Acute neurological problems: frequency, consultation patterns and the uses of a rapid access neurology clinic.

In secondary care, some patients with acute neurological symptoms are never seen by a neurologist. Rapid access neurology clinics could provide patients with timely access to neurology services. We analysed a retrospective cohort of 12,024 consecutive patients attending the 'immediate care' area of the emergency department or the acute medical admissions unit of the Royal Infirmary of Edinburgh. A total of 1,036 patients (9%) presented with a neurological complaint, of whom 680 (66%) did not have any contact with neurology services. The most common problems were epileptic seizure, cerebrovascular diseases and headache. Of the patients with epileptic seizure or headache who were not seen by a neurologist, about 40% might have benefited from neurological assessment. Following the introduction of a weekly rapid access neurology clinic, the most common problems seen were headache, symptoms that turned out to be medically unexplained and epileptic seizure.

Phase I study of pharmacologically based dosing of carboplatin with filgrastim support in women with epithelial ovarian cancer.

PURPOSE: The aim of this study was to increase the dose intensity of carboplatin in women with International Federation of Gynecology and Obstetrics (FIGO) Stage Ic-IV epithelial ovarian cancer with the use of granulocyte colony-stimulating factor (G-CSF; filgrastim; Amgen, Thousand Oaks, CA). PATIENTS AND METHODS: A phase I study of escalating target area under the curves (AUCs) of carboplatin with G-CSF (filgrastim) ws undertaken. The target AUCs were 5 mg/mL.min every 21 days for four cycles, 5 mg/mL.min every 14 days for four cycles, 7 mg/mL.min every 14 days for four cycles, 9 mg/mL.min every 14 days for four cycles, and 11 mg/mL.min every 14 days for four cycles. G-CSF was given at a dose of 5 microg/kg/d starting 24 hours after carboplatin administration and lasting until 24 hours before the next cycle and until day 14 after the last cycle. RESULTS: We were able to escalate to an AUC level of 9 mg/mL.min every 14 days for four cycles. At this dose, severe thrombocytopenia, that necessitated dosage delays, and failure to give subsequent cycles of carboplatin were observed. We then reduced the AUC level to 8 mg/mL.min every 14 days for four cycles. However, severe thrombocytopenia was also observed at this level. CONCLUSION: An AUC of 7 mg/mL.min every 14 days for four cycles is the maximum tolerated AUC level that can be achieved with G-CSF. Further escalations may be possible using either combinations of cytokines or peripheral stem-cell collections.

Long-term oral etoposide in metastatic breast cancer: clinical and pharmacokinetic results.

To evaluate the activity of long-term, single-agent oral etoposide against advanced breast cancer, this study employed etoposide 50 mg/day and 100 mg/day (given over 14 days) in previously treated and chemotherapy-naive patients with histologically confirmed, recurrent or metastatic breast cancer. Of 38 patients, 24 had had chemotherapy, 34 had prior radiotherapy, and 31 had received hormone therapy. Etoposide courses in both treatment groups were repeated every 4 weeks for at least two courses; delays were instituted when patients' total leukocyte nadir fell to or below 3.0 x 10(9)/l. Dose reductions were made in the 100-mg group (to 50 mg/day) if World Health Organization leukopenia grade 3 or higher was present. Plasma pharmacokinetic profiles were measured in selected patients to assess inter- and intrapatient variability in etoposide's oral bioavailability. No complete responses were achieved among the 36 patients evaluable for response, but eight patients had a partial response. Responses were more frequent at the 100-mg dose and in previously untreated patients (seven of eight partial responders had not had previous chemotherapy). Median duration of response was 16 weeks (range, 7 to 46). Myelosuppression (variable and unpredictable) and alopecia (universal) were the notable toxicities. Pharmacokinetic analyses of oral bioavailability revealed significant interpatient variability, but much less intrapatient variability when successive etoposide courses in individual patients were evaluated. Despite the relatively small number of patients in this study, the responses achieved by previously untreated patients suggest etoposide's value against breast cancer. Further trials should use pharmacokinetic studies to assess bioavailability as well as to help define 'target' etoposide doses, based on plasma etoposide levels, during treatment.

Association among visual hallucinations, visual acuity, and specific eye pathologies in Alzheimer's disease: treatment implications.

