Indicator Of Drug Efficacy Research Articles

Biological differences of three paclitaxel- and sirolimus-coated balloons on coronary lesions in a rabbit model.

Drug-coated balloons (DCBs) are important treatment options for coronary artery disease; however, randomised controlled trials comparing various DCB technologies are sparse, and further investigations are needed. This preclinical study aimed to histologically and biologically compare the drug effects and safety of a low-dose paclitaxel-coated DCB (PCB; AGENT), a regular-dose PCB (SeQuent Please NEO) and a sirolimus-coated DCB (SCB; MagicTouch). The DCBs were inflated in the healthy iliac arteries of 18 rabbits, which were euthanised after 28 days. The treated iliac arteries and distal skeletal muscles were histopathologically evaluated, and drug concentrations were measured. In the histopathological evaluation, the medial smooth muscle cell loss score regarding depth, an indicator of drug efficacy, was significantly higher with AGENT and SeQuent Please NEO than with MagicTouch (4.0 [3.6-4.0] vs 3.7 [3.7-4.0] vs 2.2 [2.0-2.4]), with significant differences in comparisons between AGENT and MagicTouch (p<0.01) and between SeQuent Please NEO and MagicTouch (p<0.01). AGENT and SeQuent Please NEO showed comparable drug concentrations in the treated artery (p=0.61). In contrast, the drug concentrations in distal skeletal muscles were the highest for MagicTouch, followed by SeQuent Please NEO and AGENT (28.07 [13.19-52.46] ng/mg vs 0.66 [0.22-3.76] ng/mg vs 0.25 [0.04-3.23] ng/mg, respectively). This study demonstrated that PCBs might have higher efficacy and lower drug concentrations in distal skeletal muscles than the MagicTouch SCB. The efficacy of the AGENT low-dose PCB and the SeQuent Please NEO regular-dose PCB was comparable.

Antibacterial Effects of Drug-Coated Pearl Nuclei Used for Freshwater Pearl Cultivation

In the cultivation of freshwater nucleated pearls, the treatment technology of nucleated pearls is very important for the quality and yield of pearls. Pearl nuclei treated with astragalus extract, flavomycin, and oxytetracycline were found to possess anti-inflammatory and antibacterial effects depending on drug concentrations. To optimize the concentration of various drugs for the preparation of medicinal pearl nuclei to enhance pearl production Staphylococcus aureus and Aeromonas hydrophila were used as experimental strains. A comprehensive antibacterial circle diameter was taken as an indicator of drug efficacy. The response surface method based on a central composite design (CCD) was used to explain the combined effect of drugs and optimize their concentrations. The optimal concentrations of flavomycin, oxytetracycline, and astragalus extract were 9.10, 10.50, and 1.50 g/mL, respectively. In these conditions, the predicted antibacterial circle diameter was 1.83 cm and the measured value was 1.81 cm, accounting for a 0.5% relative error. The pearl nuclei coated with the abovementioned drug combinations had a strong antibacterial effect on both A. hydrophila and S. aureus, thus establishing a basis for the development and application of medicinal pearl nuclei.

First-Line Anaplastic Lymphoma Kinase (ALK) Inhibitors for ALK-Positive Lung Cancer in Asian Populations: Systematic Review and Network Meta-Analysis.

Various anaplastic lymphoma kinase inhibitors (ALKIs) have been approved for first-line use in treating anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). To date, no head-to-head comparison of these newer generation ALKIs has been made, and different efficacies of ALKIs may present across ethnicity. This study aims to compare newer generation ALKIs for treatment efficacy in Asian groups using network meta-analysis. Phase II/III trials that enrolled treatment-naïve Asian ALK-rearranged NSCLC patients treated by ALKIs were included. Progression-free survival (PFS) and overall response rate (ORR) of each trial were extracted as indicators of drug efficacy. Surfaces under cumulative ranking curves (SUCRAs) were calculated as a numeric presentation of the overall ranking associated with each agent. After a systematic literature review, six phase III clinical trials were included. Our results showed that newer generation ALKIs, such as alectinib, brigatinib, ensartinib, and lorlatinib, all demonstrated superior efficacy to crizotinib. Among those, ensartinib exhibited the best overall SUCRA value and ranked first among all agents. According to our network meta-analysis, ensartinib may currently be the most effective first-line treatment for Asian patients with ALK-positive NSCLC. However, this conclusion needs further validation by a larger scale of clinical trials or posthoc analysis of Asian populations. Moreover, in our comparison, low-dose alectinib (300 mg twice daily) exhibited an efficacy profile similar to a higher dose regimen in Asian populations.

