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PubMed2006

Therapeutic implications of the specific inhibition of causative matrix metalloproteinases in experimental colitis induced by dextran sulphate sodium.

Extracellular matrix dynamics, crucial for tissue remodelling, are highly regulated by a cascade of matrix metalloproteinases (MMPs) during inflammation and wound healing processes in inflammatory bowel disease (IBD). Contrary to expectations, there are limited reports to date that MMP inhibitors have some beneficial therapeutic effects in experimental colitis models. Furthermore, clinical trials of MMP inhibitors against certain tumours have failed to show any therapeutic benefit. One major reason for this lack of success may be the apparent uncertainty about the precise spectrum of inhibitory activity required. Since tumour necrosis factor alpha (TNFalpha), a key mediator in colonic inflammation, promotes MMP production in a dose-dependent manner, the therapeutic success of anti-TNFalpha agents against IBD motivated us to re-evaluate the therapeutic potential of MMP inhibition. First, using a quantitative polymerase chain reaction (PCR), western blotting, and zymography, we determined which MMPs were relevant to experimental colitis induced in mice by dextran sulphate sodium. Next, we examined a distinct role for MAPK and NFkappaB signalling pathways in the regulation of the expression of these MMP genes. Finally, we examined whether transcriptional regulation of these MMPs, either indirectly using inhibitors of MAPK and/or NFkappaB signalling pathways or directly using siRNA directed against these MMPs, contributes to the prevention of colitis. Changes in the expression level of colonic MMP-3 and MMP-10 preceded the clinical course of colitis. Colitis improved in mice that received these signal inhibitors, together with suppression of MMP expression. Moreover, siRNA that targeted MMP-3 and MMP-10 effectively reduced both the transcription of these MMPs and the severity of colitis. We conclude that MMP-3 and MMP-10 play a causal role in excess tissue destruction in colitis. Specific inhibition of these MMPs should provide novel therapeutics against IBD.

Animals↗

PubMed2006

The impact of cytochrome P450-2D6 genotype on the use and interpretation of therapeutic drug monitoring in long-stay patients treated with antidepressant and antipsychotic drugs in daily psychiatric practice.

PURPOSE: This retrospective follow-up study investigates whether cytochrome P450-2D6 (CYP2D6) genotype explains variability in plasma concentrations of psychotropic drugs in daily psychiatric practice. METHODS: The study population consisted of 62 hospitalised psychiatric patients genotyped for CYP2D6. Primary endpoint was the normalised plasma concentration ratio which was defined as the [measured concentration]/[mean therapeutic concentration] allowing comparison of plasma concentrations of different substrates. Secondary endpoint was a plasma concentration above the therapeutic range. The determinant was CYP2D6 genotype classified as ultrarapid metaboliser (UM), extensive metaboliser (EM), intermediate metaboliser (IM), or poor metaboliser (PM). The relation between CYP2D6 genotype and the normalised plasma concentration ratio was assessed with a linear mixed-effects model after adjustment for the Prescribed Daily Dose (PDD). The risk of having a plasma concentration above the therapeutic range was assessed with a logistic mixed-effects model. RESULTS: For antidepressants, CYP2D6 genotype PM (1.68 (95%CI: 1.01-2.28)) and IM (1.09 (95%CI: 0.77-1.29)) were associated with higher normalised plasma concentration ratios of antidepressants compared to EMs (0.56 (95%CI: 0.26-0.74)). In addition, the risk of a plasma concentration above the therapeutic range was increased for PMs (OR 33.1 (95%CI: 2.0-544.6)) and IMs (OR 8.2 (95%CI: 1.1-60.3)) relative to EMs using antidepressants. CYP2D6 genotype could not clearly explain variability in plasma concentrations of antipsychotics possibly due to a low frequency of therapeutic drug monitoring (TDM) in antipsychotics primarily metabolised by CYP2D6 in daily psychiatric practice. CONCLUSIONS: CYP2D6 genotype contributes to clinically relevant variability in plasma concentrations of antidepressants but probably not antipsychotics in daily clinical practice.

Antidepressive Agents↗

PubMed2002

Thermal stability: a means to assure tertiary structure in therapeutic proteins.