OBJECTIVE: Studies suggest a link between visual acuity and visual hallucinations in dementia, but links with specific eye pathologies have not been evaluated. METHOD: Fifty patients (20 with visual hallucinations, 30 without) with probable Alzheimer's disease had an evaluation of psychotic symptoms. Visual acuity was measured before and after refractions, and ophthalmological examinations included standardized assessments for cataracts and macular degeneration. RESULTS: Impaired visual acuity and the severity of cognitive impairments were significantly associated with visual hallucinations. No patients with normal acuity (6/5 or 6/6 on the Snellen chart) experienced these symptoms. Impaired acuity improved with refraction in 60% (N = 12) of the patients with visual hallucinations. Of specific eye pathologies, only cataracts were significantly associated with visual hallucinations. Descriptive follow-up information suggests that an optician's assessment for glasses improves outcome. CONCLUSIONS: Glasses and cataract surgery need evaluation as prophylactic or adjunctive treatments for visual hallucinations in patients with probable Alzheimer's disease.

B lymphocyte antigen D8/17 and repetitive behaviors in autism.

OBJECTIVE: Monoclonal antibody D8/17 identifies a B lymphocyte antigen with expanded expression in rheumatic fever, Sydenham's chorea, and subgroups of obsessive-compulsive disorder and Tourette's syndrome with repetitive behaviors. The authors examined the rate of D8/17 expression in children with autism and its correlation with severity of repetitive behaviors. METHOD: Blood samples from 18 patients with autism and 14 comparable medically ill children were evaluated for percentage of D8/17-positive B cells by immunofluorescence and for streptococcal antibodies. Severity of repetitive behaviors was also determined. RESULTS: The frequency of individuals with > or =11% D8/17-positive cells was significantly higher in the autistic patients (78%) than the comparison subjects (21%), severity of repetitive behaviors significantly correlated with D8/17 expression, and D8/17-positive patients had significantly higher compulsion scores than D8/17-negative patients. CONCLUSIONS: D8/17 expression is high in patients with autism and may serve as a marker for compulsion severity within autism.

Identification of children with pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections by a marker associated with rheumatic fever.

OBJECTIVE: The authors' goal was to determine whether a trait marker of rheumatic fever susceptibility (labeled D8/17) could identify children with pediatric autoimmune neuropsychiatric disorders (obsessive-compulsive disorder and tic disorders) associated with streptococcal infections (PANDAS). METHOD: Blood samples obtained from 27 children with PANDAS, nine children with Sydenham's chorea, and 24 healthy children were evaluated for D8/17 reactivity. Individuals were defined as D8/17 positive if they had 12% or more D8/17+ cells. RESULTS: The frequency of D8/17-positive individuals was significantly higher in both patient groups than it was among the healthy volunteers: 85% of the children with PANDAS and 89% of the children with Sydenham's chorea, compared with 17% of the healthy children, were D8/17 positive. Further, the mean number of D8/17+ cells was similar in the two patient groups and was significantly higher in these groups than in the group of healthy children. CONCLUSIONS: These results suggest that there may be a subgroup of D8/17-positive children who present with clinical symptoms of obsessive-compulsive disorder and Tourette's syndrome, rather than Sydenham's chorea, but who have similar poststreptococcal autoimmunity.

Phase I and pharmacokinetic study of a water-soluble etoposide prodrug, etoposide phosphate (BMY-40481).

Etoposide phosphate is a water-soluble prodrug of etoposide. A phase I and pharmacokinetic study has been performed over the dose range 25-110 mg/m2/day for 5 days (etoposide equivalent doses). The maximum tolerated dose (MTD) was 110 mg/m2/day for 5 days every 3 weeks and the dose-limiting toxicity was neutropenia. Other toxicities were mild, with the exception of 2 patients who displayed significant hypersensitivity reactions. The etoposide phosphate:etoposide area under the plasma concentration versus time curve (AUC) ratio was < 1% and the pharmacokinetic parameters for etoposide were within previously reported ranges. Pharmacodynamic analyses demonstrated that etoposide AUC and baseline white blood cell count were significant determinants of leucopenia (model r2 = 0.51).

A flow cytometric assay for D8/17 B cell marker in patients with Tourette's syndrome and obsessive compulsive disorder.

