Death Anxiety and Correlates in Cancer Patients Receiving Palliative Care.

Background: Death anxiety is powerful, potentially contributes to suffering, and yet has to date not been extensively studied in the context of palliative care. Availability of a validated Death Anxiety and Distress Scale (DADDS) opens the opportunity to better assess and redress death anxiety in serious illness. Objective: We explored death anxiety/distress for associations with physical and psychosocial factors. Design: Ancillary to a randomized clinical trial (RCT) of Dignity Therapy (DT), we enrolled a convenience sample of 167 older adults in the United States with cancer and receiving outpatient palliative care (mean age 65.9 [7.3] years, 62% female, 84% White, 62% stage 4 cancer). They completed the DADDS and several measures for the stepped-wedged RCT, including demographic factors, religious struggle, dignity-related distress, existential quality of life (QoL), and terminal illness awareness (TIA). Results: DADDS scores were generally unrelated to demographic factors (including religious affiliation, intrinsic religiousness, and frequency of prayer). DADDS scores were positively correlated with religious struggle (p < 0.001) and dignity-related distress (p < 0.001) and negatively correlated with existential QoL (p < 0.001). TIA was significantly nonlinearly associated with both the total DADDS (p = 0.007) and its Finitude subscale (p ≤ 0.001) scores. There was a statistically significant decrease in Finitude subscale scores for a subset of participants who completed a post-DT DADDS (p = 0.04). Conclusions: Findings, if replicable, suggest that further research on death anxiety and prognostic awareness in the context of palliative medicine is in order. Findings also raise questions about the optimal nature and timing of spiritual and psychosocial interventions, something that might entail evaluation or screening for death anxiety and prognostic awareness for maximizing the effectiveness of care.

Measuring and understanding death anxiety in caregivers of patients with primary brain tumor.

OBJECTIVE: Caregivers of patients with primary brain tumor (PBT) describe feeling preoccupied with the inevitability of their loved one's death. However, there are currently no validated instruments to assess death anxiety in caregivers. This study sought to examine (1) the psychometric properties of the Death and Dying Distress Scale (DADDS), adapted for caregivers (DADDS-CG), and (2) the prevalence and correlates of death anxiety in caregivers of patients with PBT. METHODS: Caregivers (N = 67) of patients with PBT completed the DADDS-CG, Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder (GAD-7), Fear of Cancer Recurrence (FCR-7), and God Locus of Health Control (GLHC). Caregivers' sociodemographic information and patients' medical characteristics were also collected. Preliminary examination of the psychometric properties of the DADDS-CG was conducted using exploratory factor analysis, Cronbach's alpha, and correlations. The prevalence and risk factors of death anxiety were assessed using frequencies, pair-wise comparisons, and correlations. RESULTS: Factor analysis of the DADDS-CG revealed a two-factor structure consistent with the original DADDS. The DADDS-CG demonstrated excellent internal consistency, convergent validity with the PHQ-9, GAD-7, and FCR-7, and discriminant validity with the GLHC. Over two-thirds of caregivers reported moderate-to-severe symptoms of death anxiety. Death anxiety was highest in women and caregivers of patients with high-grade PBT. SIGNIFICANCE OF RESULTS: The DADDS-CG demonstrates sound psychometric properties in caregivers of patients with PBT, who report high levels of death anxiety. Further research is needed to support the measure's value in clinical care and research - both in this population and other caregivers - in order to address this unmet, psychosocial need.

Death anxiety in patients with primary brain tumor: Measurement, prevalence, and determinants.