Efficacy of furosemide-albumin compared with furosemide in critically ill hypoalbuminemia patients admitted to intensive care unit: a prospective randomized clinical trial.

Some physicians co-administer albumin with loop diuretics to overcome diuretic resistance in critically ill hypoalbuminemia patients, though previous studies have reported conflicting results on this matter. The effects of adding albumin to furosemide to enhance its efficacy in critically ill hypoalbuminemia patients are evaluated. This was a non-blinded randomized trial. 49 adult critically ill patients with hypoalbuminemia and generalized edema who received randomly furosemide and furosemide/albumin complex were enrolled. The patients' urine was collected at intervals of 2, 4, 6 and 8h after initiation of the furosemide treatment, and the urine output and urinary excretion of furosemide and sodium were measured. The urinary excretion of furosemide was considered an indicator of drug efficacy. The amount of sodium and furosemide excreted in urine showed no significant differences between the two groups; however, the mean of the urinary excretion of furosemide in the first 2h after drug infusion was significantly higher (p = 0.03) in the furosemide/albumin group. No significant correlation between APACHE II scores and serum albumin levels and the urinary excretion of furosemide was seen. The results indicated that there is not statistically significant differences between groups with furosemide alone and combined with albumin in urinary furosemide excretion. It seems that adding albumin for furosemide pharmacotherapy regime is not recommended as an intervention to increase furosemide efficacy in critically ill hypoalbuminemia patients. IRCT with the registration number IRCT201412132582N12 in 23 February 2015; https://en.irct.ir/trial/2356 Graphical abstract.

Dopaminergic and Antidopaminergic Effects on Heart Rate in Healthy Horses When Challenged With Brief 2-minute Exercise Bouts

Bromocriptine is a dopamine receptor agonist known to cause hypotension and bradycardia in several species. Five experiments were conducted to compare possible perturbations on heart rate (HR) in horses after a brief (2 minutes) exercise bout when exposed to either short-term or long-term treatment with bromocriptine, cabergoline, or pergolide (all commonly used dopaminergic agonists in horses) or sulpiride, a dopaminergic antagonist. For all experiments, prolactin was measured as an indicator of drug efficacy. Experiments 1 and 4 were conducted as a replicated Latin square, whereas experiments 2, 3, and 5 were double split plot designs. Experiment 1 tested changes in HR, adrenocorticotropin (ACTH), and growth hormone (GH) concentrations when geldings were pretreated with 50 mg of bromocriptine 12 hours before exercise. Bromocriptine pretreatment reduced (P < .05) the exercise-induced rise in HR and the ACTH and GH responses (P < .05). Experiment 2 assessed the daily responses of HR to exercise after intramuscular administration of 5 mg of cabergoline in vegetable oil, which diminished the rise in HR because of exercise for the first 2 days of the 7-day experiment. In experiment 3, daily feeding of 2g of pergolide top dressed over sweet feed had no effect on HR in response to exercise. Similar results were seen in experiments 4 and 5, when horses were intravenously administered .01 mg/kg BW sulpiride in saline or intramuscularly administered 1g of sulpiride dissolved in vegetable oil. Taken together, bromocriptine and cabergoline, but not pergolide or sulpiride, dampened the cardiac sympathetic response to exercise, thus, lowering the HR.

