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Osseointegration of oxidized and turned implants in circumferential bone defects with and without adjunctive therapies: an experimental study on BMP-2 and autogenous bone graft in the dog mandible.

The aim of the study was to compare the integration and implant stability of turned and oxidized titanium implants when placed in experimental bone defects with autogenous bone graft, BMP-2 or without adjunctive therapy. Four defects were prepared on each side of the mandible of 12 mongrel dogs five months after tooth extractions. Implants with turned and oxidized surfaces were placed in the defects. The circumferential gaps were filled with either autogenous bone grafts, a BMP-allogeneic dog mixture in a thermoplastic carrier, carrier alone or left without any treatment (control). There were no statistically significant differences between control and treated sites, neither for turned nor for oxidized implants with regard to histomorphometric measurements in ground sections and to implant stability as measured with resonance frequency analysis (RFA) after 4 and 12 weeks of healing. However, oxidized implants showed a significantly higher stability after 4 weeks and a tendency (p < 0.1) of that after 12 weeks. Histomorphometry showed more bone contacts for oxidized than for turned implants. It is concluded that oxidized implants gain stability more rapidly and integrate with more bone contacts than implants with a turned surface when placed in bone defects.

Animals↗

Use of magnesium sulphate as adjunctive therapy for resection of phaeochromocytoma.

The intraoperative control of cardiovascular disturbances associated with the resection of phaeochromocytoma is traditionally achieved by the use of deep anaesthesia in conjunction with alpha and beta blockers, calcium antagonists, nitroglycerine or sodium nitroprusside. We report the successful use of magnesium sulphate as adjunctive therapy in the control of the cardiovascular consequences associated with surgical resection of a phaeochromocytoma in a patient.

Adrenal Gland Neoplasms↗

Adjunctive therapy in bacterial meningitis--what make sense?

Bacterial meningitis continues to cause morbidity and mortality despite bactericidal antibiotic therapy. Experimental studies of pathophysiology reveal the bacteria and their surface components within cerebrospinal fluid (CSF) induce the release of inflammatory cytokines that promote CSF inflammation, injure the cerebral microvasculature and cause brain edema. Adjunctive corticosteroids reduce inflammation, ameliorate the pathophysiology, and improve neurologic outcome in children. Practical recommendations are made for children and selected adults regarding current and future directions of adjunctive therapy.

Animals↗

Long-term follow-up of patients with invasive fungal disease who received adjunctive therapy with recombinant human macrophage colony-stimulating factor.

Mortality of bone marrow transplant (BMT) patients who develop invasive fungal infection is greater than 80%. Long-term follow-up of 46 consecutive BMT patients who received recombinant human macrophage colony-stimulating factor (rhM-CSF) as adjunctive therapy with standard antifungal treatment who were entered into phase I/II trials at The Fred Hutchinson Cancer Research Center is reported. rhM-CSF (100 micrograms/m2 to 2,000 micrograms/m2; Chiron/Cetus Corporation, Emeryville, CA) was administered from day 0 to 28 after determination of progressive fungal disease. Results of long-term follow-up of fungal infection, relapse, and survival were compared with 58 similar historical controls. Multivariable analysis of the patients who received rhM-CSF showed two factors that significantly correlated with poor survival: Karnofsky score < or = 20% and Aspergillus infection. Overall, survival of patients who received rhM-CSF was greater than that of historical patients (27% v 5%) and was entirely because of a 50% survival rate in patients with Candida infection and Karnofsky scores greater than 20%. Prospective, randomized, controlled trials to determine efficiency of rhM-CSF are indicated and should be directed at patients with invasive candidiasis.

Adult↗

Efficacy and tolerability of entacapone as adjunctive therapy to levodopa in patients with Parkinson's disease and end-of-dose deterioration in daily medical practice: an open, multicenter study.

