only in 1 case using Color-Doppler scan. Before and 6/20 weeks after transplantation the TcPO2 changed on the foot from 18.80/16.78/23.83 mmHg, and on the calf from 36.66/31.25/45.00 mmHg. The laboratory parameters did not show improvement after 1 month, however, after 3 and 6 months improved parameters were recorded. No severe complications, adverse events were detected during the 6 months follow-up period.Conclusions. ABMSCT with isolated CD34+ cells was proved to be safe, effective and resulted in significant and sustained improvement of clinical parameters and quality of life for patients with SPAD. Multicentric, controlled clinical trials are required to confirm these preliminary clinical results.

Therapeutic angiogenesis of mouse hind limb ischemia by novel peptide activating GRP78 receptor on endothelial cells

Therapeutic angiogenesis emerged as a non-invasive mean of promoting neovascularization in ischemic tissues. We have searched for new molecules that induce angiogenesis by screening a phage display combinatory peptide library on endothelial cells. One of the selected peptides identified by binding to endothelial cells under hypoxic conditions was further studied. The aim of this study was to assess the therapeutic value of this peptide, RoY, in a mouse hind limb ischemia model and to identify it's receptor on endothelial cells.RoY, a 12 amino-acid synthetic peptide, induced in vitro angiogeneic activity under hypoxic conditions by increasing endothelial cell proliferation, migration and tube formation. In order to assess its therapeutic properties in ischemic tissues, a hind limb ischemia model was induced in C57BL mice by a femoral artery excision. A single local intramuscular injection of RoY peptide to the operated limb, significantly restored blood perfusion and alleviated hind limb ischemia as determined by a laser Doppler imager. Increased capillary density in histological sections corroborated these findings. Protein precipitation and mass spectroscopy studies identified GRP78, a heat shock protein, as the peptide-binding membrane receptor that was increased on endothelial cell membranes under hypoxic conditions. This study demonstrates the efficacy of RoY peptide in alleviation of hind limb ischemia. In addition, it provides evidence that GRP78 is an angiogenic receptor on hypoxic endothelial cells.

Construction and characterization of fragmented mesenchymal-stem-cell sheets for intramuscular injection

Cell transplantation via local intramuscular injection is a promising therapy. However, the cells used are usually expanded in vitro and dissociated by trypsinization, which may be harmful to the cells. In the study, a novel method for the construction of fragmented sheets of mesenchymal stem cells (MSCs) with a uniform size, without treating with any enzymes, was reported. The obtained MSC sheets preserved the intercellular junctions and endogenous extracellular matrix and kept their cell phenotype. After injection through a needle, the fragmented MSC sheets maintained intact and retained their activity upon transferring to another growth surface, while the complete cell sheets were torn into pieces. Transplantation of fragmented MSC sheets in the skeletal muscle of a syngeneic rat model via local injection was evaluated. The transplanted MSC sheets were mainly localized at the site of injection, while the dissociated MSCs were scattered around. Additionally, there were significantly more MSCs retained in the local skeletal muscle for the group injected with fragmented MSC sheets than that injected with dissociated MSCs. These results indicated that the fragmented cell sheets might be used as a novel therapeutic cell-carrier for intramuscular administration.

Exploding vs. imploding headache in migraine prophylaxis with Botulinum Toxin A

Migraine headache is routinely managed using medications that abort attacks as they occur. An alternative approach to migraine management is based on prophylactic medications that reduce attack frequency. One approach has been based on local intramuscular injections of Botulinum Toxin Type A (BTX-A). Here, we explored for neurological markers that might distinguish migraine patients who benefit from BTX-A treatment (100 units divided into 21 injections sites across pericranial and neck muscles). Responders and non-responders to BTX-A treatment were compared prospectively ( n = 27) and retrospectively ( n = 36) for a host of neurological symptoms associated with their migraine. Data pooled from all 63 patients are summarized below. The number of migraine days per month dropped from 16.0 ± 1.7 before BTX-A to 0.8 ± 0.3 after BTX-A (down 95.3 ± 1.0%) in 39 responders, and remained unchanged (11.3 ± 1.9 vs. 11.7 ± 1.8) in 24 non-responders. The prevalence of aura, photophobia, phonophobia, osmophobia, nausea, and throbbing was similar between responders and non-responders. However, the two groups offered different accounts of their pain. Among non-responders, 92% described a buildup of pressure inside their head ( exploding headache). Among responders, 74% perceived their head to be crushed, clamped or stubbed by external forces ( imploding headache), and 13% attested to an eye-popping pain ( ocular headache). The finding that exploding headache was impervious to extracranial BTX-A injections is consistent with the prevailing view that migraine pain is mediated by intracranial innervation. The amenability of imploding and ocular headaches to BTX-A treatment suggests that these types of migraine pain involve extracranial innervation as well.