Adaptive Multilevel Splitting Method for Molecular Dynamics Calculation of Benzamidine-Trypsin Dissociation Time

Adaptive multilevel splitting (AMS) is a rare event sampling method that requires minimal parameter tuning and allows unbiased sampling of transition pathways of a given rare event. Previous simulation studies have verified the efficiency and accuracy of AMS in the calculation of transition times for simple systems in both Monte Carlo and molecular dynamics (MD) simulations. Now, AMS is applied for the first time to an MD simulation of protein-ligand dissociation, representing a leap in complexity from the previous test cases. Of interest is the dissociation rate, which is typically too low to be accessible to conventional MD. The present study joins other recent efforts to develop advanced sampling techniques in MD to calculate dissociation rates, which are gaining importance in the pharmaceutical field as indicators of drug efficacy. The system investigated here, benzamidine bound to trypsin, is an example common to many of these efforts. The AMS estimate of the dissociation rate was found to be (2.6 ± 2.4) × 10(2) s(-1), which compares well with the experimental value.

DRD4/DAT1 mRNA expression in attention deficit hyperactivity disorder children before and after methylphenidate treatment

Objective To investigate mRNA expression level changes of dopamine transporter gene(DAT1) and dopamine receptor gene(DRD4) in attention deficit hyperactivity disorder(ADHD) children's peripheral blood before and after methylphenidate treatment, and to explore associations between the mRNA expression level and symptom severity, as well as methylphenidate response. Methods Forty five ADHD children by DSM-IV diagnostic criteria, aged six to fifteen years old participated in a six-week drug titration treatment of methylphenidate. ADHD-RS-Ⅳ Home Version, WCST and VCPT were used to evaluate the ADHD clinical symptoms and cognitive functions. RNA Simple Total RNA Kit was used to extract the total RNA. After reverse transcription, the obtained c-DNA was used in the following qRT-PCR to evaluate relative mRNA expression of the candidate genges before and after medication. Results The DRD4 mRNA relative expression level after taking methylphenidate was significantly higher than that before methylphenidate treatment(0.23±0.23 vs 0.16±0.18, P=0.041). There was no significant difference between DAT1 mRNA relative expression level before(0.43±0.40) and after(0.43±0.40) methylphenidate treatment. No significant difference was found on either basal DAT1/DRD4 mRNA expression or fold change of DAT1/DRD4 mRNA expression before and after medication between methylphenidate treatment responders and non-responders groups.There was a positively significant correlation between baseline DRD4 mRNA relative expression level and erroneous T score of CPT(r=0.424, P=0.025), however, no other statistically significant correlation was found between basal DRD4 mRNA relative expression level and ADHD-RS-Ⅳ total score, WCST conceptual level, CPT missing T score, and CPT reaction T score(all P>0.05). There was also no statistical significant correlation between basal DAT1 mRNA relative expression level and ADHD-RS-Ⅳ total score, WCST conceptual level, and CPT T scores(all P>0.05). Conclusion DRD4 gene function may be increased after methylphenidate treatment and play an important role in impulsivity behavior of ADHD. Therefore, DRD4 mRNA expression level might be a biomarker for ADHD diagnosis and a predicting indicator of drug efficacy. Key words: Attention deficit hyperactivity disorder; Methylphenidate; Dopamine receptor gene D4; Dopamine transporter gene; mRNA expression

Identifying an early indicator of drug efficacy in patients (pts) with metastatic colorectal cancer (mCRC): A prospective evaluation of circulating tumor cells (CTC), 18F-fluorodeoxyglucose positron-emission tomography (PET), and the RECIST criteria.

3582 Background: The early determination of drug response is a keystone in oncology, and CTC is a promising biomarker in mCRC. This study investigated the prognostic significance of a novel dual-en...