Entacapone is a potent, reversible and orally active inhibitor of catechol-O-methyltransferase. This open multicenter study evaluated the efficacy, safety and tolerability of entacapone as adjunct therapy to levodopa/dopa decarboxylase inhibitor (> or = 3 daily doses) in patients with idiopathic Parkinson's disease and end-of-dose motor fluctuations. The 8-week study included 489 patients under conditions of typical daily medical practice. Patients were treated with a 200-mg fixed dose of entacapone administered with each scheduled dose of levodopa to a maximum of 10 doses per day. Other antiparkinsonian medication should have been stable for at least 1 month. The primary efficacy criteria were: (1) Part II (activities of daily living, ADL) of the Unified Parkinson's Disease Rating Scale (UPDRS), (2) the reduction of 'off' time during the daily waking period as assessed by the percentage of patients improving by at least one category at Item 39 of Part IV of the UPDRS. Secondary outcome measures included: (1) the investigator's global assessment of change, (2) quality of life (QoL) was assessed using the Parkinson's Disease Questionnaire (PDQ-39). Adverse events, vital signs and liver enzymes were monitored at weeks 2 and 8. The baseline mean score for ADL was 10.5 (+/-7.04), which decreased to 8.5 (+/-6.37) at the end of the study (p < 0.0001). Compared to baseline, 40.8% of patients experienced a reduction in 'off' time during the waking period; this improvement was highly significant (p < 0.0001). A reduction in the daily dose of levodopa was observed in 35.8% of patients (mean decrease 209 +/- 149 mg). QoL was improved by a mean of 10% in all categories of the PDQ-39 (p < 0.001), except social support and cognition. This improvement was statistically significant (p < 0.001). The dyskinesia score (UPDRS Item 32) was decreased significantly from 2.3 to 2.1 from baseline to end of study (p < 0.001), although 52.7% of patients reported levodopa-induced dyskinesia as an adverse event. There was no case of increased liver enzymes. The study results confirm that the excellent risk/benefit ratio seen in phase III controlled studies can be seen in daily neurological practice. Moreover, the study suggests that the benefits of entacapone are associated with a significant improvement in QoL.

Adult↗

A randomized double-blind trial of intravenous trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction.

BACKGROUND: Despite high patency rates, primary angioplasty for myocardial infarction does not necessarily result in optimal myocardial reperfusion and limitation of infarct size. Experimentally, trimetazidine limits infarct size, decreases platelet aggregation, and reduces leukocyte influx into the infarct zone. To assess trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction a prospective, double-blind, placebo-controlled pilot trial was performed. METHODS: 94 patients with acute myocardial infarction were randomized to receive trimetazidine (40 mg bolus followed by 60 mg/day intravenously for 48 h) (n=44) or placebo (n=50), starting before recanalization of the infarct vessel by primary angioplasty. Patients underwent continuous ST-segment monitoring to assess return of ST-segment deviation to baseline and presence of ST-segment exacerbation at the time of vessel recanalization. Infarct size was measured enzymatically from serial myoglobin measurements. Left ventricular angiography was performed before treatment and repeated at day 14. RESULTS: Blinded ST segment analysis showed that despite higher initial ST deviation from baseline in the trimetazidine group (355 (32) vs. 278 (29) microV, P=0.07), there was an earlier and more marked return towards baseline within the first 6 h than in the placebo group (P=0.014) (change: 245 (30) vs. 156 (31) microV respectively, P=0.044). There was a trend towards less frequent exacerbation of ST deviation at the time of recanalization in the trimetazidine group (23.3 vs. 42.2%, P=0.11). There was no difference in left ventricular wall motion at day 14, or in enzymatic infarct size. There was no side effect from treatment. Clinical outcomes were similar between groups. CONCLUSION: Trimetazidine was safe and led to earlier resolution of ST-segment elevation in patients treated by primary angioplasty for acute myocardial infarction.

Adolescent↗

Recurrence and survival after abdominoperineal and low anterior resection for rectal cancer, without adjunctive therapy.

