Bretazenil, a benzodiazepine receptor partial agonist, as an adjunct in the prophylactic treatment of OP poisoning.

Benzodiazepines, mainly diazepam, are commonly used as anticonvulsants in the treatment of organophosphate casualties. Although very effective, diazepam usually is not used in prophylactic treatments because of its adverse effects on task performance and its abuse liability. Benzodiazepine (BZ) partial agonists are unique in that they are able to occupy all the population of a given receptor without eliciting the maximal physiological response. The BZ receptor agonistic occupancy was found to differ among the various physiological responses in the following order: antipanic > anticonvulsion > sedation > muscle relaxation. Thus, partial agonists, by the use of which controlled levels of agonistic activity can be achieved, might serve as effective anticonvulsants, with fewer side-effects. Bretazenil, a partial agonist, was found to counteract metrazol-induced convulsions in rats. At the anticonvulsive doses (125-250 microg x kg(-1), i.p.) bretazenil, in combination with pyridostigmine (100 microg x kg(-1), i.m.) and aprophen (4 mg x kg(-1), i.m.), conferred prophylactic protection against sarin and soman poisoning (protective ratios 2.6 and 2.1, respectively). Relevant doses of bretazenil (50-400 microg x kg(-1), i.p.) also were tested for general behavioural effects in the open field and for its anti-anxiety properties in the plus maze. The incapacitation was much lower compared with diazepam. Bretazenil should be considered as a candidate for incorporating into a prophylactic mixture as a central nervous system protectant, with significant advantages concerning incapacitation.

The involvement of the NMDA receptor complex in the protective effect of anticholinergic drugs against soman poisoning.

Organophosphate poisoning is associated with adverse effects on the central nervous system such as seizure/convulsive activity and long term changes in neuronal networks. This study reports on investigations designed to assess the consequences of soman exposure on excitatory amino acids receptors in the rat brain. In addition, the protective effects of caramiphen which acts at these receptors, and scopolamine, which does not, was determined on soman-induced alteration in rat brain functions. Administration of soman (1xLD50) to pyridostigmine pretreated rats produced seizure activity (measured by EEG monitoring) in all animals tested. Estimation of [3H]MK-801 binding to brain membranes from intoxicated rats revealed a marked decrease in Bmax value 24 but not 2 hrs following soman administration. The specific nature of these effects of soman was demonstrated by the findings that [3H]flunitrazepam binding to central benzodiazepine receptors remained unchanged in soman-poisoned rat brain membranes. Both scopolamine and caramiphen, when used prophylactically prevented the lethal effect of soman and completely blocked the development of electrographic seizure activity (EGSA). In contrast, only caramiphen abolished soman-induced modifications in NMDA/ion channel characteristics. Caramiphen displaced [3H]MK-801 bound to the NMDA/ion channel complex, possibly by interacting with the Zn2+ site whereas scopolamine did not. Moreover, caramiphen, but not scopolamine, partially protected mice from NMDA-induced lethality. Thus, it is suggested that an important component of the protective efficacy of caramiphen against organophosphate poisoning might be attributed to its ability to modulate NMDA receptors in addition to its anticholinergic properties.

Transarticular tumor invasion via ligamentum teres. A clinical-pathologic study of 12 patients.

We studied 12 patients who were operated on for malignant tumors in and around the hip joint. A correlative study, including preoperative staging studies and anatomical-pathologic aspects of the hip joint, was performed. In 4 of the 12 patients, we found direct histologic evidence of tumor invasion from the head of the femur through the ligamentum teres to the acetabular fovea and vice versa. It seems that the ligamentum teres is a potential route for transarticular spread of a tumor.

Increased rates of fibromyalgia following cervical spine injury. A controlled study of 161 cases of traumatic injury.