To be both safe and effective, a therapeutic product must have the correct chemical structure and be free of harmful contaminants. Structure in protein therapeutic products, however, implies not only the correct sequence of amino acids (primary structure) but also the proper folding of that amino acid chain in three-dimensional space (tertiary structure). This work is part of a general strategy to develop a battery of physico-chemical methods that could give assurances of structure (and hence function) in formulated therapeutic proteins in the absence of in vivo data. It focuses on recombinant human growth hormone (rhGH), a well-characterized therapeutic protein, and examines the utility of thermodynamic parameters in assessing its tertiary structure. Resistance of solutions of formulated rhGH to thermal denaturation was followed using Fourier Transform Infrared Spectroscopy (FTIR) by observing decreases in total helicity and increases in intermolecular beta-sheet formation. Under conditions known to induce changes in the intra-molecular ionic and H-bonding patterns stabilizing the tertiary structure but not affecting the protein's secondary structure or global fold, we have observed upwards of a 12 degrees C shift in the melting temperature of the protein. Furthermore, our results indicated that the T(m) of unfolding of rhGH was sensitive to much more subtle changes in the protein structure. Thus, resistance to thermal denaturation may well be a useful means to measure structure in formulations of well-characterized therapeutic proteins.

Deuterium↗

PubMed1997

Somatic delivery of catecholamines in the striatum attenuate parkinsonian symptoms and widen the therapeutic window of oral sinemet in rats.

Guidelines for clinical transplantation studies for Parkinson's disease emphasize that transplants should be considered as an adjunct to systemic L-DOPA, yet few preclinical studies have specifically assessed the potential of transplants as an adjunct to the clinical gold standard treatment. The objectives of the present study were to determine if encapsulated PC12 cells implanted in rats with severe unilateral dopamine depletions: (i) have a direct therapeutic effect on measures of parkinsonian symptoms; and/or (ii) increase the therapeutic window of oral sinemet in this model. Rats with severe unilateral dopamine depletions received striatal implants of encapsulated PC12 cells producing dopamine and L-DOPA. These rats were tested on a battery of behavioral measures of parkinsonian symptoms, at a range of doses of oral sinemet (0, 12, 24, and 36 mg/kg). Stereotypies/dyskinesias were also quantified after high doses of oral sinemet (36 and 50 mg/kg). The results confirm that parkinsonian symptoms can be quantified in rats with severe dopamine depletions, and the validity and clinical relevance of these measures are supported by the fact that the clinical gold standard treatment, oral sinemet, attenuates these parkinsonian symptoms. Somatic delivery of dopamine and L-DOPA, directly to the dopamine-depleted striatum, also attenuates parkinsonian symptoms. In fact, the magnitude of the therapeutic effect produced by continuous, site-specific, somatic delivery of dopamine and L-DOPA was larger than the effect produced by acute, systemic, oral sinemet. The beneficial effects of oral sinemet and striatal implants of catecholamine-producing devices were additive, but there were no adverse effects related to striatal catecholamine-producing devices, and these devices did not increase the adverse effects related to oral sinemet. Therefore, striatal implants of catecholamine-producing devices have direct therapeutic effects which are fairly robust, and they widen the therapeutic window of oral sinemet.

Administration, Oral↗

PubMed1989

Immunomodulatory and therapeutic properties of FK-565 in mice.

The heptanoyl tripeptide, FK-565 is a biological response modifier with potent therapeutic properties for the treatment of experimental and spontaneous metastases. Doses of FK-565 greater than 5 mg/kg are required for in vivo augmentation of natural killer cells, macrophages, and for therapeutic activity, presumably because FK-565 is a peptide small molecular mass which is rapidly degraded and excreted. Optimal therapeutic activity is observed at approximately 25-50 mg/kg FK-565, administered i.v. three times per week for 4 weeks. In addition to its therapeutic properties, which were consistently greater than the positive control at optimal doses, FK-565 had significant immunoaugmentary properties for natural killer cells, macrophages, and T cells both in vitro and in vivo, suggesting that its therapeutic activity is due to immune augmentation.

Adjuvants, Immunologic↗

PubMed1991

Racemic therapeutics--ethical and regulatory aspects.

