Psychotropics and drug interactions in the elderly patient.

This short paper attempts to provide a framework to aid the old-age psychiatrist in choosing psychotropic drugs in a way that minimizes the risks of adverse drug reactions. It concentrates on the clinical problems most frequently encountered in old-age psychiatric practice. Older people are at risk of adverse drug interactions because of their higher rate of physical morbidity and increased likelihood of receiving polypharmacy, as well as due to age-related change in drug handling. The strongest evidence for relevant interactions in older people relates to changes in renal excretion (particularly relevant for lithium) and cytochrome P450 (relevant for a wide range of psychotropic and other drugs). Awareness of potential interactions is important in ensuring safe prescribing practice for older people with mental health problems.

Eligibility criteria for elderly mentally ill continuing-care National Health Service patients: are they being met and do they need revision?

BACKGROUND: in 1996, the British government directed health authorities to draw up local eligibility criteria for National Health Service continuing health care. OBJECTIVES: to examine whether elderly mentally ill continuing-care National Health Service patients fulfilled a variety of eligibility criteria for their placement, and to identify the characteristics of patients who met local eligibility criteria. DESIGN: descriptive study. SETTING: four continuing-care units for elderly mentally ill patients in and around London. SUBJECTS: 67 continuing-care inpatients. METHODS: interview with nurse carer and, where possible, the patient with the use of standard global, functional, behavioural and cognitive rating scales. We determined fulfillment of Royal College of Psychiatrists' guideline criteria and three local eligibility criteria for elderly mentally ill continuing care. We identified clinical differences between those eligible and ineligible. RESULTS: although there were wide variations between local eligibility criteria, their effects were the same. In total, 58% of patients fulfilled all local eligibility criteria; 42% fulfilled none. Patients who fulfilled local eligibility criteria scored much higher on ratings of aggression, activity disturbance (wandering, and purposeless and inappropriate activity) and paranoid and delusional ideation. Ten percent of patients fulfilled Royal College of Psychiatrists' criteria but not local eligibility criteria. CONCLUSIONS: comprehensive and unambiguous national eligibility criteria should be introduced to reflect clinical needs and provide equity of access.

Who becomes depressed? The Islington community study of older people.

BACKGROUND: Depression in older people is common and debilitating and associated with physical ill health. This is the first study of risk factors for depression in a representative sample of older people selected for high vulnerability because of physical ill health. METHOD: Subjects identified in an epidemiological community survey of morbidity in people > or =65 years old, who had activity limitation (ADL) but no psychiatric morbidity were reinterviewed after 3 years. RESULTS: 79 (90%) of subjects were interviewed. Ten percent developed pervasive depression and 24% screened positive for depression. This latter group were more likely to consult doctors than others with similar levels of disability (P<0.005) mainly because of an acute physical illness. Frequent pain was associated with the development of depression (P<0.02). CONCLUSION: Older people who are ADL limited are known to be at high risk for depression. For the majority who do not become depressed, chronicity of illness does not lead to depression. Those who become depressed are most likely to be those with an acute illness and those who are in pain. They will usually increase their consultation rate with doctors but will not complain of depression. They may be undertreated for both pain and depression. Further studies are needed to confirm other risk factors.

5-ethyl-2'-deoxyuridine, a modulator of both antitumour action and pharmacokinetics of 5-fluorouracil.

The aim of the present studies was to elucidate the effects and optimal modulatory conditions of 5-ethyl-2'-deoxyuridine (EtdUrd) on the antitumour efficacy, pharmacokinetics and catabolism of 5-fluorouracil (5-FU) on Colon-26 and Colon-38 murine tumours. HPLC and GC-MS techniques were used to measure the concentrations of 5-FU, dihydro-5-fluorouracil, EtdUrd, 5-ethyluracil and uridine in the plasma and that of 5-FU and 5-fluoro-2'-deoxyuridine monophosphate (FdUMP) in the tumours. It was shown that EtdUrd, given 1 h before 5-FU, selectively enhanced the antitumour action of 5-FU, without significantly increasing its toxic side-effects, thus resulting in an approximately three times higher therapeutic index. Pharmacokinetic studies revealed that 1 h after 400 mg/kg EtdUrd administration - i.e. at the time of 5-FU treatment - the plasma concentration of EtdUrd was 269 microM, and that of 5-ethyluracil, as the major metabolite of EtdUrd, was 421 microM. It is of interest that EtdUrd pretreatment did not change the maximal plasma concentration of 5-FU; however, the half-life of the terminal elimination increased from 114.5 min to 171.2 min and thus the mean residence time of 5-FU rose significantly (P < 0.05). After the combined treatment, the maximal concentration of dihydro-5-fluorouracil in the plasma decreased from 61.06 microM to 29.70 microM (P < 0.01). The intratumoral concentrations of 5-FU were 34%-158% higher 6-96 h after the combined treatment than after the single 5-FU treatment. EtdUrd also caused a moderate increase in the intratumoral level of FdUMP. It is noteworthy, that EtdUrd increased the endogenous uridine concentration in the plasma from 18 microM to a maximum of 249 microM, and the level remained high for longer than 6 h. The present studies indicate that EtdUrd enhances the therapeutic index of 5-FU by reducing the catabolism, prolonging the plasma and intratumoral concentrations of 5-FU and, at the same time, offering protection to normal organs by increasing the endogenous uridine level.