Sphincter-saving operations for rectal cancer are performed with increasing frequency. In the present study outcome after low anterior resection (LAR) was compared with outcome after abdominoperineal resection (APR). Morbidity, mortality, local and distant failure and survival were retrospectively studied in 68 patients, surgically treated for rectal cancer without adjunctive therapy between 1980 and 1985. APR was performed in 29 patients (27 for cure) and LAR in 39 (32 for cure). Mean follow-up time was 60 months (range 39-95 months). Groups were comparable with regard to age and Dukes' staging, but not for location of the tumour. Anastomotic leakage was present in 15% after LAR; morbidity was otherwise similar in both groups. Hospital mortality was 5% after LAR and 0% after APR. Local recurrence occurred after a mean period of 17 months: in 15% after curative APR and in 13% after curative LAR. Distant recurrence was detected after a mean period of 28 months: in 30% after curative APR and in 26% after curative LAR. Estimated cumulative 5-year survival was not statistically different, with 72% after LAR and 59% after APR. These findings confirm that LAR does not lead to higher recurrence than APR in the treatment for rectal cancer.

Adult↗

Acute ischemic syndromes. Adjunctive therapy.

The acute coronary syndromes (ACS) represent a heterogeneous group of patients along a continuum of risk from unstable angina to non-ST-segment elevation myocardial infarction. ACS is a term that has been used to describe the constellation of clinical symptoms that represent acute myocardial ischemia. This article reviews the adjunctive medications that are used during emergency cardiovasculare care for the early management of patients experiencing the ACS. The adjunctive therapies are divided into early immediate treatment and then subsequent management in the acute care setting.

Acute Disease↗

Role of new antiplatelet agents as adjunctive therapies in thrombolysis.

Coronary thrombolysis is the treatment of choice for patients with acute Q-wave myocardial infarcts who have no contraindications to such therapy. However, the time required for thrombolysis and the possibility of reocclusion of the infarct-related artery remain problematic. Herein are described experimental animal studies and clinical evaluations in which attempts have been made to develop adjunctive therapies that, when coupled with available thrombolytic interventions, might shorten the time to thrombolysis and delay or prevent reocclusion. From the studies conducted to date, it is clear that a combined thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist and heparin shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models with copper coil-induced coronary artery thrombi. A monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor coupled with tissue plasminogen activator (t-PA) and heparin also shortens the time to thrombolysis and delays or prevents reocclusion in experimental canine models. Thrombin inhibitors, including heparin and synthetic inhibitors, given with t-PA and aspirin, appear to shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models. Aspirin coupled with intravenous streptokinase reduces mortality in patients with presumed acute myocardial infarction, and a combination of heparin and t-PA results in infarct-artery patency more frequently than t-PA without heparin. Data from these studies are encouraging with regard to the possibility of developing effective and relatively safe thrombolytic regimens that shorten the time to thrombolysis and delay or prevent coronary artery reocclusion.

Animals↗

Development of adjunctive therapies for bacterial meningitis and lessons from knockout mice.

Bacterial meningitis is a medical emergency and is optimally managed in an intensive care environment. Despite the use of antibiotics, the prognosis of this disease is poor because of central nervous system complications such as brain edema formation, cerebrovascular alterations, intracranial hemorrhage, and hydrocephalus. Effective adjunctive therapies are still missing. Experimental studies with animal models have provided new insights into the pathophysiology during the acute phase of bacterial meningitis. In recent years, knockout mice have become a powerful tool to investigate the role of particular genes and have also been applied in bacterial meningitis research. The use of these mice offered new insights into the role of different cytokines, proteases, and oxidants involved in the inflammatory cascade. Translating this knowledge into new therapies will provide new treatment strategies for this serious disease in the future.

Animals↗

Rasagiline mesylate, a new MAO-B inhibitor for the treatment of Parkinson's disease: a double-blind study as adjunctive therapy to levodopa.