OBJECTIVE: This study investigated death anxiety in patients with primary brain tumor (PBT). We examined the psychometric properties of two validated death anxiety measures and determined the prevalence and possible determinants of death anxiety in this often-overlooked population. METHODS: Two cross-sectional studies in neuro-oncology were conducted. In Study 1, 81 patients with PBT completed psychological questionnaires, including the Templer Death Anxiety Scale (DAS). In Study 2, 109 patients with PBT completed similar questionnaires, including the Death and Dying Distress Scale (DADDS). Medical and disease-specific variables were collected across participants in both studies. Psychometric properties, including construct validity, internal consistency, and concurrent validity, were investigated. Levels of distress were analyzed using frequencies, and determinants of death anxiety were identified using logistic regression. RESULTS: The DADDS was more psychometrically sound than the DAS in patients with PBT. Overall, 66% of PBT patients endorsed at least one symptom of distress about death and dying, with 48% experiencing moderate-severe death anxiety. Generalized anxiety symptoms and the fear of recurrence significantly predicted death anxiety. SIGNIFICANCE OF RESULTS: The DADDS is a more appropriate instrument than the DAS to assess death anxiety in neuro-oncology. The proportion of patients with PBT who experience death anxiety appears to be higher than in other advanced cancer populations. Death anxiety is a highly distressing symptom, especially when coupled with generalized anxiety and fears of disease progression, which appears to be the case in patients with PBT. Our findings call for routine monitoring and the treatment of death anxiety in neuro-oncology.

Metabolism and interactions of antileprosy drugs.

Leprosy is a chronic infectious disease caused my Mycobacterium leprae that primarily affects peripheral nervous system and extremities and is prevalent in tropical countries. Treatment for leprosy with multidrug regimens is very effective compared to monotherapy especially in multibacillary cases. The three major antileprosy drugs currently in use are 4, 4'-diaminodiphenyl sulfone (DDS, dapsone), rifampicin, and clofazimine. During multidrug therapy, the potent antibiotic rifampicin induces the metabolism of dapsone, which results in decreased plasma half-life of dapsone and its metabolites. Furthermore, rifampicin induces its own metabolism and decreases its half-life during monotherapy. Rifampicin upregulates several hepatic microsomal drug-metabolizing enzymes, especially cytochrome P450 (CYP) family that in turn induce the metabolism of dapsone. Clofazimine lacks significant induction of any drug-metabolizing enzyme including CYP family and does not interact with dapsone metabolism. Rifampicin does not induce clofazimine metabolism during combination treatment. Administration of dapsone in the acetylated form (acedapsone) can release the drug slowly into circulation up to 75 days and could be useful for the effective treatment of paucibacillary cases along with rifampicin. This review summarizes the major aspects of antileprosy drug metabolism and drug interactions and the role of cytochrome P450 family of drug metabolizing enzymes, especially CYP3A4 during multidrug regimens for the treatment of leprosy.

Cocrystal habit engineering to improve drug dissolution and alter derived powder properties.

OBJECTIVES: Cocrystallization of sulfadimidine (SDM) with suitable coformers, such as 4-aminosalicylic acid (4-ASA), combined with changes in the crystal habit can favourably alter its physicochemical properties. The aim of this work was to engineer SDM : 4-ASA cocrystals with different habits to investigate the effect on dissolution, and the derived powder properties of flow and compaction. METHODS: Cocrystals were prepared in a 1 : 1 molar ratio by solvent evaporation using ethanol (habit I) or acetone (habit II), solvent evaporation followed by grinding (habit III) and spray drying (habit IV). KEY FINDINGS: Powder X-ray diffraction showed Bragg peak position was the same in all the solid products. The peak intensity varied, indicating different preferred crystal orientation confirmed by SEM micrographs: large prismatic crystals (habit I), large plate-like crystals (habit II), small cube-like crystals (habit III) and microspheres (habit IV). The habit III exhibited the fasted dissolution rate; however, it underwent a polymorphic transition during dissolution. Habits I and IV exhibited the highest Carr's compressibility index, indicating poor flowability. However, habits II and III demonstrated improved flow. Spray drying resulted in cocrystals with improved compaction properties. CONCLUSIONS: Even for cocrystals with poor pharmaceutical characteristics, a habit can be engineered to alter the dissolution, flowability and compaction behaviour.

Relapses in multibacillary patients treated with multi-drug therapy until smear negativity: findings after twenty years.