Modulation of 5-fluorouracil by 5-ethyl-2'-deoxyuridine on cell lines expressing different dihydropyrimidine dehydrogenase activities.

The purpose of the present study was to clarify the significance of the inhibition of dihydropyrimidine dehydrogenase (DPD) in the modulation of 5-fluorouracil (5-FU) action by 5-ethyl-2'-deoxyuridine (EUdR). Four human cell lines, which differed in their susceptibility to 5-FU and in their DPD activity, were selected as biological objects. Several other enzymes of pyrimidine metabolism, i.e. thymidylate synthase (TS), thymidine kinase (TK) and pyrimidine nucleoside phosphorylase (PNP), which might be involved in the 5-FU action were also studied to elucidate their potential role in the modulation of 5-FU cytotoxicity. Two out of the four cell lines, i.e. COLO1 and SW620, showed low (57 and 28 pmol/min/mg protein) and the other two cell lines, i.e. CAL51 and CAL33, showed high (235 and 184 pmol/min/mg protein) DPD activity, respectively. In our study, contrary to our expectation, no correlation between the DPD and TS activity of the cell lines and their 5-FU sensitivity could be observed. EUdR alone was cytotoxic only on CAL33 cells in a concentration below 1 mM (IC50=194 microM) which might be due to the high TK activity (857 pmol/min/mg protein) measured in this cell line, favoring the formation of the phosphorylated nucleotides EdUMP and EdUTP indispensable for the inhibition of TS and DNA polymerase, respectively. Surprisingly, although EUdR by metabolizing to EUra was able to reduce the high activity of DPD in CAL33 and CAL51 cells by 47 and 55%, respectively, no potentiation of the 5-FU action occurred on these cell lines. On the contrary, enhancement of the 5-FU cytotoxicity was demonstrated on COLO1 and SW620 cells with low DPD activity. Our findings suggest that the 5-FU modulatory action of EUdR may be directed on other molecular targets than DPD as well, i.e. the augmentation of TS inhibition by EdUMP as demonstrated on SW620 cells might be one of these mechanisms.

Putative role of dihydropyrimidine dehydrogenase in the toxic side effect of 5-fluorouracil in colorectal cancer patients.

Dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting enzyme in the catabolism of 5-fluorouracil (5-FU). It has been reported from various laboratories that the plasma concentration of 5-FU was influenced by DPD activities in various normal human organs (e.g. liver or lymphocytes). Since the congenital deficiency in DPD caused severe, in some cases lethal, FU-related toxicity, it was decided to collect data about the DPD activity in colorectal cancer patients in order to investigate the possible correlation between the enzyme activity and appearance of the side effects of 5-FU. Assuming that DPD activity in lymphocytes represents the 5-FU catabolic capacity of the organism, DPD activity was determined in the lymphocytes of 48 patients with colorectal cancer after surgery during the therapeutic course with 5-FU and folinic acid. On the basis of the enzyme activity, patients were divided into three categories: low (DPD <5.03 pmol/min/10(6) lymphocytes); medium (DPD = 5.04-13.25 pmol/min/10(6) lymphocytes), and high (DPD > 13.26 pmol/min/10(6) lymphocytes) activity groups. By evaluating the toxic side effects during the 5-FU + folinic acid treatment, the following results were obtained. In the low DPD activity group, 9 of 11 patients had 5-FU-related side effects (mucositis, diarrhea, myelotoxicity, angina pectoris, hypertension). In 3 patients, no change of the therapy was needed, in 3 patients symptoms could be reversed by dose reduction of 5-FU while in 3 patients interruption of 5-FU therapy was needed. In the medium DPD activity group, mild toxicity (diarrhea, transitory hypertension) occurred in 5 of 29 and in the high activity group (diarrhea) in 1 of 8 patients, respectively. In these last two groups, no dose reduction of 5-FU was necessary. The present study furnished further evidence for the possible correlation between the 5-FU side effects and DPD function. Consequently, it is recommended to measure DPD activity prior to 5-FU based chemotherapy, which might be helpful in avoiding drug-related toxicity by adjusting the dose of 5-FU individually.

The expression of Fos within the suprachiasmatic nucleus of the diurnal rodent Arvicanthis niloticus.