D8/17 is proving to be an important diagnostic and treatment tool in patients with Tourette's syndrome (TS) and obsessive compulsive disorder (OCD). The present study represents a direct comparison of immunofluorescence microscopy and flow cytometry in terms of their relative efficiency in the detection of the DB/17 B cell marker. Analysis of 41 patients with OCD or TS and 31 control subjects by immunofluorescence microscopy and flow cytometer demonstrated an average of 6.5% of D8/17-positive B cells in controls with an average of 19.6% in OCD patients. Using the flow cytometer, values of 6.2% for controls and 22.4% for OCD patients were obtained. The flow cytometer test was able to count many more cells, induce less operator error and offer faster analysis while correlating strongly with the microscopic technique. Overall in our sample, the FACS assay test has a sensitivity of 77% and a specificity of 87%. The ease of use and close correlation to disease activity makes this an ideal test for clinical laboratories.

Carboplatin in combination with paclitaxel in advanced ovarian cancer: dose determination and pharmacokinetic and pharmacodynamic interactions.

Data from various phase I/II studies of carboplatin in combination with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) have suggested that the degree of thrombocytopenia seen is less than that expected when carboplatin is given alone. However, some studies also have suggested that the area under the plasma concentration-time curve (AUC) of carboplatin is lower than that expected, raising the possibility of a pharmacokinetic interaction. Patients with advanced epithelial ovarian cancer were treated with first-line carboplatin (AUC = 7, using the 51Cr EDTA [edetic acid] clearance method) and escalating doses of paclitaxel. Thrombocytopenia was mild and was significantly less when the paclitaxel dose was 175 mg/m2 versus 150 mg/m2. Paclitaxel kinetics were nonlinear, as previously reported. The achieved carboplatin AUC was 7 +/- 1 mg/mL.min, indicating that the pharmacokinetics of carboplatin are not affected by paclitaxel. Glomerular filtration rates measured in 184 patients using the 51Cr EDTA clearance method were compared with rates estimated from the plasma creatinine level using the Cockcroft-Gault or Jeliffe formulas and showed a significant bias of these two formulas. Clearances above 50 mL/min were underestimated by an amount that became greater as the clearance increased and was approximately 25% to 35% for patients with clearances in the normal range. Since creatinine-based methods have been used in many previous studies, care is needed in interpreting the predicted AUC values from these studies. Carboplatin and paclitaxel may be given safely in combination at full doses, and the thrombocytopenia seen is significantly less than that observed with single-agent carboplatin. No evidence exists of a pharmacokinetic interaction, and the observation in some studies that the carboplatin AUC was lower than expected was probably due to the methodology used to estimate the glomerular filtration rate.

Carboplatin and granulocyte colony-stimulating factor as first-line treatment for epithelial ovarian cancer: a phase I dose-intensity escalation study.

A phase I study of frequently administered carboplatin with recombinant human granulocyte colony-stimulating factor (filgrastim) has been performed in patients with newly diagnosed epithelial ovarian cancer. Recombinant human granulocyte colony-stimulating factor was administered at a dose of 5 micrograms/kg/d for days 1 through 12 after carboplatin treatment. Carboplatin doses were calculated using a pharmacokinetic formula on an area under the curve (AUC) basis. Four doses of carboplatin were planned for each patient. The first cohort of patients received an AUC of 5 mg/mL x min every 3 weeks. Subsequently four additional cohorts received AUCs of 5, 7, 9, and 8 every 2 weeks. Non-hematologic toxicities were mild and not significant. The dose-limiting toxicity was thrombocytopenia and occurred at an AUC of 9. Most patients could complete treatment at an AUC of 7. Results for AUC 8 are awaited. Complete and partial responses were seen in most patients at all dose levels.

Genetic control of the humoral immune response to xenografts. I. Functional characterization of rat monoclonal antibodies to hamster heart xenografts.