Racemic therapeutics are fixed ratio mixtures of stereoisomers to be regarded biologically as different compounds. Usually only one of the isomers fully contributes to the therapeutics action, and the other is often classifiable as "isomeric ballast". Due to differences in turnover and pharmacokinetics, the proportion of enantiomers (1:1 in the racemate) continuously changes in plasma. The implications of the neglect of stereoselectivity for various levels in the investigation of racemic drugs are discussed and summarized in Table 2. The fact is that clinical investigators, Ethical Committees and regulatory authorities have for decades accepted invalid pharmacokinetic data on some 25% of therapeutics. That those racemates remain in use make the benefit of and necessity for kinetics generally questionable. Exposure of patients to the "isomeric ballast" present in about 50% of the most commonly used drugs will probably contain for many decades. As a result of a change in attitude of the regulatory authorities, however, for new drugs the choice in future between the racemic therapeutic or the single isomeric ballast-free drug will largely be based on a critical evaluation of the chiral characteristics with regard to their therapeutic, toxicological and pharmacokinetic aspects.

Drug Therapy, Combination↗

PubMed2005

[Therapeutic hypothermia after cardiac arrest].

The use of therapeutic hypothermia following different hypoxic-ischaemic insults has played an important role in various concepts of non-specific protection of cells for a long time. Although the use of deep therapeutic hypothermia after cardiac arrest in the last century did not lead to an improved outcome, recent data have demonstrated very positive effects of mild therapeutic hypothermia. The data from the European multicenter trial as well as those from Australia have clearly demonstrated a decrease in mortality and a better neurological outcome for patients being cooled to 32-34 degrees C for 12 or 24 h. In 2003, this led to the implementation of mild therapeutic hypothermia (32-34 degrees C) into the International Liaison Committee on Resuscitation (ILCOR) recommendations and guidelines for the treatment of unconscious patients after prehospital cardiac arrest. This article gives an overview on existing concepts and future perspectives of therapeutic mild hypothermia.

Animals↗

PubMed2005

Therapeutic gene silencing in neurological disorders, using interfering RNA.

The development of interfering RNA (RNAi) from a naturally occurring phenomenon to a tool for mediating highly specific gene silencing provides an exciting prospect as a novel therapeutic strategy for a wide range of disorders. Although the efficacy of RNAi as a research tool for analysing gene function has been well demonstrated in several cell types, the therapeutic potential of RNAi-mediated gene silencing has only recently started to be investigated. Several neurodegenerative disorders provide particularly suitable candidates for RNAi based therapy; however, many hurdles preclude the success of therapeutic application. These include the challenge of delivering active RNAi molecules to the specific target cell populations where they are required and appropriate regulation of gene suppression, such as to maintain a long-lasting therapeutic effect. Furthermore, for safety reasons, off-target effects should be minimised. Here we review the advancement of RNAi technology for therapeutic application and highlight the potential of targeted gene silencing for the treatment of neurodegenerative diseases.

Amyotrophic Lateral Sclerosis↗

PubMed2005

[Therapeutic relevance of magnetic resonance imaging in joint injuries in children].

AIM: In this retrospective study, we assessed whether the use of MRI in children provides additional, therapeutically relevant information to assist in the diagnosis of joint injuries. In addition, we determined whether the usefulness of this approach is dependant on age of the child and localisation of the trauma. METHOD: MRI of 45 children aged between 3 and 16 years were analysed independently by four different investigators (two radiologists, two trauma surgeons) and assessed for their therapeutic relevance. RESULT: MRI of the knee (n=18) gave additional information in 11 patients (61%) and led to a change in the recommended therapy involving arthroscopy in seven patients (39%). MRI of the ankle (n=21) provided additional information in 12 patients (57%) and the decision for further therapy was influenced in six patients (29%), however, the indication for surgery was not influenced. The diagnosis of injuries of the elbow (n=6) was changed in four patients (67%), but the therapeutic decision was not influenced. CONCLUSION: MRI additional to conventional x-ray provides relevant information on the therapeutic procedure to be used for the knee, whereas for the ankle and the elbow MRI it rarely delivers additional information relevant to therapeutic decision making.

Adolescent↗

PubMed2001

Efficacy of high therapeutic doses of iodine-131 in patients with differentiated thyroid cancer and detectable serum thyroglobulin.