Rhythms in the expression of the nuclear phosphoprotein Fos, have been demonstrated in the suprachiasmatic nucleus (SCN) of nocturnal rodents. When rats are housed in a 12:12-h light/dark (LD) cycle the number of Fos-immunoreactive (-IR) cells within the SCN is higher during the day than at night [9,23]. In the two experiments reported here, Fos-IR was examined in the SCN of a diurnal murid rodent, Arvicanthis niloticus. First, thirty-six adult male A. niloticus housed in a 12:12-h LD cycle were perfused at six equally spaced time points beginning 1 h after lights on (n=6 per time point). Brains were sectioned and treated with immunohistochemical procedures for the identification of Fos. The number of Fos-IR cells in the SCN varied significantly as a function of time, and was highest 1 h after lights on and decreased thereafter. The distribution of Fos-IR within the SCN overlapped with that of arginine-vasopressin-IR (AVP-IR) and vasoactive intestinal peptide-IR (VIP-IR), but not with that of gastrin-releasing peptide-IR (GRP-IR). In the second study, double-labeling techniques revealed extensive Fos expression within SCN neurons containing AVP-IR, but not neurons containing GRP-IR. In conclusion, although the overall rhythm of Fos-IR in the SCN is similar in diurnal and nocturnal rodents, differences may exist with respect to the relative distribution of Fos-immunoreacte cells within different SCN cell populations.

[Determination of dihydropyrimidine dehydrogenase in the prediction of toxic side effects of 5-fluorouracil]. / A dihidropirimidin-dehidrogenáz meghatározás jelentösége az 5-fluorouracil toxikus mellékhatásainak elörejelzésében.

In the chemotherapy of colorectal cancers the most frequently given drug is 5-fluorouracil, which in certain cases reduces or delays the appearance of the local recurrence or metastasis. It is well known that the patient's response to 5-fluorouracil is very different concerning both, effects and side effects. More than 80% of the infused drug is catabolised in the first 20 minutes after the treatment. The first and rate limiting enzyme of the catabolism is dihydropyrimidine dehydrogenase, which has the highest activity in the liver and lymphocytes. The activity of this enzyme shows correlation with the blood level of 5-fluorouracil. The deficiency of this enzyme caused severe, in some cases lethal toxicity, its congenital deficiency is responsible for familial pyrimidinaemia. Authors intended to collect data about the dihydropyrimidine dehydrogenase activity of colorectal cancer patients, in order to screen enzyme deficiency or very low enzyme activity, which might be in connection with the appearance of severe side effects, moreover to determine the optimal dose of 5-fluorouracil before the treatment. Dihydropyrimidine dehydrogenase activity was determined in the lymphocytes of 48 colorectal cancer patients, treated by 5-fluorouracil, at the beginning of each cytostatic cycle. The enzyme activity of the patients was between 1.2 and 24.4 pmol/min/10(6) lymphocyte. The value of the enzyme activity fluctuated in a range, characteristic for the individual patients and this value was not modified by the 5-fluorouracil treatment. Dividing the patients in two groups, low (lower than 5 pmol/min 10(6) lymphocyte) and high (higher than 15 pmol/min 10(6) lymphocyte) dihydropirimidine dehydrogenase activity, we found that decrease in the white blood cell number and appearance of the side effects occurred with much higher frequency in the low activity group which resulted in the reduction of the dose or in more serious cases interruption of the treatment. Authors conclude that the determination of the dihydropyrimidine dehydrogenase activity in the lymphocytes is a valuable method in the prediction of the toxic side effects of 5-fluorouracil, in the screening of the congenital enzyme deficiency and in the individualization of the 5-fluorouracil dosage.

[Merkel cell tumor]. / Merkel-sejtes daganat.

Merkel cell cancer is a rare carcinoma arising from the neuroendocrin cells of the skin. The diagnosis is based on the clinical behaviour, histopathologic and ultrastructural findings and immunohistochemical results. An unusual case of Merkel cell carcinoma is presented. Mass from the umbiculus and a right inguinal lymph node was excised in a 63-year-old female. The histologic features of a typical, primitive small cell tumor combined with the immunohistochemical evaluations established the diagnosis. Rare polynuclear giant cells were focally present in our case. Patient was treated with combination of chemotherapy (Cisplatin, Etoposid) and radiotherapy. Control examinations showed complete respond. One year later metastasis developed. Resection of all known metastasis were performed. Two months after the laparotomy she died of metastatic disease. The autopsy did not reveal any other primary tumor. The capricious nature of the clinical course and the differences between this tumor and other carcinomas is emphasized.

Brain [3H]cAMP binding sites are unaltered in depressed suicides, but decreased by antidepressants.