Measurement of Cetuximab and Panitumumab-Unbound Serum EGFR Extracellular Domain Using an Assay Based on Slow Off-Rate Modified Aptamer (SOMAmer) Reagents

BackgroundResponse to cetuximab (Erbitux®) and panitumumab (Vectibix®) varies among individuals, and even those who show response ultimately gain drug resistance. One possible etiologic factor is differential interaction between the drug and target. We describe the development of an assay based on Slow Off-rate Modified Aptamer (SOMAmer™) reagents that can distinguish drug-bound from unbound epidermal growth factor receptor (EGFR).MethodsThis quantitative assay uses a SOMAmer reagent specific for EGFR extracellular domain (ECD) as a capturing reagent. Captured SOMAmer is quantitated using PCR. Linearity and accuracy (recovery) of the assay were assessed using normal sera and purified EGFR ECD.ResultsThis EGFR ECD assay showed linearity between 2.5 and 600 ng/mL. Average recovery was 101%. The assay detected EGFR but showed little cross-reactivity to other ErbB proteins: 0.4% for ErbB2, 6.9% for ErbB3, and 1.3% for ErbB4. Preincubation of normal serum with either cetuximab or panitumumab resulted in a dose-dependent decrease in EGFR ECD levels measured using the SOMAmer assay; preincubation did not affect measurement with an ELISA.ConclusionsThis SOMAmer-based serum EGFR ECD assay accurately and specifically measures EGFR in serum. Detection of significant amounts of drug-unbound EGFR in patients undergoing cetuximab or panitumumab treatment could be an indicator of poor drug response. Further studies are needed to evaluate the utility of the assay as an indicator of drug efficacy or as a guide to dosing.

Explaining the Determinants of First Phase HIV Decay Dynamics through the Effects of Stage-dependent Drug Action

A recent investigation of the effect of different antiretroviral drug classes on first phase dynamics of HIV RNA plasma virus levels has indicated that drugs acting at stages closer to viral production, such as the integrase inhibitor raltegravir, can produce a steeper first phase decay slope that may not be due to drug efficacy. Moreover it was found that for most drug classes the first phase transitions from a faster (phase IA) to a slightly slower decay region (phase IB) before the start of the usual second phase. Neither of these effects has been explained to date. We use a mathematical model that incorporates the different stages of the HIV viral life cycle in CD4+ T cells: viral entry, reverse transcription, integration, and viral production, to investigate the intracellular HIV mechanisms responsible for these complex plasma virus decay dynamics. We find differences in the phase IA slope across drug classes arise from a higher death rate of cells when they enter the productively infected stage post-integration, with a half-life of approximately 8 hours in this stage, whereas cells in earlier stages of the infection cycle have half-lives similar to uninfected cells. This implies any immune clearance is predominantly limited to the productive infection stage. We also show that the slowing of phase IA to phase IB at day 2 to 4 of monotherapy, depending on drug class, is a result of new rounds of infection. The level at which this slowing occurs is a better indicator of drug efficacy than the slope of the initial decay.

Evaluation of Placebo Effect in Treatment of Asthma Based Onmetaanalysis of Trials on Selected Antiasthmatic Drugs

Introduction: Apart from the well-studied mechanisms of disease course modification, many therapeutic interventions, at leastin part, exert non-specific effects on patients. These effects can be measured by patient self-assessment or by technicalanalyses. The aim of the study was to assess the extent of placebo effect in the treatment of asthma based on revaluation ofresults of high-quality trials on inhaled antiasthmatic drugs and in the context of various applied investigative methods. Material and methods: A systematic search of the Medline database (using the Entrez Pubmed browser) was performedusing international drug names and English terms: inhaled, randomised, placebo-controlled. The aim of the search was toidentify trials on the efficacy of inhaled antiasthmatic drugs. Of the returned 454 studies, 41 were further included inmetaanalysis and assessed for correlations between drug effects and respective applied investigative methods. For com-parison, analogical analysis was performed for captopril, with 232 identified published studies of which 10 were included inthe metaanalysis. Results: The placebo effect in the treatment of asthma was significantly stronger (29%) as compared to the placebo effect ofcaptopril in patients treated for arterial hypertension (17%). The placebo effect was more prominent in studies applyingclinical (subjective) indicators of drug efficacy as compared to trials using objective (device-based) methods of drug effectmeasurement. Conclusions: The placebo effect is more prominent in treatment of asthma as compared to pharmacotherapy of arterialhypertension. Its extent depends on the applied methods of drug efficacy measurement and is often greater if only clinicalindicators are used. This phenomenon can lead to different interpretations of treatment goals in asthma as perceived by thephysician and the patient. This also points out the necessity of patient activation in taking control over his/her disease so asto achieve a better and more satisfying treatment result.

