Trait mindfulness and the mental and physical health of caregivers for individuals with cancer.

BACKGROUND: Mindfulness plays a role in moderating the negative mental and physical health outcomes associated with caregiving. The aims of this study were to examine the relationship between trait mindfulness and the (1) psychological functioning, (2) health behaviors, (3) and physical health of caregivers for individuals diagnosed with cancer. METHODS: Caregivers completed a battery of questionnaires and examinations assessing sociodemographic characteristics, trait mindfulness, depression, perceived stress, caregiver stress, sleep, diet, physical activity, tobacco use, alcohol use, blood pressure, and BMI. Demographics and cancer diagnostics were collected for the individuals whom caregivers supported. Linear regression, multivariate analyses, and moderator analyses were performed. RESULTS: Of the 78 caregivers, the mean age was 63.9 (S.D.=13.1); 59% identified as female; 97% identified as White. Regression analyses indicated that caregivers who reported higher levels of trait mindfulness reported significantly less perceived stress (b= -4.38, SE= 0.88, p <.001), lower levels of depression (b= -3.74, SE= 1.10, p = .001), greater caregiver quality of life (b= -9.05, SE=2.12, p < .001), better sleep quality (b= -0.98, SE=0.44, p = 0.03), and lower rates of tobacco use (b= -10.12, SE= 3.43, p =.003). Trait mindfulness was not significantly related to diet, alcohol use, blood pressure, or BMI. CONCLUSIONS: Higher levels of trait mindfulness are associated with positive mental and physical health measure for caregivers. Future research would benefit from further examining mindfulness-based interventions and their impacts in mitigating the negative toll of caregiving in the context of cancer.

Association between hydroxychloroquine levels and disease activity in a predominantly Hispanic systemic lupus erythematosus cohort.

OBJECTIVES: Hydroxychloroquine (HCQ) is a key therapy in systemic lupus erythematosus (SLE). Medication non-adherence is reported in up to 80% of lupus patients and results in increased morbidity, mortality, and health care utilization. HCQ levels are a sensitive and reliable method to assess medication adherence. Our study evaluated the role of HCQ level measurement in routine clinical care and its association with disease activity in a predominantly Hispanic population. METHODS: SLE patients from the Columbia University Lupus cohort treated with HCQ for ≥ 6 months and reporting medication adherence were included. HCQ levels were measured by whole blood high performance liquid chromatography. Non-adherence was defined as an HCQ level <500 ng/ml. The association between HCQ levels and disease activity measured by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) was evaluated. RESULTS: One hundred and eight patients were enrolled; the median age was 38 years, 91% were female, and 63% were Hispanic. The median SLEDAI-2K was 4.3 (0-20). Forty-one percent of patients had an HCQ level <500 ng/ml consistent with non-adherence, of which 19% had undetectable levels. A higher SLEDAI-2K score was associated with low HCQ levels (p = 0.003). This association remained significant after adjusting for depression (p = 0.0007). CONCLUSION: HCQ levels < 500 ng/ml were associated with higher disease activity and accounted for 32% of the SLEDAI-2K variability. HCQ blood measurement is a simple and reliable method to evaluate medication adherence in SLE. Reasons for non-adherence (levels < 500 ng/ml) should be further explored and addressed.

Ziprasidone in the treatment of acute mania: a 12-week, placebo-controlled, haloperidol-referenced study.

This 12-week, double-blind, two-part study in 438 adults with bipolar-associated acute mania began with a 3-week period comparing ziprasidone (80-160 mg/day) and placebo with haloperidol (8-30 mg/day) as active reference. Changes from baseline Mania Rating Scale (MRS) scores for ziprasidone and haloperidol were superior to placebo from day 2 (P = 0.001) to week 3 (P < 0.001); change from baseline at week 3 was greater for haloperidol than ziprasidone (P or=50% decrease from baseline MRS score) was 36.9, 54.7 and 20.5% for ziprasidone, haloperidol and placebo, respectively (P

Simple versus double jejunal pouch for reconstruction after total gastrectomy.