Serum thyroglobulin (Tg) is usually the best marker of residual or metastatic disease after treatment of differentiated thyroid cancer. We evaluated the effect of so-called blind therapeutic doses of iodine-131 in patients with detectable Tg during suppressive levothyroxine treatment (Tg-on), and in patients with a negative diagnostic scintigram but detectable Tg during the hypothyroid phase (Tg-off). Twenty-two patients with differentiated thyroid carcinoma underwent total thyroidectomy and radioiodine ablation. During the follow-up, six patients with detectable Tg-on and 16 patients with detectable Tg-off were identified. All patients were treated with a blind therapeutic dose of 7,400 MBq iodine-131. Diagnostic scintigrams were compared with post-treatment scintigrams. Tg-off was measured in 16 cases, 1 year after the administration of the blind therapeutic dose, at the time of the follow-up diagnostic scintigram. Six patients were followed up by Tg-on only. Post-therapy scintigrams revealed previously undiagnosed local recurrence or distant metastases in 13/22 cases (59%); the remaining nine post-therapy scintigrams were negative. At the time of the blind therapeutic doses, Tg-off values ranged from 8 to 608 microg/l. After 1 year of follow-up, Tg-off decreased in 14/16 (88%) patients. In all patients who were followed by Tg-on only (n=6), a decrease in Tg values was measured. It is concluded that blind therapeutic doses resulted in a decrease in Tg levels in the majority of patients with suspected recurrence or metastases. The post-treatment scintigrams revealed pathological uptake in 59% of patients.

Adult↗

PubMed2004

Modern diagnostics in chronic myeloproliferative diseases (CMPDs).

According to the new WHO classification a group of chronic myeloproliferative diseases (CMPDs) were defined: chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia and hypereosinophilic syndrome (CEL/HES), polycythemia vera (PV), chronic idiopathic myelofibrosis (with extramedullary hematopoiesis, CIMF), essential thrombocythemia (ET), and so called CMPD/unclassifiable. As clinical features and laboratory findings differ widely between these diseases several diagnostic approaches are mandatory at diagnosis for classification and are needed also for follow up studies, especially for the measurement of minimal residual disease (MRD). We here outline the laboratory set up at diagnosis and during follow up in CMPDs with specific focus on the respective therapeutical consequences. Only by using a comprehensive diagnostic panel including cytomorphology, cytogenetics, and molecular genetic methods establishing the correct diagnosis, optimizing treatment as well as evaluating treatment response is possible in CMPDs today.

Blood Cell Count↗

PubMed1999

Diagnostic and therapeutic impact of MRI and arthrography in the investigation of full-thickness rotator cuff tears.

Investigation of shoulder pain is important before surgical treatment. The presence or absence of a full-thickness rotator cuff tear (FTRCT) may determine the type of surgical treatment. Both MRI and conventional arthrography can be used, but little is known about their relative diagnostic and therapeutic impact. We performed a prospective trial assessing: (a) the influence of MRI and arthrography results on the clinician's diagnostic thinking (diagnostic impact); (b) the influence of the results on the clinician's therapeutic thinking (therapeutic impact); and (c) the diagnostic performance of the two techniques in patients with surgical confirmation. A total of 104 consecutive patients with shoulder problems referred to a specialist orthopaedic shoulder clinic underwent pre-operative investigation with MRI and arthrography. The surgeon's diagnosis, diagnostic confidence and planned treatment were measured before the investigation, and then again after the results of each investigation. Before the presentation of the investigation, results, the patients were randomised into two groups. In one group MRI was presented first; in the other group, arthrography. The MRI results led to fewer changes in diagnostic category (14 of 46, 30%) than arthrography (20 of 54, 37%), but the difference was not significant (P > 0.5). Magnetic resonance imaging led to slightly more changes in planned management (17 of 47, 36%) than arthrography (14 of 55, 25%), but again the difference was not statistically significant (P > 0.3). The results of the second investigation always had less diagnostic and therapeutic impact than the first. The accuracy of MRI for FTRCT in 38 patients with surgical confirmation was 79%, sensitivity 81% and specificity 78%; the accuracy of arthrography was 82%, sensitivity 50% and specificity 96%. The clinical diagnosis and management plan can be adequately defined by a single radiological investigation. Magnetic resonance imaging and arthrography had fairly similar diagnostic and therapeutic impact and comparable accuracy, although MRI was more sensitive and less specific. Magnetic resonance imaging may be the preferred investigation because of its better demonstration of soft tissue anatomy.

Adult↗

PubMed2000

Apoptosis in prostate carcinogenesis. A growth regulator and a therapeutic target.