The Appropriate Indicator Should be Used to Assess Treatment Failure in STH Infections

Dear Sir: We write to comment on the article by Humphries and others1 recently published in the American Journal of Tropical Medicine and Hygiene: in our opinion, the study is well conducted, however, we respectfully disagree with the conclusions and in particular with the claim made by the authors about the failure of albendazole treatment of hookworms. We summarize here the reasons of our disagreement: Humphries and others base the claim for albendazole failure in treating hookworm infection on the analysis of cure rate (CR) results that they measured at 61%; however, in the case of infections caused by hookworm and other soil-transmitted helminths (STHs), the CR is not a good indicator of drug efficacy because it is influenced by the intensity of infection at baseline and by the sensitivity of the parasitological method used to recover eggs from stool.2 As a result, it is very difficult to compare CRs obtained in different settings and reach meaningful conclusions about differences in drug efficacy. Our opinion is that drug efficacy in STH infections should be assessed with a more apt indicator, namely the egg reduction rate (ERR). The data presented by Humphries and others show an ERR of over 80% and this corresponds to the normal range of efficacy of albendazole against this parasite,3 as correctly reported by the authors. We would also like to stress the fact that the main objective of preventive chemotherapy against hookworm and other STH infections (those by Ascaris lumbricoides and Trichuris trichiura) is not to achieve cure of infected individuals, but rather to significantly reduce the number of worms harbored by such individuals4; this is because the average observed reduction (that can be measured by counting the number of eggs passed out in feces) is sufficient to cause the parallel decrease: • of transmission (because of the reduced number of eggs contaminating the environment)5; and • of morbidity (because the few surviving worms—that cannot replicate in the human host—cause less harm to the human host).6 As an additional comment, we would also like to express our concern about the method used by the authors to assess drug quality (i.e., in vitro anthelminthic activity), because this method has never been validated for albendazole that is insoluble in water; in addition, in our experience, the key factors in determining the quality of drugs used against STH are the tablet dissolution and disintegration times, and none of them was tested by the authors. Finally, we strongly disagree with the authors' statement that “mebendazole and pyrantel are not any longer recommended for the treatment of hookworm infection”; again, the studies on which the authors formulate their conclusion are based on the evaluation of the cure rate,7,8 and therefore, for the reasons mentioned previously, not conclusive. As a matter of fact, the World Health Organization (WHO) continues to include mebendazole and pyrantel in the list of recommended drugs for the treatment of STH infections. The WHO is seriously concerned about unjustified claims of drug resistance made on the basis of incorrect interpretations of parasitological results and on the poor understanding of the STH biology and control strategies. These claims create uncertainty among the managers of control programs about the efficacy of the control measures to be implemented and undermine the scaling up of STH control activities. As a consequence, a working group reporting to the WHO Strategic and Technical Advisory Group on Neglected Tropical Diseases (NTD) was established with the aim of developing a Standard Operating Procedure to be implemented whenever a control manager suspects a reduction of the drug activity (report available at http://www.who.int/neglected_diseases/NTD_STAG_Report_2011.pdf). Although we hope that this much needed tool will be available before the end of the year, we take this opportunity to invite AJTMH and other scientific journals to carefully assess the grounds on which claims of drug failure are based should similar papers be submitted for publication.