BACKGROUND: Even though many types of reconstruction after total gastrectomy have been proposed to reduce postgastrectomy syndromes, choosing a method that would further improve the quality of life and nutrition of the gastrectomized patient is controversial. Hunt-Lawrence single pouch reconstruction seems to obtain better results compared with the more common Roux-en-Y technique, but both of these reconstructive approaches are associated with some reduction in food intake and some problems in achievement of ideal body weight. METHODS: In this prospective, randomized trial, after total gastrectomy 18 patients had reconstruction according to the Hunt-Lawrence or single pouch technique (SP group), whereas for 23 patients, the technique was modified with construction of a second pouch in the distal portion of the jejunal loop (DP group). Patients in the two groups were compared at 12 months after surgery for problems in gastrointestinal function, quality of life, improvement in body weight and nutritional parameters, serum albumin, hemoglobin level, and serum protein. RESULTS: The DP group demonstrated fewer symptom problems, better weight maintenance, and better laboratory values when compared with patients undergoing standard single jejunal pouch reconstruction. CONCLUSIONS: Reconstruction with use of a double pouch as a gastric substitute leads to better outcome assessments than with a single pouch reconstruction. Our double pouch technique has demonstrated significant improvement in quality of life and nutritional recovery in terms of functional results as well as patient satisfaction.

Single- and multiple-dose pharmacokinetics of ziprasidone under non-fasting conditions in healthy male volunteers.

AIMS: To evaluate the pharmacokinetics and tolerability of single and multiple oral doses of ziprasidone in healthy male volunteers, and to determine the influence of ziprasidone on serum prolactin levels. METHODS: Single and multiple doses of ziprasidone were given orally (as two divided daily doses), at fixed dosages of 10 and 40 mg day(-1), and using titrated regimens of 40-80 and 40-120 mg day(-1), for 14 days. All dosages were taken immediately after food. The study adopted a randomized, double-blind, placebo-controlled design. Prolactin response, sedative properties, tolerability, and extrapyramidal symptoms were also investigated. RESULTS: Steady-state exposure to ziprasidone was attained after 1 day of dosing. Mean Cmax and AUC(0,12 h) increased with increasing dose, with apparent dose-proportionality between the 20 and 60 mg dose levels. Trough-to-peak ratios at steady state ranged from 2 to 5. Accumulation ratios for the fixed-dose regimens were 1.49 and 1.48 at the 5 and 20 mg dose levels, respectively. Ziprasidone was associated with transient prolactin elevation but levels of prolactin returned to baseline within the dosing interval at steady state. There was a marginal, transient increase in serum prolactin levels which was not dose-related at the 80 and 120 mg day(-1) doses, and which was noted to attenuate with chronic dosing. Ziprasidone was generally well tolerated. The most frequent side-effect was mild or moderate headache. A minority of patients suffered first-dose postural hypotension. Ziprasidone was also associated with a mild sedative effect that became less pronounced as treatment continued. There were no drug-related changes in electrocardiogram or clinical laboratory variables that were of clinical importance. CONCLUSIONS: Ziprasidone is characterized by a predictable pharmacokinetic profile resulting in symptoms that reflect its pharmacological action.

Identification of the major human liver cytochrome P450 isoform(s) responsible for the formation of the primary metabolites of ziprasidone and prediction of possible drug interactions.

AIMS: To identify the cytochrome P450 (CYP) isoform(s) responsible for the formation of the primary metabolite of ziprasidone (ziprasidone sulphoxide), to determine the kinetics of its formation and to predict possible drug interactions by investigating CYP isoform inhibition in an in vitro study. METHODS: In vitro metabolism of [14C]-ziprasidone was studied using human liver microsomes. The metabolites were identified using mass spectrometry. The kinetics of metabolite formation were determined using [14C]-ziprasidone (10-200 microM) over 5 min, and Km and Vmax were estimated from Lineweaver-Burk plots. IC50 values for the inhibition of specific probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, by ziprasidone, risperidone and 9-hydroxyrisperidone were also determined using human liver microsomes from three subjects. Mean Ki values were calculated. RESULTS: Three CYP-mediated metabolites - ziprasidone sulphoxide, ziprasidone sulphone and oxindole acetic acid - were identified. The apparent Km and Vmax values for the formation of the major metabolite, ziprasidone sulphoxide (measured as the sum of sulphoxide and sulphone) were 235 microM and 1.14 nmol mg(-1) protein min(-1), respectively. Isoform-selective inhibitors and recombinant enzymes indicated that CYP3A4 is responsible for the formation of ziprasidone metabolites. Ziprasidone was not a substrate for the other isoforms studied. Similar in vitro inhibition of CYP2D6 (Ki 6.9-16 microM) and CYP3A4 (Ki 64-80 microM) was obtained with ziprasidone, risperidone and 9-hydroxyrisperidone. The in vivo free drug concentrations associated with clinically effective doses of ziprasidone are at least 1500-fold lower than the mean Ki for either CYP2D6 inhibition or CYP3A4 inhibition. CONCLUSIONS: Ziprasidone is predominantly metabolized by CYP3A4 in human liver microsomes and is not expected to mediate drug interactions with coadministered CYP substrates, at clinically effective doses.