Cervical Dystonia Induced by Cervical Spine Surgery

A case report. To describe an interesting patient who underwent a three-level corpectomy of the cervical spine complicated by cervical dystonia and eventually treated successfully with botulinum toxin injections. Cervical dystonia is a relatively rare disease and unfamiliar to many clinicians. Various types of peripheral trauma or peripheral lesion have been reported to induce cervical dystonia. However, to the best of our knowledge, there have been no reports about cervical dystonia following cervical spine surgery. We present a case of a 45-year-old man who developed severe axial neck pain after cervical anterior corpectomy and fibula strut grafting due to cervical myelopathy. His neck pain gradually worsened, and involuntary spasmodic neck movement developed 6 weeks after operation when his halo-vest was removed. Initially, we considered his complaint to be transient or psychogenic, and diagnosis of cervical dystonia was delayed until 14 weeks after operation. Pharmacologic treatment was unsuccessful, but he was successfully treated with local intramuscular injections of botulinum toxin. It must be kept in mind that cervical spine surgery is not an exceptional precipitator of cervical dystonia, despite the fact that it is extremely rare.

Opening the Floodgates: Clinically Applicable Hydrodynamic Delivery of Plasmid DNA to Skeletal Muscle

viruses compared to other tissues such as liver. However, the efficiency of naked plasmid gene transfer is very low following simple intramuscular injection. Fortunately, developments over the last several years have dramatically improved the efficiency of plasmid-based gene delivery. These developments are all physical, providing a motive force to drive the plasmid into close association with the muscle fiber membrane and/or transiently increasing membrane permeability. These methods include in vivo electroporation and hydrodynamic (pressure-mediated) vascular delivery. Electroporation dramatically increases the efficiency of plasmid gene transfer by several orders of magnitude, but the effect is limited to the region between the electrodes and thus multiple injections would still be required for each muscle. In contrast, using a combination of large volumes and rapid injection into the iliac artery, Jon Wolff’s group demonstrated delivery to multiple muscles of

Cervical dystonia pathophysiology and treatment options.

Dystonia is a syndrome of sustained involuntary muscle contractions, frequently causing twisting and repetitive movements or abnormal posturing. Cervical dystonia (CD) is a form of dystonia that involves neck muscles. However, CD is not the only cause of neck rotation. Torticollis may be caused by orthopaedic, musculofibrotic, infectious and other neurological conditions that affect the anatomy of the neck, and structural causes. It is estimated that there are between 60,000 and 90,000 patients with CD in the US. The majority of the patients present with a combination of neck rotation (rotatory torticollis or rotatocollis), flexion (anterocollis), extension (retrocollis), head tilt (laterocollis) or a lateral or sagittal shift. Neck posturing may be either tonic, clonic or tremulous, and may result in permanent and fixed contractures. Sensory tricks ('geste antagonistique') often temporarily ameliorate dystonic movements and postures. Commonly used sensory tricks by patients with CD include touching the chin, back of the head or top of the head. Patients with CD are classified according to aetiology into two groups: primary CD (idiopathic--may be genetic or sporadic) or secondary CD (symptomatic). Patients with primary CD have no evidence by history, physical examination or laboratory studies (except primary dystonia gene) of any secondary cause for the dystonic symptoms. CD is a part of either generalised or focal dystonic syndrome which may have a genetic basis, with an identifiable genetic association. Secondary or symptomatic CD may be caused by central or peripheral trauma, exposure to dopamine receptor antagonists (tardive), neurodegenerative disease, and other conditions associated with abnormal functioning of the basal ganglia. In the majority of patients with CD, the aetiology is not identifiable and the disorder is often classified as primary. Unless the aetiological investigation reveals a specific therapeutic intervention, therapy for CD is symptomatic. It includes supportive therapy and counselling, physical therapy, pharmacotherapy, chemodenervation [botulinum toxin (BTX), phenol, alcohol], and central and peripheral surgical therapy. The most widely used and accepted therapy for CD is local intramuscular injections of BTX-type A. Currently, both BTX type A and type B are commercially available, and type F has undergone testing. Pharmacotherapy, including anticholinergics, dopaminergic depleting and blocking agents, and other muscle relaxants can be used alone or in combination with other therapeutic interventions. Surgery is usually reserved for patients with CD in whom other forms of treatment have failed.