Development of effective therapeutic modalities for the treatment of human cancer relies heavily upon understanding the molecular alterations that result in initiation and progression of the tumorigenic process. Many of the molecular changes identified in human prostate tumorigenesis so far play key roles in apoptosis regulation. Apoptosis represents a universal and exquisitely efficient cellular suicide pathway. Since the therapeutic goal is to trigger tumor-selective apoptotic cell death (without clinically significant effects on the host), elucidation of the mechanisms underlying apoptosis deregulation will lead to the identification of specific cellular components for targeting therapeutic interventions. As our understanding of its vital role in the development and growth of the prostate gland has expanded, numerous genes that encode apoptotic regulators have been identified that are severely impaired in prostate cancer cells. In addition, the expression of apoptotic modulators within prostatic tumors appears to correlate with tumor sensitivity to traditional therapies such as hormonal ablation and radiotherapy. No strict correlation between apoptosis induction and a patient's long-term prognosis has emerged, perhaps due to the fact that the ability to achieve initial remission alone does not adequately predict long-term outcome. This review will encompass the known molecular changes intimately involved in the apoptotic pathway which have potential prognostic value in disease progression, as well as therapeutic significance in the enhancement of the apoptotic response to novel and established treatment strategies for the treatment of androgen-dependent and androgen-independent prostatic tumors. The main focus will be on the role of the transforming growth factor-beta (TGF-beta) signaling pathway, bcl-2 and the bcl-2 family members, the caspase cascade (apoptosis executioners), and the Fas pathway in induction and regulation of apoptosis following therapeutic stimuli for the management of advanced prostate cancer.

Animals↗

PubMed2006

[Oligonucleotide therapeutics - an emerging novel class of compounds].

Oligonucleotide therapeutics are short, single- or double-stranded DNA or RNA molecules consisting of strands of 10-50 nucleotides. By targeted modulation of gene expression oligonucleotides provide the chance of targeting diseases at their molecular level. Within this novel emerging class of compounds oligonucleotide therapeutics are discriminated by their structure, function and mode of action. While antisense oligonucleotides, ribozymes and siRNAs suppress the expression of a protein by complementary hybridizing with their target mRNA, aptamers bind like antibodies to their target protein and thereby inhibit its function. Immunostimulatory oligonucleotides are due to sequence motifs within their nucleotide sequence able to trigger a therapeutic exploitable immune response. Currently, there are only two oligonucleotide therapeutics approved by the FDA, namely the antisense oligonucleotide Fomivirsen and the aptamer Macugen. In this review the mode of action of the diverse oligonucleotide therapeutics and their current status in clinical development will be discussed.

Aptamers, Nucleotide↗

PubMedDate not supplied

Results of therapeutic penetrating keratoplasty.

PURPOSE: By a retrospective study of patients in the Ankara Hospital Eye Clinic, to determine the anatomical and visual results of therapeutic penetrating keratoplasty (PK) and its role in the management of corneal disease. METHODS: Therapeutic PK was performed in 36 patients (37 eyes) who had corneal perforation due to corneal disease (23 eyes) or eyes in which perforation was imminent (14 eyes). Initial indications for grafting were nonperforated descemetocele without inflammation (six eyes, 16.2%); nonperforated bacterial corneal ulcer (five eyes, 13.5%); nonperforated herpetic keratitis with active stromal inflammation (two eyes, 5.4%); acanthamoeba keratitis (one eye, 2.7%); perforation due to herpetic keratitis (13 eyes, 35.2%); perforation due to persistent epithelial defect (8 eyes, 21.6%); or perforation due to bacterial corneal ulcer (two eyes; 5.4%). The results were evaluated for each of the following criteria: anatomical integrity of the eye, cure of the disease, complications, graft clarity, and visual acuity. RESULTS: Anatomical integrity was achieved in 21 of the 23 eyes (91.3%) perforated from corneal disease. Therapeutic PK cured the disease in all bacterial keratitis cases. The proportion of clear grafts was 60.9% in the 23 eyes perforated from corneal disease, and 57.1% in the 14 eyes in which perforation was imminent. Fifteen eyes (40.5%) obtained a final visual acuity of 20/100 or better; five of these eyes were not yet perforated before the PK. CONCLUSIONS: Therapeutic PK is effective in the management of the eye with active uncontrolled infection or perforation from corneal disease. Approximately half of our patients maintained a clear graft at the last visit. Without therapeutic surgery, these eyes would have been lost.

Adolescent↗

PubMed2006

Verbal abilities as predictors of retention among adolescents in a therapeutic community.