The rejection of cardiac xenografts in the hamster-to-rat combination is characterized by the production of IgM antibodies that result in the rapid loss of the graft. We have recently produced rat monoclonal antibodies (mAb) to hamster heart xenografts in an attempt to develop reagents for use in identifying the target antigens for this reaction and to study the nature of the genetic control of the humoral response. The monoclonals were created by the fusion of myeloma cells with splenic lymphocytes from LEW rat recipients of hamster cardiac xenografts. The hybridomas were screened for antibody production, reactivity to hamster cell surface antigens, and the ability to mediate hyperacute rejection of hamster heart xenografts. A panel of monoclonal antibodies has been identified that are capable of inducing hyperacute rejection. All of these mAbs are IgM and bind strongly to hamster vascular endothelium. None of the mAbs were lymphocytotoxic or bound to hamster lymphocytes or erythrocytes. Immunopathologic studies demonstrated that these mAbs react specifically with hamster vascular endothelium and mediate a complement-dependent humoral reaction leading to the destruction of the cardiac xenografts. One of the mAbs (designated as HAR-1) has been characterized in detail. HAR-1 detects antigens distributed in the vascular endothelium, epithelium of bronchi in the lung, small intestine, tubules of kidney, and selective components of lymphoid organs--e.g., the stromal cells of the spleen and thymic medullary epithelium. Western blot analysis of hamster heart proteins with HAR-1 showed multiple bands with two major bands migrating at 80 kDa and 48 kDa. Absorption of the HAR-1 antibody with 48 individual carbohydrate molecules demonstrated that the strongest reactivity of the antibody is with a sialyl-Lea carbohydrate antigen.

Platelet-activating factor and hyperacute rejection. The effect of a platelet-activating factor antagonist, SRI 63-441, on rejection of xenografts and allografts in sensitized hosts.

The pathogenesis of hyperacute transplantation reactions includes the activation of a cascade of nonspecific inflammatory reactions that precipitates the destruction of the target organ. Platelet-activating factor (PAF) represents an important component of these inflammatory cascades, and we have examined the influence of a specific PAF receptor antagonist (SRI 63-441) on the inhibition of hyperacute rejection in two experimental models, the rejection of rat cardiac allografts by presensitized recipients and guinea pig-to-rat and mouse-to-rat cardiac xenografts. Our results demonstrate that inhibition of PAF function by SRI 63-441 has a variable effect on the survival of cardiac allografts in presensitized rat recipients. In the ACI to sensitized BN cardiac allograft model, the use of SRI 63-441 alone, or in combination with CsA, FK506, or prostaglandin E2 (PGE2), does not prolong graft survival. As we have previously reported, SRI 63-441 does act as a single agent to prolong the survival of ACI to sensitized LEW grafts, and this survival effect is synergistic when combined with CsA. Here we extend these results to demonstrate that this survival is also extended when FK506 is used in the ACI-to-LEW model. Concordant mouse-to-rat cardiac xenografts are also relatively resistant to prolongation of graft survival following treatment with SRI 63-441 alone or in combination with CsA or FK506. Discordant xenografts appear to be more susceptible to inhibition of the rejection reaction with SRI 63-441. When either donor or recipient animals were treated with SRI 63-441 alone, or in combination with CsA or FK506, there was significant prolongation of guinea pig-to-rat cardiac xenograft survival. These results are consistent with our earlier description of the effectiveness of SRI 63-441 in preventing the rejection of cat-to-rabbit kidney xenografts. We believe that these results demonstrate that the use of the SRI 63-441 to specifically interfere with the function of PAF has the effect of prolonging graft survival in those systems in which performed antibody and/or complement activation are important components of the hyperacute reaction. This synthetic drug is representative of a family of compounds whose structure can be modified to balance their therapeutic and toxicity activities, and may prove to be important components of a polytherapeutic approach to the control of graft rejection in sensitized patients or following discordant xenografting.

The prevention of accelerated cardiac allograft rejection in sensitized recipients after treatment with brequinar sodium.