Tyr→Trp-substituted peptide 115-129 of a Lys49 phospholipase A 2 expresses enhanced membrane-damaging activities and reproduces its in vivo myotoxic effect

Myotoxin II is a group II Lys49 phospholipase A 2 (PLA 2) isolated from the venom of the snake Bothrops asper. Previous studies on a synthetic peptide derived from its heparin-binding, cationic/hydrophobic sequence 115–129 demonstrated a direct functional role of this particular region in the in vitro cytolytic and bactericidal actions of the protein. Nevertheless, no significant myonecrosis has been observed after local intramuscular injection of peptide 115-129 (p115-129) in mice. Since the membrane-damaging action of p115-129 was proposed to depend on its amphiphilic character, the present study examined the effects of substituting its cluster of three tyrosine residues by tryptophan residues, on its toxic/pharmacological activities in vitro and in vivo. This substitution resulted in a drastic enhancement of the membrane-damaging activities of the peptide (p115-W3), together with the clear expression of myotoxic activity in vivo. Both the heparin-binding and antigenic characteristics of p115-129 were essentially conserved in p115-W3, suggesting that the modification did not lead to radical structural alterations. In addition to myotoxicity, cytotoxicity, and bactericidal action, p115-W3 exerted edema-forming activity in the mouse footpad assay. Thus, the synthetic 13-mer p115-W3 reproduced all the known toxic effects of myotoxin II. In spite of its potent membrane-damaging actions, p115-W3 did not acquire direct hemolytic activity upon mouse erythrocytes, an effect which is not present in myotoxin II, but that has been ascribed to the presence of tryptophan in other cationic, membrane-damaging peptides such as mellitin from bee venom. The myotoxic activity of p115-W3 herein described constitutes the first example of a short, PLA 2-based linear synthetic peptide with the ability to reproduce this effect of a parent protein in vivo. This finding is in clear support of the proposed relevance of the C-terminal region 115–129 in all the membrane-damaging mechanisms exerted by myotoxin II, including the myotoxic mechanism.

Botulinum toxin treatment of muscle cramps: a clinical and neurophysiological study.

Botulinum toxin is now widely used in the treatment of several hyperkinetic movement disorders. To evaluate its efficacy in treating muscle cramping syndromes, we studied clinical and neurophysiological variables before and after botulinum toxin injections into calf muscles and small flexor muscles of the foot in patients with an inherited benign cramp-fasciculation syndrome. At each assessment the clinical severity of cramp was scored and the cramp threshold frequency was measured with repetitive electrical peripheral nerve stimulation. Botulinum toxin injection significantly lowered our patients' clinical cramp severity scores (mean +/- SD: before, 3.80 +/- 0.44; after, 1.40 +/- 0.54), left muscle strength unchanged and significantly increased their cramp threshold frequencies (before, 4.22 +/- 2.26 Hz; after, 10.0 +/- 3.74 Hz). The clinical benefit induced by botulinum toxin lasted about 3 months. Botulinum toxin injections also significantly reduced fasciculation potentials in relaxed muscles (before, 0.86 +/- 0.19 fasciculations/sec; after, 0.45 +/- 0.11 fasciculations/sec). These findings show that local intramuscular injections of botulinum toxin provide effective, safe, and long-lasting relief of cramps possibly by reducing presynaptic cholinergic stimulation of motor nerve terminals and by impairing the input/output function of intrafusal and extrafusal motor end plates.

Cervical dystonia

We studied 300 patients, 61% women, with mean age 49.7 years and mean duration of dystonia 7.8 years, to determine the demographic and clinical characteristics of cervical dystonia (CD) and its relationships to other movement disorders. Torticollis was present in 82%, laterocollis in 42%, retrocollis in 29%, and anterocollis in 25%; however, the majority (66%) had a combination of these abnormal postures. Scoliosis was present in 39%, local pain reported by 68%, and 32% had evidence of secondary cervical radiculopathy. In addition to CD, 16% of patients had oral dystonia, 12% mandibular dystonia, 10% hand/arm dystonia, and 10% had blepharospasm. Tremor was noted in 71% of patients; head-neck tremor was present in 60%, and tremor in other body regions was present in 32%. A family history of a movement disorder was present in 44% of the CD patients. Tardive dystonia was the cause in 6%; 11% had posttraumatic dystonia. Anticholinergic drugs provided moderate improvement in 33% of patients, but local intramuscular botulinum toxin injections relieved CD, local pain, or both in over 90% of all treated patients.