OBJECTIVE: To study the relationship between cervical spine injury and the development of fibromyalgia syndrome (FMS). METHODS: One hundred two patients with neck injury and 59 patients with leg fractures (control group) were assessed for nonarticular tenderness and the presence of FMS. A count of 18 tender points was conducted by thumb palpation; and tenderness thresholds were assessed by dolorimetry at 9 tender sites. All patients were interviewed about the presence and severity of neck and FMS-related symptoms. FMS was diagnosed using the American College of Rheumatology 1990 criteria. Additional questions assessed measures of physical functioning and quality of life (QOL). RESULTS: Although no patient had a chronic pain syndrome prior to the trauma, FMS was diagnosed following injury in 21.6% of those with neck injury versus 1.7% of the control patients with lower extremity fractures (P = 0.001). Almost all symptoms were more common and severe in the group with neck injury. FMS was noted at a mean of 3.2 months (SD 1.1) after the trauma. Neck injury patients with FMS (n = 22) had more tenderness, had more severe and prevalent FMS-related symptoms, and reported lower QOL and more impaired physical functioning than did those without FMS (n = 80). In spite of the injury or the presence of FMS, all patients were employed at the time of examination. Twenty percent of patients with neck injury and 24% of patients with leg fractures filed an insurance claim. Claims were not associated with the presence of FMS, increased FMS symptoms, pain, or impaired functioning. CONCLUSION: FMS was 13 times more frequent following neck injury than following lower extremity injury. All patients continued to be employed, and insurance claims were not increased in patients with FMS.

Giant cell tumors with intraarticular fracture. Two-stage local excision, cryosurgery and cementation in 5 patients with distal femoral tumor followed for 2-4 years.

We describe a two-stage operation for intraarticular fracture through a giant cell tumor of the bone. The first stage aims at accurate reduction and fracture union, including curettage, open reduction and minimal internal fixation, autologous bone grafting and temporary bone cement filling. Following bone union, the second operation aims at tumor eradication, including meticulous recurettage, cryosurgery, cementing and stable internal fixation. We report our preliminary results in 5 patients, who were followed 2-4 years. All fractures united, there were no early complications or local recurrences and good function was achieved.

Isolated metastases to peripheral nerves. Report of five cases involving the brachial plexus.

BACKGROUND: Primary true isolated metastasis in a peripheral nerve trunk is considered a rare phenomenon. Several routes of tumor invasion of the peripheral nervous system from different types of cancer and in various anatomic locations have been described in the literature; however, the brachial plexus is an uncommon site of such blood-born metastases. METHODS: Five patients with severe brachial plexus neuropathy without obvious external signs of tumor masses and no detectable regional lymph node involvement underwent exploration of the plexus. RESULTS: Isolated metastatic deposits were identified inside the nerve trunks. Radiation therapy to the area of the lesion provided good symptomatic relief to all patients and local arrest of the disease to four of five. CONCLUSIONS: Despite its rich vascularity, the Peripheral nerve has relative resistance to metastatic spread because there are blood-nerve barriers. This barrier should be investigated further in a tumor model.

Sarin-induced neuropathology in rats.

Sarin, a highly toxic cholinesterase (ChE) inhibitor, administered at near 1 LD50 dose causes severe signs of toxic cholinergic hyperactivity in both the peripheral and central nervous systems (CNS). The present study evaluated acute and long-term neuropathology following exposure to a single LD50 dose of sarin and compared it to lesions caused by equipotent doses of soman described previously. Rats surviving 1 LD50 dose of sarin (95 micrograms/kg; IM), were sacrificed at different time intervals post exposure (4 h-90 days) and their brains were taken for histological and morphometric study. Lesions of varying degrees of severity were found in about 70% of the animals, mainly in the hippocampus, piriform cortex, and thalamus. The damage was exacerbated with time and at three months post exposure, it extended to regions which were not initially affected. Morphometric analysis revealed a significant decline in the area of CA1 and CA3 hippocampal cells as well as in the number of CA1 cells. The neuropathological findings, although generally similar to those described following 1 LD50 soman, differed in some features, unique to each compound, for example, frontal cortex damage was specific to soman poisoning. It is concluded that sarin has a potent acute and long-term central neurotoxicity, which must be considered in the design of therapeutic regimes.

Osteoporosis and increased bone fractures in cerebrotendinous xanthomatosis.

Significant osteoporosis determined by skeleton radiography and bone densitometry was found in 15 patients with cerebrotendinous xanthomatosis (CTX) whose mean age was 31 +/- 11 years. In three CTX patients, bone biopsies confirmed osteoporosis. Nine patients also sustained bone fractures following minimal trauma. Serum 25-hydroxyvitamin D ([25-OHD] 14.6 +/- 6.6 ng/mL v [normal] 30.4 +/- 8.0 ng/mL; P < .001) and 24,25-dihydroxyvitamin D ([24,25(OH)2D] 1.2 +/- 0.4 ng/mL v [normal] 2.7 +/- 0.8 ng/mL; P < .001) levels were low. Serum concentrations of 1,25(OH)2D, calcium, inorganic phosphorus, alkaline phosphatase, parathyroid hormone, and calcitonin were normal. Patients showed classic manifestations of CTX, including dementia, pyramidal and cerebellar insufficiency, peripheral neuropathy, cataracts, and tendon xanthomas associated with elevated serum cholestanol concentrations. These results demonstrate that extensive osteoporosis and increased risk of bone fractures are components of this inherited disease.