Brequinar sodium (BQR) is a novel immunosuppressive agent that is highly effective in preventing B lymphocyte-mediated antibody production. We have examined the effects of BQR treatment in sensitized recipients on graft survival, donor-specific antibody responses (IgM and IgG), and the appearance of immunopathological lesions present in the grafts. LEW rat recipients were sensitized with single ACI skin graft on day 7 and received heterotopic ACI cardiac grafts on day 0. The recipients rejected the cardiac grafts in an accelerated fashion at day 2.5 post-transplantation, compared to day 7.0 in unsensitized recipients. The animals were treated with low (3 mg/kg/day) or high (12 mg/kg/3x weekly) doses of BQR during skin graft sensitization and/or after challenge with ACI heart allografts. All groups treated with BQR showed significant prolongation of graft survival in the sensitized recipients. The best survival was observed following high-dose BQR therapy during both sensitization and effector phases (median survival time = 40.0 days, P << 0.001). Daily treatment with BQR (3 mg/kg/day) prevented IgM (but not IgG) antibody responses. Treatment with higher doses of BQR (12 mg/kg/3x weekly) before and after skin graft sensitization was effective in preventing both IgM and IgG production. In general, BQR treatment resulted in effective suppression of anti-donor antibody responses, stable graft function, and a reduction in the severity of the acute vascular lesions in the graft. The effectiveness of BQR in preventing accelerated graft rejection when used at 12 mg/kg/3x weekly was comparable to that seen with treatment of sensitized animals with CsA at 15 mg/kg/day for 30 days. Daily treatment with cyclophosphamide at 5 or 15 mg/kg/day was ineffective for preventing graft rejection in sensitized recipients. These results indicated that BQR may provide an important addition to treatment protocols designed to prevent transplantation rejection in presensitized patients. BQR has the ability to significantly inhibit host cellular and humoral immune responses to the donor graft and this facet of the immunosuppressive activity of the drug may be responsible for preventing this aggressive form of rejection.

Genetic control of the humoral immune response to xenografts. II. Monoclonal antibodies that cause rejection of heart xenografts are encoded by germline immunoglobulin genes.

The early phases of the rejection of xenografts exchanged between closely related species are dominated by a vigorous humoral immune response. We have recently used a linker-mediated polymerase chain reaction (LM-PCR) to generate Ig heavy and light chain-specific cDNA libraries to examine the Ig gene control of a prototypic IgM monoclonal antibody, HAR-1, that causes the hyperacute rejection of hamster xenografts. Recombinant clones from the library were screened directly from bacterial colonies by PCR and the nucleic acid sequences of the clones established. Our results demonstrate that the HAR-1 hybridoma is encoded by Ig VH and JH genes in a germline configuration. Comparison of the cDNA sequence for HAR-1 VH with the germline equivalent of this gene isolated from newborn LEW liver (provisionally designated VHHAR-1) showed that the two VH sequences share a nucleic acid identity of 99.3%. Similarly, the HAR-1 monoclonal uses a Ig JH gene that is 98.2% identical with the JH1 nucleic acid sequence available in the GeneBank. The use of Ig VH and JH genes in a germline configuration is similar to that seen with polyreactive natural antibodies to infectious agents and autoantibodies. These humoral responses are thought to be the result of the stimulation of a T cell-independent subset of B cells, the B-1a/B-1b subset, that is responsible for producing antibodies that serve as a primitive humoral (natural antibody) defense mechanism against infectious diseases. Our results suggest that the humoral component of the rejection of xenografts in the hamster-to-rat model may represent the stimulation of this type of B cell antibody response by xenogeneic target antigens that share antigenic epitopes with bacteria and other infectious agents.

The prolongation of concordant hamster-to-rat cardiac xenografts by brequinar sodium.

Brequinar sodium (BQR) prevents cell proliferation by virtue of its inhibition of de novo pyrimidine biosynthesis. The immunosuppressive activity of BQR is highly effective in prolonging heart, liver, and kidney allograft survival in the rat. In these experiments, we have tested the ability of BQR to prevent the rejection of concordant cardiac xenografts. LEW inbred rats transplanted with heterotopic hamster hearts were treated orally with brequinar sodium as a single agent. The survival of the cardiac xenografts was significantly prolonged with a variety of treatment regimens. The most effective treatment was the daily oral administration of BQR at 3 mg/kg. At this level, the median graft survival was approximately 25 days. Four animals had hamster heart xenografts that functioned for more than 90 days. The prolonged survival of the xenografts was associated with relatively constant plasma drug levels of approximately 1 to 3 micrograms/ml and a marked suppression of IgM production. At rejection, there was a significant rise in IgM levels compared with those of recipients with stable xenografts. In vitro MLR responses were effectively inhibited by BQR, with an IC50 of 0.08 microgram/ml. The results of these experiments demonstrate that BQR is a new immunosuppressive agent that is highly effective as a single agent in prolonging the survival of hamster-to-rat cardiac xenografts. The prolonged xenograft survival is associated with effective suppression of rat antihamster antibody production, suggesting that brequinar sodium may be an important addition to multidrug immunosuppressive regimes designed to prevent B and T lymphocyte-mediated immune responses.