The effect of carbamazepine on the steady-state pharmacokinetics of ziprasidone in healthy volunteers.

AIMS: To evaluate the effect of steady-state carbamazepine administration on the steady-state pharmacokinetics of ziprasidone in healthy young adults, in an open, randomised, parallel-group study. METHODS: Twenty-five subjects were randomized to one of two treatment groups. Group 1 received 20 mg ziprasidone twice daily on days 1 and 2, and a single dose on day 3. A single 100 mg dose of carbamazepine was given once daily on days 5 and 6 and twice daily on days 7 and 8, followed by 200 mg twice daily until day 28 and on the morning only on day 29. Ziprasidone 20 mg was also administered twice daily on days 26 and 27 and in the morning only on day 28. Group 2 received the same treatment regimen with carbamazepine replaced by placebo. Pharmacokinetic data were obtained on days 3 and 28. RESULTS: Nine subjects in group 1 and 10 in group 2 completed all three treatment periods (ziprasidone, carbamazepine or placebo; and ziprasidone plus carbamazepine or placebo). Carbamazepine administration to group 1 was associated with modest reductions in ziprasidone exposure, with mean decreases in ziprasidone AUC(0,12 h) and Cmax values of 36% and 27%, respectively, on day 28 compared with day 3 (P<0.03). The mean differences between day 28 and day 3 ziprasidone AUC(0,12 h) and Cmax values were also statistically significantly greater in the carbamazepine group than in the placebo group. The mean half-life of ziprasidone decreased by 1 h from day 3 to day 28 in the subjects receiving carbamazepine, compared with virtually no change in the placebo group. All adverse events were mild or moderate in severity and there were no serious adverse events, or clinically significant changes in ECGs and vital signs throughout the study. CONCLUSIONS: Induction of CYP3A4 with carbamazepine led to a modest reduction (<36%) in steady-state exposure to ziprasidone that is believed to be clinically insignificant.

The effects of ketoconazole on ziprasidone pharmacokinetics--a placebo-controlled crossover study in healthy volunteers.

AIMS: To assess the effects of multiple oral doses of ketoconazole on the single-dose pharmacokinetics of oral ziprasidone HCl. METHODS: This was a 14-day, open-label, randomized, crossover study in 14 healthy subjects aged 18-31 years. Group 1 received oral ketoconazole 400 mg once daily for 6 days, followed by a 2 day wash-out period and 6 days of placebo administration. Group 2 received placebo followed by ketoconazole. Single oral doses of ziprasidone HCl 40 mg were administered on days 5 and 13 in both groups. Ziprasidone pharmacokinetic parameters were compared between placebo and ketoconazole administration periods. RESULTS: Co-administration of ziprasidone with ketoconazole was associated with a modest increase in ziprasidone exposure; mean ziprasidone AUC(0,infinity) increased by 33%, from 899 ng ml(-1) h with placebo to 1199 ng ml(-1) h with ketoconazole. Mean Cmax increased by 34%, from 89 ng ml(-1) to 119 ng ml(-1), respectively. The treatment effect on both of these parameters was statistically significant (P<0.02). Most adverse events were of mild intensity. There were no serious adverse events, laboratory abnormalities, abnormal ECGs, or clinically significant alterations in vital signs throughout the study. CONCLUSIONS: The concurrent administration of ketoconazole and ziprasidone led to modest, statistically significant increases in ziprasidone exposure, although the changes seen were not considered clinically relevant. This suggests that other inhibitors of CYP3A4 are unlikely to significantly affect the pharmacokinetics of ziprasidone.