The Schieffelin Leprosy Research and Training Center at Karigiri, India participated in several of the World Health Organization (WHO) trials. The first trial on combined therapy in multi-bacillary leprosy was initiated in 1981. The main objectives of this field trial were to evaluate the efficacy of WHO recommended regimens in preventing relapses, especially drug resistance relapses. This paper reports on the relapses twenty years after patients were inducted into the WHO field trial. Between 1981 and 1982, 1067 borderline lepromatous and lepromatous patients were inducted into the WHO field trial for combined therapy in multi-bacillary leprosy trial. Among them, 357 patients were skin smear positive. During the follow-up in 2002, only 173 of them could be traced and assessed. The mean duration of follow-up was 16.4 +/- 1.83 years. Two patients relapsed 14 and 15 years after being released from treatment, the relapse rate being 0.07 per 100 person years follow-up. Drug susceptibility tests done on one of the relapsed patients revealed drug sensitive organisms to all multi-drug therapy drugs.

Effectiveness of multidrug therapy in multibacillary leprosy: a long-term follow-up of 34 multibacillary leprosy patients treated with multidrug regimens till skin smear negativity.

The World Health Organization (WHO) Field Trials of multidrug therapy (MDT) started at Schieffelin Leprosy Research and Training Centre (SLR & IC), Karigiri, India in December 1981. The patients were treated with two MDT regimens. The first (regimen A) consisted of 600mg rifampicin and 300mg of clofazimine given under supervision on 2 consecutive days monthly, 225mg injection of acedapsone bimonthly and dapsone 100mg daily. The second regimen (regimen B) was the conventional MDT (WHO/MDT), rifampicin 600mg and clofazimine 300mg supervised once a month, dapsone 100mg and clofazimine 50mg daily, unsupervised. Both the regimens were administered for a minimum period of 2 years or until skin smear negativity, whichever occurred later. Thirty-four newly detected previously untreated MB patients, 16 of whom received regimen A and 18 regimen B, were reassessed. Both regimens were well accepted and well tolerated by the patients. Clofazimine discolouration was the only adverse effect of MDT seen in these patients. After completion of treatment with MDT, the patients were followed up for a total duration of 466 person-years with a mean of 13.7 +/- 1.4 years per patient. No relapse was seen.

Activation of diacetyldapsone and a preliminary evaluation of a cyclodextrin-diacetyldapsone complex in cultured lung cells.

A diacetyldapsone-2-hydroxypropyl-beta-cyclodextrin complex (DADDS-CD) was evaluated with regard to the ability of cultured lung cells to activate DADDS to the active metabolite dapsone. The same system was used to assess the effect of the complex on cell growth. The complex was incubated with cells for periods of 24 to 72 h, followed by extraction of metabolites from the incubation medium and analysis by HPLC. In addition, the Trypan Blue exclusion technique was used to assess cell viability during this time period. Results indicated that lung cells could activate DADDS to dapsone and that, while the complex appeared to delay cell growth in the first 24 h period, no significant difference was seen between cells incubated in the presence and absence of the complex at 72 h. These results indicate that DADDS-CD has significant potential as a drug-delivery system for DADDS in the lung based upon the ability of the cells to activate DADDS. The mixed effects of the complex on cell growth may have important implications when considering the frequency of administration of the complex to the lung.

Chemoprophylaxis is effective in the prevention of leprosy in endemic countries: a systematic review and meta-analysis. MILEP2 Study Group. Mucosal Immunology of Leprosy.