Cardiac transplantation in the rat. II. Alteration of the severity of donor graft arteriosclerosis by modulation of the host immune response.

Cardiac transplantation between inbred rat strains that differ for weak histocompatibility antigens is associated with the development of arteriosclerosis in the arteries of the donor graft myocardium. The lesions are seen in donor/recipient pairs that differ for both MHC and non-MHC histocompatibility antigens that apparently stimulate a low-level, chronic rejection of the donor heart graft. The arteriosclerosis associated with this chronic rejection consists of a diffuse, concentric proliferation of the intima and pathologically resembles the lesions observed in the coronary arteries of long-term human cardiac graft recipients. We have recently examined the influence of positive and negative manipulation of the host immune response on the development of the graft arteriosclerosis. Our results demonstrate that delayed harvest of the cardiac grafts or immunization with donor skin grafts or splenic lymphocytes increases the sensitivity of the recipient to the donor heart grafts--and, under conditions that allow for the long-term survival of the graft--increases the severity of the arteriosclerotic lesions. Alternatively, suppression of the host immune responses with cyclosporine or FK506, substantially reduces the arteriosclerotic changes. These results suggest that control of accelerated graft arteriosclerosis in long-term human cardiac recipient may require more careful and effective immunosuppression of the allograft reaction.

Cardiac transplantation in the rat. I. The effect of histocompatibility differences on graft arteriosclerosis.

The development of arteriosclerosis is the most serious and common complication in long-term survivors of cardiac transplantation. We have used a variety of inbred rat strains with selected histocompatibility differences to examine the influence of prolonged, mild rejection reactions on the development of pathological changes in long-term cardiac allografts. Heterotopic cardiac allografts were exchanged between rat strains that differed for MHC class I (RT1.A and/or RT1.E) antigens or groups of minor, non-MHC antigens in MHC-compatible congenic combinations. Our results demonstrate that in strain combinations in which the allograft reaction is mild and prolonged, the donor hearts exhibit pathological changes that include a diffuse, interstitial myocardial fibrosis, perivascular fibrosis, and intimal proliferation in arteries of the graft myocardium. The lesions were less prominent in animals with more active rejection and infrequent in strains that differ for class I histocompatibility antigens or syngeneic controls. These results suggest that the comparable pathological changes seen in long-term human cardiac survivors may reflect low-level, persistent allograft reactions rather than factors associated with graft anoxia or effects of immunotherapy to prevent graft rejection.

The effect of a new immunosuppressive drug, brequinar sodium, on heart, liver, and kidney allograft rejection in the rat.

Brequinar sodium (BQR) prevents cell proliferation by virtue of its inhibition of de novo pyrimidine biosynthesis. BQR is capable of inhibiting immune responses in vitro and is effective in suppressing the development of contact sensitivity and adjuvant arthritis in rodent models. Based on the antiproliferative and immunosuppressive capacity of BQR, we have evaluated the efficacy of BQR in preventing allograft rejection utilizing experimental models of heterotopic heart and kidney and orthotopic liver transplantation in an MHC and non-MHC mismatched ACI----LEW rat strain combination. The immunosuppressive activity of BQR is illustrated by its ability to inhibit the development of delayed-type hypersensitivity to DNFB in mice. When BQR was administered orally throughout the sensitization and elicitation phases of the DNFB contact sensitivity response, it was found to be a potent immunosuppressant with an ED50 value of 0.5 mg/kg. This immunosuppressive activity is also seen in vitro, where BQR is capable of inhibiting the mixed lymphocyte response between allogeneic ACI and LEW rat strains with an IC50 of 150 ng/ml. The immunosuppressive activity of BQR is highly effective in prolonging heart, liver, and kidney allograft survival in the rat. Cardiac allografts are not rejected during the period of drug treatment at dosage levels of 12 to 24 mg/kg orally three times weekly. The grafts survive until the drug is discontinued (30 days posttransplantation), and the grafts are then rejected approximately 14 days later. Liver and kidney allografts are permanently accepted by approximately 50 to 90% of the recipient rats following 30 days of treatment with BQR at 12 mg/kg. The tolerance that is induced to the liver grafts extends in the majority of animals to greater than 250 days and is specific for the donor ACI strain. Challenge of long-term liver graft survivors with donor cardiac grafts is associated with permanent survival of donor, but not third-party, heart grafts. Combination therapy consisting of suboptimal doses of BQR and CsA demonstrates that the combination of these two immunosuppressive drugs results in an increased efficacy in prolonging graft survival. The results of these allograft experiments demonstrate that this new immunosuppressive agent is highly effective in preventing allograft rejection in the rat. The antiproliferative activity of BQR is effective for inhibiting T-lymphocyte-mediated immune responses, and Brequinar sodium should be an important addition to a polytherapeutic approach in the treatment of organ graft rejection.