[Vascular clamping in cirrhotic liver surgery]. / Il clampaggio vascolare nella chirurgia del fegato cirrotico.

Different vascular clamp methods in liver surgery have led to less complications. The aim of this study was to evaluate the results after hepatic resection involving different vascular clamping methods and liver function outcome. Our study examined 46 patients who underwent surgery for liver lesions, developed on cirrhotic and noncirrhotic livers, applying the technique of selective clamping and pedicular clamping. There was one death (1/17; 5.9%) due to postoperative liver failure which occurred in a cirrhotic liver patient who underwent left hepatectomy with pedicular clamping. Complication rate was higher, but not significant (4/7; 57.1%) in the group with selective clamping compared to those with pedicular clamping (3/10; 30%). Hemorrhagic complications were observed in a higher rate among patients with selective clamping (3/7; 42.9%) compared to those with pedicular clamping (1/10; 10%). Selective clamping seems to find major indications in patients with chronic liver disease undergoing minimal hepatic resections. Intermittent pedicular clamping seems to be more effective in regards to blood loss and postoperative hepatic function.

Metabolism and excretion of a new anxiolytic drug candidate, CP-93, 393, in healthy male volunteers.

CP-93,393 [(7S,9aS)-1-(2-pyrimidin-2-yloctahydropyrido[1,2-a] pyrazin-7-ylmethyl)pyrrolidine-2,5-dione] is a new anxiolytic drug with highly selective serotonin 5-hydroxytryptamine 1A autoreceptor agonist, alpha2-adrenergic antagonist, and dopamine D2 agonist properties. The excretion, biotransformation, and pharmacokinetics of CP-93,393 were investigated in six healthy male volunteers after oral administration of a 5-mg dose of [14C]CP-93,393. The administered radioactivity was excreted predominantly in the urine. One week after administration of the dose, cumulative excretion amounted to 67.8 +/- 2.5% in the urine and 22.0 +/- 5.6% in the feces. In total, 89.8 +/- 5.7% of the radioactive dose was recovered in urine and feces. Mean maximum plasma concentration values for unchanged CP-93,393 were 10.92 and 1.02 ng/ml for poor metabolizers (PMs) and extensive metabolizers (EMs) of dextromethorphan, respectively. AUC0-infinity values for unchanged CP-93,393 were also greater for PMs than for EMs, whereas the mean maximum plasma concentration and AUC0-infinity values for total radioactivity were similar for the two phenotypes. Less than 0.5% of the dose was excreted in urine as unchanged drug for both EMs and PMs, suggesting extensive metabolism of CP-93,393 in both phenotypes. Hydroxylation at the 5-position of the pyrimidine ring was identified as the main metabolic pathway. 5-Hydroxy-CP-93,393 (M-15) and its glucuronide and sulfate conjugates (M-7 and M-13, respectively) accounted for approximately 51% of the administered dose in excreta of both PMs and EMs. Hydrolysis of the succinimide ring, in combination with 5-hydroxylation and/or conjugation or not, accounted for approximately 9% of the dose. A novel metabolite, apparently resulting from oxidative degradation of the pyrimidine ring, was characterized as the amidine analog M-18. M-15 (47-62%), its sulfate conjugate (M-13, approximately 9%), and the pyrimidine ring-cleaved product (M-18, 7-13%) were identified as the major circulating metabolites for both EMs and PMs. Therefore, CP-93,393 undergoes metabolism by three primary pathways, i.e. 1) aromatic hydroxylation followed by conjugation with glucuronic acid and sulfuric acid, 2) oxidative degradation of the pyrimidine ring, and 3) hydrolysis of the succinimide ring. The identified metabolites accounted for approximately 90, 91, and 92% of the total radioactivity present in urine, plasma, and feces, respectively. The major in vivo oxidative metabolites were also observed after in vitro incubations with human liver microsomes.

The effect of timing of a standard meal on the pharmacokinetics and pharmacodynamics of the novel atypical antipsychotic agent ziprasidone.