Rasagiline mesylate (TVP-1012) is a potent, selective, non-reversible MAO-B inhibitor, without the tyramine-potentiating effect and with neuroprotective activities. The benefit of rasagiline as monotherapy in patients with early Parkinson's disease (PD) has already been reported. To evaluate the safety, tolerability, and clinical effect of rasagiline as adjunctive therapy to levodopa, a multicenter, double-blind, randomized, placebo-controlled, parallel-group study (0.5, 1, and 2 mg/d) was conducted for 12 weeks in 70 patients with PD (mean age, 57.4 y; mean disease duration, 5.7 y; 32 patients had motor fluctuations). A beneficial clinical effect was observed in fluctuating patients treated with rasagiline (all doses), expressed as a decrease in total Unified Parkinson's Disease Rating Scale (UPDRS) score (23.0% vs 8.5% in the placebo group). The treatment effect was still evident 6 weeks after drug discontinuation (in all doses). The safety and tolerability of rasagiline were good. Adverse events were no different than those of patients taking placebo. Almost complete platelet MAO-B inhibition was obtained at all rasagiline doses. This study has demonstrated that rasagiline (up to 2 mg/day) has a good safety profile and a beneficial clinical effect in fluctuating patients with PD when given as an add-on to chronic levodopa therapy.

Adult↗

Long-term experience with topiramate as adjunctive therapy and as monotherapy in patients with partial onset seizures: retrospective survey of open-label treatment.

Because initial studies of new antiepileptic drugs (AEDs) are add-on trials in refractory patient populations, their effectiveness as monotherapy is usually not apparent until relatively later in their development programs. The novel AED topiramate (TPM) has been found efficacious as adjunctive therapy in controlled, randomized trials in adults with partial onset seizures. We report a retrospective analysis of TPM as AED monotherapy in 214 patients from five centers who received TPM in investigational trials. Of this total, 136 (64%) were still receiving TPM at the time of the analysis, with a mean treatment duration of 2.5 years. One-third of the patients have been successfully converted to TPM monotherapy, and 62% of those converted have been seizure-free for at least 3 months. The results of this analysis suggest that TPM may prove to be a valuable new AED for both monotherapy and add-on therapy in partial onset epilepsy.

Adult↗

Fresh-frozen plasma vs. plasma protein derivative as adjunctive therapy for patients with massive burns.

Twenty patients with burn injuries involving 45% or more total body surface area were randomly allocated to receive either fresh-frozen plasma (plasma), 200 ml/m2/d (11 patients), or an approximately equal amount of plasma protein derivative (Plasmanate) (nine patients) during the first 45 days postburn. To study the potential effects of these two adjunctive therapies on host resistance to infection, measurements were made twice weekly of the antibacterial funciton of neutrophils, the opsonic index (ability to opsonize alternative pathway dependent E. coli 075), C3(B), IgG, properdin, factor B, total protein, and albumin. The average size of burn in the plasma group was 61.5% total and 42% 3 degrees compared with 61% total and 46% 3 degrees in the Plasmanate group. Ten and 18 episodes of bacteremia occurred in the plasma and Plasmanate groups, respectively. Analysis of the results indicates only slightly better support of host resistance when plasma is administered, but this is counterbalanced by the increased risk of viral hepatitis.

Adolescent↗

Adjunctive therapy in thrombolysis for acute myocardial infarction.

The value of prompt coronary reperfusion utilizing thrombolytic therapy during acute myocardial infarction has been well established. However, new data indicates that although rapid reperfusion is imperative, this positive effect may, in fact, be partially or totally negated if patency is not sustained and complete. The following manuscript discusses the role of adjunctive agents in thrombolysis that are essential in preventing coronary reocclusion. It is this important function that serves to prevent recurrent ischemia and reinfarction, thereby improving resultant left ventricular function. This, in turn, should have a positive effect on post-thrombolytic mortality. The data presented in this paper supports high dose, titrated intravenous heparin and aspirin as required adjunctive therapy to thrombolytic treatment in the setting of acute myocardial infarction.