Saturation binding of [3H]cAMP to the regulatory subunit of cAMP-dependent protein kinase (PKA) was measured in the soluble fraction of brain samples, obtained at post-mortem, from suicides with a firm retrospective diagnosis of depression and individually matched controls. Suicides were subdivided into those who had been free of antidepressant drugs for at least 3 months and those in whom prescription of antidepressants was clearly documented. In antidepressant-free suicides, we found no significant differences in the number or affinity of [3H]cAMP binding sites in the five regions studied. In antidepressant-treated suicides however, Bmax values were lower in all regions, reaching statistical significance in parietal cortex and amygdala. Kd values for antidepressant-treated suicides were significantly higher in parietal cortex, temporal cortex and amygdala. These results suggest the regulatory subunit of PKA is unaltered in depression, but is influenced by antidepressant drugs.

Screening for alcohol misuse in older people.

OBJECTIVES: To evaluate whether the CAGE, MAST-G or an abnormally high MCV are effective screening instruments for alcohol misuse and if not to devise a new instrument. DESIGN: Questionnaire survey of randomly selected patients. SETTING: Acute admission wards of two district general hospitals. PERIOD: 9 months. SUBJECTS: Randomly selected patients, aged 65 and over, admitted as emergencies. MAIN OUTCOME MEASURES: Excessive alcohol intake, alcohol dependence. RESULTS: The sensitivities of the CAGE, MAST-G and an abnormally high MCV for excess alcohol intake and alcohol abuse are low, ranging from 0.13 to 0.54. CONCLUSION: The results confirm previous UK studies which indicate that the CAGE and an abnormally high MCV are poor screening instruments for alcohol misuse in older patients and also indicate that the MAST-G is an insensitive screening instrument. A new two-step instrument with five questions in total was generated. This requires further validation.

Screening, detection and management of depression in elderly primary care attenders. I: The acceptability and performance of the 15 item Geriatric Depression Scale (GDS15) and the development of short versions.

One-hundred and ninety-eight elderly subjects attending their general practitioners (GPs) were asked to complete the 15 item Geriatric Depression Scale (GDS15). Analysable results were obtained from 194 (98%). Of these, 67 (34%) scored above the GDS15 cut-off (4/5) for significant depressive symptomatology. 87.6% found the questionnaire to be acceptable and only 3.6% found it very difficult or very stressful. The GDS15 had a high level of internal consistency (Cronbach's alpha = 0.80). All the individual items of the GDS15 associated significantly (P < 0.01) with total score and 'caseness'. A single question "do you feel that your life is empty?" identified 84% of 'cases'. In an attempt to devise short scales to screen elderly primary care patients for depression, the data were subjected to logistic regression analysis. Ten (GDS10), four (GDS4) and on (GDS1) item versions were generated. Agreement between these short scales and the GDS15 in the original sample was 95, 91 and 79% respectively. Cronbach's alpha was 0.72 for the GDS10 and 0.55 for the GDS4. The short scales were then validated in an independent sample of 120 patients in whom both GDS data and the results of a detailed psychiatric interview (the Geriatric Mental Status Schedule, GMS) were available. The sensitivity and specificity of the GDS10 against GMS caseness were 87 and 77% (cut-off 3/4); those of the GDS4 were 89 and 65% (cut-off 0/1) and 61 and 81% (cut-off 1/2). Sensitivity and specificity for the GDS1 were 59 and 75%. It is concluded that these short scales may be useful in helping GPs and practice staff to identify elderly patients with significant depressive symptoms.

Screening, detection and management of depression in elderly primary care attenders. II: Detection and fitness for treatment: a case record study.

Case note data were obtained for 186 elderly primary care attenders who also completed the 15 item Geriatric Depression Scale (GDS15). The presence or absence in the case notes of a current or past diagnosis of depression, of current treatment of depression, and of a number of clinical features of depression were noted. Case notes were also rated for the presence or absence of contraindications to the use of tricyclic antidepressants (TCAs) and to serotonin-specific reuptake inhibitors (SSRIs). Whereas 65 (35%) patients were rated as 'cases' of depression on the GDS15, only 28 (15%) had a current case note diagnosis of depression and 37 (20%) had one or more current symptoms of depression recorded in the case notes. Patients rated by their GP as having one or more current symptoms of depression scored higher on the GDS15 (P < 0.05) and were more likely to be categorized as a GDS case (P = 0.05). There was no significant relationship between GDS caseness and a current case note diagnosis of depression. Seventy-three patients (39%) had a past history of depression and 53 (28.5%) patients had previously been treated with antidepressants. The former was significantly associated with GDS caseness (P < 0.05). Twenty-four patients (13%) were currently on antidepressants, 19 of them receiving adequate doses (equivalent to at least 75 mg of amitriptyline). Current antidepressant treatment was not associated with GDS 'caseness'.(ABSTRACT TRUNCATED AT 250 WORDS)