OBJECTIVE: To quantify the efficacy of chemoprophylaxis against leprosy. METHOD: Literature searching of Medline and Embase databases, hand-searching of references and correspondence with investigators. STUDY SELECTION: published papers relating to the prevention of leprosy and the use of chemotherapy in leprosy were identified for critical appraisal. Trials were selected and grouped into three categories according to study design and control groups. DATA ANALYSIS: the relative risks (RR) with 95% confidence intervals were calculated from the original data using a random effects model. To assess the cost-effectiveness of chemoprophylaxis, a further analysis of the rates of disease in the trial and control groups was done based on the numbers needed to be treated (NNT) to prevent one new case of leprosy. RESULTS: A total of 14 trials were identified from 127 published papers on chemoprophylaxis of leprosy. The trials were categorized into randomized controlled trials, non-randomized controlled trials, and uncontrolled trials. The overall results of the meta-analysis shows that chemoprophylaxis gives around 60% protection against leprosy. The NNT are low in trials of household contacts. CONCLUSIONS: The evidence shows that chemoprophylaxis against leprosy is an effective way to reduce the incidence of leprosy, particularly in household contacts. The role of chemoprophylaxis needs to be re-examined using newer drugs given the continuing case detection rates globally.

Relapse as histoid leprosy after receiving multidrug therapy (MDT); a report of three cases.

The histoid type of leprosy has been described as occurring in lepromatous leprosy patients who relapse after many years of apparently successful dapsone monotherapy. Three patients who had received the World Health Organization-recommended regimens of multidrug therapy (WHO/MDT) relapsed as histoid leprosy 12-15 years after completion of treatment. In one patient, through mouse foot pad studies, the bacilli were found to be sensitive to rifampin and clofazimine and resistant to dapsone. In the other two patients mouse foot pad studies were inconclusive. The patients were re-started on WHO/MDT. Two patients took regular treatment and improved, both clinically and bacteriologically. One patient was irregular in treatment, and 1 year after re-starting WHO/MDT nodules were still present although the bacterial index had fallen slightly.

The effect of acetylation and deacetylation on the disposition of dapsone and monoacetyl dapsone hydroxylamines in human erythrocytes in-vitro.

The fates of both dapsone and monoacetyl hydroxylamine have been studied in terms of acetylation and deacetylation within the human erythrocyte in-vitro. A comparison between the two metabolites showed equipotency in methaemoglobin generation at 15 min, although the monoacetyl derivative was the more rapid haemoglobin oxidizer. Within the erythrocytes, both dapsone and monoacetyl hydroxylamines were found to undergo acetylation, deacetylation and diacetylation. Of the inhibitors of acetylation studied, folate caused an increase in methaemoglobin formation associated with both metabolites, which led to a rise in both acetylated and non-acetylated amine formation. Amethopterin was associated with a rise in hydroxylamine mediated methaemoglobin formation which coincided with a fall in acetylated products. It is possible that the hydroxylamines undergo erythrocytic processes of acetylation and deacetylation before methaemoglobin-mediated reduction to their respective amines.

[Bacteriologic study in patients with multibacillary leprosy treated with rifampicin and acedapsone]. / Estudio bacteriológico en pacientes con lepra multibacilar tratados con rifampicina y acedapsone.

A bacteriologic study of 116 patients with multibacillary leprosy from Guantanamo City is made. Samples for bacteriologic examination were derived from both auricular lobules, the two elbows, and the middle phalanges of the third finger. The microscopic examination found acid-alcohol-resistant bacilli in 19% of patients, while failure to find any of these organisms occurred in 81%.

[Automated determination of 4,4'-diaminodiphenylsulfone (DDS) and acetyl metabolites (MADDS and DADDS) in milk with the FAST-LC system]. / Automatisierte Bestimmung von 4,4'-Diaminodiphenylsulfon (DDS) und Acetylmetaboliten (MADDS und DADDS) in Milch mit dem FAST-LC-System.

With the described method it is possible to determinate residues of Dapsone (DDS) and its acetylated metabolites (mono- and diacetyldapsone) in milk. The determination is being carried out with a FAST-LC system (Fully Automated Sample Treatment Liquid Chromatography). The purification is a combination of dialysing the milk against water and absorption of the nonpolar components from the dialysate on the preconcentration column of the LC-system used (RP, 40 microns). With back-flush, the concentrate is being injected into the analytical column (RP-8, 5 microns). The detection is being carried out with the help of a UV-absorbance detector, at a wavelength of 296 mm. The detection limit is approximately 2 micrograms/l (DADDS: 5 micrograms/l). The required amount of the sample is 5 ml. The recovery, reproducibility and linearity for the three components in milk are good.