Aspirin↗

Role of granulocyte colony-stimulating factor as adjunct therapy for septicemia in children with acute leukemia.

The granulocyte colony-stimulating factor (G-CSF) has been shown to accelerate recovery from severe neutropenia and to decrease the incidence of documented infections after intensive chemotherapy in cancer patients. However, the routine prophylactic use of G-CSF is expensive. This study was conducted to determine the role of G-CSF as adjunct therapy for septicemia following neutropenia caused by chemotherapy in children with acute leukemia. Fifty consecutive episodes of septicemia were studied involving 34 episodes of Gram-negative, 7 episodes of Gram-positive, 5 episodes of polymicrobial bacterial septicemia, one episode of fungemia, and 3 episodes of disseminated fungal infection. In the first 25 episodes, G-CSF was not used (group A). For the next 16 episodes, G-CSF 200 micrograms per square meter per day subcutaneously was given immediately after the septicemia was documented until the absolute neutrophil count was maintained at more than 1,500 per cubic millimeter (group B). Thereafter, G-CSF at the same dose as that of group B was prophylactically used in all the children who received high-dose cytosine arabinoside-containing regimens. Nine episodes of septicemia occurred (group C). The incidences of mortality per episode of septicemia in groups A, B, and C were 12.0% (3/25), 12.5% (2/16) and 0% (0/9), respectively. Statistically, there was no difference between the three groups overall and in pair-wise comparisons (all P > 0.5). The durations of G-CSF administration in group B ranged from 6 to 26 days with a median of 12 days and the durations of G-CSF administration in group C ranged from 10 to 23 days with a median of 19 days. With or without G-CSF, there may be no significant difference in the mortality of septicemia following neutropenia caused by chemotherapy in children with acute leukemia.

Acinetobacter Infections↗

Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials.

BACKGROUND: Uncontrolled bleeding is a leading cause of death in trauma. Two randomized, placebo-controlled, double-blind trials (one in blunt trauma and one in penetrating trauma) were conducted simultaneously to evaluate the efficacy and safety of recombinant factor VIIa (rFVIIa) as adjunctive therapy for control of bleeding in patients with severe blunt or penetrating trauma. METHODS: Severely bleeding trauma patients were randomized to rFVIIa (200, 100, and 100 microg/kg) or placebo in addition to standard treatment. The first dose followed transfusion of the eighth red blood cell (RBC) unit, with additional doses 1 and 3 hours later. The primary endpoint for bleeding control in patients alive at 48 hours was units of RBCs transfused within 48 hours of the first dose. RESULTS: Among 301 patients randomized, 143 blunt trauma patients and 134 penetrating trauma patients were eligible for analysis. In blunt trauma, RBC transfusion was significantly reduced with rFVIIa relative to placebo (estimated reduction of 2.6 RBC units, p = 0.02), and the need for massive transfusion (>20 units of RBCs) was reduced (14% vs. 33% of patients; p = 0.03). In penetrating trauma, similar analyses showed trends toward rFVIIa reducing RBC transfusion (estimated reduction of 1.0 RBC units, p = 0.10) and massive transfusion (7% vs. 19%; p = 0.08). Trends toward a reduction in mortality and critical complications were observed. Adverse events including thromboembolic events were evenly distributed between treatment groups. CONCLUSION: Recombinant FVIIa resulted in a significant reduction in RBC transfusion in severe blunt trauma. Similar trends were observed in penetrating trauma. The safety of rFVIIa was established in these trauma populations within the investigated dose range.