Determination of CGS 16617 and stable isotope-labeled CGS 16617, an angiotensin-converting enzyme inhibitor, in human plasma by gas chromatography/mass spectrometry.

An analytical method has been developed for the simultaneous determination of a novel orally active angiotensin-converting enzyme inhibitor (CGS 16617) and a stable isotope-labeled analog. Both compounds are isolated from human plasma using an ion-exchange column, derivatized with pentafluoropropionic anhydride and pentafluoropropanol, and analyzed by gas chromatography/mass spectrometry. After splitless injection on a methyl-silicon column, the compound is detected using negative ion chemical ionization with nitrous oxide as a reagent gas. CGS 16617 labeled with four deuteriums and two 13C is used as an internal standard. The accuracy and precision of the method, expressed as the overall mean +/- SD recovery obtained from two sets of 36 quality-control samples used during a clinical study (concentration range 0.2-100 ng ml-1 plasma), was 96.1 +/- 16.2% for unlabeled drug and 97.6 +/- 14.4% for the D4-labeled drug (concentration range 0.2-100 ng ml-1 plasma). The limit of quantification using 1 ml plasma is 0.2 ng ml-1 for both labeled and unlabeled drug.

Quantitative determination of arecoline in plasma by gas chromatography chemical ionization mass spectrometry.

A capillary gas chromatography/mass spectrometry (GC/MS) method for the quantitative analysis of arecoline in plasma has been developed for concentrations in the range 1-50 ng ml-1. Hexadeuterated arecoline was utilized as the internal standard. The removal of drug from plasma was accomplished by a two-step liquid/liquid extraction procedure involving a wash step followed by extraction with 5% triethyl amine in ethyl acetate. The GC/MS determinations were carried out with temperature-programmed capillary GC and ammonia chemical ionization mass spectrometry. The [M + H]+ ions of both analyte and internal standard were monitored at m/z 156 and 162, respectively. The method is linear and has sufficient sensitivity, precision, accuracy and selectivity for analysis of drug levels in human plasma.

Serum and bone vitamin D metabolites in elective patients and patients after fracture.

Vitamin D metabolite levels were measured in serum and bone samples obtained from 27 patients undergoing elective bony procedures and from 28 patients operated on after a fracture. Serum 25 hydroxyvitamin D3 (25-OH-D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) did not differ significantly between the elective and fracture patients, but serum 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) was significantly reduced in the fracture patients. Very little 25-OH-D3 was found in bone, although it was the major vitamin D metabolite in serum (90%). In elective patients bone levels of 24,25(OH)2D3 and 1,25(OH)2D3 were similar to those in serum; however, in bone from around pertrochanteric fractures, but not from subcapital or patellar fractures, the concentrations of these compounds were considerably increased. These findings may shed light on the mechanism of callus formation and on the role of vitamin D metabolites in bone healing.

Simultaneous closed dislocation of both interphalangeal joints in one finger.

A rare case of simultaneous dislocation of both interphalangeal joints in one finger in a table-tennis player is presented. The second dislocation took place when the first dislocated joint became the fixed part of the finger as it hit a wall. Treatment was, first, hyperextension to unlock the base of the phalanx, then traction along the phalanx: its base was then pushed into contact with the head of the proximal phalanx. Splinting was applied with the joint in slight flexion.

Bioavailability and kinetics of maprotiline.