STUDY OBJECTIVE: To evaluate the influence of a high-fat meal on the pharmacokinetics and pharmacodynamics of the novel atypical antipsychotic drug ziprasidone. DESIGN: Open, randomized, three-way crossover study. SETTING: University-based research facility. SUBJECTS: Eight healthy male volunteers. INTERVENTIONS: Ziprasidone 20 mg was administered under fasting conditions (treatment A), and directly after (treatment B) and 2 hours after (treatment C) a standard high-fat breakfast. MEASUREMENTS AND MAIN RESULTS: Serial blood samples were obtained over 36 hours. Three objective psychometric tests were employed to evaluate daytime vigilance at baseline and 2 hours after each dose. Ziprasidone had a significant effect on area under the curve (AUC0-infinity), maximum serum concentration, and half-life (analysis of variance all p<0.05), with the mean AUC0-infinity being significantly greater (627.2 +/- 206.4 vs 371.0 +/- 126.5 ng x hr/ml, ANOVA with Bonferroni's criteria p<0.016) and half-life significantly shorter (4.7 +/- 0.8 vs 6.6 +/- 1.3 hrs, ANOVA with Bonferroni's criteria p<0.016) after treatment B compared with treatment A. Although similar trends were observed after treatment C compared with treatment A, the differences did not reach statistical significance when Bonferroni's correction criteria were applied (p>0.016). CONCLUSION: These data suggest an increase in systemic exposure to the highly lipophilic compound ziprasidone when taken after fatty foods, possibly due to improved drug dissolution and solubilization. The drug's longer half-life under fasting conditions may reflect dissolution-limited absorption, although this could not be directly assessed. Despite postprandial increases in ziprasidone AUC0-infinity and maximum concentration, daytime vigilance was not affected.

Bioavailability studies of drugs with nonlinear pharmacokinetics: II. Absolute bioavailability of intravenous phenytoin prodrug at therapeutic phenytoin serum concentrations determined by double-stable isotope technique.

Measurement of the absolute bioavailability of phenytoin (PHT) derived from test doses of phenytoin prodrug (PPD) at therapeutic PHT serum concentrations is complicated by two problems: 1) the area under the serum concentration versus time curve (AUC) produced by a given size of test dose will vary directly with background PHT serum concentration due to the nonlinear pharmacokinetic properties of PHT; 2) PPD is more water soluble than PHT, making renal excretion of PPD more likely. The authors describe a double-stable isotope method that obviates these two problems. Using only six subjects, the authors were able to demonstrate bioequivalence of PHT derived from intravenous PPD with intravenous PHT by current FDA standards for AUC ratio of test/reference formulation (90% confidence intervals between 0.80 and 1.20; ratio > or = 0.80 in > or = 80% of subjects; statistical power to detect a difference of 0.20 with a probability of 0.80).

Pharmacokinetics and dynamics of furosemide in the newborn piglet.

Furosemide was administered as either an i.v. bolus (6 mg/kg) or primed continuous infusion (4 mg/kg/hr) with quantitative fluid replacement to 10 3-day-old and 9 18-day old piglets. Total and unbound plasma as well as urinary furosemide concentrations were measured for up to 6 hr and drug disposition and renal sodium excretory dynamics were compared at the two ages. The plasma clearance of furosemide was concentration-independent over the range studied (0.1-10 mg/l). Steady-state volume of distribution and unbound fraction of furosemide in plasma were both considerably higher in the younger piglets (618 +/- 320 vs. 201 +/- 71 ml/kg, p less than .01 and 0.22 +/- 0.08 vs. 0.06 +/- 0.02 ml/kg, p less than .001, respectively) while unbound secretory clearance was several-fold lower in this age group (49.2 +/- 23 vs. 107 +/- 55 ml/min/kg, P less than .01). A log-logistic equation was fitted to sigmoidal plots of sodium excretion rate vs. log furosemide excretion rate. While basal response and slope parameters did not differ significantly, maximal response and stimulus required for half-maximal response were both reduced in the younger piglets (0.70 +/- 0.24 vs. 1.18 +/- 0.30 mmol/min and 0.06 +/- 0.04 vs. 0.14 +/- 0.06 mumol/min, respectively, P less than 0.05). Thus, younger piglets were more sensitive to the natriuretic effects of the drug. While term piglets were useful for studying the maturation of protein binding and renal drug excretory processes for furosemide, drug disposition was not comparable to that in human premature infants because of the higher secretory capability of the piglet.

Renal response to furosemide in very low birth weight infants during chronic administration.