Adult↗

Continuous intravenous infusion of dipyridamole as adjunctive therapy in the treatment of thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is an uncommon hematologic thrombotic disorder characterized by fever, hemorrhagic and neurologic signs. The advent of plasma exchange has dramatically improved the prognosis of this disease, which was once inevitably fatal. However, mortality rates remain significant. Antiplatelet drugs have been widely used in combination with plasma exchange. In this pilot study we investigated the effects of an adjunctive therapy consisting of the continuous, intravenous infusion of dipyridamole, a modality of administration that has not been previously tested in this setting. Sixteen untreated TTP patients, diagnosed consecutively at our clinic, received daily plasma exchange together with intravenous methylprednisolone (1-2 mg/kg/twice daily) and a continuous i.v. infusion of dipyridamole (100 mg/day). A complete response was defined as an improvement in the platelet count to more than 150 x 10(9)/l for two consecutive days and no neurologic deterioration. The overall response rate was 87.5%. One patient failed to respond to the combination therapy but attained a consistent remission after autologous stem cells transplant. One patient was refractory to the combination therapy and died, after an initial but unsustained response. The results of this pilot study suggest that the continuous infusion of dipyridamole is safe and might provide additional benefit in the treatment of TTP when combined with plasma exchange and steroids. However, a randomized study will be necessary to properly test whether the addition of dipyridamole improves the efficacy of plasma exchange in patient with TTP.

Adult↗

A randomized, investigator-masked, 4-week study comparing timolol maleate 0.5%, brinzolamide 1%, and brimonidine tartrate 0.2% as adjunctive therapies to travoprost 0.004% in adults with primary open-angle glaucoma or ocular hypertension.

OBJECTIVE: The objective of this study was to assess the hypotensive efficacy of timolol maleate 0.5%, brinzolamide 1%, or brimonidine tartrate 0.2% ophthalmic solution, administered in conjunction with travoprost 0.004%, in patients with primary open-angle laucoma (OAG) or ocular hypertension (OHT) whose intraocular pressure (IOP) did not meet the treatment target using travoprost 0.004% monotherapy. METHODS: This was a randomized, comparative, investigator-masked study. Patients with OAG or OHT treated with travoprost 0.004% monotherapy were randomized to receive 1 of the 3 adjunctive therapies (timolol maleate 0.5%, brinzolamide 1%, or brimonidine tartrate 0.2%), 1 drop BID in each randomized eye, in addition to 1 drop QD of travoprost for a period of 4 weeks. IOP was measured on days 0 (travoprost 0.004%) and 28 (travoprost 0.004% and adjunctive treatment). Adverse events were monitored on days 0 and 28 by patient interview. RESULTS: Twenty-nine patients with OAG (46 eyes) and 3 patients with OHT (6 eyes), with a total of 52 eligible eyes, completed the study; 28 eyes were from male patients and 24 were from female patients. In addition to continuing travoprost treatment, 20 eyes received timolol, 16 eyes received brinzolamide, and 16 eyes were treated with brimonidine. There were no significant differences among the groups in the mean (SD) IOP at baseline on day 0 (19.0 [4.1], 17.2 [3.5], and 17.0 [3.1] mm Hg, respectively; P=NS). On day 28, the reduction in mean (SD) IOP in eyes treated with brimonidine tartrate 0.2% was significantly smaller (2.3 [1.8] mm Hg vs 3.9 [1.8] mm Hg [P=0.01]) and the mean (SD) percentage reduction in IOP was significantly smaller (13.4% [9.1%] vs 20.2% [7.5%] [P=0.01]) when compared with timolol maleate 0.5%, and likewise when compared with brinzolamide 1% (4.0 [2.1] mm Hg [P=0.02] and 22.7% [8.6%] [P=0.006], respectively). The group treated with brinzolamide was associated with a similar reduction in IOP to timolol (P=NS for both mean [SD] IOP and percentage reduction in IOP compared with timolol monotherapy). Barring the occasional conjunctival hyperemia, which was excluded as an adverse event for the purposes of this study, no adverse events were recorded. CONCLUSION: Brinzolamide 1% and timolol maleate 0.5% treatment were both associated with a significantly greater reduction in IOP compared with brimonidine 0.2% when administered as a nonfixed adjuvant to travoprost 0.004% in the treatment of patients with OAG and OHT whose IOP was inadequately controlled with travoprost monotherapy. All treatments were well tolerated.

Adrenergic alpha-Agonists↗