Six male subjects received simultaneously single 50-mg oral doses of a maprotiline hydrochloride tablet and a trideuterated maprotiline hydrochloride aqueous solution. No side effects or other problems were encountered. The blood levels of unlabeled and isotope-labeled maprotiline for each subject were essentially superimposable. Peak levels, averaging about 50 ng/ml, were attained between 8 and 24 hr after drug. The biologic t1/2 (beta-phase) averaged 58 hr for the unlabeled and 60.5 hr for the labeled drug. The total areas under the curves (extended to time infinity) averaged 3,862 and 3,944 ng . hr/ml for maprotiline and trideuterated maprotiline, respectively (differences between the two are not significant). At the 95% degree of confidence the Westlake confidence limits show less than 10% differences between the formulations with respect to area under the curve data (calculated both to 168 hr and extended to time infinity), peak blood levels, and biologic t1/2s. There were no differences between formulations with respect to times of peak concentrations. Estimates were made for apparent volumes of distribution (about 1,000 l), apparent blood clearance (about 14 l/hr), lag times (about 1.42 hr for tablets and 1.31 hr for solution), and absorption rate constants (about 0.34 hr-1 for the tablets and 0.42 hr-1 for the solution).

Selected ion monitoring assay for the antidepressant maprotiline.

A procedure is described which permits the determination of maprotiline in biological fluids at concentrations ranging from 0.5 to 150 ng ml-1. It relies on the use of N-desmethylclomipramine or isotope labeled maprotiline as the internal standard, on derivatization of the secondary amines with heptafluorobutyric anhydride, and on the combined use of gas chromatography with chemical ionization mass spectrometry and computerized data handling. The assaying procedure is specific, accurate and precise. It is suitable for routine analyses and has sufficient sensitivity to permit monitoring the human blood levels expected from a single therapeutic dose for a week or longer. The method, which can monitor simultaneously isotope labeled and unlabeled maprotiline, can be used to great advantage for reducing variability problems encountered in bioavailability studies.

A sensitive method for the simultaneous determination in biological fluids of imipramine and desipramine or clomipramine and N-desmethylclomipramine by gas chromatography mass spectrometry.

A procedure is described which permits the simultaneous determination of imipramine and desipramine or clomipramine and N-desmethylclomipramine in serum or plasma for concentrations in the range of 1-200 ng ml-1. Detection limits of 0.2 ng ml-1 for imipramine and 0.1 ng ml-1 for desipramine were demonstrated with a signal-to-noise ratio maintained at 2:1 or better. The method relies on the derivatization of the secondary amines with heptafluorobutyric anhydride and is based on the combined use of gas chromatography, electron impact mass spectrometry and computerized data handling. The assaying procedure is specific, accurate and precise. It is suitable for routine analyses and has sufficient sensitivity to permit monitoring the drug and metabolite levels in human plasma or serum resulting from a single therapeutic dose.

Metabolism, plasma or serum levels, and elimination of phenformin in guinea pigs, rats, and dogs.

14C-Phenformin hydrochloride was used for investigating the metabolism, plasma or serum levels, and elimination of the drug following 1.5-mg/kg po or iv doses to guinea pigs, rats, and dogs. The amounts of individual metabolites and unchanged drug were assessed in urine as well as in plasma or serum. The glucuronide of 1-(p-hydroxyphenethyl)biguanide was a major metabolite in the blood and urine of all three species. Guinea pig serum and urine contained a sizable quantity of unchanged drug. Dog plasma and urine had significant amounts of nonconjugated 1-(p-hydroxyphenethyl)biguanide and of an unidentified major metabolite. In all three species following intravenous drug administration, unchanged drug contributed significantly to the radioactivity found in blood and urine. The apparent half-lives of phenformin eliminateion were 0.3-0.8 day for guinea pigs and rats and 1-1.5 days for dogs. Urinary excretion data indicate apparent half-lives of approximately 1.3-1.5 days for the elimination of each of the three major metabolites in dogs.

Conversion of biguanides into substituted s-triazines assayable by GC or mass fragmentography.

Substituted s-triazines were prepared by the treatment of biguanides with various organic acid anhydrides. This reaction permits the ready conversion of the hypoglycemic drugs phenformin, buformin, and metformin and of other analogous biguanides into compounds suitable for GC and mass fragmentographic determination with a high degree of sensitivity. Mass spectral data and Kováts retention indexes are presented for all s-triazines prepared for this study.

Pharmacokinetics of phenformin in man.

Phenformin was assayed in urine, plasma, and sputum specimens, obtained from two healthy volunteers during the four-day period following oral administration of a single therapeutic dose. Approximately one third of the drug was excreted unchanged in the urine. Phenformin profiles were obtained for urinary excretion rates and for plasma and saliva concentrations. The terminal exponential declines indicate a half-life of approximately 11 hours. At 37 degrees C, plasma bound 19 per cent of added phenformin.