Comparison of monophasic and biphasic defibrillating pulse waveforms for transthoracic cardioversion. Biphasic Waveform Defibrillation Investigators.

All transthoracic defibrillators on the US market use nominally monophasic shock waveforms. However, biphasic waveforms have a lower defibrillation threshold than monophasic waveforms for transthoracic defibrillation of animals and for defibrillation of humans by implantable cardioverter defibrillators. The relative efficacies of Edmark monophasic and Gurvich biphasic transthoracic cardioversion waveforms (200 J into 50 omega) were compared for transthoracic cardioversion in 171 patients undergoing electrophysiologic study for evaluation of ventricular arrhythmias. Patients were randomized in a blinded fashion to receive either a monophasic or a biphasic waveform for the initial shock for conversion of induced ventricular arrhythmias (ventricular fibrillation [VF] = 53, monomorphic ventricular tachycardia [VT] = 80, polymorphic VT = 30, ventricular flutter = 8). Delivered energies for the Edmark and Gurvich waveforms were 215 +/- 11 and 171 +/- 11 J, respectively. There were no significant differences in patient characteristics, use of antiarrhythmic agents, arrhythmia cycle length, or duration of arrhythmia prior to shock for monophasic and biphasic waveform groups. The first shock for all arrhythmias was successful in 75 of 88 patients (85.2%) for the monophasic waveform compared with 81 of 83 patients (97.6%) for the biphasic waveform, p = 0.0054. The first shock for VF was successful in 22 of 28 patients (78.6%) for the monophasic waveform compared with 25 of 25 (100%) for the biphasic waveform, p = 0.0241. The Gurvich biphasic waveforms delivering a mean of 171 J were superior to Edmark monophasic waveforms delivering a mean of 215 J for transthoracic cardioversion of arrhythmias of short duration. This finding may have important implications for the development of future transthoracic defibrillators.

Inhibition of the pyrimidine biosynthetic pathway with S-8660, an analogue of brequinar sodium, prolongs cardiac allograft survival in rats.

The compound S-8660 is a member of a family of antiproliferative drugs that act on de novo pyrimidine synthesis through selective inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase. S-8660 is highly effective in preventing the development of delayed-type hypersensitivity in mice and in suppressing human mixed-lymphocyte responses. We have tested its ability to prevent cardiac allograft rejection in the ACI (RT1a) to Lewis (RT1(1)) rat strain combination, based on the immunosuppressive activity of this compound and its similarity to another member of this group, brequinar sodium. Daily oral administration of the drug (5 to 20 mg/kg) was begun 2 days before transplantation and extended for periods of time up to 30 days after graft placement. Control grafts were promptly rejected (median survival time, 7.0 +/- 0.5 days). Administration of S-8660 was effective in extending graft survival in a dose-dependent fashion. The efficacy of S-8660 could be improved with a high initial concentration of the drug, followed by a reduction ("tapering") in the level of drug administration (median survival time, 32.0 +/- 4.6 days) or by use in combination with cyclosporine. The differences in the mode of action of S-8660, when compared to cyclosporine or FK 506, suggest that the disruption of de novo pyrimidine synthesis may be an effective and safe addition to a polytherapeutic approach for the prevention of allograft rejection in clinical transplantation.