Blood dapsone levels in leprosy patients treated with acedapsone.

The metabolism of the repository drug acedapsone (DADDS,4,4'-diacetyldiaminodiphenyl sulfone) was studied in 15 individuals receiving 225 mg of DADDS, intramuscularly for a period of 75 days. Plasma levels of DDS were determined on the 2nd, 7th, 15th, 30th, 60th and 75th day after administration of the drug by spectrophoto-fluorometric technique. The mean peak levels of DDS (85.36 ng/ml) were noticed on 7th day followed by a gradual decrease in DDS concentration. The mean half-life level (44.53 ng/ml) of DDS were observed around the 15th day. The mean DDS level for the entire period of observation after one dose was 41.95 ng/ml. On the 75th day, the DDS level reached the minimum value of 14.76 ng/ml which was still about 5 times more than the minimal inhibitory concentration (MIC) level of DDS against M. leprae (3 ng/ml). The results are discussed.

Limited duration acedapsone prophylaxis in leprosy.

A randomized controlled chemoprophylaxis trial was carried out in Madras city using 560 disease-free household child contacts of 264 multibacillary cases as study subjects. In the study, 13 cases were diagnosed among 280 contacts who received 3 injections of acedapsone at 10 weeks interval as against 30 cases among 280 contacts who had the same number of placebo injections, during the follow-up period of 225 weeks. The difference in the incidences in the two groups was statistically significant. (X2 6.45; P less than 0.02). The protection due to the limited duration of acedapsone prophylaxis was 56.7 percent. There were no cases of multi-bacillary leprosy in either group. The efficacy of prophylaxis was significant in male children over 9 years of age and female children in the age-group 1-8 years. The other prognostic factors like the infectivity status of the index cases in the household and the duration of exposure to them could have possibly influenced the effectiveness of prophylaxis in preventing progression from infection to clinical disease among the subjects studied. Their effects could not be assessed in this study.

Activities of respository preparations of cycloguanil pamoate and 4,4'-diacetyldiaminodiphenylsulfone, alone and in combination, against infections with Plasmodium cynomolgi in rhesus monkeys.

The studies summarized in this report were concerned with the capacities of repository preparations of cycloguanil pamoate (CGT-P) to protect rhesus monkeys against infections with drug-susceptible and pyrimethamine-resistant strains of Plasmodium cynomolgi. Administered intramuscularly as a suspension in an oleaginous vehicle, CGT-P (i) provided long-term protection against single and repetitive challenges of rhesus monkeys with sporozoites of the drug-susceptible B and Ro strains, (ii) effected prompt clearance of parasitemia in established infections, and (iii) delayed relapse. Protection was equated to absence of parasites on thick blood films, negative results when blood was transferred to susceptible recipients, and inability to activate infection by splenectomy. Eventual loss of protection was not related to emergence of parasites resistant to cycloguanil (CGT). Although protection varied from monkey to monkey, its mean duration was related directly to size of CGT-P dose and size of particles in the suspension. Urinary excretion studies indicated that protection persisted as long as the daily output of CGT did not fall below that attained with the parenterally administered hydrochloride salt at a dose equivalent to 0.015 mg of CGT per kg. Studies on infections with the resistant Ro/PM strain showed that the activity of CGT-P was compromised severely by resistance to pyrimethamine. Attempts to minimize this liability by concomitant administration of 4,4'-diacetyldiaminodiphenylsulfone met with limited success. These results suggest that even the best of the repository preparations of CGT-P, with or without 4,4'-diacetyldiaminodiphenylsulfone, would be useful only in areas where Plasmodium falciparum and Plasmodium vivax are fully susceptible to chlorguanide and pyrimethamine.