The relationship between verbal skills and retention among adolescents in substance abuse treatment is understudied. In order to assess verbal predictors of retention, twenty-eight 16-19 year old adolescents in a therapeutic community for substance abuse were evaluated between 30 and 90 days after admission. These adolescents were then followed prospectively for 1 year. Verbal and non-verbal cognitive screens, audio taped narrative responses, and self-reports of socio-emotional function and psychiatric symptoms were completed. Verbal scores were associated with self-restraint and counselor reports of therapeutic engagement and comprehension. General verbal scores predicted attrition, while therapeutic expressiveness (verbal expressiveness in a therapeutic context) predicted retention. Remediation of verbal communication skills may be an overlooked aspect of the therapeutic process in treating adolescent substance abusers.

Adolescent↗

PubMed2006

Bacterial meningitis in young adults in Southern Taiwan: clinical characteristics and therapeutic outcomes.

BACKGROUND: To delineate the epidemiologic trend, clinical characteristics and therapeutic outcomes of bacterial meningitis in young adults in Southern Taiwan. PATIENTS AND METHODS: Over a period of 18 years, 329 cases of culture-proven adult bacterial meningitis were identified at our hospital. Among these 329 cases, 62 were identified as young adults (< or = 40 years) and their clinical features, laboratory data and therapeutic outcomes were reviewed. The prognostic factors between fatal and non-fatal groups were compared. RESULTS: The 62 young adults were 48 men and 14 women, aged 17-40 years. Thirty of the 62 patients belonged to nosocomial infection, and the other 32 belonged to community-acquired infection. A total of 74% (46/62) of the patients had a post-neurosurgical state as the underlying condition. Alcoholism (n = 8) was the most common underlying condition of the other 16 patients with spontaneous meningitis. Of these 62 patients, Klebsiella pneumoniae and Pseudomonas aeruginosa were the most common implicated gram-negative pathogens. During the late study period, there was an increase in coagulase-negative staphylococcus and Staphylococcus aureus infections. The therapeutic results of this group of patients are as follows: 13 patients died, 18 had full recovery and 31 had varying degrees of neurologic deficits. Impaired consciousness and thrombocytopenia were significant prognostic factors. CONCLUSION: A post-neurosurgical state is an important preceding event for young adults to develop bacterial meningitis. Of the implicated gram-negative pathogens, K. pneumoniae and P. aeruginosa are common; however, there has been an increase in staphylococcal infection in recent years. Therapeutic results of this specific group of patients showed that 20% (13/62) of the patients died, and 50% (31/61) of the patients in this study had neurologic deficits. However, the small case number and possible bias of case selection has limited the analytical conclusions of this study. Further large-scale studies are needed to delineate the clinical characteristics and therapeutic outcomes of bacterial meningitis in this specific group of patients.

Adolescent↗

PubMed1975

Inefficacy of "therapeutic" serum levels of digoxin in controlling the ventricular rate in atrial fibrillation.

Although therapeutic and toxic serum concentrations of digoxin have been established, there is sparse information permitting correlation of drug level with clinical effect. This study was undertaken to assess the radioimmunoassay serum digoxin levels in 30 patients with acute atrial fibrillation (38 determinations) and 30 patients with chronic atrial fibrillation (54 determinations). Those with chronic fibrillation were subdivided into those in clinically stable condition (14 patients), and those seriously ill and in clinically unstable condition (16 patients). Slowing of ventricular rate in patients with stable, chronic atrial fibrillation was accomplished in 10 of 16 instances by "therapeutic" and "subtherapeutic" levels of digoxin (less than 2 ng/ml). Ventricular rate was "controlled" (65 to 95 beats/min) with therapeutic levels of serum digoxin in only five instances of acute atrial fibrillation and seven of unstable chronic atrial fibrillation. In 43 studies (23 of acute atrial fibrillation, 20 of chronic atrial fibrillation), a rapid ventricular rate (95 to 140 beats/min) persisted in the presence of "therapeutic" or high levels of digoxin. Thirty-nine of these were in patients who were seriously ill with conditions such as infection, hypoxia or recent thoracotomy. Slowing of the ventricular rate required "toxic" concentrations of digoxin (2.5 to 6 ng/ml) in 15 instances. We conclude that sufficient amounts of digoxin to achieve "therapeutic" serum concentrations may fall to lower the ventricular rate in atrial fibrillation to less than 100 beats/min, especially when a serious, complicating illness coexists.

Atrial Fibrillation↗