4SC-101, a novel immunosuppressive drug, inhibits IL-17 and attenuates colitis in two murine models of inflammatory bowel disease†

Dihydroorotate dehydrogenase (DHODH) is a key enzyme involved in pyrimidine biosynthesis. DHODH is a known target for the treatment of autoimmune diseases. 4SC-101 is a novel immunosuppressive drug that inhibits DHODH. A goal of our study was to examine the in vitro effects of 4SC-101 on IL-17 production by mononuclear cells. In addition, we evaluated the efficacy of 4SC-101 against acute TNBS (2,4,6-tritrobenzene sulfonic acid) and chronic dextran sodium sulfate (DSS)-induced colitis in mice. Peripheral blood mononuclear cells (PBMCs) from healthy human donors were used to evaluate cellular proliferation and cytokine (IL-17, TNF-α) production. The oral effects of 4SC-101 (100 or 200 mg/kg) were examined following induction of chronic colitis by the administration of 3% DSS (4 cycles) to Balb/c mice. Morphometric and histological indices of colitis were evaluated as indicators of drug efficacy. 4SC-101 was also administered for 6 days after the intracolonic administration of TNBS (20 mg in 50% ethanol) to female Balb/c mice. The colons were analyzed for overall macroscopic damage, ulceration, total length, distal segment weight, MPO activity, and histological pathology as indicators for the effectiveness of 4SC-101. In vitro, 4SC-101 is a potent inhibitor of human DHODH, inhibits lymphocyte proliferation, and uniquely blocks phytohemagglutinin-stimulated IL-17 production by lymphocytes. In vivo, oral administration of 4SC-101 effectively improved both chronic DSS and acute TNBS colitis in mice. In these colitis models the overall efficacy profile of 4SC-101 was similar to that of dexamethasone. 4SC-101 is a novel immunosuppressive drug with excellent potential for the treatment of intestinal inflammation.

Endothelin Receptor Antagonism and Renin Inhibition as Treatment Options for Scleroderma Kidney

Scleroderma renal crisis (SRC) is an important complication of scleroderma associated with significant morbidity and mortality. Current treatment of patients with SRC focuses on renin-angiotensin-aldosterone system (RAAS) blockade, ideally using angiotensin-converting enzyme inhibitors. We present a case of SRC in a patient established on maximal tolerable RAAS-blocking treatment. Introduction of a selective endothelin-A receptor antagonist followed by a direct renin inhibitor provided excellent blood pressure control and complete abrogation of heavy proteinuria. This was associated with a decrease in kidney function, with serum creatinine level increasing by approximately 30%. This increase is considered acceptable after the introduction of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, is regarded as an indicator of drug efficacy, and confers longer term renal protection. Both endothelin receptor antagonism and direct renin inhibition offer alternate novel therapies for patients with SRC. Their ability to preserve or improve kidney function is unclear.

‘Raising the bar’ for the treatment of pulmonary arterial hypertensionThe opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