Bone Morphogenetic Protein-Mediated Interaction of Periosteum and Diaphysis

In rabbits, after long-bone growth is complete and the cambium layer regresses, mesenchymal-type cells with embryonic potential (competence) for bone development persist in the adventitial layer of periosteum. These cells are not determined osteoprogenitor cells (stem cells) because bone tissue differentiation does not occur when adult periosteum is transplanted into a heterotopic site. In this respect, adventitial cells differ from bone marrow stroma cells. In a parosteal orthotopic site in the space between the adult periosteum and diaphysis, implants of bone morphogenetic protein (BMP) and associated noncollagenous proteins (BMP/NCP) induce adventitia and adjacent muscle connective-tissue-derived cells to switch from a fibrogenetic to a chondroosteoprogenetic pattern of bone development. The quantity of induced bone is proportional to the dose of BMP/NCP in the range from 10 to 50 mg; immature rabbits produced larger deposits than mature rabbits in response to BMP/NCP. Preoperative local intramuscular injections of citric, edetic, or hyaluronic acids in specified concentrations markedly enhanced subperiosteal BMP/NCP-induced bone formation. The quantity of bovine or human BMP/NCP-induced bone formation in rabbits is also increased by very low-dose immunosuppression but not by bone mineral, tricalcium phosphate ceramic, inorganic calcium salts, or various space-occupying, unspecific chemical irritants. Although composities of BMP/NCP and allogeneic rabbit tendon collagen increased the quantity of bone in a parosteal site, in a heterotopic site the composite failed to induce bone formation. In a parosteal site, the conditions permitting BMP/NCP-induced bone formation develop, and the end product of the morphogenetic response is a duplicate diaphysis. How BMP reactivates the morphogenetic process in postfetal mesenchymal-type adventitial cells persisting in adult periosteum (including adjacent muscle attachments) is not known.

Mechanism of paradoxical resistance of the digastric muscle to the action of tetanus toxin

Excitability parameters of m. masseter and m. digastricus fibers (resting minute potential--MP, action potential--AP, critical level of depolarization--CLD and rheobase currents) were determined in anesthetized rats (nembutal, 40 mg/kg) on days 3-4 and 10-15 after local intramuscular tetanus toxin injection (20 and 40 mouse Dlm, respectively). The development of local tetanus in m. masseter was characterized by typical excitability changes--a decrease in MP and AP. Local spasm in m. digastricus under analogous conditions of tetanus toxin injection was absent, while excitability tests demonstrated MP, AP and CLD augmentation. As m. digastricus motoneurons are devoid of inhibitory synaptic regions, these nervous cells are not affected by tetanus toxin.

Povidone Panniculitis

Multiple subcutaneous nodules and recurrent flu-like episodes developed in a 60-year-old woman after she had received local intramuscular injections of procaine povidone for a seven-year period. A skin biopsy specimen showed distinctive gray-blue material in the histiocytes in sections stained with hematoxylin-eosin. Povidone is an inert substance that may accumulate in multiple organs, including the skin. Its presence can be verified by its affinity for special stains or by spectrophotometric analysis. In our patient, ultrastructural study showed amorphous inrahistiocytic deposits in the tissues. -revious reports have indicated that this substance may eventually accumulate in noninjected skin sites and may lead to pulmonary and arthritic symptoms in some patients, but no other patients, to our knowledge, have had complications associated with fever.

Povidone panniculitis. Polyvinylpyrrolidone panniculitis

• Multiple subcutaneous nodules and recurrent flu-like episodes developed in a 60-year-old woman after she had received local intramuscular injections of procaine povidone for a seven-year period. A skin biopsy specimen showed distinctive grayblue material in the histiocytes in sections stained with hematoxylin-eosin. Povidone is an inert substance that may accumulate in multiple organs, including the skin. Its presence can be verified by its affinity for special stains or by spectrophotometric analysis. In our patient, ultrastructural study showed amorphous intrahistiocytic deposits in the tissues. Previous reports have indicated that this substance may eventually accumulate in noninjected skin sites and may lead to pulmonary and arthritic symptoms in some patients, but no other patients, to our knowledge, have had complications associated with fever. (<i>Arch Dermatol</i>116:704-706, 1980)

IRITIS CAUSED BY ASYMPTOMATIC SPHENOIDITIS WITH ANOMALY OF THE SPHENOID SINUSES

In 1934, while he was in New York, O. H., a man aged 41 at the time of writing, suffered his first attack of iritis. An extensive search for a focus of infection resulted in entirely negative findings. The treatment consisted of local therapy and intramuscular injections of milk, and was followed by gradual improvement and a return to normal but not until the end of three months. Approximately two years later, on April 18, 1936, he presented himself to Dr. Samuel Hirshfeld for examination. The night previous he had suddenly suffered intense pain in the left eye, which immediately became "bloodshot," with sudden marked lacrimation, pronounced photophobia and blurring of vision. He was referred to Dr. Maurice Beigelman, an ophthalmologist, who reported the left pupil to be contracted, with marked pericorneal congestion, cells within the aqueous and reduction in visual acuity to 20/50. The diagnosis was acute iritis. It