Renal response to furosemide following initial and chronic doses was investigated in premature infants with bronchopulmonary dysplasia. Seven infants (mean birth weight = 890 +/- 216 g, mean gestational age at birth = 27.7 +/- 2.6 weeks, mean postnatal age at the start of diuretic therapy = 2.7 +/- 0.9 weeks) were studied. Twelve-hour urine collections were performed after the initial dose, and following chronic doses after 1 week and 3 weeks of therapy. Volume of each urine sample was measured and concentrations of furosemide, sodium and creatinine determined. Linear dose-response relationships were found between the logarithm of the urinary furosemide excretion rate and diuretic/natriuretic response (urine output and urinary sodium excretion rate). The furosemide excretion rate required to achieve midrange diuretic and natriuretic responses was significantly greater during chronic dosing than following initial doses, indicating a decrease in renal responsiveness to drug with sustained use. Increasing postconceptional age was associated with a decrease in initial responsiveness to furosemide. These data demonstrate that in premature infants renal sensitivity to furosemide decreases with chronic use as well as with increasing postconceptional age at the start of therapy. The decrease in renal sensitivity to drug with chronic use is of much greater magnitude, and appears to represent renal compensation for drug-induced diuresis and natriuresis.

Furosemide pharmacokinetics in very low birth weight infants.

The pharmacokinetics of furosemide were studied longitudinally during long-term administration in 10 very low birth weight infants with bronchopulmonary dysplasia. Mean birth weight of the infants was 829 +/- 217 g, mean gestational age at birth was 26.6 +/- 2.9 weeks, and mean postnatal age at the start of therapy was 2.4 +/- 1.0 weeks. Serial determinations of furosemide pharmacokinetic parameters were performed during 2 weeks to 3 months of long-term therapy. Plasma half-life was prolonged in infants less than 31 weeks postconceptional age (gestational + postnatal age), frequently exceeding 24 hours. All infants less than 29 weeks postconceptional age whose dosing schedule was once every 12 hours accumulated furosemide to potentially ototoxic levels. Furosemide renal clearance increased and plasma half-life decreased in association with increasing postconceptional age. Furosemide secretory clearance was very low in patients less than 31 weeks postconceptional age, resulting in a reliance on glomerular filtration to deliver drug to its main site of action within the lumen of the loop of Henle. Thus elevated plasma levels may be required to ensure adequate luminal delivery and adequate diuresis in these infants with low secretory clearance. Nevertheless, the current dosing schedule (once every 12 hours) of furosemide should be modified to once every 24 hours in infants of low postconceptional age to avoid possible toxic effects.

Pharmacokinetics of propylthiouracil in children and adolescents with Graves' disease in the hyperthyroid and euthyroid states.

The pharmacokinetics of propylthiouracil (PTU) was studied in 7 patients having Graves' disease when they were hyperthyroid and then again when they were euthyroid. Two additional euthyroid patients were also studied. The t1/2, Ke, Ka, apparent Vd, AUC and clearance were calculated. Serum T3 and T4 were also measured. PTU had an immediate effect in reducing T3 levels. Although there were intraindividual variations, the mean PTU elimination half-time did not change from the hyperthyroid state (1.47 h) to the euthyroid state (1.53 h). The mean Ka when hyperthyroid (2.12 h-1) was significantly increased (p less than 0.005) compared to when euthyroid (1.00 h-1). The calculated kinetic information indicates that the disposition of PTU in children is similar to that reported in adults.

Model for gradient formation in polycrystalline germanium-silicon alloy GRIN crystals via Czochralski crystal growing.

A mathematical model has been developed which describes the silicon composition gradient produced in germanium-silicon alloy GRIN crystals formed via Czochralski crystal growing. This model is based on the naturally occurring segregation effect of silicon in germanium. The refractive index of the alloy is described in terms of its relation to the band gap energy, which is itself dependent on the silicon composition. A relationship between refractive index and silicon composition of the alloy is derived.

Measurement of the refractive-index profile in polycrystalline germanium-silicon alloy GRIN crystals.

The refractive index as a function of spatial coordinate in three Czochralski grown germanium-silicon alloy GRIN crystals has been measured using ac interferometric techniques. The interferometer is capable of high phase resolution and is computer controlled for real-time data processing. The measured refractive-index profiles were compared to theoretical profiles which were calculated from a model based on the segregation effect of silicon in germanium.