Historically, idiopathic pulmonary arterial hypertension (IPAH, formerly referred to as primary pulmonary hypertension) has been considered a fatal disease. The natural history of IPAH was well described by the American National Institutes of Health (NIH) Registry of the 1980s. A median survival of 2.8 years with estimated single-year survival rates at 1, 3, and 5 years of 68, 48, and 35%, respectively were documented. Predictors of a poor prognosis included advanced functional class and haemodynamics (right atrial pressure, cardiac index, and pulmonary artery pressure). Fortunately, much has changed since the 1980s. We now several novel therapeutic options including prostacyclins, endothelin receptor antagonists, and phosphodiesterase type-5 inhibitors, all of which have improved exercise endurance in clinical trials. Surely, we have improved survival in IPAH, haven’t we? Classically, controlled clinical trials in pulmonary arterial hypertension (PAH) have studied the primary endpoint of 6-min walk distance over a short duration (12–16 weeks). Regulatory authorities have accepted the 6-min walk distance as a reliable and reproducible indicator of drug efficacy. Withholding therapy for more than 12–16 weeks was felt to be unethical, particularly early on, when the most ill patients were being entered into clinical trials. The only randomized controlled trial to ever demonstrate a survival benefit in IPAH was the open label trial with intravenous (IV) epoprostenol reported by Barst et al. In that 81-patient trial, 8 patients, all of whom were randomized to conventional therapy alone, died over the 12-week study, resulting in a mortality of 20%. Notably, a quarter of the patients in that trial were functional class IV at baseline. Subsequent open label observational experiences have also demonstrated a survival benefit with IV epoprostenol, either compared with historical controls, or the expected survival based on the NIH equation. Despite this apparent survival benefit, the 3-year survival with IV epoprostenol monotherapy in both these series of functional class III and IV IPAH patients was 63%. In both series, functional class was predictive of survival, both at the initiation of therapy, and when assessed after 3 or more months of therapy. Consequently, and appropriately, the most ill patients are no longer entered into clinical trials, but are treated with active medications. With less ill patients in clinical trials, over short periods of time, other therapies such as bosentan, sildenafil, treprostinil, and iloprost have established improvements in 6-min walk, leading to regulatory approval. The important question of longer term outcomes has not been answered by these brief trials. Provencher et al. describe the long-term outcomes of 103 consecutive functional class III and IV IPAH patients treated with the oral endothelin receptor antagonist, bosentan, as first-line therapy. Using a stringent treatment algorithm, additional therapy with prostanoids (primarily IV epoprostenol) was recommended for patients with functional class IV symptoms on treatment, or persistent functional class III symptoms after at least 4 months of treatment, together with (1) a 6-min walk distance of ,250 m; (2) a .10% decrease in 6-min walk distance from the previous value in two tests performed at least 2 weeks apart; or (3) a cardiac index of ,2.2 L min m. At 4 months, improvements in 6-min walk distance (42 m) and haemodynamics were similar to the findings of the randomized controlled trials. Functional class improved in 48% of patients, remained stable in 42%, and deteriorated in 9%. Overall survival estimates at 1 and 2 years were 90 and 87%, respectively. However, event-free survival estimates were 61 and 44% at 1 and 2 years, respectively. During the mean follow-up period of 24+ 15 months, 13 patients died (8 after the initiation of a prostanoid) and 36 were treated with a prostanoid. Prostanoid therapy was proposed to an additional nine patients who either declined (n 1⁄4 5) or were unable to manipulate the complex delivery system (n 1⁄4 4). Important predictors of outcome included the 6-min walk distance and right atrial pressure at baseline, and the 6-min walk distance, increase in 6-min walk distance, and decrease in total pulmonary resistance at 4 months of therapy. These overall survival data are similar to those previously reported among the 169 IPAH patients who were followed in an open label fashion after

Issues and Practices in Multiple Sclerosis

The objective of this roundtable discussion of experts in the field of multiple sclerosis (MS) was to summarize the current understanding of MS and its therapeutic options. The experts discussed subjects ranging from the etiology of MS to the current standards for patient care. Specific topics included the subtypes of MS, with a focus on the benign subtype, brain atrophy, the role of magnetic resonance imaging or “neuroimaging studies,” disease-modifying therapies, biological markers as indicators of drug efficacy, and combination therapies. In addition, the experts speculated as to what will be available in the near future for the improved diagnosis and management of MS. This review summarizes the main points of this discussion and is intended to serve as a reference for neurologists involved in the care of patients with MS.

Polymerase chain reaction detection of cytomegalovirus DNA in peripheral blood leukocytes as a predictor of cytomegalovirus disease in HIV-infected patients

To describe and evaluate a polymerase chain reaction (PCR) method for early diagnosis and prompt management of cytomegalovirus (CMV) retinitis in HIV-infected patients. A total of 110 HIV-infected patients (Centers for Disease Control and Prevention stages II to IV) were sampled sequentially for isolation of CMV from peripheral blood leukocytes (PBL; n = 560) and for amplification of CMV DNA in PBL. Semiquantitative analysis of the PCR product was performed and each PCR-positive specimen was assigned a score between 1+ and 4+ (corresponding to four points on a standard curve of dilutions: 80, 800, 8000 and 80,000 CMV genome copies). Levels of CMV DNA in blood increased with HIV infection stage. We focused on eight patients who developed one or more episodes of retinitis during longitudinal follow-up, in whom we found a strong correlation between viraemia, high PCR signal (3+ or 4+) (P < 0.0001) and clinical symptoms. Relapse was preceded by an increase in CMV DNA and resolution correlated with clearance of CMV DNA from blood. Persistent high PCR levels always preceded virus isolation and may be the first indication of organ involvement and thus early treatment. PCR scores were consistently useful as indicators of drug efficacy and for monitoring of treatment.

An animal model of Pneumocystis carinii pneumonia and therapeutic efficacy of interferon-gamma in this model

To evaluate the efficacy of drugs for treatment, we tried to make an animal model of Pneumocystis carinii (P. carinii) pneumonia. Specific pathogen free (SPF) rats immunosuppressed with corticosteroid were intratracheally inoculated with P. carinii. Six weeks after the inoculation, the lung sections of infected rat lung showed increased numbers of P. carinii in the alveoli and thickening of alveolar septa with mononuclear cell infiltration. From 7 to 9 weeks after inoculation, the intensity of infection became more severe, and some rats died at this period. Then, to evaluate drug efficacy in this model, we finished the drug therapy by the 6th week and used the number of P. carinii in the lung and the inflammation score as an indicator of drug efficacy. In this P. carinii pneumonia animal model, both sulfamethoxazole-trimethoprim clinically established anti P. carinii drug and interferon-gamma which is one of the lymphokines mainly produced by T lymphocytes indicated therapeutic and synergistic efficacy against P. carinii pneumonia.

Relationship of blood markers to disease severity and drug efficacy in rat adjuvant arthritis

Rat adjuvant arthritis (AA) was used as a model to evaluate several blood markers as possible predictive indicators of drug efficacy. AA was induced in Sprague-Dawley rats by the injection of complete Freund's adjuvant into the right hind foot pad. The rats were dosed p.o. from day 18 to day 31 with levamisole (10 mg/kg), indomethacin (1 mg/kg), diclofenac sodium (0.5 & 1 mg/kg), and prinomide (10 & 20 mg/kg). Disease severity was assessed by paw circumference on day 31. The following blood markers were analyzed: hyaluronate by ELISA, prostaglandin E2 by RIA, ESR by micro-dispette, total PMN by Technicon H-1, and albumin by BCG dye. Blood marker correlation (r) to disease severity was: hyaluronate (0.71), prostaglandin E2 (0.58), ESR (0.52), PMN (0.58), and albumin (-0.71). The relative rank order of drug efficacy (indomethacin, diclofenac sodium, and prinomide) did not differ using the change in paw circumference (day 31-day 17) or blood markers. Levamisole exacerbated the disease as measured by all the above parameters. Thus, these blood markers provide additional information for the statistical evaluation of drugs in rat adjuvant arthritis.

PH-dependent uptake and macrofilaricidal effects of chloroquine on adult filarial parasites in vitro

Uptake and macrofilaricidal effects of chloroquine (CQ) and other aminoquinolines were found to be highly pH dependent in Brugia pahangi, Acanthocheilonema viteae, Onchocerca volvulus, and Dirofilaria immitis. Using [ 3H]CQ, it was found that all of the parasites took up more drug under alkaline conditions (RPMI 1640 at pH 8.4) than in neutral (pH 7.4) or acidic (pH 6.8) media. Differences were seen in the amount of drug taken up among the filariae studied. B. pahangi and A. viteae took up 7 times more chloroquine per milligram of tissue than did O. volvulus, and 30 times more than D. immitis during a 60-min incubation period at pH 8.4. Sensitivity to the aminoquinolines also increased with increasing media pH, and was measured using parasite motility as an indicator of drug efficacy. Potency of chloroquine against B. pahangi increased 100-fold at pH 8.4 compared to pH 7.4. A. viteae and O. volvulus showed similar sensitivity to chloroquine compared to B. pahangi; D. immitis was less sensitive. While uptake of chloroquine was linear from pH 6.8 to 8.4, B. pahangi was unaffected by 32 μ M of the drug below pH 7.6; at any pH above this, motility of this parasite was completely inhibited. Calculations of the internal pH of this parasite indicated that it shifted upwards significantly with changes in media pH. It was concluded that these shifts in internal pH may render parasites more sensitive to the effects of chloroquine.